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ADVOKAADIBÜROO HETA Ülemiste Ärimaja Peterburi tee 2f 11415 Tallinn Tel 699 66 11 Faks 644 28 89 Reg.kood 10285794 [email protected] www.heta.ee Riigihangete vaidlustuskomisjon Tartu mnt 85, Tallinn 10115 [email protected] 03.märts 2023.a PUUDUSTE KÕRVALDAMINE VAIDLUSTUSES ja VAIDLUSTUSE TERVIKTEKST Riigihanke nimetus: Biokeemiliste ja immunoloogiliste analüüside automaatse teostamisvõimaluse hankimine (hanke viitenumber 248294) Hankija: Sihtasutus NARVA HAIGLA Registrikood: 90003217 Haigla tn 7, 20104 Narva linn Tel: 3571802; e-post: [email protected] Vaidlustaja: ISIS Medical OÜ Registrikood: 10958649 Kangru tee 6b, Vaela küla, Kiili vald, Harju maakond, 75413 Vaidlustaja esindaja: Advokaat Teet Lehiste Advokaadibüroo HETA E-post: [email protected] Kolmas isik: aktsiaselts Surgitech Registrikood: 10453754 Pärnu mnt 148, 11317 Tallinn E-post: [email protected] Palun tuvastada hankija ja aktsiaselts Surgitech vahel 20.12.2022 sõlmitud raamlepingu nr 20/12/22 tühisus. 1 Menetluslikud avaldused 1.1 Vaidlustaja sai hankemenetluse viitenumbriga 248294 läbiviimise tulemusel sõlmitud raamlepingu nr 20/12/22 (edaspidi raamleping) sõlmimisest teada 31.01.2023. RHS § 189 lg-e 7 järgi tuleb vaidlustus antud juhul esitada 30 päeva jooksul alates hankelepingu sõlmimise teate avaldamisest. Seega on vaidlustus esitatud tähtaegselt. 1.2 Vaidlustaja soovib asja arutamist istungil. 2 (9) . 1.3 Juhindudes RHS § 190 lg-st 7 ei ole käesolevale vaidlustusele lisatud neid hankega seotud dokumente, mis on Riigihangete registri vahendusel kättesaadavad. Kui vaidlustuskomisjonile ei ole asja lahendamiseks olulised dokumendid/andmed kättesaadavad, on vaidlustaja valmis need viivituseta esitama. 1.4 Juhindudes RHS § 190 lg-st 11 ei ole vaidlustusele lisatud vaidlustaja esindaja volikirja. Vaidlustaja esindaja kinnitab, et tal on volitus vaidlustaja esindamiseks käesolevas asjas ning on valmis vaidlustuskomisjoni nõudmisel selle esitama. 1.5 Vastavalt RLS § 258 tasutakse käesoleva vaidlustuse esitamisel riigilõivu 1280 eurot, kuivõrd vaidlustatava riigihanke maksumus ületab rahvusvahelist piirmäära, mis RHS § 14 lg 3 järgi on 140 000 eurot1. Riigilõivu tasumist tõendav maksekorraldus on lisatud vaidlustusele (vt lisa 1). 2 Asjaolude kokkuvõte ja vaidlustuse ese 2.1 Hankija avaldas 30.01.2023 Riigihangete registris hankelepingu nr 20/12/22 sõlmimise teate (ID 3470741) riigihankes „Biokeemiliste ja immunoloogiliste analüüside automaatse teostamisvõimaluse hankimine“ viitenumbriga 248294 (edaspidi hange). Hankija korraldas hanke väljakuulutamiseta läbirääkimistega hankemenetlusena ning sõlmis raamlepingu aktsiaseltsiga Surgitech 20.12.2022. 2.2 Hanke lühikirjelduse kohaselt sõlmitakse hankeleping (raamleping) 7-aastaks, mille eesmärk on võtta kasutusse analüsaatoritest, preanalüütilisest seadmest, veesüsteemist, vahevarast ja laoprogrammist koosnev automaatne testimissüsteem biokeemiliste ja immunoloogiliste analüüside teostamiseks. Muu hulgas soovib hankija osta lepinguperioodi jooksul analüüside tegemiseks vajalikke reaktiive, kalibratsiooni- ja kontrollmaterjale ja teisi kuluvahendeid vastavalt reaalsele vajadusele. 2.3 Väljakuulutamiseta läbirääkimistega hankemenetluse liigi valikut ning raamlepingu sõlmimist on hankija põhjendanud konkurentsi puudumisega tehnilistel põhjustel järgmiselt: „Hankeobjekti keskseks tehniliseks põhjuseks on uuringu Troponiin-T määramine, mille võimalus on ainult aktsiaseltsi Surgitech poolt müüdavatel seadmetel.“2 Seega on hankija lähtunud eeldusest, et üksnes aktsiaselts Surgitech poolt pakutavat analüüti Troponiin T kasutades on võimalik saavutada selle testiga kontrollitav järeldus – tuvastada müokardiinfarkti tagajärjel tekkinud südamelihase kahjustus (vt p-s 3). 1 Komisjoni 10.11.2021 delegeeritud määrus (EL) 2021/1952 artikkel 1 lõige 1 punkt b. 2 Vt hanke üldandmete menetluse liigi selgitusest. 3 (9) . Vaidlustaja leiab, et hankija järeldus on ennatlik ning ebaõige, sest vaidlustaja pakutav kõrgtundlik analüüt Troponiin I võimaldab südamelihase kahjustuse olemasolu kontrollimist analüüdiga Troponiin T samaväärselt. Seetõttu ei pea vaidlustaja hankija konkurentsi piiravat tegevust hankemenetluse korraldamisel proportsionaalseks ega hanke suunamist üksnes aktsiaseltsile Surgitech õiguspäraseks. 2.4 Vaidlustaja vaidlustab raamlepingu, sest hankija on põhjendamatult asunud läbirääkimistesse aktsiaseltsiga Surgitech ning piiranud seeläbi hankemenetlusest osavõttu olukorras, kus raamlepingu sõlmimise keskse põhjusena3 väljatoodud tingimuse kaudu saavutatavat eesmärki on võimeline täitma ka muu isik, s.o vaidlustaja. Vaidlustaja on kõnealusest hankemenetlusest huvitatud isik ning teinuks avatud hankemenetluse korraldamisel pakkumuse või soovinuks väljakuulutamiseta läbirääkimistega hankemenetluses asuda läbirääkimistesse hankijaga. Arvestades, et vaidlustajal ei võimaldatud pakkumust teha ning raamleping sõlmiti ilma teisi võimalikke pakkujaid hankemenetlusse kaasamata, ei ole hankija järginud riigihangete korraldamise võrdse kohtlemise ning läbipaistvuse põhimõtet. Aktsiaseltsiga Surgitech raamlepingu sõlmimise aluseks olevad kaalutlusalused ei ole kontrollitavad. Ühe pakkuja põhjendamatu eelistamisega teiste ees on rikutud muu hulgas konkurentsi efektiivse ärakasutamise põhimõtet, mis ei võimalda veenduda ka avalike vahendite säästliku ja otstarbeka kasutamise põhimõtte järgimises, sest puuduvad võrreldavad pakkumused. 2.5 Eeltoodud kaalutlustel ei ole väljakuulutamiseta läbirääkimistega hankemenetluse läbiviimine konkurentsi piiraval kujul põhjendatud ega lubatav, mistõttu palub vaidlustaja käesoleva vaidlustuse esitamisega tuvastada raamlepingu tühisus. 3 Kõrgtundlikud Troponiin I ning Troponiin T on samaväärsed analüüdid 3.1 Vaidlustaja peamine etteheide hankijale seoses raamlepingu sõlmimisega seondub asjaoluga, et hankija väidab ebaõigesti konkurentsi puudumist tehnilistel põhjustel. Vaidlustaja hinnangul ei ole hankija väidetud tehnilistele põhjustele tuginemine kõnealuses hankemenetluses võimalik, sest vaidlustaja pakutav kõrgtundlik analüüt Troponiin I võimaldab saavutada sama tulemuse analüüdiga Troponiin T. Seega on hankija poolt seatud tingimus üksnes analüüdi Troponiin T ostmiseks ja selle ettekäändel hanke suunamine aktsiaseltsile Surgitech põhjendamatu. 3 Vt ülal p-s 2.3. 4 (9) . 3.2 Troponiin on valk, mis reguleerib lihaste kokkutõmbeid. Südame- ja skeletilihastes leiduv troponiinikompleks koosneb kolmest troponiini alaühikust: troponiin T (TnT), troponiin I (Tnl) ja troponiin C (TnC). Ägeda müokardiinfarkti tagajärjel südamelihase kahjustumisel vabanevad organismis troponiin T ja troponiin I. Südamelihase kahjustumist on seega võimalik tuvastada kahel üksteise suhtes alternatiivsel viisil – määrates veres sisalduva troponiin T või troponiin I väärtus. Kummagi väärtuse eraldi määramisel on võimalik järeldada üksnes sama faktilist asjaolu. Seega järeldub, et väärtuste määramiseks kasutatavad analüüdid on kontrollitava asjaolu suhtes ekvivalentsed, hoolimata sellest, et järeldusele jõutakse erinevate väärtuste määramise kaudu. See väljendub ka selles, et erinevates asutustes on kasutusel üks kõnealustest analüütidest, mitte mõlemad korraga. 3.3 Vaidlustaja pakutava kõrgtundliku troponiin I (cTnI-hs)4 tuvastamist võimaldava analüüdi tootjaks on Abbott, mis on hankija poolt tänaseni kasutusel (vt all p-s 5.4). Aktsiaseltsi Surgitech poolt pakutava kõrgtundliku troponiin T (cTnT-hs)5 tuvastamist võimaldava analüüdi tootjaks on Roche. Erialakirjandus on läbi viinud võrdluse ning on leidnud, et eelnimetatud analüüdid Troponiin I ja T toimivad ägedate kliiniliste seisundite (müokardiinfarkt) puhul diagnostilise järelduse tegemiseks sarnaselt. 3.4 Hankija on vaidlusaluse hanke menetluse liigi selgitustes märkinud, et SA Tartu Ülikooli Kliinikum on teostanud analoogse6 seadmete komplekti ostmiseks riigihanke viitenumbriga 245630. Viimati nimetatud riigihanke (viitenumbriga 245630) HD lisa 3 p-s 4.3 sätestab, et Troponiin T asemel võib pakkuda Troponiin I (mõlemad kõrgtundlikud). Seega järeldub, et mõlemad analüüdid omavad võimekust sama funktsiooni teostamiseks, mistõttu ei ole ka SA Tartu Ülikooli Kliinikum pidanud põhjendatuks analüüdi Troponiin T eelistamist analüüdile Troponiin I, vaid pakkunud mõlemat alternatiivselt. Selle valguses jääb ebaselgeks hankija selgitus patsiendi uuringumeetodite ühtlustamise kohta (vt hanke menetluse liigi selgituses). 4 Analüüdi Troponiin T eelistamine on konkurentsi kunstlikult kitsendav 4.1 RHS § 49 lg 1 p-i 2 kohaselt võib riigihanke korraldada väljakuulutamiseta läbirääkimistega hankemenetlusena muu hulgas, kui hankelepingu saab sõlmida ainult 4 kardiaalne troponiin I (kõrgtundlik). 5 kardiaalne troponiin T (kõrgtundlik). 6 Eesti õigekeelsussõnaraamat ÕS 2018 kohaselt mõiste „analoogne“ bioloogia valdkonnas tähendab: eri algupära, kuid sama funktsiooniga. 5 (9) . ühe ettevõtjaga tehnilistel või ainuõiguste, sealhulgas intellektuaalomandi õiguste kaitsega seotud põhjustel, kui puudub mõistlik alternatiiv ja konkurentsi puudumine ei tulene riigihankes esitatud tingimuste kunstlikust kitsendamisest. Eelviidatud sättele on hankija tuginenud hankemenetluse liigi valikul (vt ülal p-s 2.3). Tallinna Ringkonnakohus on selgitanud, et väljakuulutamiseta läbirääkimistega hankemenetluse kohaldamise aluseks olevaid sätteid tuleb tõlgendada kitsalt (TlnRnKo nr 3-15-853 p 16 ja vt täiendavalt all p-s 4.3). 4.2 Ülaltoodust järelduvalt puudub mõistlik alternatiiv juhul, kui ei ole olemas samaväärset vahendit, mis oleks võimeline saavutama sama tulemust või täitma sama funktsiooni. Vaidlustaja hinnangul on raamlepingu sõlmimise põhjenduseks seatud tingimus kunstlikult konkurentsi kitsendav. Antud juhul eksisteerib olukord, kus leidub arvestatav alternatiiv analüüdile Troponiin T (vt ülal p-s 3). 4.3 Väljakuulutamiseta läbirääkimistega hankemenetlus on kõige vähem läbipaistev ja konkurentsi kõige enam piirav hankemenetluse liik, kuna hankel saavad osaleda vaid hankija poolt valitud isikud ja hankija on suhteliselt vaba reeglite kujundamisel. Euroopa Kohtu praktika kohaselt tuleb läbirääkimistega hankemenetlust pidada rangelt erandlikuks ning erandeid reeglist, mille eesmärk on tagada asutamislepinguga tunnustatud riigihankelepingute sektorit puudutavate õiguste efektiivsus, tuleb tõlgendada kitsalt. Seejuures tõendamiskoormust erandi tegelikku esinemist kinnitavate erandlike asjaolude osas kannab erandile tugineda sooviv isik (Euroopa Kohtu 08.04.2008 otsus C-337/05, komisjon vs Itaalia, p-d 56-58). Samuti on Riigikohus viidanud kõnealuse hankeliigi vähesele läbipaistvusele (RKHKo nr 3-3-1- 65-11 p 13). Vaidlustaja leiab, et täna puuduvad õigustavad faktilised asjaolud ning tõendid, millele tuginedes võiks hankija põhjendada oma tegevust hanke korraldamiseks teisi pakkujaid kaasamata ning raamlepingu sõlmimiseks aktsiaseltsiga Surgitech. Hankija väidetud põhjendus konkurentsi puudumise kohta on ekslik, sest hanke läbiviimise aluseks olevatele asjaoludele on antud ebaõige hinnang. 4.4 Hankija ei ole põhjendanud, miks ei oleks teised ettevõtjad, sh vaidlustaja või ettevõtjad muudes EU liikmesriikides, muus EMP7 lepinguriigis või WTO8 riigihankelepinguga ühinenud riigis (RHS § 3 p 2), võimelised hanketingimustele vastama ja raamlepingut täitma. Samuti ei nähtu kaalutlusalused, millest võiks eeltoodut järeldada või tegevusi, mille kaudu jõudis hankija veendumusele, et teised 7 Euroopa Majanduspiirkond. 8 Maailma Kaubandusorganisatsioon. 6 (9) . pakkujad ei ole võimelised hankel kvalifitseeruma. Seega rikkus hankija muu hulgas oma kohustust tagada riigihanke korraldamine läbipaistvalt ja kontrollitavalt (RHS § 3 p 1). 4.5 Vaidlustajale ei ole teada millise osa hankest moodustab analüüdi Troponiin T osakaal ning isegi juhul, kui analüüdi Troponiin T ostmine oleks hüpoteetiliselt põhjendatud, ei saaks pidada sellele tuginedes hanke suunamist ühele ettevõtjale proportsionaalseks. Raamlepingu esemeks on ka muud analüsaatorid, seadmed ning tarvikud. Näiteks moodustas 2017.a sarnases hankes troponiini analüütide osakaal ca 10% hangitavate analüüside kogumahust9 (vt all p-s 5.4 viidet 11). Seetõttu peab vaidlustaja vajalikuks raamlepingu sõlmimise põhjendatust analüüdi Troponiin T hankimise põhjendusel hinnata prognoositava müügikoguse järgi ja võrrelda seda teiste hankelepingu esemeks olevate toodete osakaaluga kogu hankelepingust. Eeltoodu teostamiseks on vajalik tutvuda raamlepinguga, millise vaidlustaja palub hankijal esitada käesolevas vaidlustusmenetluses läbivaatamiseks. 5 Hankija ei viinud hankemenetlust läbi õiguspäraselt 5.1 Euroopa Kohus on täiendavalt leidnud, et väljakuulutamiseta läbirääkimistega hankemenetlust kasutades ning ühe pakkujaga hankelepingu sõlmimisel läbi rääkides tulenevalt tehnilistest põhjustest, on hankija kohustatud uurima, kas on olemas ettevõtjaid, kes oleksid võimelised samadel tingimustel või isegi edukaks tunnistatud pakkujast parematel tingimustel hanketeatele vastama. Seejuures peab teiste kvalifitseeruvate ettevõtjate välistamine tuginema konkreetsetele asjaoludele, milleks muu hulgas võib vajalikuks osutuda põhjaliku otsingu läbiviimine (Euroopa Kohtu 15.01.2013 otsus T‑54/11, komisjon vs Hispaania Kuningriik, p-d 53-55). Seega peavad hankija põhjendused välistuse tegemisel olema ammendavad ega jätma üles kahtlusi teiste ettevõtjate võimaliku kvalifitseerumise osas. Vaidlustajale ei ole teada, et hankija oleks võtnud meetmeid asjaolude väljaselgitamiseks. 5.2 Hankija ei ole toonud välja aluseid ega muid andmeid, milledele tugineb hankija veendumus keskse põhjusena10 väidetu kohta, mistõttu ei ole hankija põhjendus kontrollitav ega otsuse tegemine läbipaistev. Euroopa Kohtu praktika peab vajalikuks hinnata, kas hankija toimis hankemenetluse liigi valikut otsustades hoolikalt ja kas ta võis eeldada, et tingimused hankemenetluse läbiviimiseks olid 9 Analüüside prognoositavaks mahuks aastas oli märgitud kokku 44 365 analüüsi, millest 4427 moodustasid analüütide Troponiin T või I (kõrgtundlik meetod) analüüsid. 10 Vt ülal p-s 2.3. 7 (9) . tegelikult täidetud (Euroopa Kohtu 11.09.2014 otsus C19/13, punkt 50). Seega pidanuks hankija hanke ettevalmistamisel planeerimis- ja hoolsuskohustuse täitmise raames selgitama välja RHS § 49 lg 1 p-i 2 mõttes pakutavad mõistlikud alternatiivid ja muud ettevõtjad. Viimane näinuks ette teiste hulgas ka vaidlustajaga läbirääkimistesse astumist, et selgitada välja vaidlustaja võimekus raamlepingu sõlmimise eesmärkide täitmiseks. Sellega saanuks hankija kaardistada ka raamlepingu vaidlustamise võimalikud stsenaariumid ja selle mõju hankele, mida tuleks pidada samuti hanke korraldaja hoolsuskohustuse raames täidetavaks ülesandeks. Hankija otsust raamlepingu sõlmimisel vaid ühe ettevõtjaga läbirääkimisi pidades ei saa seetõttu pidada õiguspäraseks. 5.3 Alternatiivselt võib hankijale ette heita, et kuigi seadus võimaldab hankedokumentide saatmist ja ettepaneku tegemist sama hankeliigi raames ka teistele ettevõtjatele, siis ei astunud hankija vaidlustajaga läbirääkimistesse. RHS § 72 lg 1 kohaselt teeb hankija ühele või mitmele ettevõtjale, kelle majanduslik ja finantsseisund ning tehniline ja kutsealane pädevus on hankelepingu nõuetekohaseks täitmiseks eeldatavalt piisavad, ettepaneku pidada läbirääkimisi hankelepingu sõlmimiseks. 5.4 Vaidlustajale on teadmata põhjused, miks ei peetud vajalikuks vaidlustajaga läbirääkimisi pidada, kui vaidlustaja on hankijale teada kui meditsiiniseadmete varustamisega tegeleva ettevõtjana. Vaidlustaja varustas hankijat hankemenetluses viitenumbriga 168237 sõlmitud 09.01.2017 raamlepingu raames kõrgtundliku analüüdiga Troponiin I, kusjuures sama riigihanke raames loeti samaväärseteks nii analüüdid Troponiin I ja Troponiin T.11 Seega pidanuks hankija olema teadlik vaidlustaja huvist vaidlusaluse raamlepingu sõlmimise vastu ning korraldama vaidlustaja hankes osalemise õigust silmas pidades avatud hankemenetluse või tegema ettepaneku läbirääkimiste pidamiseks. 6 Hankija on rikkunud muid riigihanke korraldamise üldpõhimõtteid 6.1 Väljakuulutamiseta läbirääkimistega hankemenetluse korraldamisel vaid ühe ettevõtja kaasamisega ja raamlepingu sõlmimisega rikkus hankija teiste võimalike ettevõtjate (pakkujate) õigusi osaleda hankemenetluses. Hankija poolt valitud hankemenetluse liik RHS § 49 lg 1 p-i 2 mõttes piiras konkurentsi ning tõi kaasa ühe ettevõtja põhjendamatu eelistamise. Hankija on kohustatud riigihanke korraldamisel järgima, 11Vt samaväärsena käsitamise kohta riigihanke viitenumbriga 168237 HD reaktiivide loetelu (050216) – rida 31(avaldatud 05.02.2016). 8 (9) . et kõiki isikuid koheldakse võrdselt ning jälgib, et kõik isikutele seatavad piirangud ja kriteeriumid oleksid riigihanke eesmärgi suhtes proportsionaalsed, asjakohased ja põhjendatud (RHS § 3 p 2). 6.2 Hankija ei ole teiste ettevõtjate osavõttu piirates taganud konkurentsi efektiivset ärakasutamist, mistõttu ei saa tuvastada avalike ressursside säästlikku ja otstarbekat kasutamist ning et raamlepingu sõlmimine oleks saavutatud parima hinna ja kvaliteedi suhet silmas pidades (RHS § 3 p-d 3 ja 5). 6.3 Muu hulgas ei ole vaidlustajale teada olevatel asjaoludel võimalik väita, et konkurentsivabaduse riive olnuks käesoleval juhul proportsionaalne. 6.4 Ülaltoodud kaalutlustel ei ole vaidlustaja hinnangul raamlepingu sõlmimise aluseks olev hankemenetlus läbi viidud õiguspäraselt, mistõttu ei olnuks selle tulemusel raamlepingu sõlmimine lubatav. 7 Raamlepingu sõlmimine 7 aastaks on põhjendamata 7.1 RHS eristab hankelepingut ning raamlepingut. RHS § 4 p 15 kohaselt on raamleping ühe või mitme ettevõtja ja ühe või mitme hankija vahel sõlmitud leping, millega kehtestatakse lepingu kehtivusaja vältel selle alusel sõlmitavaid hankelepinguid reguleerivad tingimused. Vastavalt RHS § 29 lg-le 2 võib raamlepingu sõlmida tähtajaga kuni 4 aastat, välja arvatud juhul, kui pikem tähtaeg on põhjendatud. Hanke üldandmetest nähtub (vt hanke lühikirjeldus), et raamleping on sõlmitud 7 aastaks ning täitmise tähtajaks on märgitud 21.06.2030 (vt lepingu andmed). Hankija ei ole põhjendanud vajadust raamlepingu sõlmimiseks pikemaks kui 4 aastaseks tähtajaks. 7.2 Vaidlustaja peab vajalikuks märkida, et raamlepingu sõlmimine 7 aastaks on muu hulgas vastuoluline. Hankelepingu sõlmimise teate (ID 3470741) VI osa alapunkti 3 lisateabe kohaselt vajab hankija analüüsideks kasutatavaid lisatarvikuid üksnes 48 kuuks. Seega järeldub, et kui raamleping sõlmitakse 7 aastaks, kuid tarvikuid vajatakse üksnes järgmiseks 48 kuuks, siis on hankelepingu sõlmimine 48 kuud ületavas, s.o 3 aastat, osas ebavajalik ning põhjendamata. 8 Tõendid Vaidlustaja palub, et vaidlustuskomisjon hindaks eeltoodud väiteid järgnevalt loetletud tõendite uurimise alusel. Vaidlustaja on lisanud tõendi originaali ning selle kohta käiva eestikeelse tõlke. Lisad 2-5 on tõlgitud osaliselt ning 9 (9) . originaaldokumendis tähistatud vastavalt kollase värviga. Lisa 6 on originaalis eestikeelne ning lisa 7 on tõlgitud täies mahus. 8.1 Lisadega 2 – lk 1; 3 – lk 1; 4 – lk 3; 5 – lk 1-2; 6 – lk 1; lisa 7 – lk 1-2 tõendab vaidlustaja, et troponiinide I ja T taset mõõdetakse müokardiinfarkti ehk südamelihase kahjustuse tuvastamiseks, mis kutsub esile nii troponiin I ja troponiin T vabanemise organismi. 8.2 Lisadega 4 – lk 1-3; 5 – lk 2; 7 – lk 2 ja 4 tõendab vaidlustaja, et analüüdid Troponiin I ja Troponiin T on samaväärsed vahendid müokardiinfarkti tagajärjel tekkinud südamelihase kahjustuse diagnoosimiseks. 8.3 Lisaga 6 – lk 8 (vt lisa 6 ravijuhendi lisa 1) tõendab vaidlustaja, et erinevates asutustes on kasutusel üks kõnealustest analüütidest (Troponiin T või Troponiin I), kuid mitte mõlemad analüüdid. Vaidlustaja tõendab sellega asjaolu, et näiteks Rakvere Haigla, Pärnu Haigla ning hankija kasutasid seisuga 16.04.2019 analüüti Troponiin I. Lisad: 1) Riigilõivu maksekorraldus 2) Südamehaiguste markerid troponiinid I ja T 3) Kardiaalse troponiini analüüs 4) Troponiinide I ja T otsene võrdlus 5) Euroopa Kardioloogide Seltsi juhend 6) Ravijuhend Eesti Arst 2019 7) Kõrgtundliku troponiin I ja T samaväärsusest Lugupidamisega, /allkirjastatud digitaalselt/ Teet Lehiste Advokaat European Heart Journal (2014) 35, 2303–2311 CLINICAL RESEARCH doi:10.1093/eurheartj/ehu188 Acute coronary syndromes Direct comparison of high-sensitivity-cardiac troponin I vs. T for the early diagnosis of acute myocardial infarction Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 Maria Rubini Gimenez1,2†, Raphael Twerenbold 1,3†, Tobias Reichlin1,4, Karin Wildi 1, Philip Haaf1, Miriam Schaefer 1, Christa Zellweger 1, Berit Moehring 1, Fabio Stallone 1, Seoung Mann Sou 1, Mira Mueller 1, Kris Denhaerynck1, Tamina Mosimann 1, Miriam Reiter 1, Bernadette Meller 1, Michael Freese 1, Claudia Stelzig 1, Irina Klimmeck 1, Janine Voegele 1, Beate Hartmann 1, Katharina Rentsch 5, Stefan Osswald 1, and Christian Mueller 1* 1 Department of Cardiology, University Hospital Basel, Basel, Switzerland; 2Servicio de Urgencias y Pneumologia, CIBERES ISC III, Hospital del Mar – Institut Municipal D’Investigació Mèdica, Barcelona, Spain; 3Universitäres Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; 4Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; and 5Laboratory Medicine, University Hospital Basel, Basel, Switzerland Received 8 September 2013; revised 19 March 2014; accepted 15 April 2014; online publish-ahead-of-print 19 May 2014 See page 2273 for the editorial comment on this article (doi:10.1093/eurheartj/ehu201) Aim It is unknown whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the early diagnosis of acute myocardial infarction without ST segment elevation (NSTEMI). ..................................................................................................................................................................................... Methods In a prospective multicentre study, we measured cTnI and cTnT using clinically available high-sensitivity assays (hs-cTnI and results Abbott and hs-cTnT Roche) and compared their diagnostic and prognostic accuracies in consecutive patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by two independent cardiologists using all information pertaining to the individual patient. The mean follow-up was 24 months. Among 2226 consecutive patients, 18% had an adjudicated final diagnosis of NSTEMI. Diagnostic accuracy at presentation as quantified by the area under the receiver-operating-characteristics curve (AUC) for NSTEMI was very high and similar for hs-cTnI [AUC: 0.93, 95% confidence interval (CI) 0.92– 0.94] and hs-cTnT (0.94, 95% CI: 0.92–0.94) P ¼ 0.62. In early presenters (,3 h since chest pain onset) hs-cTnI showed a higher diagnostic accuracy (AUC: 0.92, 95% CI: 0.89–0.94) when compared with hs-cTnT AUC (0.89, 95% CI: 0.86– 0.91) (P ¼ 0.019), while hs-cTnT was superior in late presenters [AUC hs-cTnT 0.96 (95% CI: 0.94– 0.96) vs. hs-cTnI 0.94 (95% CI: 0.93– 0.95); P ¼ 0.007]. The prognostic accuracy for all-cause mortality, quantified by AUC, was significantly higher for hs-cTnT (AUC: 0.80; 95% CI: 0.78– 0.82) when compared with hs-cTnI (AUC: 0.75; 95% CI: 0.73–0.77; P , 0.001). ..................................................................................................................................................................................... Conclusion Both hs-cTnI and hs-cTnT provided high diagnostic and prognostic accuracy. The direct comparison revealed small but potentially important differences that might help to further improve the clinical use of hs-cTn. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Acute myocardial infarction † High-sensitive cardiac troponin for 10% of all emergency departments (ED) consultations, even Introduction though only 10 –20% of them eventually suffer from AMI. Rapid Acute myocardial infarction (AMI) is a major cause of death and dis- identification of AMI is of paramount clinical importance for early ability worldwide. Patients with symptoms suggestive of AMI account treatment and management.1 * Corresponding author. Tel: +41 613286549, Fax: +41 61265353, Email: [email protected] † M.R.G. and R.T. have contributed equally and should be considered first author. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]. 2304 M. Rubini Gimenez et al. Cardiac troponins (cTn) I and T are proteins unique to heart and indicated. Timing and treatment of patients were left to discretion of the specific and sensitive biomarkers of myocardial damage.2 – 4 Cardiac attending physician. troponin and 12-lead electrocardiogram (ECG) complement patient history and physical examination in the evaluation of patients, Adjudicated final diagnosis presenting with acute chest pain.5,6 A limitation of conventional cTn Adjudication of the final diagnosis was performed centrally in the core lab assays is their low sensitivity at the time of patient presentation, owing (University Hospital Basel) for all patients twice: Once according to con- to a delayed increase in circulating levels requiring serial sampling for ventional cTn levels used onsite (this method was used in the initial ana- 6 –9 h in a significant number of patients.2 Recent studies found that lyses to examine the performance of hs-cTn assays7,11 – 13 and once more sensitive cTn assays can improve the accuracy of the diagnosis including levels of Roche hs-cTnT in order to also take advantage of the higher sensitivity and higher overall diagnostic accuracy offered by of AMI at the time of presentation to the ED.7,8 hs-cTn assays,14,15 this allows the additional detection of small AMIs The cTn complex is immobilized on the thin filament of the that were missed by the adjudication based on conventional cTn contractile apparatus and plays a critical role in the regulation of assays. Two independent cardiologists reviewed all available medical Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 excitation–contraction coupling in the heart.6 In AMI, cTnI and records—patient history, physical examination, results of laboratory cTnT are released from necrotic myocardium both as intact proteins testing, radiological testing, ECG, echocardiography, cardiac exercise and degradation products.6 The clinical availability of fully developed test, lesion severity, and morphology in coronary angiography—pertain- high-sensitivity assays for both cTnI (Abbott) and cTnT (Roche) in ing to the patient from the time of ED presentation to 90-day follow-up. In Europe and other countries now for the first time provides the meth- situations of disagreement about the diagnosis, cases were reviewed and odological requirement to appropriately test the hypothesis whether adjudicated in conjunction with a third cardiologist. the substantial biochemical differences including molecular weight Non-ST segment myocardial infarction was defined and cTn levels between cTnI (23 kDa) and cTnT (35 kDa) could result in differ- interpreted as recommended in current guidelines.16,17 In brief, NSTEMI was diagnosed when there was evidence of myocardial necrosis ent diagnostic and prognostic performances for both biomarkers.6,9 in association with a clinical setting consistent with myocardial ischaemia. This hypothesis is based on preliminary findings from subgroup ana- Myocardial necrosis was diagnosed by at least one cTn value above the lyses as well as very recent observations with pre-commercial and still 99th percentile (or for the conventional cTn assays above the 10% impre- experimental hs-cTnI assays.10 – 12 cision value if not fulfilled at the 99th percentile) together with a signifi- The aim of our large prospective multicentre study was to directly cant rise and/or fall.9,18,19 The criteria used to define rise and/or fall in compare the diagnostic accuracy of clinically available hs-cTnI and conventional cTn and hs-cTnT are described in detail in the Supplemen- hs-cTnT for NSTEMI, as well as their prognostic accuracy for all- tary material online, Methods. cause mortality during 24-month follow-up, in consecutive patients All other patients were classified as ‘No NSTEMI’ for this analysis, in- presenting to the ED with acute chest pain. cluding in this group the categories of unstable angina (UA), non-cardiac chest pain (NCCP), cardiac but non-coronary disease (e.g. tachyarrhyth- mias, perimyocarditis), and symptoms of unknown origin with normal Methods levels of cTn and hs-cTnT (thereby ruling-out AMI). Unstable angina was defined according to recent guidelines as follows: Study design and population (i) new onset (de novo) of severe angina, or recent destabilization of pre- Advantageous Predictors of Acute Coronary Syndrome Evaluation viously stable angina with at least severe (class III) angina characteristics (APACE) is an ongoing prospective international multicentre study (per- (crescendo angina), or post-MI angina, and (ii) either coronary artery formed in nine different study centres in Switzerland, Spain, and Italy) stenosis .70% on angiogram, or positive cardiac exercise testing, or in designed and coordinated by the University Hospital Basel Switzerland ambiguous cases when AMI or sudden death occurred within 60 days, to advance the early diagnosis of AMI.7,10 – 12 From April 2006 to and (iii) absence of alternative diagnosis.20 August 2012, consecutive patients older than 18 years presenting to the ED with symptoms suggestive of AMI with an onset or peak within Measurement of high-sensitivity cardiac the last 12 h were recruited, after informed consent was obtained. troponin I and high-sensitivity cardiac Patients with terminal kidney failure requiring regular dialysis were troponin T excluded. For this analysis, patients were also excluded if (i) hs-cTnI Blood samples for determination of hs-cTnI (Abbott) and hs-cTnT (Abbott) or hs-cTnT (Roche) levels were not available (n ¼ 661) or (ii) (Roche) were collected at presentation to the ED, in serum and EDTA the final diagnosis remained unclear after adjudication and at least one plasma tubes for hs-cTnT, and in serum for hs-cTnI. Additional samples cTn or hs-cTnT level was elevated (possibly indicating the presence of were collected at 1, 2, 3, and 6 h. When treatment required transferring AMI) (n ¼ 69) (iii) patients with a final diagnosis of ST segment myocar- the patient to the catheter laboratory or coronary care unit, because the dial infarction (STEMI) (n ¼ 75). diagnosis of AMI was certain, serial sampling was disrupted. After centri- The study was carried out according to the principles of the Declar- fugation, samples were frozen at 2808C until assayed in a blinded fashion ation of Helsinki and approved by the local Ethics Committees. The in a dedicated core laboratory. The Abbott hs-cTnI assay used was the authors designed the study, gathered, and analysed the data, vouch for final pre-commercial release version of the ARCHITECT High Sensitive the data and analysis, wrote the paper, and decided to publish. STAT Troponin I assay (Abbott Laboratories, Abbott Park, IL, USA). Samples were thawed, mixed, and centrifuged (for 30 min at 3000 RCF Routine clinical assessment and 48C for serum samples or for 10 min, twice, at 3000 RCF for All the patients underwent a clinical assessment that included medical plasma samples) prior to analysis and according to manufacturer’s history, physical examination, 12-lead ECG, continuous ECG monitoring, instructions. The hs-cTnI assay has a 99th percentile concentration of pulse oximetry, standard blood test, and chest radiography. Levels of cTn 26.2 ng/L with a corresponding coefficient of variation (CV) of ,5% were measured at presentation and serially thereafter as long as clinically and a limit of detection (LoD) of 1.9 ng/L.21 The Roche hs-cTnT assay Comparison of hs-cTn I and T 2305 was measured on the Elecsys 2010 (Roche Diagnostics). The limit of blank compared with the 1827 patients in the no-NSTEMI group [hs-cTnI and LoD were determined to be 3 and 5 ng/L, respectively. The median 115.4 ng/L (IQR: 21.7–627.9) vs. 3.5 ng/L (IQR: 2.2– 7.2) 99th-percentile of a healthy reference population was reported at P , 0.001; hs-cTnT median 65.0 ng/L (IQR: 28.0– 152.5) vs. 7.0 ng/ 14 ng/L with an imprecision corresponding to 10% CV at 13 ng/L.22 L (IQR: 4.0 –12.4) P , 0.001]. Diagnostic accuracy of hs-cTn for This study does not include any measurements with hs-cTnT lots that NSTEMI, as quantified by the AUC, was similar for hs-cTnI and required the revision of the calibration curve.23 – 26 Calculation of the hs-cTnT (AUC hs-cTnI 0.93, 95% CI: 0.92–0.94; AUC hs-cTnT glomerular filtration rate was performed using the abbreviated Modifica- 0.94, 95% CI: 0.92– 0.94; P ¼ 0.619; Figure 2A). tion of Diet in Renal disease formula.27 Follow-up and prognostic endpoints Diagnostic performance of high-sensitivity After hospital discharge, patients were contacted by telephone interview cardiac troponin I and T in early presenters or written form after 3, 12, and 24 months of follow-up. In case of Among patients presenting to the ED with chest pain onset within 3 h reported clinical events—in particular cardiovascular events—since Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 (representing 25% of the overall cohort), hs-cTnI showed a signifi- presentation to the ED, details were reviewed by asking the patients and traced by establishing contact with the respective family physician cantly higher diagnostic accuracy for NSTEMI compared with or treating institution. The primary prognostic endpoint was all-cause hs-cTnT (Table 2). As shown in Figure 2B, among the early presenters mortality during 24-month follow-up; non-fatal AMI during the follow-up the AUC at presentation for hs-cTnI was 0.92, 95% CI: 0.89–0.94 vs. was a secondary prognostic end-point. Information regarding death and hs-cTnT 0.89, 95% CI: 0.86–0.91 (P ¼ 0.019). In patients presenting AMI was obtained from the national registry on mortality, the hospital’s to the ED with chest pain onset of .3 h the AUC for hs-cTnI was sig- diagnosis registry or family physician’s records. nificantly lower compared with hs-cTnT [0.94 (95% CI: 0.93–0.95) vs. 0.96 (95% CI: 0.94–0.96)] (P ¼ 0.007). Statistical methods Diagnostic performance of high-sensitivity The data are expressed as medians + IQR for continuous variables, cardiac troponin I and T during serial and for categorical variables as numbers and percentages. Con- tinuous variables were compared with the Mann–Whitney U test, sampling and categorical variables using the Pearson x2 test. Receiver- During serial sampling as well as when combining the level obtained at operating-characteristics (ROC) curves were constructed to assess presentation with changes within the first hours, diagnostic accuracy the sensitivity and specificity of both assays to compare their ability for NSTEMI of both assays further increased (Table 3). While individ- to diagnose AMI and UA, as well as their prognostic accuracy. Prog- ual measurements performed at 1, 2, and 3 h showed similar accur- nostic accuracy was quantified by three complementary methods: acy, hs-cTnI showed a slightly lower diagnostic accuracy during AUC using the dichotomy of survival, AUC using survival analysis serial sampling compared with hs-cTnT when combining the level techniques and estimate the concordance index (Harrell’s c) using obtained at presentation with changes within the first hours (AUC the survival model, and a Cox proportional-hazard model. The com- hs-cTnI 0.95, 95% CI: 0.94–0.96 vs. hs-cTnT 0.96, 95% CI: 0.95– parison of areas under the ROC curves (AUC) was performed as 0.97, P ¼ 0.004) (Figure 3). In early presenters, serial sampling pro- recommended by deLong et al.28 Pre-defined subgroups include vided similar accuracy with both assays. patients with recent onset of symptoms (,3 h).7 All hypothesis testing was two-tailed and P-value of ,0.05 was Diagnostic performance of high-sensitivity considered statistically significant. All statistical analyses were per- cardiac troponin I and high-sensitivity formed using SPSS for Windows 21.0 (SPSS, Inc., Chicago, IL, USA) and MedCalc 9.6.4.0 (MedCalc software, Mariakerke, Belgium). cardiac troponin T for unstable angina Among all consecutive patients, 9.7% had a final diagnosis of UA. Levels at presentation of both hs-cTn assays were significantly Results higher among patients whose final diagnosis was UA compared with those with NCCP, hs-cTnI median 6.4 ng/L (IQR: 3.6 –12.1) Patient characteristics vs. 3.0 ng/L (IQR: 1.9 –5.1) P , 0.001; hs-cTnT median 10.7 ng/L The baseline characteristics of 2226 patients with suspected NSTEMI (IQR: 6.9– 15.9) vs. 6.0 ng/L (IQR: 3.9 –9.7) P , 0.001). High- are shown in Table 1. The adjudicated final diagnosis was NSTEMI in sensitivity-cTnI had a slightly higher diagnostic accuracy for UA as 18% of patients, UA in 10%, cardiac but non-coronary symptoms in quantified by the AUC compared with hs-cTnT (0.74, 95% CI: 13%, non-cardiac cause in 54%, and symptoms of unknown origin 0.72 –0.77, vs. 0.72, 95% CI: 0.69– 0.74; P ¼ 0.07). in 5%. Among the 399 NSTEMI patients, 85% had type I AMI and 15% had type II AMI. Correlation with angiographic findings Among all patients in whom coronary angiography was performed Diagnostic performance of high-sensitivity (n ¼ 530), 83% (n ¼ 441) had positive angiographic findings (one cardiac troponin I and T for acute vessel, two vessels or three vessels disease). The accuracy to myocardial infarction predict a positive angiographic finding as quantified by the AUC As shown in Figure 1, levels of the two hs-cTn at presentation were was significantly higher for hs-cTnI when compared with hs-cTnT significantly higher among the 399 patients who had NSTEMI (0.82, 95% CI: 0.78– 0.84, vs. 0.79, 95% CI: 0.76–0.81; P , 0.001). 2306 M. Rubini Gimenez et al. Table 1 Baseline characteristics of patients Characteristic All (n 5 2226) NSTEMI (n 5 399) No NSTEMI (n 5 1827) P-valuea ............................................................................................................................................................................... Age, years Median 62 72 60 ,0.001 IQR 50– 75 59– 72 48– 73 Risk factors, n (%) Hypertension 1383 (62) 319 (80) 1064 (58) ,0.001 Hypercholesterolaemia 1111 (50) 273 (68) 838 (46) ,0.001 Diabetes 384 (17) 108 (27) 276 (15) ,0.001 Current or previous smoking 1367 (61) 254 (64) 1113 (61) 0.31 Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 Family history 744 (33) 153 (38) 591 (32) 0.021 History, n (%) Coronary artery disease 777 (35) 203 (51) 574 (31) ,0.001 Previous AMI 514 (23) 137 (34) 377 (21) ,0.001 Previous revascularization 612 (28) 147 (37) 465 (26) ,0.001 Peripheral artery disease 142 (6) 57 (14) 85 (5) ,0.001 Previous stroke 122 (6) 39 (10) 83 (5) 0.001 ECG findings, n (%) Left bundle branch block 67 (3) 23 (6) 44 (2) ,0.001 ST-segment elevation 43 (2) 11 (3) 32 (2) ,0.001 ST-segment depression 232 (10) 121 (30) 111 (6) ,0.001 T-wave inversion 296 (13) 100 (25) 196 (11) ,0.001 No significant changes 1688 (76) 144 (36) 1464 (80) ,0.001 Body mass index (kg/m2) Median 26 26 27 0.49 IQR 24– 30 24– 29 24– 30 eGFR (mL/min/1.73 m2) Median 85 74 87 ,0.001 IQR 68– 101 57– 94 71– 103 Medication at presentation, n (%) ASA 809 (36) 200 (50) 609 (33) ,0.001 Vitamin K antagonists 191 (9) 41 (10) 150 (8) 0.18 Beta-blockers 770 (35) 174 (44) 596 (33) ,0.001 Statins 777 (35) 178 (45) 599 (33) ,0.001 ACEIs/ARBs 843 (38) 207 (52) 636 (35) ,0.001 Calcium antagonists 321 (14) 82 (21) 239 (13) ,0.001 Nitrates 257 (12) 85 (21) 172 (9) ,0.001 AMI, acute myocardial infarction; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ASA, acetyl salicylic acid; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. Values are expressed in percentage or medians + IQR. a Comparisons between NSTEMI and no-NSTEMI patients. Prognostic accuracy of high-sensitivity Similar findings were obtained regarding cardiac death. Among all cardiac troponin I and T for mortality patients 3% (n ¼ 69) suffered from a cardiac death during the follow- up. The accuracy to predict cardiac death as quantified by the AUC Patients were followed during a mean period of 24 months. During was significantly higher for hs-cTnT when compared with hs-cTnI this time a total of 153 patients died, 44% of them had a diagnosis (0.82, 95% CI: 0.80–0.84, vs. 0.79, 95% CI: 0.78–0.81; P ¼ 0.004. of NSTEMI and 56% had a different diagnosis than NSTEMI (P , 0.001). Prognostic accuracy as quantified by the AUC was high for both and significantly higher for hs-cTnT when compared Prediction of acute myocardial infarction with hs-cTnI (0.80, 95% CI: 0.77–0.83, vs. 0.75, 95% CI: 0.73–0.79; in the future P , 0.001; Figure 4). The prognostic superiority of hs-cTnT was con- Among all patients in the no-NSTEMI group (n ¼ 1827), 3.6% sistent in the NSTEMI group (P , 0.001) and in the non-NSTEMI (n ¼ 65) suffered an AMI during the follow-up. The accuracy to group (P ¼ 0.001). predict AMI among these patients as quantified by the AUC was Comparison of hs-cTn I and T 2307 moderate for both and slightly higher for hs-cTnI when compared Discussion with hs-cTnT (0.70, 95% CI: 0.68–0.72 vs. 0.66, 95% CI: 0.64–0.68; P ¼ 0.07. Among all patients in the NSTEMI group (n ¼ 399), While hs-cTn assays still await approval for clinical use in the USA, 14.8% (n ¼ 59) suffered an AMI during the follow-up. The accuracy two fully developed hs-cTn assays have become clinically available to predict AMI among these patients as quantified by the AUC was in Europe and many other countries in 2010 (hs-cTnT, Roche) and very low for both (hs-cTnI 0.56, 95% CI: 0.51– 0.61 vs. hs-cTnT 2013 (hs-cTnI, Abbott). This large prospective multicentre study 0.54, 95% CI: 0.49–0.59; P ¼ 0.49). directly compared the diagnostic and prognostic accuracy of these clinically available hs-cTn assays in consecutive patients presenting to the ED with acute chest pain. We report six major findings. First, in our analysis both hs-cTnI and hs-cTnT showed very high diagnostic accuracy for NSTEMI (AUC 0.93 and 0.94) already at pres- entation, confirming and extending similar previous findings for both Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 clinically available as well as pre-commercial s-cTn and hs-cTn assays.7,8,29 Secondly, in the overall group diagnostic accuracy at pres- entation for NSTEMI was similar with both assays. This finding is of major clinical relevance for clinicians, laboratory experts, and hospital administrators as it will help these decision-makers in planning the future laboratory strategies of their institutions. However, our data also suggested that time from symptom onset may impact on the re- spective diagnostic superiority of either test over the other: hs-cTnI seemed to be superior in early presenters, while hs-cTnT seemed to be superior in late presenters. It is important to highlight that the diag- nostic superiority of hs-cTnI vs. T in early presenters methodologic- ally is very sound, as our methodology introduced a small but unavoidable bias in favour of hs-cTnT regarding diagnostic accuracy. While local levels of both cTnI and cTnT were used for the adjudica- tion, only hs-cTnT levels were available for the additional adjudica- Figure 1 Levels of high-sensitivity cardiac troponin according to tion of small AMIs and more patients were enrolled in sites using final diagnoses. Troponins levels at the time of patients’ presenta- (hs-)cTnT rather than cTnI. In addition, the finding of diagnostic tion to the emergency department. The boxes represent median superiority of hs-cTnI in early presenters is supported by similar and inter-quartile ranges. hs-cTn, high-sensitivity cardiac troponin; recent observations with s-cTnI in critical subgroups such as the AMI, acute myocardial infarction; CAD, coronary artery disease. elderly and patients with pre-existing coronary artery disease11,12 Figure 2 Diagnostic performance of high-sensitivity cardiac troponins I and T. Receiver-operation-characteristic curves show the diagnostic ac- curacy of high-sensitivity cardiac troponins I and T for non-ST segment myocardial infarction at presentation to the emergency department with acute chest pain in the overall cohort (A) and in the patients with a chest pain onset within 3 h (B). 2308 M. Rubini Gimenez et al. Table 2 Diagnostic accuracy of changes in high-sensitivity cardiac troponin I vs. changes in high-sensitivity cardiac troponin T in early presenters Time point AUC (95% CI) AUC (95% CI) P-valuea hs-cTnI hs-cTnT ................................................................................ 0ha 0.92 (0.89– 0.94) 0.89 (0.86–0.91) 0.019 1hb 0.95 (0.92– 0.96) 0.95 (0.92–0.96) 0.97 0h+1hb 0.95 (0.92– 0.96) 0.94 (0.92–0.96) 0.74 1h+D0h21hb 0.95 (0.92– 0.97) 0.95 (0.93–0.97) 0.44 2hc 0.98 (0.95– 0.99) 0.97 (0.95–0.98) 0.88 Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 0h+2hc 0.95 (0.92– 0.97) 0.96 (0.94–0.98) 0.05 2h+D0h22hc 0.96 (0.93– 0.98) 0.96 (0.94–0.98) 0.42 3hd 0.98 (0.94– 0.99) 0.98 (0.95–1.00) 0.60 0h+3hd 0.97 (0.94– 0.99) 0.99 (0.96–0.99) 0.18 3h+D0h23hd 0.98 (0.95– 0.99) 0.99 (0.96–0.99) 0.29 a ¼ 558; b ¼ 456; c ¼ 385; d ¼ 181. a Comparisons between hs-cTnI vs. hs-cTnT. Figure 3 Diagnostic performance of high-sensitivity cardiac troponin T and I within time. Receiver-operation-characteristic curves displaying the diagnostic accuracy for non-ST segment myo- cardial infarction of serial sampling of high-sensitivity cardiac tropo- Table 3 Diagnostic accuracy of changes in nin I vs. high-sensitivity cardiac troponin T. high-sensitivity cardiac troponin I vs. changes in high-sensitivity cardiac troponin T Time point AUC (95% CI) AUC (95% CI) P-valuea hs-cTnI hs-cTnT ................................................................................ 0ha 0.93 (0.92– 0.94) 0.94 (0.92–0.94) 0.62 1hb 0.95 (0.94– 0.96) 0.95 (0.94–0.96) 0.48 0h+1hb 0.95 (0.94– 0.96) 0.95 (0.94–0.96) 0.19 1h+D0h21hb 0.95 (0.94– 0.96) 0.96 (0.95–0.97) 0.004 2hc 0.95 (0.94– 0.96) 0.95 (0.94–0.96) 0.92 0h+2hc 0.94 (0.92– 0.95) 0.96 (0.95–0.97) 0.05 2h+D0h22hc 0.96 (0.95– 0.97) 0.97 (0.96–0.98) 0.06 3hd 0.95 (0.93– 0.97) 0.96 (0.95–0.98) 0.07 0h+3hd 0.95 (0.93– 0.97) 0.97 (0.95–0.98) 0.032 3h+D0h23hd 0.96 (0.94– 0.97) 0.97 (0.96–0.98) 0.017 a ¼ 2226; b ¼ 1735; c ¼ 1374; d ¼ 642. a Comparisons between hs-cTnI vs. hs-cTnT. and therefore quite certainly real. Although early presenters can be assumed to derive the greatest benefit from early revascularization, Figure 4 Prognostic performance of high-sensitivity cardiac it remains uncertain whether the magnitude of the difference is suffi- troponin T and I. Receiver-operation-characteristiccurves display- ing the prognostic accuracy for all-cause mortality during the cient to achieve clinical relevance. Even small differences in the diag- 24-month follow-up of high-sensitivity cardiac troponin I and high- nostic accuracy for AMI in early presenters may have sufficient effect sensitivity cardiac troponin T. on the early management of patients. In addition, these differences may impact also on, e.g. the negative predictive value of specific rule-out algorithms.14 For their acceptance and adoption, clinicians might see a difference between an algorithm that offers, e.g. a NPV similar accuracy for both, the comparison of the respective combina- of 99.9% vs. an algorithm that offers an NPV of 99.5%. Thirdly, tions of levels at presentation with serial measurements showed a during serial sampling, diagnostic accuracy of both hs-cTnI and very small but statistically significant higher diagnostic accuracy of hs-cTnT further increased. While the direct comparisons of hs-cTnT vs. hs-cTnI. Fourthly, comparing the diagnostic accuracy hs-cTnI and hs-cTnT at the individual later time points showed of both assays to differentiate UA from NCCP, hs-cTnI was slightly Comparison of hs-cTn I and T 2309 superior to hs-cTnT. However, it is important to highlight that overall correlations close to 1,6,9 the use of two sample types might have the diagnostic accuracy of hs-cTn for UA was only moderate, corrob- introduced a minor disadvantage for the hs-cTnT assay. orating the data reported in earlier pilot studies in which the adjudi- The observed differences should not distract from the enormous cation of the final diagnosis was based on conventional cTn assays amount of similarities between hs-cTnI and hs-cTnT, neither should only.7 Further studies are needed to define the best possible clinical they be misinterpreted as a suggestion to use two hs-cTn assays in use of hs-cTn in conjunction with all other clinical information in the parallel.5,29 In addition, it is important to highlight that hs-cTn must differentiation of UA from NCCP. Fifthly, prognostic accuracy for all- always be used and interpreted in conjunction with all other clinical cause mortality during 24-month FU was high for both hs-cTnI and information. T. In fact, hs-cTnT was significantly superior compared with Some limitations of this study merit to be considered. First, we ana- hs-cTnI. Our data corroborate and extend recent studies in which lysed the diagnostic and prognostic performance of cTnI and cTnT hs-cTnT was compared with a s-cTnI and pre-commercial hs-cTnI using the two clinically available hs-cTn assays. Future studies will assays and shown to be the better prognosticator.9,10,30 – 32 As need to evaluate whether our findings also apply to other hs-cTnI Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 follow-up was performed blinded to levels of both hs-cTnT and assays once they will become clinically available. Secondly, since hs-cTnI and revealed a substantial number of deaths, and was consist- our study was prospective and observational, we cannot determine ent using three different statistical models to quantify prognostic ac- with precision the clinical benefit associated with the clinical use of curacy, also the finding of prognostic superiority of hs-cTnT over either hs-cTnI or hs-cTnT. Thirdly, as patients with terminal kidney hs-cTnI methodologically seems very robust. The observed differ- failure requiring dialysis were excluded from this study, we cannot ence in prognostic accuracy (DAUC 0.05) was consistent in the comment on the diagnostic and prognostic performance of cTnI or NSTEMI and non-NSTEMI group and clearly seems clinically mean- cTnT in those patients. Fourth, our data set does not allow to ingful.33 Sixthly, prognostic accuracy to predict non-fatal AMI address the question whether and if to what extent the difference during 24-month FU among patients in the no-NSTEMI group was in molecular weight (23 vs. 35 kDa) between cTnI and cTnT contrib- low-to-moderate for both biomarkers, and slightly higher for uted to our findings. hs-cTnI compared with hs-cTnT. This finding is supported by a In conclusion, both hs-cTnI and hs-cTnT provided high diagnostic similar observation in another chest pain cohort34 and highlights and prognostic accuracy. The direct comparison revealed small but the fact that different pathophysiological signals may be helpful in potentially important differences between the performance of the the prediction of death vs. the prediction of acute plaque rupture cTnI molecule and the cTnT molecule that might help to further resulting in non-fatal AMI. improve the clinical use of hs-cTn in the management of patients We can only speculate which pathophysiological differences presenting with suspected AMI. between cTnI and T or the specific hs-cTn assays used were the major drivers for the observed differences. First, release of cTn occurs first from the early appearing cytosol pool and subsequently Supplementary material from the structural pool.6,35 – 37 Release from the latter is the reason Supplementary material is available at European Heart Journal online. for the sustained elevations observed clinically in AMI and is a surro- gate for irreversible break down of sarcomeric proteins.6 It is con- Acknowledgements ceivable that the early appearing pool contains larger amounts of We thank the patients who participated in the study, the staff of cTnI than cTnT, which would explain that cTnI seems to be the super- the EDs, the research coordinators, and the laboratory technicians ior signal in early presenters. On the other hand, if the cTnT signal (particularly Esther Garrido, Melanie Wieland, Kathrin Meissner, results to large extent from the irreversible break down of sarco- and Fausta Chiaverio) for their most valuable efforts. We also wish meric proteins, this more profound injury could then be well under- to thank Stefanie von Felten for her help with the quantification of stood to be more closely linked to mortality when compared with a the prognostic accuracy. signal that may be induced also from less severe injury. Recent obser- vations from studies of exercise-induced myocardial ischaemia Funding support this hypothesis.38 Silent coronary plaque rupture with subse- This study was supported by research grants from the Swiss National quent microembolization may be the possible mechanisms linking Science Foundation, the Swiss Heart Foundation, the Cardiovascular hs-cTn with the risk of AMI in the future.39 – 41 As microembolization Research Foundation Basel, the University Hospital Basel, Abbott, represents a minor injury, it may result in a predominate release of Roche, Nanosphere, Siemens, 8sense, Bühlmann and BRAHMS. cTn from the early appearing cytosol pool and may therefore be better reflected by levels of hs-cTnI. Patients experiencing silent Conflict of interest: Prof. Mueller has received research grants from plaque rupture with microembolization may well be considered the Swiss National Science Foundation and the Swiss Heart Foundation, at an increased risk of subsequent plaque ruptures that may not the Cardiovascular Research Foundation Basel, 8sense, Abbott, ALERE, Brahms, Critical Diagnostics, Nanosphere, Roche, Siemens, and the Uni- heal spontaneously and that may result in clinically apparent AMI. versity Hospital Basel, as well as speaker honoraria from Abbott, ALERE, Secondly, we think it is unlikely that pre-analytical or analytical Brahms, Novartis, Roche, and Siemens. We disclose that T.R. has issues of one of the assays played a relevant role as each assay received research grants from the Swiss National Science Foundation proved superior in at least one category. Measurements of hs-cTnT (PASMP3-136995), the Swiss Heart Foundation, the University of were performed from two types of samples (serum and EDTA Basel, the Professor Max Cloetta Foundation and the Department of In- plasma), while hs-cTnI was measured from only one type (serum). ternal Medicine, University Hospital Basel as well as speakers honoraria While these sample types have been shown to reveal very high from Brahms and Roche. All other authors declare that they have no 2310 M. Rubini Gimenez et al. conflict of interest with this study. The sponsors had no role in the design Windecker S, Achenbach S, Badimon L, Bertrand M, Botker HE, Collet JP, Crea F, of the study, the analysis of the data, the preparation of the manuscript, or Danchin N, Falk E, Goudevenos J, Gulba D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD, Lancellotti P, Mehilli J, Merkely B, Montalescot G, the decision to submit the manuscript for publication. 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Sub- Downloaded from https://academic.oup.com/eurheartj/article/35/34/2303/2481219 by guest on 09 February 2023 of acute myocardial infarction by creatine kinase MB isoenzyme and cardiac troponin sequent silent plaque rupture of nonculprit lesion in a patient with acute myocardial I. Clin Chem 1994;40(7 Pt 1):1291 – 1295. infarction. Int J Cardiol 2012;157:e60– e62. 2.1.1 Müokardi infarkti (südamelihase infarkti) üldtunnustatud määratlus Äge müokardi infarkt (AMI) määratleb kliinilistes tingimustes kardiomüotsüütide nekroosi koos ägeda müokardi isheemiaga.1, 3 AMI diagnoosimiseks peab esinema kriteeriumite kombinatsioon - nimelt südame biomarkeri, eelistatavalt kõrgtundliku kardiaalse troponiini (hs-cTn) T või I tõus ja/või langus, kusjuures vähemalt üks väärtus peab ületama ülemise võrdluspiiri 99. protsentiili, ja vähemalt üks järgmistest tingimustest: (1) Müokardi isheemia sümptoomid. (2) Uued isheemilised muutused EKG-uuringul. (3) Patoloogiliste Q-lainete avaldumine EKG-uuringul. (4) Radioloogilise uuringuga tuvastatud elujõulise müokardi vähenemine või südame selline kontraktiilsuse häire uues piirkonnas, mis vastab isheemia etioloogiale. (5) Angiograafial või lahkamisel avastatud südamesisene tromb. 3.3.2 Biomarkerid: kõrgtundlik kardiaalne troponiin Biomarkerid täiendavad kliinilist hindamist ja 12 lülitusega EKG-uuringut ST-segmendi elevatsioonita ägeda koronaarsündroomi kahtlusega patsientide diagnoosimisel, riskipõhisel hindamisel ja ravimisel. Kardiomüotsüütide kahjustuse biomarkeri, eelistatavalt hs-cTn mõõtmine on kohustuslik kõigil ST- segmendi elevatsioonita ägeda koronaarsündroomi kahtlusega patsientidel.1, 3, 10–13 Kardiaalsed troponiinid on kardiomüotsüütide kahjustusele tundlikumad ja spetsiifilisemad markerid kui kreatiini kinaas, selle südamelihasega seotud isoensüüm (CK-MB) ja müoglobiin. 1, 3, 4, 10–13, 29, 30 Kui kliinilised sümptoomid viitavad müokardi isheemiale, siis näitab kardiaalse troponiini dünaamiline tõus üle 99. protsentiili tervete inimeste väärtusest, et tegemist on müokardi infarktiga. Müokardi infarktiga patsientidel tõuseb kardiaalse troponiini tase pärast sümptomite ilmnemist kiiresti (kui kasutatakse kõrgtundlikke analüüse, siis on see nähtav tavaliselt ühe tunni jooksul alates sümptoomite tekkimisest) ja püsib kõrge erineva aja jooksul (tavaliselt mitu päeva).1, 3, 4, 10–13, 29, 30 Tehnoloogia areng on täiustanud kardiaalsete troponiinide analüüse ning parandanud kardiomüotsüütide kahjustuste tuvastamise ja mõõtmise võimet.1, 3, 4, 6, 8, 10–13, 29, 30, 34–36 Mahukate mitmekeskuseliste uuringute andmed on järjekindlalt näidanud, et võrreldes eelnevalt kasutatud analüüsidega suurendavad hs-cTn analüüsid müokardi infarkti diagnostika võimekust haiglasse pöördumisel (vt joonis 2), seda eriti patsientidel, kes pöörduvad haiglasse varakult pärast valu tekkimist rinnus, ning võimaldavad kiiremini müokardi infarkti kahtluse kinnitada või selle välistada (vt lõik 3.3.3 ja tabel 3).1, 3, 4, 6–8, 10–13, 29, 30, 35, 36 Kokkuvõtvalt: hs-cTn T ja hs-cTn I analüüsid võimaldavad müokardiinfarkti diagnoosida võrreldava täpsusega. 37–40 • Troponiini analüüsid Väiksema tundlikkusega analüüside asemel soovitatakse teostada kõrgtundlikke troponiini analüüse, kuna need tagavad suurema diagnostilise täpsuse samaväärselt madalate kuludega. Tuleb märkida, et lisaks müokardi infarktile põhjustavad veel paljud teised südame patoloogiad samuti kardiomüotsüütide kahjustust ja seetõttu kardiaalsete troponiinide tõusu. • Muud biomarkerid Muudel biomarkeritel võib konkreetsetes kliinilistes tingimustes olla kliiniline olulisus, kui neid kasutatakse koos mittekõrgtundliku cTn T/I-ga. Kreatiini kinaasi südamelihasega seotud isoensüümi kontsentratsioon langeb pärast müokardi infarkti kiiresti ja võib anda varajase korduva infarkti tuvastamisel lisaväärtuse. Kopeptiini regulaarset kasutamist täiendava biomarkerina müokardi infarkti varajaseks välistamiseks tuleb kaaluda neis üha harvemates olukordades, kus hs-cTn analüüsid ei ole kättesaadavad. European Heart Journal (2021) 42, 12891367 ESC GUIDELINES doi:10.1093/eurheartj/ehaa575 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) Authors/Task Force Members: Jean-Philippe Collet * (Chairperson) (France), Holger Thiele * (Chairperson) (Germany), Emanuele Barbato (Italy), Olivier Barthélémy (France), Johann Bauersachs (Germany), Deepak L. Bhatt (United States of America), Paul Dendale (Belgium), Maria Dorobantu (Romania), Thor Edvardsen (Norway), Thierry Folliguet (France), Chris P. Gale (United Kingdom), Martine Gilard (France), Alexander Jobs (Germany), Peter Jüni (Canada), Ekaterini Lambrinou (Cyprus), Basil S. Lewis (Israel), Julinda Mehilli (Germany), Emanuele Meliga (Italy), Béla Merkely (Hungary), Christian Mueller (Switzerland), Marco Roffi (Switzerland), Frans H. Rutten (Netherlands), Dirk Sibbing (Germany), George C.M. Siontis (Switzerland) * Corresponding authors: Jean-Philippe Collet, Sorbonne Université, ACTION Study Group, INSERM UMRS 1166, Institut de Cardiologie, Hôpital Pitié-Salp^etrière (Assistance Publique- Hôpitaux de Paris) (AP-HP), 83, boulevard de l’Hôpital, 75013 Paris, France. Tel þ 33 01 42 16 29 62, E-mail: [email protected] Holger Thiele, Department of Internal Medicine/Cardiology, Heart Center Leipzig at University of Leipzig, Strümpellstr. 39, 04289 Leipzig, Germany. Tel: þ49 341 865 1428, Fax: þ49 341 865 1461, E-mail: [email protected] ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers, and Author/Task Force Member affiliations: listed in the Appendix. ESC entities having participated in the development of this document: Associations: Association for Acute CardioVascular Care (ACVC), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA). Councils: Council for Cardiology Practice. Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Thrombosis. The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]). Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge, and the evidence avail- able at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other offi- cial recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of pre- ventive, diagnostic, or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription. C The European Society of Cardiology 2020. All rights reserved. For permissions, please email: [email protected]. V 1290 ESC Guidelines Document Reviewers: Adnan Kastrati (CPG Review Coordinator) (Germany), Mamas A. Mamas (CPG Review Coordinator) (United Kingdom), Victor Aboyans (France), Dominick J. Angiolillo (United States of America), Hector Bueno (Spain), Raffaele Bugiardini (Italy), Robert A. Byrne (Ireland), Silvia Castelletti (Italy), Alaide Chieffo (Italy), Veronique Cornelissen (Belgium), Filippo Crea (Italy), Victoria Delgado (Netherlands), Heinz Drexel (Austria), Marek Gierlotka (Poland), Sigrun Halvorsen (Norway), Kristina Hermann Haugaa (Norway), Ewa A. Jankowska (Poland), Hugo A. Katus (Germany), Tim Kinnaird (United Kingdom), Jolanda Kluin (Netherlands), Vijay Kunadian (United Kingdom), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino (Italy), Leena Meinila (Finland), Darren Mylotte (Ireland), Gjin Ndrepepa (Germany), Elmir Omerovic (Sweden), Roberto F. E. Pedretti (Italy), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Gianluca Pontone (Italy), Bogdan A. Popescu (Romania), Tatjana Potpara (Serbia), Kausik K. Ray (United Kingdom), Flavio Luciano Ribichini (Italy), Dimitrios J. Richter (Greece), Evgeny Shlyakhto (Russian Federation), Iain A. Simpson (United Kingdom), Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Miguel Sousa-Uva (Portugal), Robert F. Storey (United Kingdom), Rhian M. Touyz (United Kingdom), Marco Valgimigli (Switzerland), Pascal Vranckx (Belgium), Robert W. Yeh (United States of America) The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website www.escardio.org/guidelines For the Supplementary Data which include background information and detailed discussion of the data that have provided the basis for the Guidelines see European Heart Journal online. ................................................................................................................................................................................................... Keywords Guidelines • acute cardiac care • acute coronary syndrome • angioplasty • anticoagulation • antiplatelet • apixaban • aspirin • atherothrombosis • betablockers • bleedings • bivalirudin • bypass surgery • can- grelor • chest pain unit • clopidogrel • dabigatran • diabetes • dual antithrombotic therapy • early inva- sive strategy • edoxaban • enoxaparin • European Society of Cardiology • fondaparinux • glycoprotein IIb/ IIIa inhibitors • heparin • high-sensitivity troponin • minoca • myocardial ischaemia • myocardial infarction • nitrates • non-ST-elevation myocardial infarction • platelet inhibition • prasugrel • recommendations • revascularization • rhythm monitoring • rivaroxaban • stent • ticagrelor • triple therapy • unstable angina .. Table of contents .. 3.3.2.2 Other biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 .. 3.3.3 Rapid ‘rule-in’ and ‘rule-out’ algorithms . . . . . . . . . . . . . . . . . 1301 .. Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1293 .. 3.3.4 Observe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303 1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1295 .. 3.3.4.1 Caveats of using rapid algorithms . . . . . . . . . . . . . . . . . . 1303 .. 2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296 .. 3.3.4.2 Confounders of cardiac troponin concentration . . . . 1303 2.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296 .. 3.3.4.3 Practical guidance on how to implement the .. 2.1.1 Universal definition of myocardial infarction . . . . . . . . . . . . 1296 .. European Society of Cardiology 0 h/1 h algorithm . . . . . . . . . 1304 2.1.1.1 Type 1 myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . 1296 .. 3.3.4.4 Avoiding misunderstandings: time to decision .. 2.1.1.2 Type 2 myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . 1297 .. = time of blood drawrn-around time . . . . . . . . . . . . . . . . . . . . . 1304 2.1.1.3 Types 35 myocardial infarction . . . . . . . . . . . . . . . . . . 1297 .. 3.3.5 Non-invasive imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305 .. 2.1.2 Unstable angina in the era of high-sensitivity cardiac .. 3.3.5.1 Functional evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305 troponin assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297 .. 3.3.5.2 Anatomical evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305 .. 2.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297 .. 3.4 Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305 2.3 What is new? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297 .. 4 Risk assessment and outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307 .. 2.4 Number and breakdown of classes of .. 4.1 Electrocardiogram indicators (Supplementary Data) . . . . . . . . 1307 recommendations (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . 1298 .. 4.2 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307 .. 3 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1298 .. 4.3 Clinical scores for risk assessment (Supplementary Data) . . . . 1307 3.1 Clinical presentation (Supplementary Data) . . . . . . . . . . . . . . . . 1298 .. 4.4 Bleeding risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308 .. 3.2 Physical examination (Supplementary Data) . . . . . . . . . . . . . . . . 1298 .. 4.5 Integrating ischaemic and bleeding risks . . . . . . . . . . . . . . . . . . . . . 1309 .. 3.3 Diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1298 .. 5 Pharmacological treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309 3.3.1 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1298 .. 5.1 Antithrombotic treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309 .. 3.3.2 Biomarkers: high-sensitivity cardiac troponin . . . . . . . . . . . 1299 .. 5.1.1 Antiplatelet drugs and pre-treatment . . . . . . . . . . . . . . . . . . . 1311 3.3.2.1 Central laboratory vs. point-of-care . . . . . . . . . . . . . . . . 1300 .. 5.1.1.1 Antiplatelet drugs and dual antiplatelet therapy . . . . . 1311 . ESC Guidelines 1291 5.1.1.2 Pre-treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312 .. 6.2.1 Patients who are not candidates for invasive coronary .. 5.1.2 Peri-interventional anticoagulant treatment . . . . . . . . . . . . . 1314 .. angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 .. 5.1.3 Peri-interventional antiplatelet treatment . . . . . . . . . . . . . . . 1315 .. 6.2.2 Patients with coronary artery disease not amenable to 5.1.4 Post-interventional and maintenance treatment . . . . . . . . 1315 .. revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 .. 5.2 Pharmacological treatment of ischaemia .. 6.3 Technical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 .. 6.3.1 Technical aspects and challenges . . . . . . . . . . . . . . . . . . . . . . . 1327 .. 5.2.1 Supportive pharmacological treatment .. 6.3.2 Vascular access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 .. 6.3.3 Revascularization strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 .. 5.2.2 Nitrates and beta-blockers (Supplementary Data) . . . . . . 1318 .. 6.4 Coronary artery bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 5.3 Managing oral antiplatelet agents in patients requiring .. 6.5 Percutaneous coronary intervention vs. coronary artery .. long-termoral anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 .. bypass surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 5.3.1 Patients with atrial fibrillation without mechanical .. 6.6 Specific situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1328 .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 prosthetic heart valves or moderate-to-severe mitral .. 6.6.1 Management of patients with ongoing myocardial stenosis undergoing percutaneous coronary intervention .. ischaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1328 .. or managed medically (Supplementary Data) . . . . . . . . . . . . . . . . 1318 .. 6.6.2 Management of patients with cardiac arrest . . . . . . . . . . . . . 1328 5.3.2 Patients requiring vitamin K antagonists or undergoing .. 6.7 Recommendations for coronary revascularization . . . . . . . . . . 1328 .. coronary artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320 .. 7 Myocardial infarction with non-obstructive coronary arteries 5.4 Management of acute bleeding events .. and alternative diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1329 .. (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8 Special populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331 5.4.1 General supportivemeasures .. 8.1 Heart failure and cardiogenic shock . . . . . . . . . . . . . . . . . . . . . . . . 1331 .. (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8.2 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1332 5.4.2 Bleeding events on antiplatelet agents .. 8.3 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333 .. (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8.4 Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 .. 5.4.3 Bleeding events on vitamin K antagonists .. 8.5 Thrombocytopenia (Supplementary Data) . . . . . . . . . . . . . . . . . . 1334 (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8.5.1 Thrombocytopenia related to glycoprotein IIb/IIIa .. 5.4.4 Bleeding events on non-vitamin K antagonist oral .. inhibitors (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 anticoagulants (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8.5.2 Heparin-induced thrombocytopenia .. 5.4.5 Non-access-related bleeding events .. (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8.6 The older person . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 .. 5.4.6 Bleeding events related to percutaneous coronary .. 8.7 Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 intervention (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 8.8 Sex disparities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 .. 5.4.7 Bleeding events related to coronary artery bypass .. 9 Long-term management of non-ST-segment elevation acute coronary surgery (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. syndrome (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335 .. 5.4.8 Transfusion therapy (Supplementary Data) . . . . . . . . . . . . . 1322 .. 9.1 Lifestyle management (Supplementary Data) . . . . . . . . . . . . . . . 1335 5.4.9 Recommendations for bleeding management and .. 9.1.1 Smoking (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . 1335 .. blood transfusion in non-ST-segment elevation acute .. 9.1.2 Diet and alcohol (Supplementary Data) . . . . . . . . . . . . . . . . 1335 coronary syndromes for anticoagulated patients . . . . . . . . . . . . . 1322 .. 9.1.3 Weight management (Supplementary Data) . . . . . . . . . . . . 1335 .. 6 Invasive treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 9.1.3 Physical activity (Supplementary Data) . . . . . . . . . . . . . . . . . 1335 6.1 Invasive coronary angiography and revascularization . . . . . . . . 1322 .. 9.1.4 Cardiac rehabilitation (Supplementary Data) . . . . . . . . . . . 1335 .. 6.1.1 Routine invasive vs. selective invasive .. 9.1.5 Psychosocial factors (Supplementary Data) . . . . . . . . . . . . . 1335 approach (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. 9.1.6 Environmental factors (Supplementary Data) . . . . . . . . . . . 1335 .. 6.1.2 Timing of invasive strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1323 .. 9.1.7 Sexual activity (Supplementary Data) . . . . . . . . . . . . . . . . . . . 1335 6.1.2.1 Immediate invasive strategy (<2 h) . . . . . . . . . . . . . . . . . 1323 .. 9.1.8 Adherence and sustainability (Supplementary Data) . . . . . 1335 .. 6.1.2.2 Early invasive strategy (<24 h) . . . . . . . . . . . . . . . . . . . . . 1323 .. 9.1.9 Influenza vaccination (Supplementary Data) . . . . . . . . . . . . 1335 6.1.2.3 Selective invasive strategy . . . . . . . . . . . . . . . . . . . . . . . . . 1324 .. 9.2 Pharmacological management (Supplementary Data) . . . . . . . 1335 .. 6.1.3 Pattern of coronary artery disease in non-ST-segment .. 9.2.1 Anti-ischaemic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335 .. elevation acute coronary syndrome (Supplementary Data) . . . 1325 .. 9.2.1.1 Beta-blockers (Supplementary Data) . . . . . . . . . . . . . . . 1335 6.1.4 How to identify the culprit lesion? (Supplementary .. 9.2.2 Antithrombotic treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335 .. Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1325 .. 9.2.3 Proton pump inhibitors (Supplementary Data) . . . . . . . . . . 1335 6.1.5 Spontaneous coronary artery dissection . . . . . . . . . . . . . . . . 1325 .. 9.2.4 Statins and other lipid-lowering agents . . . . . . . . . . . . . . . . . 1335 .. 6.1.6 Fractional flow reserve, instantaneous wave-free .. 9.2.5 Glucose-lowering therapy in patients with diabetes . . . . . 1336 ratio, and other resting indices (Supplementary Data) . . . . . . . . 1326 .. 9.2.6 Renin-angiotensin-aldosterone system .. 6.1.6.1 Fractional flow reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 .. blockers (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336 6.1.6.2 Instantaneous wave-free ratio and other .. 9.2.7 Mineralocorticoid receptor antagonist .. resting indices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 .. therapy (Supplementary Data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336 6.1.7 Intracoronary imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 .. 9.2.8 Antihypertensive therapy (Supplementary Data) . . . . . . . . 1336 .. 6.2 Conservative treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 . 9.2.9 Hormone replacement therapy (Supplementary Data) . . 1336 1292 ESC Guidelines .. 10 Quality indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337 .. Table 4 Conditions other than acute type 1 myocardial infarction 11 Management strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340 .. associated with cardiomyocyte injury (= cardiac troponin .. 12 Key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341 .. elevation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 13 Gaps in evidence for non-ST-segment elevation acute .. Table 5 Assay specific cut-off levels in ng/l within the 0 h/1 h .. coronary syndrome care and future research . . . . . . . . . . . . . . . . . . . . . 1342 .. and 0 h/2 h algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303 14 ‘What to do’ and ‘what not to do’messages . . . . . . . . . . . . . . . . . . . . 1343 .. Table 6 Differential diagnoses of acute coronary syndromes in .. 15 Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347 .. the setting of acute chest pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306 16 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347 .. Table 7 Major and minor criteria for high bleeding risk .. 17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348 .. according to the Academic Research Consortium for High .. Bleeding Risk at the time of percutaneous coronary intervention .. .. (bleeding risk is high if at least one major or two minor criteria Tables of Recommendations ... aremet) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309 .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 .. Table 8 Dose regimen of antiplatelet and anticoagulant drugs in Recommendations for diagnosis, risk stratification, imaging, and .. non-ST-segment elevation acute coronary syndrome patients . . . . . 1311 rhythm monitoring in patients with suspected non-ST-segment .. .. Table 9 P2Y12 receptor inhibitors for use in non-ST-segment elevation acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306 .. elevation acute coronary syndrome patients . . . . . . . . . . . . . . . . . . . . . . 1312 Recommendations on biomarker measurements for prognostic .. .. Table 10 Treatment options for extended dual antithrombotic or stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308 .. antiplatelet therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316 Recommendations for antithrombotic treatment in non-ST- .. .. Table 11 Risk criteria for extended treatment with a second segment elevation acute coronary syndrome patients .. antithrombotic agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316 undergoing percutaneous coronary intervention . . . . . . . . . . . . . . . . . . 1314 .. .. Table 12 Suggested strategies to reduce bleeding risk related to Recommendations for post-interventional and maintenance .. percutaneous coronary intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 treatment in patients with non-ST-segment elevation acute .. .. Table 13 Randomized controlled trials including patients with coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 .. non-ST-segment elevation acute coronary syndrome requiring Recommendations for anti-ischaemic drugs in the acute phase .. .. anticoagulation and antiplatelet therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 of non-ST-segment elevation acute coronary syndrome . . . . . . . . . . . 1318 .. Table 14 Diagnostic criteria of myocardial infarction with Recommendations for combining antiplatelet agents and .. .. non-obstructive coronary arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330 anticoagulants in non-ST-segment elevation acute coronary .. Table 15 Quality indicators in non-ST-segment elevation acute syndrome patients requiring chronic oral anticoagulation . . . . . . . . . . 1321 .. .. coronary syndrome care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337 Recommendations for bleeding management and blood .. transfusion in non-ST-segment elevation acute coronary .. .. syndromes for anticoagulated patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322 .. Recommendations for coronary revascularization . . . . . . . . . . . . . . . . 1328 .. List of figures .. Recommendations for myocardial infarction with non-obstructive .. coronary arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331 .. Figure 1 Diagnostic algorithm and triage in acute coronary .. syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1299 Recommendations for non-ST-segment elevation acute coronary .. .. Figure 2 Value of high-sensitivity cardiac troponin. . . . . . . . . . . . . . . . . . 1300 syndrome patients with heart failure or cardiogenic shock . . . . . . . . . 1332 .. Figure 3 0 h/1 h rule-out and rule-in algorithm using high-sensitivity Recommendations for diabetes mellitus in non-ST-segment .. .. cardiac troponin assays in haemodynamically stable patients elevation acute coronary syndrome patients . . . . . . . . . . . . . . . . . . . . . . 1333 .. Recommendations for patients with chronic kidney disease .. presenting with suspected non-ST-segment elevation acute .. coronary syndrome to the emergency department. . . . . . . . . . . . . . . . 1302 and non-ST-segment elevation acute coronary syndrome . . . . . . . . . 1333 .. Recommendations for older persons with non-ST-segment .. Figure 4 Timing of the blood draws and clinical decisions when .. using the European Society of Cardiology 0 h/1 h algorithm. . . . . . . . 1304 elevation acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 .. Recommendations for lifestyle managements after non-STsegment .. Figure 5 Determinants of antithrombotic treatment in coronary .. artery disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1310 elevation acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335 .. Recommendations for pharmacological long-term management .. Figure 6 Antithrombotic treatments in non-ST-segment elevation .. acute coronary syndrome patients: pharmacological targets. . . . . . . . 1310 after non-ST-segment elevation acute coronary syndrome .. (excluding antithrombotic treatments) . . . . . . . . . . . . . . . . . . . . . . . . . . . 1336 .. Figure 7 Algorithm for antithrombotic therapy in non-ST-segment eleva- .. tion acute coronary syndrome patients without atrial fibrillation under- .. .. going percutaneous coronary intervention . . . . . . . . . . . . . . . . . . . . . . . . 1313 .. Figure 8 Algorithm for antithrombotic therapy in non-ST-segment eleva- List of tables .. .. tion acute coronary syndrome patients with atrial fibrillation undergoing Table 1 Classes of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1295 .. percutaneous coronary intervention or medical management . . . . . 1320 .. Table 2 Levels of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296 .. Figure 9 Selection of non-ST-segment elevation acute Table 3 Clinical implications of high-sensitivity cardiac troponin .. coronary syndrome treatment strategy and timing according to .. assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 . initial risk stratification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1323 ESC Guidelines 1293 Figure 10 Time to coronary angiography in the early/immediate .. CHA2DS2-VASc Congestive heart failure, Hypertension, Age .. invasive and delayed invasive groups of included trials. . . . . . . . . . . . . . 1324 .. >_75 years (2 points), Diabetes, Stroke (2 Figure 11 Diagnosis and treatment of patients with non-ST-segment .. points)Vascular disease, Age 6574, Sex .. elevation acute coronary syndrome related to spontaneous .. category (female) coronary artery dissection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1325 .. CHAMPION Cangrelor versus Standard Therapy to .. Figure 12 Diagnostic algorithm for myocardial infarction with .. Achieve Optimal Management of Platelet non-obstructive coronary arteries using a traffic light scheme. . . . . . 1331 .. .. Inhibition Figure 13 Central illustration. Management strategy for .. CI Confidence interval non-ST-segment elevation acute coronary syndrome patients. . . . . . 1340 .. .. CK Creatine kinase .. CKD Chronic kidney disease .. .. CK-MB Creatine kinase myocardial band Abbreviations and acronyms .. CMR Cardiac magnetic resonance .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ACCOAST Comparison of Prasugrel at the Time of .. COACT Coronary Angiography after Cardiac Arrest .. COMPASS Cardiovascular OutcoMes for People using Percutaneous Coronary Intervention or as .. Pretreatment at the Time of Diagnosis in .. Anticoagulation StrategieS .. CPG Clinical practice guidelines Patients with Non-ST Elevation Myocardial .. Infarction .. CPR Cardiopulmonary resuscitation .. CrCl Creatinine clearance ACE Angiotensin-converting enzyme .. ACS Acute coronary syndromes .. CRUSADE Can Rapid risk stratification of Unstable .. angina patients Suppress ADverse outcomes ACUITY Acute Catheterization and Urgent .. Intervention Triage strategY ... with Early implementation of the ACC/AHA ACVC Association for Acute Cardiovascular Care .. guidelines .. CS Cardiogenic shock ADP Adenosine diphosphate .. AF Atrial fibrillation .. CT Computed tomography .. CULPRIT- Culprit Lesion Only PCI versus Multivessel AGRIS Australian GRACE Risk score Intervention .. Study .. SHOCK PCI in Cardiogenic Shock .. CVD Cardiovascular disease AHA American Heart Association .. .. CYP Cytochrome P450 AMI Acute myocardial infarction .. ARB Angiotensin receptor blocker .. DAPT Dual antiplatelet therapy .. DAT Dual antithrombotic therapy ARC-HBR Academic Research Consortium for High .. Bleeding Risk .. DES Drug-eluting stent .. EACTS European Association for Cardio-Thoracic ATLAS ACS 2 Anti-Xa Therapy to Lower Cardiovascular .. TIMI 51 Events in Addition to Standard Therapy in .. Surgery .. ECG Electrocardiogram/electrocardiography Subjects with Acute Coronary .. SyndromeThrombolysis In Myocardial .. Echo Echocardiogram .. eGFR Estimated glomerular filtration rate Infarction 51 .. AUGUSTUS Antithrombotic Therapy after Acute .. ELISA Early or Late Intervention in unStable Angina .. ENTRUST- EdoxabaN TRreatment versUS VKA in Coronary Syndrome or PCI in Atrial .. Fibrillation .. AF PCI paTients with AF undergoing PCI .. ESC European Society of Cardiology BARC Bleeding Academic Research Consortium .. BEST Randomized Comparison of Coronary .. FAMOUS- Fractional flow reserve versus angiography in .. NSTEMI guiding management to optimize outcomes in Artery Bypass Surgery and Everolimus- .. Eluting Stent Implantation in the Treatment .. non-ST-elevation myocardial infarction .. FFR Fractional flow reserve of Patients with Multivessel Coronary Artery .. Disease .. FFR-CT Fractional flow reserve-computed .. tomography b.i.d . Bis in die (twice a day) .. BNP B-type natriuretic peptide .. GDF-15 Growth differentiation factor 15 .. GP Glycoprotein CABG Coronary artery bypass graft(ing) .. CAD Coronary artery disease .. GRACE Global Registry of Acute Coronary Events .. HAS-BLED Hypertension, abnormal renal and liver CCS Chronic coronary syndromes .. .. function (1 point each), stroke, bleeding CCTA Coronary computed tomography .. angiography .. history or predisposition, labile INR, elderly .. (>65 years), drugs and alcohol (1 point each) CCU Coronary care unit .. CFR Coronary flow reserve .. HBR High bleeding risk .. h-FABP Heart-type fatty acid-binding protein 1294 ESC Guidelines HIT Heparin-induced thrombocytopenia ... PEGASUS-TIMI 54 Prevention of Cardiovascular Events in HR Hazard ratio .. Patients with Prior Heart Attack Using .. hs-cTn High-sensitivity cardiac troponin .. Ticagrelor Compared to Placebo on a IABP Intra-aortic balloon pump .. Background of Aspirin-Thrombolysis in .. IABP-SHOCK II Intraaortic Balloon Pump in cardiogenic .. Myocardial Infarction 54 shock II .. PLATO PLATelet inhibition and patient Outcomes .. ICA Invasive coronary angiography .. POCT Point-of-care test .. iFR Instantaneous wave-free ratio .. PPV Positive predictive value IMR Index of microcirculatory resistance .. PRECISE-DAPT PREdicting bleeding Complications In patients .. INR International normalized ratio .. undergoing Stent implantation and ISAR-REACT Intracoronary stenting and Antithrombotic .. subsEquent Dual Anti Platelet Therapy .. regimenRapid Early Action for Coronary .. PRECOMBAT Premier of Randomized Comparison of Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Treatment .. Bypass Surgery versus Angioplasty Using .. ISAR-TRIPLE Triple Therapy in Patients on Oral .. Sirolimus-Eluting Stent in Patients with Left Anticoagulation After Drug Eluting Stent .. Main Coronary Artery Disease .. Implantation .. PROMs Patient-reported outcome measures i.v. Intravenous .. QI Quality indicator .. IVUS Intravascular ultrasound .. RBBB Right bundle branch block LBBB Left bundle branch block .. RCT Randomized controlled trial .. LD Loading dose .. RE-DUAL PCI Randomized Evaluation of Dual LDL-C Low-density lipoprotein cholesterol .. Antithrombotic Therapy with Dabigatran .. LIPSIA-NSTEMI Leipzig Immediate versus early and late .. versus Triple Therapy with Warfarin in PercutaneouS coronary Intervention triAl in .. Patients with Nonvalvular Atrial Fibrillation .. NSTEMI .. Undergoing Percutaneous Coronary LMWH Low-molecular-weight heparin .. Intervention .. LV Left ventricular .. REDUCE-IT Reduction of Cardiovascular Events with LVEF Left ventricular ejection fraction .. Icosapent EthylIntervention Trial .. MACE Major adverse cardiovascular events .. RFR Resting full-cycle ratio MATRIX Minimizing Adverse Haemorrhagic Events by .. RIDDLE-NSTEMI Randomized Study of Immediate Versus .. TRansradial Access Site and Systemic .. Delayed Invasive Intervention in Patients .. Implementation of angioX .. With Non-ST-Segment Elevation Myocardial MD Maintenance dose .. Infarction .. MDCT Multidetector computed tomography .. RIVAL RadIal Vs femorAL access for coronary MI Myocardial infarction .. intervention .. MINOCA Myocardial infarction with non-obstructive .. RR Relative risk coronary arteries .. SAPT Single antiplatelet therapy .. MRA Mineralocorticoid receptor antagonist .. SCAAR Swedish Coronary Angiography and NOAC Non-vitamin K antagonist oral anticoagulant .. Angioplasty Registry .. NPV Negative predictive value .. SCAD Spontaneous coronary artery dissection NSTE-ACS Non-ST-segment elevation acute coronary .. SISCA Comparison of Two Treatment Strategies in .. syndrome .. Patients With an Acute Coronary Syndrome NSTEMI Non-ST-segment elevation myocardial .. Without ST Elevation .. infarction .. SMILE Impact of Different Treatment in Multivessel NT-proBNP N-terminal pro-B-type natriuretic peptide .. Non ST Elevation Myocardial Infarction .. OAC Oral anticoagulation/anticoagulant ... Patients: One Stage Versus Multistaged OASIS-5 Fifth Organization to Assess Strategies in .. Percutaneous Coronary Intervention Acute Ischemic Syndromes .. SPECT Single-photon-emission tomography .. OCT Optical coherence tomography .. STEMI ST-segment elevation myocardial infarction o.d. Once daily .. STS Society of Thoracic Surgeons .. OR Odds ratio .. SYNTAX Synergy between PCI with Taxus and cardiac P Prasugrel .. surgery .. PAD Peripheral artery disease .. TAT Triple antithrombotic therapy .. PCI Percutaneous coronary intervention .. TIMACS Timing of Intervention in Patients with Acute PCSK9 Proprotein convertase subtilisin kexin 9 .. Coronary Syndromes .. Pd/Pa Distal coronary to aortic pressure ratio .. TIMI Thrombolysis In Myocardial Infarction ESC Guidelines 1295 .. TRITON-TIMI 38 TRial to Assess Improvement in Therapeutic .. decisions concerning an individual patient must be made by the Outcomes by Optimizing Platelet InhibitioN .. responsible health professional(s) in consultation with the patient .. with PrasugrelThrombolysis In Myocardial .. and caregiver as appropriate. Infarction 38 .. A great number of guidelines have been issued in recent years by .. TROPICAL-ACS Testing Responsiveness to Platelet Inhibition .. the European Society of Cardiology (ESC), as well as by other soci- .. eties and organizations. Because of their impact on clinical practice, on Chronic Antiplatelet Treatment for Acute .. Coronary Syndromes .. quality criteria for the development of guidelines have been estab- .. lished in order to make all decisions transparent to the user. The rec- TWILIGHT Ticagrelor With Aspirin or Alone in High- .. Risk Patients After Coronary Intervention .. ommendations for formulating and issuing ESC Guidelines can be .. found on the ESC website (https://www.escardio.org/Guidelines/ UFH Unfractionated heparin .. UKGRIS UK GRACE Risk Score Intervention Study .. Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC- .. Guidelines). The ESC Guidelines represent the official position of the ULTIMATE Intravascular Ultrasound Guided Drug Eluting .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Stents Implantation in “All-Comers” .. ESC on a given topic and are regularly updated. .. In addition to the publication of Clinical Practice Guidelines, the Coronary Lesions .. VALIDATE- Swedish Web-system for Enhancement and .. ESC carries out the EurObservational Research Programme of inter- .. national registries of cardiovascular diseases and interventions which SWEDEHEART Development of Evidence-based care in .. Heart disease Evaluated According to .. are essential to assess, diagnostic/therapeutic processes, use of .. resources and adherence to Guidelines. These registries aim at pro- Recommended Therapies .. VERDICT Very EaRly vs Deferred Invasive evaluation .. viding a better understanding of medical practice in Europe and .. using Computerized Tomography .. around the world, based on high-quality data collected during routine VKA Vitamin K antagonist .. clinical practice. .. WOEST What is the Optimal antiplatElet and .. Furthermore, the ESC has developed and embedded in this docu- anticoagulant therapy in patients with oral .. ment a set of quality indicators (QIs), which are tools to evaluate the .. anticoagulation and coronary StenTing .. level of implementation of the Guidelines and may be used by the .. ESC, hospitals, healthcare providers and professionals to measure .. 1 Preamble .. clinical practice as well as used in educational programmes, alongside .. the key messages from the guidelines, to improve quality of care and .. Guidelines summarize and evaluate available evidence with the aim of .. clinical outcomes. assisting health professionals in proposing the best management .. The Members of this Task Force were selected by the ESC, includ- .. strategies for an individual patient with a given condition. Guidelines .. ing representation from its relevant ESC sub-specialty groups, in and their recommendations should facilitate decision making of .. order to represent professionals involved with the medical care of .. health professionals in their daily practice. However, the final . patients with this pathology. Selected experts in the field undertook a Table 1 Classes of recommendations Wording to use Classes of recommendations Class I Evidence and/or general agreement Is recommended or is indicated that a given treatment or procedure is Class II Class IIa Weight of evidence/opinion is in Should be considered Class IIb May be considered established by evidence/opinion. Class III Evidence or general agreement that the Is not recommended ©ESC 2020 given treatment or procedure is not useful/effective, and in some cases may be harmful. 1296 ESC Guidelines Table 2 Levels of evidence Level of Data derived from multiple randomized clinical trials evidence A or meta-analyses. Level of Data derived from a single randomized clinical trial evidence B or large non-randomized studies. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Level of Consensus of opinion of the experts and/or small studies, evidence C retrospective studies, registries. comprehensive review of the published evidence for management .. ST-segment elevation, persistent or transient ST-segment .. of a given condition according to ESC Committee for Practice .. depression, T-wave inversion, flat T waves, or pseudo- Guidelines (CPG) policy. A critical evaluation of diagnostic and .. normalization of T waves; or the ECG may be normal. .. therapeutic procedures was performed, including assessment of .. the riskbenefit ratio. The level of evidence and the strength of .. The pathological correlate at the myocardial level is cardiomyo- .. cyte necrosis [non-ST-segment elevation myocardial infarction the recommendation of particular management options were .. weighed and graded according to predefined scales, as outlined .. (NSTEMI)] or, less frequently, myocardial ischaemia without cell .. damage (unstable angina). A small proportion of patients may present below. .. .. with ongoing myocardial ischaemia, characterized by one or more of .. the following: recurrent or ongoing chest pain, marked ST-segment .. 2 Introduction .. .. depression on 12-lead ECG, heart failure, and haemodynamic or .. electrical instability.1 Due to the amount of myocardium in jeopardy 2.1 Definitions .. and the risk of developing CS and/or malignant ventricular arrhyth- .. mias, immediate coronary angiography and, if appropriate, revascula- The clinical presentation of acute coronary syndromes (ACS) is .. broad. It ranges from cardiac arrest, electrical or haemodynamic .. rization are indicated (see section 6). .. instability with cardiogenic shock (CS) due to ongoing ischaemia or .. mechanical complications such as severe mitral regurgitation, to .. 2.1.1 Universal definition of myocardial infarction .. patients who are already pain free again at the time of presentation.1 .. Acute myocardial infarction (AMI) defines cardiomyocyte necrosis in The leading symptom initiating the diagnostic and therapeutic cascade .. a clinical setting consistent with acute myocardial ischaemia.1,3 A .. in patients with suspected ACS is acute chest discomfort described as .. combination of criteria is required to meet the diagnosis of AMI, pain, pressure, tightness, and burning. Chest pain-equivalent symp- .. namely the detection of an increase and/or decrease of a cardiac bio- .. toms may include dyspnoea, epigastric pain, and pain in the left arm. .. marker, preferably high-sensitivity cardiac troponin (hs-cTn) T or I, Based on the electrocardiogram (ECG), two groups of patients .. with at least one value above the 99th percentile of the upper refer- .. should be differentiated: .. ence limit and at least one of the following: .. • Patients with acute chest pain and persistent (>20 min) .. (1) Symptoms of myocardial ischaemia. .. ST-segment elevation. This condition is termed ST-segment ele- .. (2) New ischaemic ECG changes. vation ACS and generally reflects an acute total or subtotal coro- .. (3) Development of pathological Q waves on ECG. .. nary occlusion. Most patients will ultimately develop ST-segment .. (4) Imaging evidence of loss of viable myocardium or new regional wall elevation myocardial infarction (STEMI). The mainstay of treat- .. motion abnormality in a pattern consistent with an ischaemic .. ment in these patients is immediate reperfusion by primary per- .. aetiology. cutaneous coronary intervention (PCI) or, if not available in a .. (5) Intracoronary thrombus detected on angiography or autopsy. .. timely manner, by fibrinolytic therapy.2 .. • Patients with acute chest discomfort but no persistent .. 2.1.1.1 Type 1 myocardial infarction .. ST-segment elevation [non-ST-segment elevation ACS (NSTE- .. Type 1 myocardial infarction (MI) is characterized by atheroscler- ACS)] exhibit ECG changes that may include transient .. otic plaque rupture, ulceration, fissure, or erosion with resulting ESC Guidelines 1297 .. intraluminal thrombus in one or more coronary arteries leading .. 2.3 What is new? to decreased myocardial blood flow and/or distal embolization .. .. and subsequent myocardial necrosis. The patient may have under- .. New key recommendations lying severe coronary artery disease (CAD) but, on occasion .. .. (510% of cases), there may be non-obstructive coronary athe- .. Diagnosis rosclerosis or no angiographic evidence of CAD, particularly in .. .. women.1,35 .. As an alternative to the ESC 0 h/1 h algorithm, it is recommended to use the ESC 0 h/2 h .. algorithm with blood sampling at 0 h and 2 h, if an hs-cTn test with a validated 0 h/2 h .. algorithm is available. 2.1.1.2 Type 2 myocardial infarction .. Type 2 MI is myocardial necrosis in which a condition other than cor- .. For diagnostic purposes, it is not recommended to routinely measure additional biomarkers such .. as CK, CK-MB, h-FABP, or copeptin, in addition to hs-cTn. onary plaque instability causes an imbalance between myocardial .. oxygen supply and demand.3 Mechanisms include hypotension, .. .. Risk stratification Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 hypertension, tachyarrhythmias, bradyarrhythmias, anaemia, hypo- .. xaemia, but also by definition, coronary artery spasm, spontaneous .. Measuring BNP or NT-proBNP plasma concentrations should be considered to gain prognostic .. information. coronary artery dissection (SCAD), coronary embolism, and coro- .. nary microvascular dysfunction.68 .. .. .. Antithrombotic treatment 2.1.1.3 Types 35 myocardial infarction .. .. Prasugrel should be considered in preference to ticagrelor for NSTE-ACS patients The universal definition of MI also includes type 3 MI (MI resulting in .. who proceed to PCI. death when biomarkers are not available) and types 4 and 5 MI .. .. It is not recommended to administer routine pre-treatment with a P2Y receptor inhibitor to [related to PCI and coronary artery bypass grafting (CABG), .. patients in whom the coronary anatomy is not known and early invasive management is 12 .. planned. respectively].3 .. .. .. In patients with NSTE-ACS who cannot undergo an early invasive strategy, pre-treatment with 2.1.2 Unstable angina in the era of high-sensitivity cardiac 12 .. a P2Y receptor inhibitor may be considered depending on bleeding risk. .. troponin assays .. De-escalation of P2Y inhibitor treatment (e.g. with a switch from prasugrel or ticagrelor to Unstable angina is defined as myocardial ischaemia at rest or on mini- .. clopidogrel) may be considered as an alternative DAPT strategy, especially for ACS patients 12 .. deemed unsuitable for potent platelet inhibition. De-escalation may be done unguided based on mal exertion in the absence of acute cardiomyocyte injury/necrosis. .. clinical judgment, or guided by platelet function testing, or CYP2C19 genotyping depending Among unselected patients presenting to the emergency department .. on the patient’s risk profile and availability of respective assays. .. with suspected NSTE-ACS, the introduction of hs-cTn measure- .. In patients with AF (CHA DS -VASc score ≥1 in men and ≥2 in women), after a short period ments in place of standard troponin assays resulted in an increase in .. of TAT (up to 1 week from the acute event), DAT is recommended as the default strategy using 2 2 .. a NOAC at the recommended dose for stroke prevention and single oral antiplatelet agent the detection of MI (4% absolute and 20% relative increases) and a .. (preferably clopidogrel). reciprocal decrease in the diagnosis of unstable angina.913 .. .. Discontinuation of antiplatelet treatment in patients treated with OACs is recommended after 12 Compared with NSTEMI patients, individuals with unstable angina do .. months. not experience acute cardiomyocyte injury/necrosis, have a substan- .. .. DAT with an OAC and either ticagrelor or prasugrel may be considered as an alternative to tially lower risk of death, and appear to derive less benefit from inten- .. TAT with an OAC, aspirin, and clopidogrel in patients with a moderate or high risk of stent sified antiplatelet therapy, as well as an invasive strategy within .. thrombosis, irrespective of the type of stent used. .. 72 h.1,35,919 Pathophysiology and epidemiology are discussed in .. detail elsewhere.1 .. Invasive treatment .. .. An early invasive strategy within 24 h is recommended in patients with any of the following .. high-risk criteria: 2.2 Epidemiology .. • Diagnosis of NSTEMI. • Dynamic or presumably new contiguous ST/T-segment changes suggesting ongoing The proportion of patients with NSTEMI in MI surveys increased .. .. ischaemia. • Transient ST-segment elevation. from one third in 1995 to more than half in 2015, mainly accounted .. • GRACE risk score >140. for by a refinement in the operational diagnosis of NSTEMI20. As .. .. opposed to STEMI, no significant changes are observed in the base- .. A selective invasive strategy after appropriate ischaemia testing or detection of obstructive line characteristics of the NSTEMI population with respect to age and .. CAD by CCTA is recommended in patients considered at low risk. .. smoking, while diabetes, hypertension, and obesity increased sub- .. Delayed, as opposed to immediate, angiography should be considered in haemodynamically stantially. The use of early angiography (<_72 h from admission) .. stable patients without ST-segment elevation successfully resuscitated after an out-of-hospital .. cardiac arrest. increased from 9% in 1995 to 60% in 2015 [adjusted odds ratio (OR) .. .. Complete revascularization should be considered in NSTE-ACS patients without cardiogenic 16.4, 95% confidence interval (CI) 12.022.4, P<0.001] and PCI dur- .. shock and with multivessel CAD. ing the initial hospital stay increased from 12.5% to 67%. The main .. .. Complete revascularization during index PCI may be considered in NSTE-ACS patients with consequences of these changes are a reduction in 6-month mortality .. multivessel disease. from 17.2% to 6.3% and the adjusted hazard ratio (HR) decreased to .. .. FFR-guided revascularization of non-culprit NSTE-ACS lesions may be used during index 0.40 (95% CI 0.300.54) in 2010, remaining stable at 0.40 .. PCI. (0.300.52) in 2015.20 .. .. .. .. . Continued 1298 ESC Guidelines .. .. antithrombotic therapy; ECG = electrocardiogram/electrocardiogra- Major changes in recommendations .. phy; ESC = European Society of Cardiology; FFR = fractional flow .. .. reserve; GP = glycoprotein; GRACE = Global Registry of Acute 2015 2020 .. Coronary Events; h-FABP = heart-type fatty acid-binding protein; .. Diagnosis .. hs-cTn = high-sensitivity cardiac troponin; MDCT = multidetector .. computed tomography; MINOCA = myocardial infarction with non- .. .. obstructive coronary arteries; NOAC = non-vitamin K antagonist A rapid rule-out protocol at 0 h and 3 h is A rapid rule-out and rule-in protocol with blood sampling at 0 h and 3 h should be .. oral anticoagulant; NSTE-ACS = non-ST-segment elevation acute recommended if hs-cTn tests are available. considered if an hs-cTn test with a validated .. 0 h/3 h algorithm is available. .. coronary syndrome; NSTEMI = non-ST-segment elevation myocar- .. dial infarction; NT-proBNP = N-terminal pro-B-type natriuretic pep- .. MDCT coronary angiography should be CCTA is recommended as an alternative to .. tide; OAC = oral anticoagulation/anticoagulant; PCI = percutaneous considered as an alternative to invasive invasive angiography to exclude ACS .. coronary intervention; QI = quality indicator; RCT = randomized angiography to exclude ACS when there is when there is a low-to-intermediate .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 a low-to-intermediate likelihood of CAD likelihood of CAD and when cardiac .. controlled trial; SCAD = spontaneous coronary artery dissection; and when cardiac troponin and/or ECG are inconclusive. troponin and/or ECG are normal or inconclusive. .. TAT = triple antithrombotic therapy; UFH = unfractionated heparin. .. .. Rhythm monitoring up to 24 h or PCI Rhythm monitoring up to 24 h or to PCI .. (whichever comes first) should be (whichever comes first) is recommended in .. 2.4 Number and breakdown of classes of considered in NSTEMI patients at low risk NSTEMI patients at low risk for cardiac .. recommendations (Supplementary Data) for cardiac arrhythmias. arrhythmias. .. .. The total number of recommendations is 131. The breakdown of the .. Rhythm monitoring for >24 h should be considered in NSTEMI patients at Rhythm monitoring for >24 h is .. recommendations according to ESC classes of recommendations intermediate-to-high risk for cardiac recommended in NSTEMI patients at .. and levels of evidence are summarized in Supplementary Figure 1. arrhythmias. increased risk for cardiac arrhythmias. .. .. .. Risk assessment .. 3 Diagnosis .. .. It is recommended to use established risk GRACE risk score models should be .. 3.1 Clinical presentation (Supplementary scores for prognosis estimation. considered for estimating prognosis. .. .. Data) Pharmacological treatments .. .. .. Bivalirudin (0.75 mg/kg i.v. bolus, .. 3.2 Physical examination (Supplementary followed by 1.75 mg/kg/h for up to 4 h .. Data) after the procedure) is recommended as an Bivalirudin may be considered as an .. alternative to UFH plus GP IIb/IIIa alternative to UFH. .. inhibitors during PCI. .. .. 3.3 Diagnostic tools Adding a second antithrombotic agent to .. 3.3.1 Electrocardiogram P2Y12 inhibitor administration in addition aspirin for extended long-term secondary .. to aspirin beyond 1 year may be prevention should be considered in .. The resting 12-lead ECG is the first-line diagnostic tool in the assess- considered after careful assessment of the patients at high risk of ischaemic events .. ment of patients with suspected ACS (Figure 1). It is recommended ischaemic and bleeding risks of the patient. and without increased risk of major or .. life-threatening bleeding. .. to perform it within 10 min of the patient’s arrival in the emergency .. room or, ideally, at first contact with the emergency medical services Class I Class IIa Class IIb .. .. in the pre-hospital setting and to have it immediately interpreted by a .. qualified physician.21 While the ECG in the setting of NSTE-ACS may New sections .. .. be normal in more than 30% of patients, characteristic abnormalities • MINOCA .. • SCAD .. include ST-segment depression, transient ST-segment elevation, and • QIs in NSTE-ACS treatment .. T-wave changes.68,1013,22 .. .. If the standard leads are inconclusive and the patient has signs or .. symptoms suggestive of ongoing myocardial ischaemia, additional New/revised concepts .. .. leads should be recorded; left circumflex artery occlusion may be • Rapid rule-in and rule-out algorithms .. detected only in V7V9 or right ventricular MI only in V3R and • Risk stratification for an early invasive approach .. .. V4R.3 In patients with suggestive signs and symptoms, the finding of ©ESC 2020 • Definition of high bleeding risk • Definitions of very high and high ischaemic risk .. persistent ST-segment elevation indicates STEMI, which mandates • .. The gap in evidence and corresponding RCTs to be performed .. immediate reperfusion.2 Comparison with previous tracings is valua- .. ble, particularly in patients with pre-existing ECG abnormalities. It is .. ACS = acute coronary syndromes; AF = atrial fibrillation; BNP = B- .. recommended to obtain additional 12-lead ECGs in case of persis- type natriuretic peptide; CAD = coronary artery disease; CCTA = .. tent or recurrent symptoms or diagnostic uncertainty. In patients .. coronary computed tomography angiography; CHA2DS2-VASc = .. with left bundle branch block (LBBB), specific ECG criteria Congestive heart failure, Hypertension, Age >_75 years (2 points), .. (Sgarbossa’s criteria) may help in the detection of candidates for .. Diabetes, Stroke (2 points)Vascular disease, Age 6574, Sex cate- .. immediate coronary angiography.23,24 Patients with a high clinical sus- gory (female); CK = creatine kinase; CK-MB = creatine kinase myo- .. picion of ongoing myocardial ischaemia and LBBB should be managed .. cardial band; DAPT = dual antiplatelet therapy; DAT = dual . in a way similar to STEMI patients, regardless of whether the LBBB is ESC Guidelines 1299 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 1 Diagnostic algorithm and triage in acute coronary syndrome. The initial assessment is based on the integration of low likelihood and/or high likelihood features derived from the clinical setting (i.e. symptoms, vital signs), the 12-lead ECG, and the cardiac troponin concentration determined at presentation to the emergency department and serially thereafter. ‘Other cardiac’ includes among others myocarditis, Takotsubo syndrome, or congestive heart failure. ‘Non- cardiac’ refers to thoracic diseases such as pneumonia or pneumothorax. Cardiac troponin and its change during serial sampling should be interpreted as a quanti- tative marker: the higher the 0 h level or the absolute change during serial sampling, the higher the likelihood for the presence of MI. In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin, echocardiography should be performed/interpreted by trained physicians immedi- ately following a 12-lead ECG. If the initial evaluation suggests aortic dissection or pulmonary embolism, D-dimers and CCTA are recommended according to dedicated algorithms.1,2933 CPR = cardiopulmonary resuscitation; ECG = electrocardiogram/electrocardiography; MI = myocardial infarction; NSTEMI = non- ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction. Listen to the audio guide of this figure online. .. previously known.2 In contrast, haemodynamically stable patients .. with acute chest pain and RBBB to the emergency department will presenting with chest pain and LBBB only have a slightly higher risk of .. ultimately be found to have a diagnosis other than MI and should, .. having MI compared to patients without LBBB. Therefore, the result .. therefore, also await the result of the hs-cTn T/I measurement at of the hs-cTn T/I measurement at presentation should be integrated .. presentation.25 .. into the decision regarding immediate coronary angiography.24 .. In patients with right bundle brunch block (RBBB), ST-elevation is .. 3.3.2 Biomarkers: high-sensitivity cardiac troponin .. indicative of STEMI while ST-segment depression in lead I, aVL, and .. Biomarkers complement clinical assessment and 12-lead ECG in the V56 is indicative of NSTE-ACS.25 In patients with paced ventricular .. diagnosis, risk stratification, and treatment of patients with suspected .. beats, the ECG is often of no help for the diagnosis of NSTE-ACS. .. NSTE-ACS. Measurement of a biomarker of cardiomyocyte injury, Novel ECG algorithms using digital ECG data are in devel- .. preferably hs-cTn, is mandatory in all patients with suspected NSTE- .. opment.2628 In general, it is advisable to perform ECG interpreta- .. ACS.1,3,1013 Cardiac troponins are more sensitive and specific tion using remote technologies at the pre-hospital stage. .. markers of cardiomyocyte injury than creatine kinase (CK), its myo- .. It is important to highlight that more than 50% of patients pre- .. cardial band isoenzyme (CK-MB), and myoglobin.1,3,4,1013,29,30 If the senting with acute chest pain and LBBB to the emergency depart- .. clinical presentation is compatible with myocardial ischaemia, then a .. ment or chest pain unit will ultimately be found to have a diagnosis .. dynamic elevation of cardiac troponin above the 99th percentile of other than MI.24 Similarly, more than 50% of patients presenting .. healthy individuals indicates MI. In patients with MI, levels of cardiac 1300 ESC Guidelines Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 2 Value of high-sensitivity cardiac troponin. hs-cTn assays (right) are reported in ng/L and provide identical information as conventional assays (left, reported in lg/L) if the concentration is substantially elevated, e.g. above 100 ng/L. In contrast, only hs-cTn allows a precise differentiation between ‘normal’ and mildly elevated. Therefore, hs-cTn detects a relevant proportion of patients with previously undetectable cardiac troponin concentrations with the conventional assay who have hs-cTn concentrations above the 99th percentile possibly related to AMI. ??? = unknown due to the inability of the assay to measure in the normal range;68,1013,2931 AMI = acute myocardial infarction; CoV = coefficient of variation; hs-cTn = high-sensitivity cardiac troponin; POCT = point-of-care test. aThe limit of detection varies among the different hs-cTn assays between 1 ng/L and 5 ng/L. Similarly, the 99th percen- tile varies among the different hs-cTn assays, mainly being between 10 ng/L and 20 ng/L. Listen to the audio guide of this figure online. .. troponin rise rapidly (i.e. usually within 1 h from symptom onset if .. obvious advantage of POCTs, namely the shorter turn-around time, using high-sensitivity assays) after symptom onset and remain ele- .. is counterbalanced by lower sensitivity, lower diagnostic accuracy, .. vated for a variable period of time (usually several .. and lower negative predictive value (NPV). Overall, automated assays days).1,3,4,1013,29,30 Advances in technology have led to a refinement .. have been more thoroughly evaluated than POCTs and seem to be .. in cardiac troponin assays and have improved the ability to detect .. preferable at this point in time.1,3,4,68,1013,29,30,33,35,36 and quantify cardiomyocyte injury.1,3,4,68,1013,29,30,3436 Data from .. As these techniques continue to improve, and performance char- .. large multicentre studies have consistently shown that hs-cTn assays .. acteristics are both assay and hospital dependent, it is important to increase diagnostic accuracy for MI at the time of presentation as .. re-evaluate this preference once extensively validated high-sensitivity .. compared with conventional assays (Figure 2), especially in patients .. POCTs become clinically available.42 The first hs-cTn I POCTs have presenting early after chest pain onset, and allow for a more rapid .. recently been shown to provide comparable performance character- .. ‘rule-in’ and ‘rule-out’ of MI (see section 3.3.3 and .. istics to that of central laboratory hs-cTn I/T assays.43,44 Table 3).1,3,4,68,1013,29,30,35,36 Overall, hs-cTn T and hs-cTn I assays .. Many cardiac pathologies other than MI also result in cardiomyo- .. seem to provide comparable diagnostic accuracy in the early diagno- .. cyte injury and, therefore, cardiac troponin elevations (Table 4). sis of MI.3740 .. Tachyarrhythmias, heart failure, hypertensive emergencies, critical ill- .. .. ness, myocarditis, Takotsubo syndrome, and valvular heart disease 3.3.2.1 Central laboratory vs. point-of-care .. are the most frequent ones. Most often in elderly patients with renal .. The vast majority of cardiac troponin assays that are run on auto- .. dysfunction, elevations in cardiac troponin should not be primarily .. attributed to impaired clearance and considered harmless, as cardiac mated platforms in the central laboratory are sensitive (i.e. allow for .. detection of cardiac troponin in 2050% of healthy individuals) or .. conditions such as chronic coronary syndromes (CCS) or hyperten- .. high-sensitivity (detection in 5095% of healthy individuals) assays. .. sive heart disease seem to be the most important contributor to car- High-sensitivity assays are recommended over less sensitive ones, as .. diac troponin elevation in this setting.35,45 Other life-threatening .. they provide higher diagnostic accuracy at identical low .. conditions presenting with chest pain, such as aortic dissection and cost.1,3,4,68,1013,29,30,33,35,36 .. pulmonary embolism, may also result in elevated cardiac troponin .. The majority of currently used point-of-care tests (POCTs) cannot .. concentrations and should be considered as differential diagnoses be considered sensitive or high-sensitivity assays41. Therefore, the .. (Table 4). ESC Guidelines 1301 Table 3 Clinical implications of high-sensitivity cardiac troponin assays Compared with standard cardiac troponin assays, hs-cTn assays: • Have higher NPV for AMI. • Reduce the ‘troponin-blind’ interval leading to earlier detection of AMI. • Result in 4% absolute and 20% relative increases in the detection of type 1 MI and a corresponding decrease in the diagnosis of unstable angina. • Are associated with a 2-fold increase in the detection of type 2 MI. Levels of hs-cTn should be interpreted as quantitative markers of cardiomyocyte damage (i.e. the higher the level, the greater the like- lihood of MI): • Elevations beyond 5-fold the upper reference limit have high (>90%) PPV for acute type 1 MI. • Elevations up to 3-fold the upper reference limit have only limited (5060%) PPV for AMI and may be associated with a broad spectrum of conditions. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 • It is common to detect circulating levels of cardiac troponin in healthy individuals. Rising and/or falling cardiac troponin levels differentiate acute (as in MI) from chronic cardiomyocyte damage (the more pronounced the change, the higher the likelihood of AMI). AMI = acute myocardial infarction; hs-cTn = high-sensitivity cardiac troponin; MI = myocardial infarction; NPV = negative predictive value; PPV = positive predictive value. .. provide added value for the timing of myocardial injury and the detec- Table 4 Conditions other than acute type 1 myocardial .. .. tion of early reinfarction.1 However, it is important to highlight that lit- infarction associated with cardiomyocyte injury .. (5 cardiac troponin elevation) .. tle is known on how to best diagnose early reinfarction. Detailed .. clinical assessment including chest pain characteristics (same character- Tachyarrhythmias .. .. istics as index event), 12-lead ECG for the detection of new ST- Heart failure .. segment changes or T-wave inversion, as well as serial measurement of .. Hypertensive emergencies .. cardiac troponin T/I and CK/CK-MB is recommended. Myosin-binding Critical illness (e.g. shock/sepsis/burns) .. protein C is more abundant than cardiac troponin and may therefore .. Myocarditisa .. provide value as an alternative to, or in combination with, cardiac tro- .. ponin.46 Assessment of copeptin, the C-terminal part of the vasopres- Takotsubo syndrome .. Valvular heart disease (e.g. aortic stenosis) .. sin prohormone, may quantify the endogenous stress level in multiple .. medical conditions including MI. As the level of endogenous stress Aortic dissection .. .. appears to be high at the onset of MI in most patients, the added value Pulmonary embolism, pulmonary hypertension .. of copeptin to conventional (less sensitive) cardiac troponin assays is Renal dysfunction and associated cardiac disease .. .. substantial.49,50,53 Therefore, the routine use of copeptin as an addi- Acute neurological event (e.g. stroke or subarachnoid .. tional biomarker for the early rule-out of MI should be considered in .. haemorrhage) .. the increasingly uncommon setting where hs-cTn assays are not avail- Cardiac contusion or cardiac procedures (CABG, PCI, ablation, pacing, .. able. However, copeptin does not have relevant added value for insti- .. cardioversion, or endomyocardial biopsy) .. tutions using one of the well-validated hs-cTn-based rapid protocols in Hypo- and hyperthyroidism .. the early diagnosis of MI.47,48,51,52,5458 Other widely available labora- .. Infiltrative diseases (e.g. amyloidosis, haemochromatosis, sarcoidosis, .. tory variables, such as estimated glomerular filtration rate (eGFR), glu- .. cose, and B-type natriuretic peptide (BNP) provide incremental scleroderma) .. Myocardial drug toxicity or poisoning (e.g. doxorubicin, 5-fluorouracil, .. prognostic information and may therefore help in risk stratification.59 .. herceptin, snake venoms) .. The determination of D-dimer is recommended in outpatients/emer- .. gency department patients with low or intermediate clinical probabil- Extreme endurance efforts .. Rhabdomyolysis .. ity, or those that are unlikely to have pulmonary embolism, to reduce .. the need for unnecessary imaging and irradiation. D-dimers are key Bold = most frequent conditions. .. CABG = coronary artery bypass graft(ing); PCI = percutaneous coronary .. diagnostic elements whenever pulmonary embolism is suspected.32,60 intervention. .. a Includes myocardial extension of endocarditis or pericarditis. .. .. .. 3.3.3 Rapid ‘rule-in’ and ‘rule-out’ algorithms .. .. Due to the higher sensitivity and diagnostic accuracy for the detec- .. tion of MI at presentation, the time interval to the second cardiac tro- 3.3.2.2 Other biomarkers .. .. ponin assessment can be shortened with the use of hs-cTn assays. Among the multitude of additional biomarkers evaluated for the diag- .. This seems to substantially reduce the delay to diagnosis, translating .. nosis of NSTE-ACS, only CK-MB, myosin-binding protein C,46 and .. into shorter stays in the emergency department and lower copeptin4758 may have clinical relevance in specific clinical settings .. costs.11,56,6166 It is recommended to use the 0 h/1 h algorithm (best .. when used in combination with cardiac troponin T/I. Compared with .. option, blood draw at 0 h and 1 h) or the 0 h/2 h algorithm (second- cardiac troponin, CK-MB shows a more rapid decline after MI and may .. best option, blood draw at 0 h and 2 h) (Figure 3). These have been 1302 ESC Guidelines Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 3 0 h/1 h rule-out and rule-in algorithm using high-sensitivity cardiac troponin assays in haemodynamically stable patients presenting with sus- pected non-ST-segment elevation acute coronary syndrome to the emergency department. 0 h and 1 h refer to the time from first blood test. NSTEMI can be ruled out at presentation if the hs-cTn concentration is very low. NSTEMI can also be ruled out by the combination of low baseline levels and the lack of a relevant increase within 1 h (no 1hD). Patients have a high likelihood of NSTEMI if the hs-cTn concentration at presentation is at least moderately elevated or hs-cTn concentrations show a clear rise within the first hour (1hD).1,68,1013,2931,33 Cut-offs are assay specific (see Table 3) and derived to meet predefined criteria for sensitivity and specificity for NSTEMI. CCU = coronary care unit; CCTA = coronary computed tomography angiography; CPO = chest pain onset; hs-cTn = high-sensitivity cardiac troponin; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; NSTEMI = non- ST-segment elevation myocardial infarction. aOnly applicable if CPO >3 h. Listen to the audio guide of this figure online. .. derived and well-validated in large multicentre diagnostic studies .. presentation.33,35,36,39,68,69,75,76 The cut-off concentrations within the using central adjudication of the final diagnosis for all currently avail- .. 0 h/1 h and 0 h/2 h algorithms are assay specific .. able hs-cTn assays.33,35,36,39,6769 Optimal thresholds for rule-out .. (Table 5).33,35,36,39,68,69,75,76 The NPV for MI in patients assigned ‘rule- were selected to allow for a minimal sensitivity and NPV of 99%. .. out’ exceeded 99% in several large validation cohorts.35,36,39,68,69,77 .. Optimal thresholds for rule-in were selected to allow for a minimal .. Used in conjunction with clinical and ECG findings, the 0 h/1 h and 0 positive predictive value (PPV) of 70%. The algorithms were devel- .. h/2 h algorithm will allow the identification of appropriate candidates .. oped in large derivation cohorts and then validated in large independ- .. for early discharge and outpatient management. Even after the rule- ent validation cohorts. As an alternative, the previous European .. out of MI, elective non-invasive or invasive imaging may be indicated .. Society of Cardiology (ESC) 0 h/3 h algorithm70 should be consid- .. according to clinical assessment. Invasive coronary angiography (ICA) ered.1 However, three recent large diagnostic studies have suggested .. will still be the best option in patients with very high clinical likelihood that the ESC 0 h/3 h algorithm seems to balance efficacy and safety ... of unstable angina, even after NSTEMI has been ruled out. In contrast, .. less well in comparison to more rapid protocols using lower rule-out .. stress testing with imaging or coronary computed tomography concentrations including the ESC 0 h/1 h algorithm.7173 Moreover, .. angiography (CCTA) will be the best option in patients with low-to- .. the very high safety and high efficacy of applying the ESC 0 h/1 h algo- .. modest clinical likelihood of unstable angina. No testing is necessary rithm has recently been confirmed in three real-life implementation .. in patients with a clear alternative diagnosis. .. studies, including one randomized controlled trial (RCT) .66,73,74 .. The PPV for MI in patients meeting the ‘rule-in’ criteria is about The 0 h/1 h and 0 h/2 h algorithms rely on two concepts: first, hs- .. 7075%.35,36,39,69 Most of the ‘rule-in’ patients with diagnoses other .. cTn is a continuous variable and the probability of MI increases with .. than MI did have conditions that usually still require ICA or cardiac increasing hs-cTn values,35,36,39,68,69,75,76 second, early absolute .. magnetic resonance (CMR) imaging for accurate diagnosis, including .. changes of the levels within 1 h or 2 h can be used as surrogates .. Takotsubo syndrome and myocarditis.35,36,39,68,69,75,76 Therefore, the .. for absolute changes over 3 h or 6 h and provide incremental .. vast majority of patients triaged towards the rule-in group are candi- diagnostic value to the cardiac troponin assessment at .. dates for early ICA and admission to a coronary care unit (CCU). ESC Guidelines 1303 Table 5 Assay specific cut-off levels in ng/l within the 0 h/1 h and 0 h/2 h algorithms 0 h/1 h algorithm Very low Low No 1hD High 1hD hs-cTn T (Elecsys; Roche) <5 <12 <3 >_52 >_5 hs-cTn I (Architect; Abbott) <4 <5 <2 >_64 >_6 hs-cTn I (Centaur; Siemens) <3 <6 <3 >_120 >_12 hs-cTn I (Access; Beckman Coulter) <4 <5 <4 >_50 >_15 hs-cTn I (Clarity; Singulex) <1 <2 <1 >_30 >_6 hs-cTn I (Vitros; Clinical Diagnostics) <1 <2 <1 >_40 >_4 hs-cTn I (Pathfast; LSI Medience) <3 <4 <3 >_90 >_20 hs-cTn I (TriageTrue; Quidel) <4 <5 <3 >_60 >_8 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 0 h/2 h algorithm Very low Low No 2hD High 2hD hs-cTn T (Elecsys; Roche) <5 <14 <4 >_52 >_10 hs-cTn I (Architect; Abbott) <4 <6 <2 >_64 >_15 hs-cTn I (Centaur; Siemens) <3 <8 <7 >_120 >_20 hs-cTn I (Access; Beckman Coulter) <4 <5 <5 >_50 >_20 hs-cTn I (Clarity; Singulex) <1 TBD TBD >_30 TBD hs-cTn I (Vitros; Clinical Diagnostics) <1 TBD TBD >_40 TBD hs-cTn I (Pathfast; LSI Medience) <3 TBD TBD >_90 TBD hs-cTn I (TriageTrue; Quidel) <4 TBD TBD >_60 TBD These cut-offs apply irrespective of age and renal function. Optimized cut-offs for patients above 75 years of age and patients with renal dysfunction have been evaluated, but not consistently shown to provide better balance between safety and efficacy as compared to these universal cut-offs.35,36,69 The algorithms for additional assays are in development. hs-cTn = high-sensitivity cardiac troponin; TBD = to be determined.3537,39,40,68,69,7584 .. These algorithms should always be integrated with a detailed clini- .. ii. The ESC 0 h/1h and 0 h/2 h algorithms apply to all patients irrespec- cal assessment and 12-lead ECG, and repeat blood sampling is man- .. tive of chest pain onset. The safety (as quantified by the NPV) and .. datory in case of ongoing or recurrent chest pain. .. sensitivity are very high (>99%), including in the subgroup of patients The same concept applies to the 0 h/2 h algorithm. Cut-off levels .. presenting very early (e.g. <2 h).69 However, due to the time depend- .. are assay-specific and shown in Table 5. Cut-off levels for other hs- .. ency of troponin release and the only moderate number of patients cTn assays are in development. .. presenting <1 h after chest pain onset in previous studies, obtaining .. .. an additional cardiac troponin concentration at 3 h in patients pre- .. senting <1 h and triaged towards rule-out should be considered. 3.3.4 Observe .. .. iii. As late increases in cardiac troponin have been described in 1% of Patients who do not qualify for ‘rule-out’ or ‘rule-in’, are assigned to .. patients, serial cardiac troponin testing should be pursued if the clini- observe. They represent a heterogeneous group that usually requires .. .. cal suspicion remains high or whenever the patient develops recur- a third measurement of cardiac troponin at 3 h and echocardiography .. rent chest pain.35,36,39,68,69,75,76,86 as the next steps.85 ICA should be considered in patients for whom .. .. there is a high degree of clinical suspicion of NSTE-ACS (e.g. relevant .. .. 3.3.4.2 Confounders of cardiac troponin concentration. In patients pre- increase in cardiac troponin from presentation to 3 h), while in patients .. senting with suspected NSTE-ACS, beyond the presence or with low-to-intermediate likelihood for this condition according to .. clinical judgment, non-invasive imaging using CCTA or stress testing .. absence of MI, four clinical variables affect hs-cTn .. concentrations:35,36,39,69,79,8793 [stress echocardiography, positron emission tomography, single- .. photon-emission tomography (SPECT), or CMR for the detection of ... i. Age (to a large extent as a surrogate for pre-existing cardiac disease). ACS features (oedema, late gadolinium enhancement, perfusion defect, .. .. ii. Renal dysfunction (to a large extent as a surrogate for pre-existing etc.)] should be considered after discharge from the emergency .. cardiac disease). department to the ward. No further diagnostic testing is indicated .. .. iii. Time from chest pain onset. when alternative conditions, such as rapid ventricular rate response to .. iv. Sex. atrial fibrillation (AF) or hypertensive emergency, have been identified. .. .. The effect of age (differences in concentration between healthy very .. 3.3.4.1 Caveats of using rapid algorithms. When using any algorithm, .. young vs. healthy very old individuals up to 300%), renal dysfunction .. (differences in concentration between otherwise healthy patients three main caveats apply .. .. with very high vs. very low eGFR up to 300%), and chest i. Algorithms should only be used in conjunction with all available clini- .. pain onset (>300%) is substantial, and modest for sex .. cal information, including detailed assessment of chest pain character- .. (40%).11,35,36,39,69,79,8893 Until information technology tools that istics and ECG. .. allow the incorporation of the effect of all four variables are available, 1304 ESC Guidelines the use of uniform cut-off concentrations should remain the standard .. further increases patient safety. Documentation of the time of the 0 h .. of care in the early diagnosis of MI.35,36,39,68,69,75,76 .. blood draw allows exact determination of the time window .. (± 10 min) of the 1 h blood draw. If the 1 h (± 10 min) blood draw .. 3.3.4.3 Practical guidance on how to implement the European Society of .. was not feasible, then blood should be drawn at 2 h and the ESC Cardiology 0 h/1 h algorithm .. 0 h/2 h algorithm applied. .. In order to maximize the safety and feasibility of the process, the .. nursing team should, in general, obtain blood samples for hs-cTn at .. 3.3.4.4 Avoiding misunderstandings: time to decision ¼ time of blood .. 0 h and 1 h irrespective of other clinical details and pending results. .. draw þ turn-around time This introduces unnecessary cardiac troponin measurements in per- .. The use of the ESC 0 h/1 h algorithm is irrespective of the local turn- .. haps 1015% of patients with very low 0 h concentrations and chest .. around time. 0 h and 1 h refer to the time point at which blood is .. pain onset >3 h, but substantially facilitates the process and thereby . taken (Figure 4). Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 4 Timing of the blood draws and clinical decisions when using the European Society of Cardiology 0 h/1 h algorithm. 0 h and 1 h refer to the time points at which blood is taken. The turn-around time is the time period from blood draw to reporting back the results to the clinician. It is usually about 1 h using an automated platform in the central laboratory. It includes transport of the blood tube to the lab, scanning of the probe, centrifugation, putting plasma on the automated platform, the analysis itself, and the reporting of the test result to the hospital information technology/electronic patient record. The turn-around time is identical whether using a hs-cTn assay vs. a conventional assay, as long as both are run on an automated platform. Adding the local turn-around time to the time of blood draw determines the earliest time point for clinical decision making based on hs-cTn concentrations. e.g. for the 0 h time point, time to decision is at 1 h if the local turn-around time is 1 h. For the blood drawn at 1 h, the results are reported back at 2 h (1 h þ 1 h) if the local turn-around time is 1 h. Relevant 1 h changes are assay dependent and listed in Table 3. CPO = chest pain onset; CPR = cardiopulmonary resuscita- tion; ECG = electrocardiogram/electrocardiography; hs-cTn = high-sensitivity cardiac troponin; MACE = major adverse cardiovascular events; MI = myo- cardial infarction. Listen to the audio guide of this figure online. ESC Guidelines 1305 .. The clinical and economic benefit of the ESC 0 h/1 h algorithm vs. .. study is associated with an excellent outcome.106,107 Stressrest the ESC 0 h/3 h algorithm or other algorithms with the second blood .. imaging modalities are usually not widely available on 24 h service .. draw later than 1 h is therefore independent of the local turn-around .. and some (e.g. SPECT) are associated with substantial radiation time.61 .. exposure. .. .. .. 3.3.5.2 Anatomical evaluation .. 3.3.5 Non-invasive imaging .. CCTA allows visualization of the coronary arteries and a normal scan 3.3.5.1 Functional evaluation .. excludes CAD. CCTA has a high NPV to exclude ACS (by excluding .. Transthoracic echocardiography should be routinely available in emer- .. CAD) and an excellent outcome in patients presenting to the emer- gency rooms and chest pain units and performed/interpreted by .. gency department with low-to-intermediate pre-test probability for .. trained physicians in all patients during hospitalization for NSTE-ACS. .. ACS and a normal CCTA.108 Seven RCTs have tested CCTA vs. This imaging modality is useful to identify abnormalities suggestive of .. usual care in the triage of low-to-intermediate-risk patients present- .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 myocardial ischaemia or necrosis (i.e. segmental hypokinesia or akine- .. ing with acute chest pain to emergency departments without signs of sia). In the absence of significant wall motion abnormalities, impaired .. ischaemia on ECG and normal cardiac troponins.109 However, the .. myocardial perfusion detected by contrast echocardiography or .. majority of studies used only conventional, less sensitive reduced regional function using strain and strain rate imaging might .. assays.110113 At a follow-up of 16 months, there were no deaths, .. improve the diagnostic and prognostic value of conventional .. and a meta-analysis demonstrated comparable outcomes with the .. echocardiography.9496 Moreover, echocardiography can help in .. two approaches (i.e. no difference in the incidence of MI, post- detecting alternative pathologies associated with chest pain, such as .. discharge emergency department visits, or re-hospitalizations) and .. showed that CCTA was associated with a reduction in emergency acute aortic dissection, pericardial effusion, aortic valve stenosis, hyper- .. trophic cardiomyopathy, mitral valve prolapse, or right ventricular dila- .. department costs and length of stay.114 However, none of these stud- .. tation suggestive of acute pulmonary embolism. Similarly, .. ies used hs-cTn assays, which also reduce hospital stay. In a random- echocardiography is the diagnostic tool of choice for patients with hae- .. ized study, in which the standard of care included hs-cTn, CCTA was .. modynamic instability of suspected cardiac origin.96,97 Evaluation of left .. no longer able to improve patient flow.115 It was also noted that ventricular (LV) systolic function, at the latest by the time of hospital .. CCTA was associated with an increase in the use of invasive angiogra- .. discharge, is important to estimate prognosis, and echocardiography .. phy.114 In contrast, in a recent randomized trial of unclear NSTEMI (as well as other imaging modalities) can provide this information. .. diagnosis, upfront imaging with CCTA reduced the need for ICA105 .. In patients without ischaemic changes on 12-lead ECGs and normal .. Similar results were observed in a sub-analysis of the Very EaRly vs hs-cTn, who are free from chest pain for several hours, stress imaging .. Deferred Invasive evaluation using Computerized Tomography .. can be performed during hospitalization or shortly after discharge. .. (VERDICT) trial, where upfront CCTA in NSTE-ACS patients had an Stress imaging is preferred over exercise ECG due to its greater diag- .. NPV of 90.9%.116 However, a relatively large patient group had to be .. nostic accuracy.98 Various studies have shown that normal exercise or .. excluded for specific reasons and an NPV of 90.9% is not entirely per- dobutamine or dipyridamole stress echocardiograms have high NPV .. fect.116 Accordingly, CCTA can be used to exclude CAD and is thus .. for ischaemia and are associated with excellent patient outcomes.99,100 .. less useful in patients with known CAD. Other factors limiting CCTA Moreover, stress echocardiography has demonstrated superior prog- .. include severe calcifications (high calcium score) and elevated or .. nostic value over exercise ECG.101 If the acoustic window is not .. irregular heart rate; in addition, a 24 h service is currently not widely adequate to assess regional wall motion abnormalities, the use of echo- .. available. Finally, the use of CCTA in the acute setting in patients with .. cardiographic contrast is recommended to improve the accuracy of .. stents or previous CABG has not been validated. Importantly, com- such an assessment and facilitate the detection of ischaemia.98,101103 .. puted tomography (CT) imaging can effectively exclude other causes .. CMR can assess both perfusion and wall motion abnormalities, and .. of acute chest pain that, if untreated, are associated with high mortal- .. ity, namely pulmonary embolism and aortic dissection. patients presenting with acute chest pain with a normal stress CMR .. have an excellent short- and mid-term prognosis.104 Additionally, .. .. CMR permits detection of scar tissue (using late gadolinium enhance- .. ment) and can differentiate this from recent infarction (using T2- .. .. 3.4 Differential diagnosis weighted imaging to delineate myocardial oedema).98 Moreover, .. .. Among unselected patients presenting with acute chest pain to the CMR can facilitate the differential diagnosis between infarction, myo- .. emergency department, disease prevalence can be expected to be carditis, or Takotsubo syndrome, among others.98 In a recent .. .. the following: 510% STEMI, 1520% NSTEMI, 10% unstable randomized trial in patients with unclear NSTEMI diagnosis, upfront .. angina, 15% other cardiac conditions, and 50% non-cardiac dis- imaging with CMR reduced the need for ICA and provided an alter- .. .. eases.35,36,39,69,79,8793 Several cardiac and non-cardiac conditions native diagnosis in a relevant proportion of patients.105 .. may mimic NSTE-ACS (Table 6). Similarly, SPECT has been shown to be useful for the risk stratifica- .. tion of patients with acute chest pain suggestive of ACS. Resting myo- .. Conditions that should always be considered in the differential .. diagnosis of NSTE-ACS because they are potentially life-threatening cardial scintigraphy, by detecting fixed perfusion defects suggestive of .. myocardial necrosis, can be helpful for the initial triage of patients .. but also treatable include aortic dissection, pulmonary embolism, and .. tension pneumothorax. Echocardiography should be performed presenting with chest pain without ECG changes or elevated cardiac .. troponins.98 Combined stressrest imaging and/or stress-only imag- .. urgently in all patients with haemodynamic instability of suspected .. cardiovascular origin. Takotsubo syndrome has recently been ing may further enhance assessment of ischaemia, while a normal . 1306 ESC Guidelines Table 6 Differential diagnoses of acute coronary syndromes in the setting of acute chest pain Cardiac Pulmonary Vascular Gastro-intestinal Orthopaedic Other Myopericarditis Pulmonary Aortic dissection Oesophagitis, Musculoskeletal Anxiety embolism reflux, or spasm disorders disorders Cardiomyopathiesa (Tension)- Symptomatic aortic Peptic ulcer, gastritis Chest trauma Herpes zoster pneumothorax aneurysm Tachyarrhythmias Bronchitis, pneumonia Stroke Pancreatitis Muscle injury/inflammation Anaemia Acute heart failure Pleuritis Cholecystitis Costochondritis Hypertensive emergencies Cervical spine pathologies Aortic valve stenosis Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Takotsubo syndrome Coronary spasm Cardiac trauma Bold = common and/or important differential diagnoses. a Dilated, hypertrophic and restrictive cardiomyopathies may cause angina or chest discomfort. observed more often as a differential diagnosis and usually requires .. concentrations). The majority of patients presenting to the emer- .. coronary angiography to rule out ACS.117 .. gency department with acute chest pain have non-cardiac condi- Chest X-ray is recommended in all patients in whom NSTE- .. tions causing the chest discomfort.35,36,39,69,79,8793 In many .. ACS is considered unlikely in order to detect pneumonia, pneu- .. instances, the pain is musculoskeletal and is therefore benign, self- .. mothorax, rib fractures, or other thoracic disorders. Stroke may .. limiting, and does not require hospitalization. Chest pain charac- be accompanied by ECG changes, myocardial wall motion abnor- .. teristics help to some extent in the early identification of .. malities, and cardiomyocyte injury (= increase in cardiac troponin . these patients. Recommendations for diagnosis, risk stratification, imaging, and rhythm monitoring in patients with suspected non-ST- segment elevation acute coronary syndrome Recommendations Classa Levelb Diagnosis and risk stratification It is recommended to base diagnosis and initial short-term risk stratification on a combination of clinical history, symptoms, I B vital signs, other physical findings, ECG, and laboratory results including hs-cTn.3 It is recommended to measure cardiac troponins with high-sensitivity assays immediately after admission and obtain the I B results within 60 min of blood sampling.3,1013,2931,34 It is recommended to obtain a 12-lead ECG within 10 min after first medical contact and to have it immediately interpreted I B by an experienced physician.21 It is recommended to obtain an additional 12-lead ECG in case of recurrent symptoms or diagnostic uncertainty. I C The ESC 0 h/1 h algorithm with blood sampling at 0 h and 1 h is recommended if an hs-cTn test with a validated 0 h/1 h I B algorithm is available.30,33,35,36,39,68,69,75,76 Additional testing after 3 h is recommended if the first two cardiac troponin measurements of the 0 h/1 h algorithm are not I B conclusive and the clinical condition is still suggestive of ACS.85 As an alternative to the ESC 0 h/1 h algorithm, it is recommended to use the ESC 0 h/2 h algorithm with blood sampling at 0 I B h and 2 h, if an hs-cTn test with a validated 0 h/2 h algorithm is available.33,39,75,78,84 Additional ECG leads (V3R, V4R, V7V9) are recommended if ongoing ischaemia is suspected when standard leads are I C inconclusive. As an alternative to the ESC 0 h/1 h algorithm, a rapid rule-out and rule-in protocol with blood sampling at 0 h and 3 h should IIa B be considered, if a high-sensitivity (or sensitive) cardiac troponin test with a validated 0 h/3 h algorithm is available.7073 The routine use of copeptin as an additional biomarker for the early rule-out of MI should be considered where hs-cTn assays IIa B are not available. It should be considered to use established risk scores for prognosis estimation. IIa C For initial diagnostic purposes, it is not recommended to routinely measure additional biomarkers such as h-FABP or copep- III B tin, in addition to hs-cTn.47,48,51,52,54,118 Continued ESC Guidelines 1307 Imaging In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin, echocardiography is I C recommended and should be performed by trained physicians immediately following a 12-lead ECG. In patients with no recurrence of chest pain, normal ECG findings, and normal levels of cardiac troponin (preferably high sensitiv- ity), but still with a suspected ACS, a non-invasive stress test (preferably with imaging) for inducible ischaemia or CCTA is recom- I B mended before deciding on an invasive approach.91,92,98,101,105108 Echocardiography is recommended to evaluate regional and global LV function and to rule in or rule out differential I C diagnoses.c CCTA is recommended as an alternative to ICA to exclude ACS when there is a low-to-intermediate likelihood of CAD and I A when cardiac troponin and/or ECG are normal or inconclusive.105,108,110114 Monitoring Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Continuous rhythm monitoring is recommended until the diagnosis of NSTEMI has been established or ruled out. I C It is recommended to admit NSTEMI patients to a monitored unit. I C Rhythm monitoring up to 24 h or to PCI (whichever comes first) is recommended in NSTEMI patients at low risk for cardiac I C arrhythmias.d Rhythm monitoring for >24 h is recommended in NSTEMI patients at increased risk for cardiac arrhythmias.e I C In the absence of signs or symptoms of ongoing ischaemia, rhythm monitoring in unstable angina may be considered in IIb C selected patients (e.g. suspicion of coronary spasm or associated symptoms suggestive of arrhythmic events). 0 h = time of first blood test; 1 h, 2 h, 3 h = 1, 2, or 3 h after the first blood test. ACS = acute coronary syndromes; CAD = coronary artery disease; CCTA = coronary computed tomography angiography; ECG = electrocardiogram/electrocardiography; ESC = European Society of Cardiology; GRACE = Global Registry of Acute Coronary Events; h-FABP = heart-type fatty acid-binding protein; hs-cTn = high-sensitivity cardiac troponin; ICA = invasive coronary angiography; LV = left ventricular; LVEF = left ventricular ejection fraction; NSTEMI = non-ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention. a Class of recommendation. b Level of evidence. c Does not apply to patients discharged the same day in whom NSTEMI has been ruled out. d If none of the following criteria: haemodynamically unstable, major arrhythmias, LVEF <40%, failed reperfusion, additional critical coronary stenoses of major vessels, complica- tions related to percutaneous revascularization, or GRACE risk score >140 if assessed. e If one or more of the above criteria are present. .. 4 Risk assessment and outcomes .. confirmation in randomized trials and has not been tested in NSTE- .. ACS patients so far. Similarly, natriuretic peptides provide prognostic .. 4.1 Electrocardiogram indicators .. information on top of cardiac troponin.121,125,126 Other biomarkers, .. such as high-sensitivity C-reactive protein, mid-regional pro-adreno- (Supplementary Data) .. .. medullin, growth differentiation factor 15 (GDF-15), heart-type fatty .. acid-binding protein (h-FABP), and copeptin may also have some 4.2 Biomarkers .. .. prognostic value.50,118,127132 However, the assessment of these Beyond diagnostic utility, initial cardiac troponin levels add prognostic .. markers has, so far, not been shown to improve patient management information in terms of short- and long-term mortality to clinical and .. .. and their added value in risk assessment on top of the GRACE risk ECG variables. While hs-cTn T and I have comparable diagnostic .. calculation and/or BNP/NT-proBNP seems marginal. At the present .. accuracy, hs-cTn T has greater prognostic accuracy.38,119 Serial meas- .. time, the routine use of these biomarkers for prognostic purposes is urements are useful to identify peak levels of cardiac troponin for risk .. not recommended. .. stratification purposes in patients with established MI. The higher the .. hs-cTn levels, the greater the risk of death.12,76,120 However, evi- .. .. 4.3 Clinical scores for risk assessment dence is limited regarding the optimal time points of serial hs-cTn .. measurement. Serum creatinine and eGFR should also be deter- .. (Supplementary Data) .. mined in all patients with NSTE-ACS because they affect prognosis .. A number of prognostic models that aim to estimate the future and are key elements of the Global Registry of Acute Coronary .. risk of all-cause mortality or the combined risk of all-cause mortal- .. Events (GRACE) risk score (see section 4.3). Similarly, natriuretic pep- .. ity or MI have been developed. These models have been formu- tides [BNP and N-terminal pro-BNP (NT-proBNP)] provide prog- .. lated into clinical risk scores and, among these, the GRACE risk .. nostic information regarding the risk of death, acute heart failure, as .. score offers the best discriminative performance.133135 It is well as the development of AF in addition to cardiac troponin.121 In .. important to recognize, however, that there are several GRACE .. addition, quantifying the presence and severity of haemodynamic .. risk scores, and each refers to different patient groups and pre- stress and heart failure using BNP or NT-proBNP concentrations in .. dicts different outcomes.136139 The GRACE risk score models .. patients with left main CAD or three-vessel CAD without NSTE- .. have been externally validated using observational data.140 ACS may help the heart team to select either PCI or CABG as the .. Further information concerning the GRACE risk scores is pre- .. revascularization strategy of choice.122124 However, this needs . sented in Supplementary Data section 4.3, Supplementary Table 1, 1308 ESC Guidelines .. and Supplementary Figure 3. The nomogram to calculate the origi- .. 4.4 Bleeding risk assessment nal GRACE risk score, which estimates the risk of in-hospital .. .. Major bleeding events are associated with increased mortality in death, is shown in Supplementary Figure 3 and online risk calcula- .. NSTE-ACS.157 In order to estimate bleeding risk in this setting, tors are available for other GRACE risk scores: https://www.out .. .. scores such as the Can Rapid risk stratification of Unstable angina comes-umassmed.org/risk_models_grace_orig.aspx for the .. patients Suppress ADverse outcomes with Early implementation GRACE risk score 1.0 and www.outcomes-umassmed.org/grace/ .. .. of the ACC/American Heart Association (AHA) guidelines acs_risk2/index.html for the GRACE risk score 2.0. .. (CRUSADE; https://www.mdcalc.com/crusade-score-post-mi- Given that the GRACE risk score predicts clinical outcomes, it is .. .. bleeding-risk) and the Acute Catheterization and Urgent possible to stratify patients according to their estimated risk of .. Intervention Triage strategY (ACUITY) bleeding risk scores have future ischaemic events. A GRACE risk score-based risk assess- .. .. been developed. Overall, the two scores have reasonable predic- ment has been found to be superior to (subjective) physician .. tive value for major bleeding in ACS patients undergoing coronary assessment for the occurrence of death or MI.141,142 Moreover, it is .. .. angiography, with CRUSADE being the most discriminatory.155157 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 well recognized that the delivery of guideline-directed care is inver- .. Changes in interventional practice, such as the use of radial access sely related to the estimated risk of the patient with NSTE-ACS143 .. .. for coronary angiography and PCI, as well as in antithrombotic the so called ‘risk-treatment paradox’.144,145 Guideline-directed .. treatment, may modify the predictive value of risk scores. In addi- care is associated with proportionally greater survival gains among .. .. tion, in medically treated patients or those on oral anticoagulants those with higher baseline risk, therefore objective risk assessment .. (OACs), the predictive value of these scores has not been estab- .. may help to identify NSTE-ACS patients who would benefit from .. lished. Given these limitations, the use of the CRUSADE bleeding risk-determined care interventions.144,145 The Australian GRACE .. risk score may be considered in patients undergoing coronary .. Risk score Intervention Study (AGRIS)146 and the ongoing UK .. angiography to quantify bleeding risk. GRACE Risk score Intervention Study (UKGRIS)147 have or are .. An alternative to these scores may be the assessment of bleeding .. for the first time investigating the impact of the utilization of the .. risk according to the Academic Research Consortium for High GRACE risk score on outcomes of patients with NSTE-ACS in a .. .. Bleeding Risk (ARC-HBR) (Table 7).158 This consensus definition of randomized manner. The AGRIS cluster-randomized trial failed to .. patients at high bleeding risk (HBR) was recently developed to pro- demonstrate any add-on value, especially for the guideline-directed .. .. vide consistency for clinical trials evaluating the safety and effective- treatments with the routine implementation of the GRACE risk .. ness of devices and drug regimens for patients undergoing PCI.158 score. This was largely explained by better-than-expected perform- .. .. This proposed ARC-HBR represents a pragmatic approach that ance of the control hospitals. Given temporal improvements in .. includes the most recent trials performed in HBR patients, who were early mortality from NSTE-ACS,148 the prediction of long-term risk .. .. previously excluded from clinical trials of dual antiplatelet therapy is important. Deaths in the early phase following NSTE-ACS are .. (DAPT) duration or intensity (Table 7).159161 However, bleeding more attributable to ischaemia/thrombosis-related events, whereas .. .. risk assessment based on ARC-HBR criteria may be difficult to apply in the later phase they are more likely to be associated with the .. in routine clinical practice as several of the criteria are quite detailed progression of atherosclerosis and non-cardiovascular .. .. and so far, this score has not been validated. causes.149152 . Recommendations on biomarker measurements for prognostic stratification Recommendations Classa Levelb Beyond its diagnostic role, it is recommended to measure hs-cTn serially for the estimation of prognosis.12,13,119,120 I B 121,125,126 Measuring BNP or NT-proBNP plasma concentrations should be considered to gain prognostic information. IIa B The measurement of additional biomarkers, such as mid-regional pro-A-type natriuretic peptide, high-sensitivity C-reactive protein, mid-regional pro-adrenomedullin, GDF-15, copeptin, and h-FABP is not recommended for III B routine risk or prognosis assessment.50,127,129 Score to risk stratify in NSTE-ACS GRACE risk score models should be considered for estimating prognosis.137139 IIa B 153,154 The use of risk scores designed to evaluate the benefits and risks of different DAPT durations may be considered. IIb A To estimate bleeding risk, the use of scores may be considered in patients undergoing coronary angiography.155,156 IIb B BNP = B-type natriuretic peptide; DAPT = dual antiplatelet therapy; GDF-15 = growth differentiation factor 15; GRACE = Global Registry of Acute Coronary Events; h-FABP = heart-type fatty acid-binding protein; hs-cTn = high-sensitivity cardiac troponin; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; NT-proBNP = N-terminal pro-B-type natriuretic peptide. a Class of recommendation. b Level of evidence. ESC Guidelines 1309 Table 7 Major and minor criteria for high bleeding risk according to the Academic Research Consortium for High Bleeding Risk at the time of percutaneous coronary intervention (bleeding risk is high if at least one major or two minor criteria are met) Major Minor • Anticipated use of long-term OACa • Age >_ 75 years • Severe or end-stage CKD (eGFR <30 mL/min) • Moderate CKD (eGFR 3059 mL/min) • Haemoglobin <11 g/dL • Haemoglobin 1112.9 g/dL for men or 1111.9 g/dL for women • Spontaneous bleeding requiring hospitalization and/or • Spontaneous bleeding requiring hospitalization and/or transfusion in the past 6 months or at any time, if recurrent transfusion within the past 12 months not meeting the major criterion • Moderate or severe baseline thrombocytopeniab • Chronic use of oral non-steroidal anti-inflammatory drugs or steroids (platelet count <100 109/L) Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 • Chronic bleeding diathesis • Any ischaemic stroke at any time not meeting the major criterion • Liver cirrhosis with portal hypertension • Active malignancyc (excluding non-melanoma skin cancer) within the past 12 months • Previous spontaneous intracranial haemorrhage (at any time) • Previous traumatic intracranial haemorrhage within the past 12 months • Presence of a brain arteriovenous malformation • Moderate or severe ischaemic stroked within the past 6 months • Recent major surgery or major trauma within 30 days prior to PCI • Non-deferrable major surgery on DAPT CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate; OAC = oral anticoagulation/anticoagulant; PCI = percutaneous coronary intervention. a This excludes vascular protection doses.162 b Baseline thrombocytopenia is defined as thrombocytopenia before PCI. c Active malignancy is defined as diagnosis within 12 months and/or ongoing requirement for treatment (including surgery, chemotherapy, or radiotherapy). d National Institutes of Health Stroke Scale score >5. .. 4.5 Integrating ischaemic and bleeding .. composite ischaemic endpoint of MI, definite stent thrombosis, .. stroke, and target vessel revascularization. The findings remained risks .. Major bleeding events affect prognosis in a similar way to sponta- .. valid in analyses restricted to ACS. However, for the majority of .. patients in the study, DAPT consisted of aspirin and clopidogrel. neous ischaemic complications.163,164 Given the trade-off between .. ischaemic vs. bleeding risks for any antithrombotic regimen, the .. An external validation of the PRECISE-DAPT score in 4424 .. ACS patients undergoing PCI and treated with prasugrel or tica- use of scores might prove useful to tailor antithrombotic duration, .. as well as intensity, to maximize ischaemic protection and mini- .. grelor showed a modest predictive value for major bleeding at a .. median follow-up of 14 months (c-statistic = 0.653).165 In addition, mize bleeding risk in the individual patient. Specific risk scores have .. been developed for patients on DAPT following PCI, in the setting .. none of these risk prediction models have been prospectively .. tested in RCTs, therefore, their value in improving patient out- of both CCS as well as ACS. To date, no risk score has been tested .. in patients requiring long-term anticoagulation. The DAPT and the .. comes remains unclear. The DAPT study has been less well vali- .. dated, with a retrospective analysis in 1970 patients and a score PREdicting bleeding Complications In patients undergoing Stent .. implantation and subsEquent Dual Anti Platelet Therapy .. calculation at a different time point (6 vs. 12 months) than in the .. derivation cohort used to generate the score.166 (PRECISE-DAPT) scores have been designed to guide and inform .. .. decision making on DAPT duration.153,154 The applicability of the ... PRECISE-DAPT score is at patient discharge, while the DAPT .. 5 Pharmacological treatments score is a bleeding risk estimation to be calculated at 1 year from .. .. the index event. The usefulness of the PRECISE-DAPT score was .. 5.1 Antithrombotic treatment retrospectively assessed within patients randomized to different .. .. Antithrombotic treatment is mandatory in NSTE-ACS patients with DAPT durations (n = 10 081) to identify the effect on bleeding and .. and without invasive management. Its choice, the combination, the ischaemia of a long (1224 months) or short (36 months) treat- .. .. time point of initiation, and the treatment duration depend on vari- ment duration in relation to baseline bleeding risk.154 Among HBR .. ous intrinsic and extrinsic (procedural) factors (Figure 5). Notably, patients based on PRECISE-DAPT (i.e. PRECISE-DAPT score .. .. both ischaemic and bleeding complications significantly influence the >_25), prolonged DAPT was associated with no ischaemic benefit .. outcome of NSTE-ACS patients and their overall mortality risk.167 but a large bleeding burden.154 Conversely, longer treatment in .. .. Thus, the choice of treatment should equally reflect the ischaemic patients without HBR (i.e. PRECISE-DAPT score <25) was associ- .. and bleeding risk of the patient. ated with no increase in bleeding and a significant reduction in the .. 1310 ESC Guidelines Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 5 Determinants of antithrombotic treatment in coronary artery disease. Intrinsic (in blue: patient’s characteristics, clinical presentation & comor- bidities) and extrinsic (in yellow: co-medication & procedural aspects) variables influencing the choice, dosing, and duration of antithrombotic treatment. ACS = acute coronary syndromes; CABG = coronary artery bypass graft(ing); CCS = chronic coronary syndromes; CKD = chronic kidney disease; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction. ©ESC 2020 Figure 6 Antithrombotic treatments in non-ST-segment elevation acute coronary syndrome patients: pharmacological targets. Drugs with oral adminis- tration are shown in black letters and drugs with preferred parenteral administration in red. Abciximab (in brackets) is not supplied anymore. ADP = adenosine diphosphate; DAPT = dual antiplatelet therapy; FXa = factor Xa; GP = glycoprotein; TxA2 = thromboxane A2; UFH = unfractionated heparin; VKA = vitamin K antagonist. ESC Guidelines 1311 Table 8 Dose regimen of antiplatelet and anticoagulant drugs in non-ST-segment elevation acute coronary syndrome patientsa I. Antiplatelet drugs Aspirin LD of 150300 mg orally or 75250 mg i.v. if oral ingestion is not possible, followed by oral MD of 75100 mg o.d. P2Y12 receptor inhibitors (oral or i.v.) Clopidogrel LD of 300600 mg orally, followed by a MD of 75 mg o.d., no specific dose adjustment in CKD patients. Prasugrel LD of 60 mg orally, followed by a MD of 10 mg o.d. In patients with body weight <60 kg, a MD of 5 mg o.d. is recommended. In patients aged >_75 years, prasugrel should be used with caution, but a dose of 5 mg o.d. should be used if treatment is deemed necessary. No specific dose adjustment in CKD patients. Prior stroke is a contraindication for prasugrel. Ticagrelor LD of 180 mg orally, followed by a MD of 90 mg b.i.d., no specific dose adjustment in CKD patients. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Cangrelor Bolus of 30 mg/kg i.v. followed by 4 mg/kg/min infusion for at least 2 h or the duration of the procedure (whichever is longer). GP IIb/IIIa receptor inhibitors (i.v.) Abciximab Bolus of 0.25 mg/kg i.v. and 0.125 lg/kg/min infusion (maximum 10 lg/min) for 12 h (drug is not supplied anymore). Eptifibatide Double bolus of 180 lg/kg i.v. (given at a 10-min interval) followed by an infusion of 2.0 lg/kg/min for up to18 h. Tirofiban Bolus of 25 lg/kg i.v. over 3 min, followed by an infusion of 0.15 lg/kg/min for up to 18 h. II. Anticoagulant drugs (for use before and during PCI) UFH 70100 U/kg i.v. bolus when no GP IIb/IIIa inhibitor is planned followed up by an IV infusion until the invasive procedure. 5070 U/kg i.v. bolus with GP IIb/IIIa inhibitors. Enoxaparin 0.5 mg/kg i.v. bolus. Bivalirudin 0.75 mg/kg i.v. bolus followed by i.v. infusion of 1.75 mg/kg/h for up to 4 h after the procedure as clinically warranted. Fondaparinux 2.5 mg/d subcutaneously (only before PCI). III. Oral anticoagulant drugsb Rivaroxaban Very low MD of 2.5 mg b.i.d. (in combination with aspirin) for long-term extended antithrombotic treatment in a secondary prevention setting of CAD patients. AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CKD = chronic kidney disease; GP = glycoprotein; i.v. = intravenous; MD = maintenance dose; LD = loading dose; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation/anticoagulant; o.d. = once daily; PCI = percutaneous coronary intervention; UFH = unfractionated heparin; VKA = vitamin K antagonist. a All dosing regimens refer to doses given for the respective drugs for protection against thrombosis within the arterial system. b Section III lists the dosing for rivaroxaban in a secondary prevention setting in CAD patients. For a comprehensive summary on dosing of OACs (NOACs and VKAs) in a set- ting of full-dose anticoagulation please see: The 2018 European Heart Rhythm Association Practical Guide on the use of NOACs in patients with AF.168 .. Infarction 38 (TRITON-TIMI 38) trials,170,171 DAPT including aspirin Recommended anticoagulant and antiplatelet drugs and their dos- .. .. and a potent P2Y12 receptor inhibitor (ticagrelor or prasugrel) is the ing (for use during and after NSTE-ACS) are summarized in Figure 6 .. recommended standard treatment for NSTE-ACS patients. and Table 8. .. .. Clopidogrel, characterized by less potent and variable platelet inhibi- .. tion,172,173 should only be used when prasugrel or ticagrelor are con- .. 5.1.1 Antiplatelet drugs and pre-treatment .. traindicated, not available, or cannot be tolerated due to an .. unacceptable HBR. P2Y12 receptor inhibitors differ with respect to 5.1.1.1 Antiplatelet drugs and dual antiplatelet therapy .. Activation of blood platelets and the coagulation cascade play a key .. their pharmacokinetic and pharmacodynamic properties. Table 9 .. summarizes the essential features of the available oral and intrave- role in the initial phase and evolution of NSTE-ACS. Hence, sufficient ... platelet inhibition and (temporary) anticoagulation is essential in .. nous (i.v.) drugs. For further details on recent DAPT trials, please NSTE-ACS patients, especially in those undergoing myocardial revas- .. refer to the 2017 ESC focused update on DAPT in CAD.169 .. cularization by PCI. Aspirin is considered to be the cornerstone of .. Trial data on the head-to-head comparison of prasugrel vs. ticagre- treatment for inhibition of thromboxane A2 generation (Figure 6), .. lor became available with the open-label randomized Intracoronary .. which is normally complete with a dose >_75 mg/d. Aspirin treatment .. stenting and Antithrombotic regimenRapid Early Action for is started with a loading dose (LD) followed by maintenance treat- .. Coronary Treatment (ISAR-REACT) 5 trial.174 This study was con- .. ment (Table 8). Current evidence supports a maintenance dose (MD) .. ducted in 4018 ACS patients (NSTE-ACS and STEMI) for whom an of 75100 mg once daily (o.d.).169 Based on the results of the phase .. invasive evaluation was planned. The trial demonstrated that treat- .. III PLATelet inhibition and patient Outcomes (PLATO) and TRial to .. ment with prasugrel vs. ticagrelor significantly reduced the composite Assess Improvement in Therapeutic Outcomes by Optimizing .. rate of death, MI, or stroke (6.9 vs. 9.3%, P=0.006) without any .. Platelet InhibitioN with PrasugrelThrombolysis In Myocardial . increase in bleeding complications (4.8 vs. 5.4%, P=0.46). Limitations 1312 ESC Guidelines Table 9 P2Y12 receptor inhibitors for use in non-ST-segment elevation acute coronary syndrome patients Oral administration i.v. administration Clopidogrel Prasugrel Ticagrelor Cangrelor Drug class Thienopyridine Thienopyridine Cyclopentyl-triazolopyrimidine Adenosine triphosphate analogue Reversibility Irreversible Irreversible Reversible Reversible Bioactivation Yes (pro-drug, CYP Yes (pro-drug, CYP Noa No dependent, 2 steps) dependent, 1 step) (Pretreatment)-Dose 600 mg LD, 75 mg MD 60 mg LD, 10 (5) mg MD 180 mg LD, 2 90 (60) mg MD 30 mg/kg i.v. bolus, 4 mg/kg/min i.v. infusion for PCI Onset of effect Delayed: 26 h Rapid: 0.54 h Rapid: 0.52 h Immediate: 2 min Offset of effect 310 days 510 days 34 days 3060 min Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Delay to surgery 5 days 7 days 5 days No significant delay Kidney failure No dose adjustment No dose adjustment No dose adjustment No dose adjustment Dialysis or CrCl Limited data Limited data Limited data Limited data <15 mL/min CrCl = creatine clearance; CYP = cytochrome P450; i.v. = intravenous; LD = loading dose, MD = maintenance dose, PCI = percutaneous coronary intervention. a Following intestinal absorption, ticagrelor does not need to be metabolized to inhibit platelets. Of note, a metabolite (AR-C124910XX) of ticagrelor is also active. of the study, amongst multiple others, include its open-label design .. prasugrel, and clopidogrel were reported from the Swedish .. and the limited data on medically managed or CABG-treated .. Coronary Angiography and Angioplasty Registry (SCAAR) in 64 patients, which were more prominent in the PLATO trial.170 .. 857 NSTE-ACS patients.178 In this large dataset on pre-treatment, .. Ticagrelor also led to more patients stopping medication because of .. the authors reported that P2Y12 receptor inhibitor pre-treatment side effects. The actual treatment strategy was PCI in >80% of .. in NSTE-ACS patients was not associated with improved ischae- .. randomized patients and, consequently, prasugrel should be consid- .. mic outcomes, but instead, with a significantly increased risk of ered the preferred P2Y12 receptor inhibitor for NSTE-ACS patients .. bleeding events. With respect to pre-treatment data for ticagrelor, .. who proceed to PCI. The possible benefit of prasugrel, in comparison .. the recently published ISAR-REACT 5 trial showed that a .. with ticagrelor or clopidogrel, may be related to improved endothe- .. prasugrel-based strategy with deferred loading after knowledge of lial function.175 Recommended treatment algorithms and treatment .. coronary anatomy in NSTE-ACS patients was superior to a .. durations, as well as options for extended treatment (>12 months) in .. ticagrelor-based strategy that implied a routine pre-treatment NSTE-ACS patients, are shown in Figure 7. ... strategy.174 Importantly, there was no apparent benefit of a pre- .. treatment strategy (that utilized ticagrelor) in that study. .. 5.1.1.2 Pre-treatment .. Based upon the available evidence,174,177 it is not recommended to Pre-treatment defines a strategy according to which antiplatelet .. administer routine pre-treatment with a P2Y12 receptor inhibitor in .. drugs, usually a P2Y12 receptor inhibitor, are given before coro- .. NSTE-ACS patients in whom coronary anatomy is not known and an nary angiography and when the coronary anatomy is unknown.176 .. early invasive management is planned. For patients with a delayed .. Although a rationale for pre-treatment in NSTE-ACS may seem .. invasive management, pre-treatment with a P2Y12 receptor inhibitor obvious, for achieving sufficient platelet inhibition at the time of .. may be considered in selected cases and according to the bleeding .. PCI, large-scale randomized trials supporting a routine pre- .. risk of the patient. treatment strategy with either clopidogrel or the potent P2Y12 .. Fortunately, the recommended standard treatment with potent .. receptor inhibitors prasugrel and ticagrelor are lacking. The .. P2Y12 receptor inhibitors (ticagrelor or prasugrel) exhibits a fast randomized Comparison of Prasugrel at the Time of Percutaneous .. onset of action (Table 9), thereby allowing LD administration after .. Coronary Intervention or as Pretreatment at the Time of .. diagnostic coronary angiography and directly before PCI. Of note, a Diagnosis in Patients with Non-ST Elevation Myocardial Infarction .. routine pre-treatment strategy may be deleterious for a relevant pro- .. (ACCOAST) trial177 demonstrated a lack of any ischaemic benefit .. portion of patients with diagnoses other than NSTE-ACS (e.g. aortic for pre-treatment in NSTE-ACS patients, but instead, a substan- .. dissection or bleeding complications including intracranial bleeding) .. tially higher bleeding risk with prasugrel pre-treatment. In line with .. and may increase bleeding risk or delay procedures in patients sched- these results, observational data on pre-treatment with ticagrelor, .. uled for CABG after diagnostic angiography. . ESC Guidelines 1313 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 7 Algorithm for antithrombotic therapy in non-ST-segment elevation acute coronary syndrome patients without atrial fibrillation undergoing percutaneous coronary intervention. HBR is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25 or ARC-HBR158). Colour-coding refers to the ESC classes of recommendations (green = class I; yellow = IIa; orange = Class IIb). Very HBR is defined as recent bleeding in the past month and/or not deferrable planned surgery. A = aspirin; ARC-HBR = Academic Research Consortium High Bleeding Risk; C = clopidogrel; DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy (here: aspirin þ rivaroxaban); eGFR = estimated glomerular filtra- tion rate; ESC = European Society of Cardiology; HBR = high bleeding risk; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; P = prasu- grel; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; R = rivaroxaban; T = ticagrelor; UFH = unfractionated heparin. aClopidogrel during 12 months DAPT if patient is not eligible for treatment with prasugrel or ticagrelor or in a setting of DAPT de-escalation with a switch to clopidogrel (class IIb). bClopidogrel or prasu- grel if patient is not eligible for treatment with ticagrelor. cClass IIa indication for DAT or DAPT >12 months in patients at high risk for ischaemic events (see Table 11 for definitions) and without increased risk of major bleeding (= prior history of intracranial haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, renal failure requiring dialysis, or with eGFR <15 mL/min/1.73 m2); Class IIb indication for DAT or DAPT >12 months in patients with moderately increased risk of ischaemic events (see Table 11 for definitions) and without increased risk of major bleeding. Listen to the audio guide of this figure online. 1314 ESC Guidelines Recommendations for antithrombotic treatment in non-ST-segment elevation acute coronary syndrome patients with- out atrial fibrillation undergoing percutaneous coronary intervention Recommendations Classa Levelb Antiplatelet treatment Aspirin is recommended for all patients without contraindications at an initial oral LD of 150300 mg (or 75250 mg i.v.), and at a I A MD of 75100 mg o.d. for long-term treatment.179181 A P2Y12 receptor inhibitor is recommended in addition to aspirin, and maintained over 12 months unless there are contraindications or an excessive risk of bleeding.170,171,182 I A Options are: Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Prasugrel in P2Y12 receptor inhibitor-naı̈ve patients proceeding to PCI (60 mg LD, 10 mg/d as standard dose, 5 mg/d for patients I B aged >_75 years or with a body weight <60 kg).171 Ticagrelor irrespective of the planned treatment strategy (invasive or conservative) (180 mg LD, 90 mg b.i.d.).170 I B Clopidogrel (300600 mg LD, 75 mg daily dose), only when prasugrel or ticagrelor are not available, cannot be tolerated, or are I C contraindicated.182,183 Prasugrel should be considered in preference to ticagrelor for NSTE-ACS patients who proceed to PCI.174 IIa B GP IIb/IIIa antagonists should be considered for bail-out if there is evidence of no-reflow or a thrombotic complication. IIa C Cangrelor may be considered in P2Y12 receptor inhibitor-naı̈ve patients undergoing PCI.184187 IIb A Pre-treatment with a P2Y12 receptor inhibitor may be considered in patients with NSTE-ACS who are not planned to undergo an IIb C early invasive strategy and do not have an HBR. Treatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known is not recommended.188,189 III A It is not recommended to administer routine pre-treatment with a P2Y12 receptor inhibitor in patients in whom coronary anatomy is III A not known and an early invasive management is planned.174,177,178,190,191 Peri-interventional anticoagulant treatment Parenteral anticoagulation is recommended for all patients, in addition to antiplatelet treatment, at the time of diagnosis and, espe- I A cially, during revascularization procedures according to both ischaemic and bleeding risks.192,193 UFH (weight-adjusted i.v. bolus during PCI of 70100 IU/kg, or 5070 IU/kg in combination with a GP IIb/IIIa inhibitor; activated I A clotting time target range of 250350 s, or 200250 s if a GP IIb/IIIa inhibitor is given) is recommended in patients undergoing PCI. In cases of medical treatment or logistical constraints for transferring the patient to PCI within the required time frame, fondaparinux I B is recommended and, in such cases, a single bolus of UFH is recommended at the time of PCI.183 It is recommended to select anticoagulation according to both ischaemic and bleeding risks, and according to the efficacysafety pro- I C file of the chosen agent. Enoxaparin (i.v.) should be considered in patients pre-treated with subcutaneous enoxaparin.194196 IIa B Discontinuation of parenteral anticoagulation should be considered immediately after an invasive procedure. IIa C Bivalirudin may be considered as an alternative to UFH.189,197,198 IIb A 196 Crossover of UFH and LMWH is not recommended. III B b.i.d. = bis in die (twice a day); GP = glycoprotein; HBR = high bleeding risk; i.v. = intravenous; LD = loading dose; LMWH = low-molecular-weight heparin; MD = maintenance dose; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; o.d. = once daily; PCI = percutaneous coronary intervention; UFH = unfractionated heparin. a Class of recommendation. b Level of evidence. 5.1.2 Peri-interventional anticoagulant treatment .. The respective drugs should be discontinued immediately after PCI, .. Peri-interventional treatment for NSTE-ACS patients consists of anti- .. except in specific clinical settings such as the confirmed presence of coagulation to inhibit thrombin generation and thrombin activity .. LV aneurysm with thrombus formation or AF requiring anticoagula- .. (Figure 6). Anticoagulation is recommended for all patients in addition .. tion, which is usually done with UFH in (per)-acute settings. to antiplatelet therapy during invasive management for NSTE- .. Adjunctive treatment [e.g. glycoprotein (GP) IIb/IIIa inhibitors] and .. ACS.192 Table 8 provides an overview of the relevant drugs and their .. procedural aspects (radial vs. femoral access) have been subject to dosing in NSTE-ACS patients. Unfractionated heparin (UFH) is the .. change in recent years. In contrast to older studies, recent and con- .. standard of care for NSTE-ACS patients due to its favourable risk- .. temporary trials have pursued a balanced and more selective use of .. benefit profile. In general, a crossover between anticoagulants should .. GP IIb/IIIa inhibitors, with both bivalirudin and UFH. These trials have be avoided [especially between UFH and low-molecular-weight hep- .. been reviewed extensively in a number of meta-analyses.200203 A .. arin (LMWH)], with the exception of adding UFH to fondaparinux .. recent meta-analysis, which included the Minimizing Adverse when a patient proceeds to PCI after fondaparinux treatment.196,199 .. Haemorrhagic Events by TRansradial Access Site and Systemic ESC Guidelines 1315 .. Implementation of angioX (MATRIX) trial,197 showed no significant .. patients without pre-treatment with P2Y12 receptor inhibitors (see benefit of bivalirudin vs. UFH for ischaemic outcomes.202 Bivalirudin .. 2018 ESC/EACTS Guidelines on myocardial revascularization for .. was associated with a significant increase in the risk of stent thrombo- .. more details).205 sis and a significant decrease in bleeding risk. Bleeding risk reduction .. Cangrelor is a direct reversible, short-acting P2Y12 receptor inhibi- .. was linked to unbalanced use of GP IIb/IIIa inhibitors, predominantly .. tor that has been evaluated during PCI for stable CCS and ACS in with UFH. Recently, the Swedish Web-system for Enhancement and .. clinical trials comparing cangrelor with clopidogrel, administered .. Development of Evidence-based care in Heart disease Evaluated .. before PCI [Cangrelor versus Standard Therapy to Achieve Optimal According to Recommended Therapies (VALIDATE- .. Management of Platelet Inhibition (CHAMPION)] or after PCI .. SWEDEHEART) study204 compared UFH vs. bivalirudin on a back- .. (CHAMPION PLATFORM and CHAMPION PHOENIX).185187 A ground of radial access and limited use of GP IIb/IIIa inhibitors. The .. meta-analysis of these trials showed a benefit with respect to major .. study demonstrated similar risks for both ischaemia and bleeding .. ischaemic endpoints that was counter-balanced by an increase in when comparing the two drugs. Another meta-analysis, updated with .. minor bleeding complications.184 Moreover, the benefit of cangrelor .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 the results of the VALIDATE-SWEDEHEART study, confirmed that .. with respect to ischaemic endpoints was attenuated in CHAMPION bivalirudin vs. UFH was associated with a similar incidence of all- .. PCI with upfront administration of clopidogrel, while data for its use .. cause death and ischaemic events after PCI in ACS.203 A significant .. in conjunction with ticagrelor or prasugrel treatment are limited. association between bivalirudin and decreased risk of bleeding was .. Due to its proven efficacy in preventing intra-procedural and post- .. only found with unbalanced use of GP IIb/IIIa inhibitors in conjunction .. procedural stent thrombosis in P2Y12 receptor inhibitor-naı̈ve with UFH. .. patients, cangrelor may be considered on a case-by-case basis in .. In summary, and based on the aforementioned trials, UFH is pri- .. P2Y12 receptor inhibitor-naı̈ve NSTE-ACS patients undergoing PCI marily recommended as an anticoagulant for PCI. Due to its short .. (see 2018 ESC/EACTS Guidelines on myocardial revascularization .. half-life and favourable results in some of the studies, bivalirudin may .. for more details).205 .. be considered as an alternative to UFH in selected cases. For a more .. detailed description and a historical summary of the older clinical tri- .. .. als (with unbalanced use of GP IIb/IIIa inhibitors) comparing UFH .. 5.1.4 Post-interventional and maintenance treatment with bivalirudin, please refer to the 2018 ESC/EACTS Guidelines on .. Following PCI for NSTE-ACS, DAPT consisting of a potent P2Y12 .. myocardial revascularization.205 .. receptor inhibitor in addition to aspirin is generally recommended Patients may undergo cardiac catheterization after a conservative .. for 12 months, irrespective of the stent type, unless there are contra- .. treatment phase and these patients might be treated with fondapari- .. indications.170,171,182 In specific clinical scenarios, DAPT duration can nux during this period. This regimen is based on the Fifth .. be shortened (<12 months), extended (>12 months, see Figure 7 and .. Organization to Assess Strategies in Acute Ischemic Syndromes .. Tables 10 and 11), or modified (switching DAPT, DAPT de- (OASIS-5) trial.206 Of note, catheter thrombus formation was an .. escalation) and these decisions depend on individual clinical judge- .. issue with fondaparinux and, therefore, full-dose UFH must be added .. ment being driven by the patient’s ischaemic and bleeding risk, the to prevent thrombus formation when the patient proceeds to PCI. .. occurrence of adverse events, comorbidities, co-medications, and .. Enoxaparin, a LMWH with a predictable dose-effect relationship .. the availability of the respective drugs. For a detailed description of and a lower risk for heparin-induced thrombocytopenia (HIT) com- .. the pertinent and numerous trials that have compared different .. pared to UFH, should be considered as an anticoagulant for PCI in .. DAPT treatment durations (especially 36 vs. 12 months in NSTE- patients pre-treated with subcutaneous enoxaparin. A benefit of .. ACS patients), please refer to the 2017 ESC focused update on .. enoxaparin over UFH reduced mortality and bleeding complica- .. DAPT in CAD169 and recent trial publications.208,209 In patients with tions was reported in a meta-analysis that included NSTE-ACS .. NSTE-ACS and stent implantation who are at high risk of bleeding .. patients,194 but dedicated large-scale trials comparing enoxaparin vs. .. (e.g. PRECISE-DAPT >_25 or ARC-HBR criteria met), discontinuation UFH in NSTE-ACS are lacking. .. .. of P2Y12 receptor inhibitor therapy after 36 months should be con- .. sidered.154 In patients at very high risk of bleeding, defined as a recent .. .. bleeding episode in the past month or planned, not deferrable sur- 5.1.3 Peri-interventional antiplatelet treatment .. gery in the near future, 1 month of aspirin and clopidogrel should be .. Drugs for peri-interventional i.v. antiplatelet treatment include can- .. considered. grelor and GP IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban). .. Four recent trials (n = 29 089) have explored the benefit of a .. Most of the trials evaluating GP IIb/IIIa inhibitors in PCI-treated ACS .. shortened DAPT duration of 13 months.208211 Low-to-inter- patients predated the era of routine DAPT with early DAPT initiation .. mediate ischaemic risk and low bleeding risk patients were included .. including a P2Y12 receptor inhibitor LD.205,207 Today, with routine .. and early monotherapy with clopidogrel/ticagrelor was used. All and potent oral P2Y12 receptor inhibitors, there is no compelling evi- .. bleeding events were reduced, with a favourable trend towards less .. dence for an additional benefit of routine upstream use of GP IIb/IIIa .. ischaemic events including MI. Importantly, more than 50% had ACS inhibitors in NSTE-ACS patients scheduled for coronary angiogra- .. as an inclusion criterion. In particular, the Ticagrelor With Aspirin or .. phy.188,189 Even more so, in a setting of potent platelet inhibition with .. Alone in High-Risk Patients After Coronary Intervention ticagrelor or prasugrel, where randomized data on GP IIb/IIIa use is .. (TWILIGHT) trial211 examined the effect of ticagrelor alone vs. tica- .. limited, routine use of these agents cannot be recommended. .. grelor plus aspirin with regard to clinically relevant bleeding among Nevertheless, use should be considered for bail-out situations or .. patients at high risk for bleeding or ischaemic events who had under- .. thrombotic complications and may be considered for high-risk PCI in . gone PCI, according to the inclusion criteria. However, these patients 1316 ESC Guidelines Table 10 Treatment options for extended dual antithrombotic or antiplatelet therapies Drug Dose Indication NNT NNH (ischaemic (bleeding outcomes) outcomes) DAT regimens for extended treatment (including aspirin 75100 mg o.d.) Rivaroxaban (COMPASS trial) 2.5 mg b.i.d. Patients with CAD or symptomatic 77 84 PAD at high risk of ischaemic events DAPT regimens for extended treatment (including aspirin 75100 mg o.d.) Clopidogrel (DAPT trial) 75 mg/d Post MI in patients who have tolerated DAPT for 1 year 63 105 Prasugrel (DAPT trial) 10 mg/d (5 mg/d if body weight Post PCI for MI in patients who have 63 105 <60 kg or age >75 years) tolerated DAPT for 1 year Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Ticagrelor (PEGASUS-TIMI 54) 60/90 mg b.i.d. Post MI in patients who have tolerated DAPT for 1 year 84 81 Drugs (in addition to aspirin 75100 mg/d) for extended DAPT treatment options are in alphabetical order. For indications and definitions for high/moderately increased risk and bleeding risk see Table 9 and Figure 7. NNT refers to the primary ischaemic endpoints of the respective trials and NNH refers to the key safety (bleeding) endpoints. NNT and NNH numbers from the DAPT trial are pooled numbers for clopidogrel and prasugrel. b.i.d. = bis in die (twice a day); CAD = coronary artery disease; COMPASS = Cardiovascular OutcoMes for People using Anticoagulation StrategieS; DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; MI = myocardial infarction; NNH = number needed to harm; NNT = number needed to treat; o.d. = once daily; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PEGASUS-TIMI 54 = Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54. Table 11 Risk criteria for extended treatment with a second antithrombotic agent High thrombotic risk (Class IIa) Moderate thrombotic risk (Class IIb) Complex CAD and at least 1 criterion Non-complex CAD and at least 1 criterion Risk enhancers Diabetes mellitus requiring medication Diabetes mellitus requiring medication History of recurrent MI History of recurrent MI Any multivessel CAD Polyvascular disease (CAD plus PAD) Polyvascular disease (CAD plus PAD) CKD with eGFR 1559 mL/min/1.73 m2 Premature (<45 years) or accelerated (new lesion within a 2-year time frame) CAD Concomitant systemic inflammatory disease (e.g. human immunodeficiency virus, systemic lupus erythematosus, chronic arthritis) CKD with eGFR 1559 mL/min/1.73 m2 Technical aspects At least 3 stents implanted At least 3 lesions treated Total stent length >60 mm History of complex revascularization (left main, bifurcation stenting with >_2 stents implanted, chronic total occlusion, stenting of last patent vessel) History of stent thrombosis on antiplatelet treatment In line with guideline recommendations, CAD patients are stratified into two different risk groups (high vs. moderately increased thrombotic or ischaemic risk). Stratification of patients towards complex vs. non-complex CAD is based on individual clinical judgement with knowledge of patients’ cardiovascular history and/or coronary anatomy. Selection and composition of risk-enhancing factors are based on the combined evidence of clinical trials on extended antithrombotic treatment in CAD patients162,212,214 and on data from related registries.228230 CAD = coronary artery disease; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; MI = myocardial infarction; PAD = peripheral artery disease. were not at HBR according to current HBR criteria and event rates .. CI 0.450.68, P<0.001), with a significant interaction according to .. at follow-up. Based on this, these patients were more a low bleeding .. ACS at presentation. The trial was not powered for the composite .. and ischaemic risk cohort even though more than two thirds had an .. endpoint of death from any cause, non-fatal MI, or non-fatal stroke. ACS. After 3 months of treatment with ticagrelor plus aspirin, .. However, in exploratory non-inferiority hypothesis testing, there .. patients who did not have a major bleeding or ischaemic event con- .. was no signal of increased ischaemic risk.211 It should be acknowl- tinued to take ticagrelor and were randomly assigned to receive .. edged that the actual ischaemic event rate in TWILIGHT was low .. aspirin or placebo for 1 year. The primary endpoint of Bleeding .. compared to other trials for deemed high-risk PCI patients. Academic Research Consortium (BARC) type 2, 3, or 5 bleeding was .. Contrary to this, and based on the results of the DAPT and .. significantly reduced by omitting aspirin (4.0 vs. 7.1%; HR 0.56, 95% . Prevention of Cardiovascular Events in Patients With Prior Heart ESC Guidelines 1317 Attack Using Ticagrelor Compared to Placebo on a Background of Recommendations for post-interventional and Aspirin-Thrombolysis in Myocardial Infarction (PEGASUS-TIMI) maintenance treatment in patients with 54 trials, in patients with ACS who have tolerated DAPT without non-ST-segment elevation acute coronary syndrome a bleeding complication, a prolonged DAPT course >12 months Recommendations Classa Levelb should be considered in those with high thrombotic risk and with- out an increased risk for major or life-threatening bleeding, and In patients with NSTE-ACS treated with coronary may be considered in patients with moderately elevated throm- stent implantation, DAPT with a P2Y12 receptor botic risk (see Figure 7 and Tables 10 and 11).212,213 Of note, the inhibitor on top of aspirin is recommended for 12 I A 60 mg bis in die [b.i.d. (twice a day)] dose for ticagrelor was better months unless there are contraindications such as tolerated than the 90 mg b.i.d dose214,215 and this dose is now excessive risk of bleeding.170,171,225 approved in many (albeit not all) countries for this indication. Prolonging antithrombotic treatment duration Switching between oral P2Y12 receptor inhibitors is common and Adding a second antithrombotic agent to aspirin Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 triggers may include bleeding complications (or concerns for bleed- for extended long-term secondary prevention ing), non-bleeding side effects (e.g. dyspnoea on ticagrelor, allergic should be considered in patients with a high risk IIa A reactions), as well as socio-economic factors.216,217 Switching of ischaemic events and without increased risk between oral P2Y12 receptor inhibitors may be considered in of major or life-threatening bleeding (see selected cases, and for a more detailed description on switching anti- Tables 9 and 11 for options).162,212,213,214,223 platelet drugs, please refer to the International Expert Consensus on Adding a second antithrombotic agent to aspirin Switching Platelet P2Y12 Receptor-Inhibiting Therapies217 and the for extended long-term secondary prevention may 2017 ESC DAPT focused update.169 be considered in patients with moderately DAPT de-escalation (switch from potent drugs like prasugrel or IIb A increased risk of ischaemic events and without ticagrelor to clopidogrel) in NSTE-ACS patients may be consid- increased risk of major or life-threatening bleeding ered as an alternative treatment regimen.216,217 However, it is (see Tables 9 and 11 for options).162,212,213,214,223 important to note that there is a potential for increased ischaemic In ACS patients with no prior stroke/transient risk with a uniform de-escalation of P2Y12 receptor inhibiting ther- ischaemic attack who are at high ischaemic risk and apy after PCI, particularly if performed early (<30 days) after the low bleeding risk and are receiving aspirin and clo- index event. Indeed, dedicated large-scale trials on a uniform and IIb B pidogrel, low-dose rivaroxaban (2.5 mg b.i.d. for unguided DAPT de-escalation are lacking and the available data on approximately 1 year) may be considered after dis- uniform de-escalation are conflicting.218,219 Based on the results continuation of parenteral anticoagulation.224 of the Testing Responsiveness to Platelet Inhibition on Chronic Shortening antithrombotic treatment duration Antiplatelet Treatment for Acute Coronary Syndromes After stent implantation with high risk of bleed- (TROPICAL-ACS) and POPULAR Genetics trials,220,221 an ing (e.g. PRECISE-DAPT >_25 or ARC-HBR cri- approach of DAPT de-escalation guided by either platelet function teria met), discontinuation of P2Y12 receptor IIa B testing (TROPICAL-ACS: NSTE-ACS and STEMI patients) inhibitor therapy after 3 months should be or CYP2C19-directed genotyping (POPULAR Genetics: STEMI considered.154,226 patients) may be considered in selected NSTE-ACS patients After stent implantation in patients undergoing a as an alternative to 12 months of potent platelet inhibition, strategy of DAPT, stopping aspirin after 36 especially for patients deemed unsuitable for maintained months should be considered, depending on the IIa A potent platelet inhibition. For further details, please refer to the balance between the ischaemic and bleeding updated expert consensus statement on platelet function and risk.208,209,227 genetic testing for guiding P2Y12 receptor inhibitor treatment in PCI.222 De-escalation of P2Y12 receptor inhibitor treat- Recently, data on a novel strategy of dual antithrombotic ther- ment (e.g. with a switch from prasugrel or tica- apy (DAT) consisting of factor-Xa inhibition with a very low dose grelor to clopidogrel) may be considered as an of rivaroxaban (2.5 mg b.i.d.) plus aspirin has emerged, and such a alternative DAPT strategy, especially for ACS regimen should be considered as a treatment option for mainte- patients deemed unsuitable for potent platelet IIb A nance treatment beyond 12 months post ACS PCI. In a secondary inhibition. De-escalation may be done unguided prevention setting, the Cardiovascular OutcoMes for People using based on clinical judgment or guided by platelet Anticoagulation StrategieS (COMPASS) trial162,223 investigated function testing or CYP2C19 genotyping, very low-dose rivaroxaban (2.5 mg b.i.d.) in combination with depending on patient’s risk profile and availabil- aspirin vs. aspirin alone or rivaroxaban 5 mg b.i.d. alone. ity of respective assays.218,220,221 Rivaroxaban 2.5 mg b.i.d. plus aspirin 100 mg o.d. reduced the risk ACS = acute coronary syndromes; ARC-HBR = Academic Research Consortium of the combined ischaemic endpoint, overall mortality (without High Bleeding Risk; b.i.d. = bis in die (twice a day); DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; reaching the threshold P-value according to the Hochberg proce- PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing dure), and cardiovascular mortality alone, while this combination Stent implantation and subsEquent Dual Anti Platelet Therapy. a increased the risk for major bleeding complications without a Class of recommendation. b Level of evidence. 1318 ESC Guidelines significant increase in the risk of fatal, intracranial, or critical organ .. .. 5.3 Managing oral antiplatelet agents in bleeding events. Greater absolute risk reductions were seen in .. patients requiring long-term oral high-risk patients, including those with diabetes or polyvascular .. .. anticoagulants disease [CAD plus peripheral artery disease (PAD)]. Thus, rivar- .. oxaban (2.5 mg b.i.d.) should be considered, in addition to aspirin .. 5.3.1 Patients with atrial fibrillation without mechanical .. prosthetic heart valves or moderate-to-severe mitral 75 - 100 mg/d in patients at high thrombotic risk and without an .. increased risk for major or life-threatening bleeding, and may be .. stenosis undergoing percutaneous coronary intervention .. or managed medically (Supplementary Data) considered in patients with moderately elevated thrombotic risk .. (see Figure 7 and Tables 10 and 11 for selection criteria and for .. In 68% of patients undergoing PCI, long-term OAC is indicated and .. should also be continued during the procedure because its interrup- ischaemic and bleeding risk definitions). .. .. tion and bridging with parenteral anticoagulants may lead to Rivaroxaban has also been studied in the Anti-Xa Therapy to .. increased thromboembolic episodes and bleeds.232234 In patients Lower Cardiovascular Events in Addition to Standard Therapy in .. .. undergoing PCI, it is unknown whether it is safe to bridge Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Subjects with Acute Coronary Syndrome 2Thrombolysis In .. Myocardial Infarction 51 (ATLAS ACS 2TIMI 51) trial on a back- .. non-vitamin K antagonist (VKA) OACs (NOACs) with parenteral .. anticoagulants or continue NOACs without additional parenteral ground of clopidogrel treatment. The study showed a reduction of .. ischaemic events and cardiovascular mortality along with a higher risk .. anticoagulation, while no parenteral anticoagulation is needed if the .. international normalized ratio (INR) is >2.5 in VKA-treated for bleeding.224 However, data are lacking on a background of tica- .. grelor or prasugrel treatment and it is therefore difficult to extrapo- .. patients.235237 Strategies to minimize PCI-related complications in .. patients on OACs are listed in Table 12. late trial results to contemporary practice including the use of potent .. P2Y12 receptor inhibitors. .. In NSTE-ACS patients, evidence on the management of patients .. undergoing PCI requiring long-term OAC is derived from subgroups .. .. of RCTs (see Table 13 and Supplementary Data section 5.3.1).238242 5.2 Pharmacological treatment of .. Overall, in patients with AF without mechanical prosthetic valves ischaemia (Supplementary Data) .. .. or moderate-to-severe mitral stenosis, the evidence supports the 5.2.1 Supportive pharmacological treatment .. use of NOACs over VKA in terms of safety (i.e. lower bleeding risk). .. (Supplementary Data) .. DAT with a NOAC at the recommended dose for stroke prevention .. and single antiplatelet therapy (SAPT) (preferably clopidogrel, chosen .. 5.2.2 Nitrates and beta-blockers (Supplementary .. in more than 90% of cases in available trials) is recommended as the Data) .. default strategy up to 12 months after a short period (up to 1 week) .. .. of triple antithrombotic therapy (TAT) (with NOAC and DAPT) .. (Figure 8). Although none of the available RCTs were designed to .. .. detect subtle differences in ischaemic events, the numerically higher .. risk of stent thrombosis or MIs observed in some trials might have .. Recommendations for anti-ischaemic drugs in the acute .. been offset by the higher risk of bleeding, resulting in a neutral effect phase of non-ST-segment elevation acute coronary .. on major adverse cardiovascular events (MACE) or overall syndrome .. .. death.243,244 At variance with the default strategy, in patients with .. Recommendations Classa Levelb .. HBR, DAT should be shortened to 6 months by withdrawing the .. ongoing antiplatelet therapy; while in patients with high coronary .. Sublingual or i.v. nitrates and early initiation of .. ischaemic risk, TAT should be prolonged up to 1 month, followed by beta-blocker treatment are recommended in .. DAT for up to 12 months. There is currently limited evidence to sup- I C .. patients with ongoing ischaemic symptoms and .. port the use of OACs with ticagrelor or prasugrel as dual therapy without contraindications. .. after PCI as an alternative to TAT.241,245 Following coronary stenting, .. It is recommended to continue chronic beta- .. DAPT with aspirin and ticagrelor or prasugrel, without OAC, may be blocker therapy unless the patient is in overt I C .. considered as an alternative to TAT in patients with high ischaemic .. heart failure. .. risk NSTE-ACS and AF and one non-sex stroke risk factor within the i.v. nitrates are recommended in patients with .. first 4 weeks. Regarding the need to continue with any antiplatelet .. uncontrolled hypertension or signs of heart I C .. agent beyond 12 months, the AFIRE trial randomized 2236 AF .. patients treated with PCI or CABG more than 1 year earlier or with failure. .. In patients with suspected/confirmed vasospas- .. documented CAD to receive either monotherapy with rivaroxaban .. or combination therapy with rivaroxaban plus a single antiplatelet tic angina, calcium channel blockers and nitrates IIa B .. should be considered and beta-blockers .. agent.246 Rivaroxaban monotherapy (15 mg o.d. or 10 mg o.d. with .. creatinine clearance (CrCl) 1549 mL/min) was non-inferior to avoided.231 .. .. combination therapy for the primary efficacy composite endpoint of i.v. = intravenous. .. stroke, systemic embolism, MI, unstable angina requiring revasculari- a Class of recommendation. .. b Level of evidence. .. zation, or overall death (HR 0.72, 95% CI 0.550.95). ESC Guidelines 1319 Table 12 Suggested strategies to reduce bleeding risk related to percutaneous coronary intervention • Anticoagulant doses adjusted to body weight and renal function, especially in women and older patients • Radial artery approach as default vascular access • Proton pump inhibitors in patients on DAPT at higher-than-average risk of gastrointestinal bleeds (i.e. history of gastrointestinal ulcer/haemorrhage, anti- coagulant therapy, chronic non-steroidal anti-inflammatory drugs/corticosteroid use, or two or more of: a. Age >_65 years b. Dyspepsia c. Gastro-oesophageal reflux disease d. Helicobacter pylori infection e. Chronic alcohol use • In patients on OAC Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 a. PCI performed without interruption of VKAs or NOACs b. In patients on VKAs, do not administer UFH if INR >2.5 c. In patients on NOACs, regardless of the timing of the last administration of NOACs, add low-dose parenteral anticoagulation (e.g. enoxaparin 0.5 mg/kg i.v. or UFH 60 IU/kg) • Aspirin is indicated but avoid pre-treatment with P2Y12 receptor inhibitors • GP IIb/IIIa inhibitors only for bailout or periprocedural complications DAPT = dual antiplatelet therapy; GP = glycoprotein; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation/anticoagulant; PCI = percutaneous coronary intervention; UFH = unfractionated heparin; VKA = vitamin K antagonist. Table 13 Randomized controlled trials including patients with non-ST-segment elevation acute coronary syndrome requiring anticoagulation and antiplatelet therapy RCT n Comparison Primary Endpoint Secondary endpoints WOEST239 573 DAT (VKA þ C) for 12 months vs. TIMI bleeding lower with DAT vs. TAT MI þ stroke þ target vessel revasculariza- TAT (VKA þ A þ C) for at 1 year (HR 0.36, 95% CI 0.260.50) tion þ stent thrombosis: no difference. 12 months All-cause mortality lower with DAT vs. TAT at 1 year (HR 0.39, 95% CI 0.160.93) ISAR-TRIPLE250 614 6 weeks TAT (VKA þ A þ C) fol- Death þ MI þ stent thrombosis þ Cardiac death þ MIþ stent thrombosis lowed by DAT (VKA þ A) vs. stroke or TIMI major bleeds at þ stroke: no difference. TIMI major 6 months TAT (VKA þ A þ C) 9 months: no difference bleeding: no difference PIONEER 2124 DAT (rivaroxaban 15 mg/day þ C) Clinically significant bleeding lower Cardiovascular death þ MI þ stroke: AF-PCI240 for 12 months) vs. modified TAT with DAT (HR 0.59, 95% CI no difference. All-cause death þ reho- (rivaroxaban 2.5 mg b.i.d. þ A þ C 0.470.76) or modified TAT (HR 0.63, spitalization lower with DAT (HR 0.79, for 1, 6, or 12 months) vs. TAT (VKA 95% CI 0.500.80) vs. TAT CI 0.690.94) or modified TAT (HR þ A þ C for 1, 6, or 12 months) 0.75, CI 0.620.90) vs. TAT RE-DUAL PCI238 2725 TAT (VKA þ A þ C) up to 3 Major or clinically relevant non-major MI þ stroke þ systemic embolism, months vs. DAT (dabigatran 110 or bleeding lower in DAT 110 mg (HR 0.52, death, unplanned revascularization: no 150 mg b.i.d. þ C or T) 95% CI 0.420.63) or DAT 150 mg (HR difference 0.72, 95% CI 0.580.88) vs. TAT AUGUSTUS241 4614 DAT1 (apixaban 5 mg b.i.d. þ C or T Major or clinically relevant non-major Death þ hospitalization lower with or P) vs. DAT2 (VKA þ C or T or P) bleeds lower with DAT1 (HR 0.69, apixaban (HR 0.83, 95% CI 0.740.93) vs. TAT1 (apixaban 5 mg b.i.d. þ A þ 95% CI 0.580.81) vs. other regimens No difference with aspirin C or T or P) vs. TAT2 (VKA þ A þ C or T or P) ENTRUST- 1506 DAT (edoxaban 60 mg þ C or T or Major or clinically relevant non-major Cardiovascular death þ stroke þ sys- AF PCI251 P) vs. TAT (VKA þ A þ C or T or bleeds non-inferior between DAT or temic embolism þ MI þ stent throm- P) TAT (HR 0.83, 95% CI 0.651.05, bosis not different between DAT and P=0.0010 for non-inferiority) TAT A = aspirin; AF = atrial fibrillation; AUGUSTUS = Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation; b.i.d. = bis in die (twice a day); C = clo- pidogrel; CI = confidence interval; DAT = dual antithrombotic therapy; ENTRUST-AF PCI = EdoxabaN TRreatment versUS VKA in paTients with AF undergoing PCI; HR = hazard ratio; ISAR-TRIPLE = Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation; MI = myocardial infarction; OAC = oral anticoagulation/ anticoagulant; P = prasugrel; PIONEER AF-PCI = Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose- Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention; RCT = randomized controlled trial; RE-DUAL PCI = Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; T = ticagrelor; TAT = triple antithrombotic therapy; TIMI = Thrombolysis In Myocardial Infarction; VKA = vitamin K antagonist; WOEST = What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing. 1320 ESC Guidelines Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ©ESC 2020 Figure 8 Algorithm for antithrombotic therapy in non-ST-segment elevation acute coronary syndrome patients with atrial fibrillation undergoing percu- taneous coronary intervention or medical management. Green (class I) and yellow (class IIa) colours denote the classes of recommendation. OAC: prefer- ence for a NOAC over VKA for the default strategy and in all other scenarios if no contraindications. For both TAT and DAT regimens, the recommended doses for the NOACs are as follows: 1) Apixaban 5 mg b.i.d.241 2) Dabigatran 110 mg or 150 mg b.i.d.238 3) Edoxaban 60 mg/d 4) Rivaroxaban 15 mg or 20 mg/d240 NOAC dose reductions are recommended in patients with renal failure and may be considered in patients with ARC-HBR (see Table 7).158 SAPT: prefer- ence for a P2Y12 receptor inhibitor over aspirin. Ticagrelor may be considered in patients with high ischaemic risk and low bleeding risk. Treatment >1 month: OAC þ DAPT (TAT) may be considered for up to 6 months in selected patients with high ischaemic risk (IIa C). Treatment >12 months: OAC þ SAPT may be considered in selected patients with high ischaemic risk. ARC-HBR = see Table 7 and in addition with a PRECISE-DAPT score of >_25. High thrombotic or ischaemic risk is defined in Table 11. AF = atrial fibrillation; ARC-HBR = Academic Research Consortium High Bleeding Risk; b.i.d. = bis in die (twice a day); DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; NOAC = non-vitamin K antagonist oral anticoagulant; NSTE- ACS = non-ST-segment elevation acute coronary syndrome; OAC = oral anticoagulation/anticoagulant; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; SAPT = single antiplatelet therapy; TAT = triple antithrombotic therapy; VKA = vitamin K antagonist. Listen to the audio guide of this figure online. Rivaroxaban monotherapy was superior for the primary safety end- .. higher bleeding events (HR 1.49, 95% CI 0.982.26), but no signifi- .. point of major bleeding (HR 0.59, 95% CI 0.390.89). .. cant differences in death or hospitalization (HR 1.16, 95% CI In NSTE-ACS patients managed medically, available data support .. 0.901.51) or ischaemic events (HR 1.01, 95% CI 0.661.55). .. DAT over TAT, with a single antiplatelet agent (most commonly clo- .. pidogrel) for at least 6 months.247 In a registry, bleeding risk was .. .. 5.3.2 Patients requiring vitamin K antagonists or increased on TAT compared to VKA plus a single antiplatelet agent .. undergoing coronary artery bypass surgery .. at 90 days, but not at 1 year, without differences in ischaemic .. In patients where VKA is mandated (e.g. patients with mechanical events.248 In addition, warfarin plus clopidogrel resulted in a non- .. prosthetic valves), DAT with VKA and SAPT (preferably clopidogrel) .. significant reduction in major bleeds compared with TAT, with a .. is indicated after a short in-hospital period of TAT (with aspirin and non-significant reduction in MI or cardiovascular death.249 In the .. clopidogrel).239 Compared with TAT (consisting of VKA plus aspirin .. randomized Antithrombotic Therapy after Acute Coronary .. and clopidogrel), DAT (VKA plus clopidogrel) was associated with a Syndrome or PCI in Atrial Fibrillation (AUGUSTUS) trial,241 approxi- .. trend towards a reduction in Thrombolysis In Myocardial Infarction .. mately 23% of enrolled patients presented with medically managed .. (TIMI) major bleeding (OR 0.58, 95% CI 0.311.08) in a network ACS. In these patients, apixaban significantly reduced bleeding events .. meta-analysis, while no significant difference was observed in MACE .. vs. VKA (HR 0.44, 95% CI 0.280.68) and death or hospitalization .. (OR 0.96, 95% CI 0.601.46).243 (HR 0.71, 95% CI 0.540.92), while no significant differences were .. CABG in fully anticoagulated patients is associated with an .. observed in death or ischaemic events (HR 0.71, 95% CI .. increased bleeding risk, thus interruption of VKA prior to CABG is 0.461.09]). Aspirin vs. placebo presented a strong trend towards .. recommended in non-emergent cases. In emergency surgery, a ESC Guidelines 1321 .. combination of prothrombin complex concentrate of four inacti- .. patients.254 In the setting of planned CABG, a 48-h interruption of vated factors (25 IU/kg) and oral vitamin K is required to obtain fast .. NOACs is recommended (a longer period might be necessary in .. and sustained restoration of haemostasis at the time of surgery.252 .. patients with impaired renal function). In ACS patients with an estab- While experience with urgent major surgery in patients treated with .. lished indication for OAC, anticoagulation should be resumed after .. NOACs is limited, it has been suggested to use prothrombin com- .. CABG as soon as the bleeding is controlled, possibly with a combina- plex concentrate of activated factors to restore haemostasis.253 .. tion with SAPT, while TAT should be avoided. For antithrombotic .. Reversal agents might represent an additional option in these .. therapy and CABG, see Valgimigli et al.169 Recommendations for combining antiplatelet agents and anticoagulants in non-ST-segment elevation acute coronary syndrome patients requiring chronic oral anticoagulation Classa Levelb Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Recommendations Stroke prevention is recommended to AF patients with >_1 non-sex CHA2DS2-VASc stroke risk factors (score of >_1 in males or I A >_2 in females).For patients with >_2 non-sex stroke risk factors, OAC is recommended.255259 For patients with 1 non-sex stroke risk factor, OAC should be considered and treatment may be individualized based on net clini- IIa B cal benefit and consideration of patient values and preferences.260263 An early ICA should be considered in HBR patients, irrespective of OAC exposure, to expedite treatment allocation (medical vs. IIa C PCI vs. CABG) and to determine the optimal antithrombotic regimen. Patients undergoing coronary stenting Anticoagulation During PCI, additional parenteral anticoagulation is recommended, irrespective of the timing of the last dose of all NOACs and if I C INR is <2.5 in VKA-treated patients. In patients with an indication for OAC with VKA in combination with aspirin and/or clopidogrel, the dose intensity of VKA should IIa B be carefully regulated with a target INR of 2.02.5 and a time in the therapeutic range >70%.236,238241 Uninterrupted therapeutic anticoagulation with VKA or NOACs should be considered during the periprocedural phase. IIa C Antiplatelet treatment In patients with AF and CHA2DS2-VASc score >_1 in men and >_2 in women, after a short period of TAT (up to 1 week from the acute event), DAT is recommended as the default strategy using a NOAC at the recommended dose for stroke prevention and a I A single oral antiplatelet agent (preferably clopidogrel).238241,244,245 Periprocedural DAPT administration consisting of aspirin and clopidogrel up to 1 week is recommended.238241,244,245 I A Discontinuation of antiplatelet treatment in patients treated with an OAC is recommended after 12 months.236239,246 I B In patients treated with a VKA (e.g. mechanical prosthetic valves), clopidogrel alone should be considered in selected patients IIa B (HAS-BLED >_3 or ARC-HBR met and low risk of stent thrombosis) for up to 12 months.236 When rivaroxaban is used and concerns about HBR prevail over stent thrombosis or ischaemic stroke, rivaroxaban 15 mg o.d. IIa B should be considered in preference to rivaroxaban 20 mg o.d. for the duration of concomitant SAPT or DAPT.240,245 In patients at HBR (HAS-BLED >_3), dabigatran 110 mg b.i.d. should be considered in preference to dabigatran 150 mg b.i.d. for IIa B the duration of concomitant SAPT or DAPT to mitigate bleeding risk.238 In patients treated with an OAC, aspirin plus clopidogrel for longer than 1 week and up to 1 month should be considered in those IIa C with high ischaemic risk or other anatomical/procedural characteristics which outweigh the bleeding risk (Table 11). DAT (with an OAC and either ticagrelor or prasugrel) may be considered as an alternative to TAT (with an OAC, aspirin, and IIb C clopidogrel) in patients with a moderate or high risk of stent thrombosis, irrespective of the type of stent used. The use of ticagrelor or prasugrel as part of TAT is not recommended. III C Medically managed patients One antiplatelet agent in addition to an OAC should be considered for up to 1 year.241,247 IIa C 241,247 In patients with AF, apixaban 5 mg b.i.d. and SAPT (clopidogrel) for at least 6 months may be considered. IIb B AF = atrial fibrillation; ARC-HBR = Academic Research Consortium High Bleeding Risk; b.i.d. = bis in die (twice a day); CABG = coronary artery bypass graft(ing); CHA2DS2-VASc = Congestive heart failure, Hypertension, Age >_75 years (2 points), Diabetes, Stroke (2 points)Vascular disease, Age 6574, Sex category (female); DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; HAS-BLED = hypertension, abnormal renal and liver function (1 point each), stroke, bleeding history or predispo- sition, labile INR, older patients (>65 years), drugs and alcohol (1 point each); HBR = high bleeding risk (see Table 7); ICA = invasive coronary angiography; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation/anticoagulant; o.d. = once daily; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy; TAT = triple antithrombotic therapy; VKA = vitamin K antagonist. a Class of recommendation. b Level of evidence. 1322 ESC Guidelines .. .. 6 Invasive treatments 5.4 Management of acute bleeding events .. (Supplementary Data) .. .. 6.1 Invasive coronary angiography and 5.4.1 General supportive measures (Supplementary Data) .. .. revascularization .. Coronary angiography facilitates clarification as to whether pre- 5.4.2 Bleeding events on antiplatelet agents .. .. sumed anginal chest pain originates from myocardial ischaemia, as a (Supplementary Data) .. consequence of a culprit lesion, or not. In the former case, the culprit .. .. lesion can subsequently be treated by means of PCI within the same 5.4.3 Bleeding events on vitamin K antagonists ... procedure or by CABG, depending on lesion morphology and the (Supplementary Data) .. .. patient’s risk profile (see section 6.4). In the latter case, exclusion of a .. culprit lesion paves the way to subsequent diagnostic investigations 5.4.4 Bleeding events on non-vitamin K antagonist oral .. .. ultimately revealing the cause of chest pain and/or myocardial injury Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 anticoagulants (Supplementary Data) .. (see section 7). However, ICA carries a certain risk for procedure- .. .. related complications, which has to be considered in management 5.4.5 Non-access-related bleeding events (Supplementary .. decisions. .. Data) .. .. 6.1.1 Routine invasive vs. selective invasive approach .. 5.4.6 Bleeding events related to percutaneous coronary .. (Supplementary Data) intervention (Supplementary Data) .. Routine invasive strategy means the patient is deemed to undergo .. .. ICA. Following a selective invasive strategy, ICA will only be per- .. formed after recurrent symptoms, objective evidence of inducible 5.4.7 Bleeding events related to coronary artery bypass .. surgery (Supplementary Data) .. ischaemia on non-invasive testing, or detection of obstructive CAD .. by CCTA. Multiple RCTs comparing a routine invasive with a selec- .. .. tive invasive strategy have been conducted and their results have 5.4.8 Transfusion therapy (Supplementary Data) .. 266270 .. been pooled in several meta-analyses. The available evidence .. (Supplementary Table 2) indicates that a routine invasive strategy: 5.4.9 Recommendations for bleeding management and .. blood transfusion in non-ST-segment elevation acute cor- .. • Does not reduce all-cause mortality risk in the overall population .. onary syndromes for anticoagulated patients . of NSTE-ACS patients. Recommendations for bleeding management and blood transfusion in non-ST-segment elevation acute coronary syn- dromes for anticoagulated patients Recommendations Classa Levelb In patients with dabigatran-associated ongoing life-threatening bleeding, the administration of the specific antidote for dabigatran IIa B idarucizumab should be considered.264 In patients with VKA-associated life-threatening bleeding events, rapid reversal of anticoagulation with four-factor prothrombin complex concentrate rather than with fresh frozen plasma or recombinant activated factor VII should be considered. IIa C In addition, repetitive 10 mg i.v. doses of vitamin K should be administered by slow injection. In patients with NOAC-associated ongoing life-threatening bleeding, the administration of prothrombin complex concentrates or IIa C activated prothrombin complex concentrates should be considered when the specific antidote is unavailable. In patients with rivaroxaban-, apixaban-, or edoxaban-associated ongoing life-threatening bleeding, the administration of the spe- IIb B cific antidote andexanet-alpha may be considered.265 In patients with anaemia and no evidence of active bleeding, blood transfusion may be considered in case of compromised haemo- IIb C dynamic status, haematocrit <25%, or haemoglobin level <8 g/dL. i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; VKA = vitamin K antagonist. a Class of recommendation. b Level of evidence. ESC Guidelines 1323 .. • Increases the risk of periprocedural complications such as peri- .. perform revascularization is recommended, irrespective of ECG or procedural MI and bleeding. .. biomarker findings. Centres without 24/7 PCI availability must trans- .. • Reduces the risk of composite ischaemic endpoints, particularly .. fer the patient immediately. in high-risk patients. .. .. However, the currently available evidence is based on old RCTs .. 6.1.2.2 Early invasive strategy (<24 h) .. An early invasive strategy is defined as coronary angiography that were conducted before critical improvements such as radial .. access, modern drug-eluting stents (DES), complete functional revas- .. performed within 24 h of hospital admission. It is recommended in .. high-risk patients defined according to Figure 9. Multiple RCTs have cularization for multivessel CAD, modern DAPT, intensified lipid .. .. investigated the optimal timing of ICA and revascularization in NSTE- lowering therapy, and contemporary biomarker assays and/or cut-off .. ACS (Figure 10, Supplementary Table 3). A main limitation for the values for diagnosing spontaneous/periprocedural MI became .. .. interpretation of these RCTs is the calculation of time to ICA, which available. .. rather than being based on pain onset or on hospital admission time, .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 In summary, the results of RCTs and their meta-analyses highlight .. was based on randomization time. While ICA was virtually always the role of risk stratification in the decision process and support a .. performed within 24 h of randomization in the early invasive strategy routine invasive strategy in high-risk patients. .. .. groups, the time from randomization to ICA was more heterogene- .. ous in the delayed invasive groups (Figure 10). The two largest RCTs, .. .. with more than 1000 patients in each treatment group, are Timing of 6.1.2 Timing of invasive strategy .. Intervention in Patients with Acute Coronary Syndromes (TIMACS) 6.1.2.1 Immediate invasive strategy (<2 h) .. .. and the more contemporary VERDICT trial.271,272 There are several Very high-risk NSTE-ACS patients (i.e. with at least one very high- .. important messages that can be derived from these RCTs: risk criterion according to Figure 9) have generally been excluded .. .. from RCTs. Owing to a poor short- and long-term prognosis if left .. (1) Among unselected NSTE-ACS patients, an early invasive strategy is untreated, an immediate invasive strategy (i.e. <2 h from hospital .. not superior over a delayed invasive strategy with regard to compo- .. admission, analogous to STEMI management) with the intent to . site clinical endpoints (Supplementary Table 3).271,272 ©ESC 2020 Figure 9 Selection of non-ST-segment elevation acute coronary syndrome treatment strategy and timing according to initial risk stratification. EMS = emergency medical services; GRACE = Global Registry of Acute Coronary Events; MI = myocardial infarction; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; NSTEMI = non-ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention. Listen to the audio guide of this figure online. 1324 ESC Guidelines Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Figure 10 Time to coronary angiography in the early/immediate invasive and delayed invasive groups of included trials.271,272,279287 Bars depict inter- quartile ranges and median times from randomization to coronary angiography in the early invasive group (red) and delayed invasive group (blue). In addi- tion, description of the main finding of the primary endpoint with an early vs. delayed invasive strategy. Adapted and updated from Jobs et al.277 Based on the individual patient-based meta-analysis patients with elevated biomarkers, GRACE score >140, age >75 years, and diabetes showed a mortality benefit from an early invasive approach.277 ABOARD = Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes Randomized for an Immediate or Delayed Intervention; CK-MB = creatine kinase myocardial band; EARLY = Early or Delayed Revascularization for Intermediate- and High-Risk Non- ST-Segment Elevation Acute Coronary Syndromes?; ELISA = Early or Late Intervention in unStable Angina; GRACE = Global Registry of Acute Coronary Events; ISAR-COOL = Intracoronary Stenting and Antithrombotic Regimen - Cooling off strategy; LIPSIA-NSTEMI = Leipzig Immediate versus early and late PercutaneouS coronary Intervention triAl in NSTEMI; MACE = major adverse cardiovascular events; MI = myocardial infarction; PCI = percutaneous coronary intervention; RIDDLE-NSTEMI = Randomized Study of Immediate Versus Delayed Invasive Intervention in Patients With Non-ST-Segment Elevation Myocardial Infarction; SISCA = Comparison of Two Treatment Strategies in Patients With an Acute Coronary Syndrome Without ST Elevation; TIMACS = Timing of Intervention in Patients with Acute Coronary Syndromes; VERDICT = Very EaRly vs Deferred Invasive evaluation using Computerized Tomography. .. (2) Benefit with an early invasive strategy is strongly associated with the .. Several meta-analyses have pooled data of multiple RCTs assessing patient’s risk profile. In a pre-specified subgroup analysis, patients .. different timing intervals of ICA (Supplementary Table 4). None of .. with a GRACE risk score >140 benefited from an early invasive .. them observed a benefit with an early invasive strategy with respect strategy while those with a GRACE risk score <140 did not .. to the endpoints death, non-fatal MI, or stroke among unselected .. (TIMACS trial: HR 0.65, 95% CI 0.480.89 vs. HR 1.12, 95% CI .. NSTE-ACS patients.274278 However, a collaborative meta-analysis 0.811.56, Pinteraction = 0.01;271 VERDICT trial: HR 0.81, 95% CI .. comparing an early/immediate invasive to a delayed invasive strategy .. 0.671.00 vs. HR 1.21, 95% CI 0.921.60; Pinteraction = 0.02).272 .. using a modified individual patient data approach observed a survival With regard to the GRACE risk score, it must be highlighted that .. benefit in high-risk patients, although tests for interaction were incon- .. both RCTs calculated the original GRACE risk score for in-hospital .. clusive.277 Only the VERDICT trial studied the impact of timing on death (see Supplementary Figure 3).139 Due to different weighting of .. the endpoint hospital admission for heart failure and observed a .. variables, scores of other GRACE risk scores (see Supplementary .. trend towards less heart failure hospitalization in favour of an early Table 1 for more details) might be considerably different for the .. invasive strategy (HR 0.78, 95% CI 0.601.01).272Meta-analyses have .. same patient, possibly leading to different treatment decisions. .. consistently reported that an early invasive strategy is associated with Furthermore, in both studies, GRACE risk score calculation was .. a lower risk of recurrent/refractory ischaemia and a shorter length of .. based on elevations of CK-MB or conventional troponin. The value .. hospital stay.274276,278 Taken together, an early invasive strategy is of a GRACE risk score >140 to guide timing of ICA and revasculari- .. .. recommended in patients with at least one high-risk criterion zation in the era of hs-cTn has not been determined. .. (Figure 9). .. (3) Benefit with an early invasive strategy is not modified by ST- .. segment/T-wave changes, despite the fact that ST-segment depres- .. 6.1.2.3 Selective invasive strategy .. sion has been consistently identified as a predictor for an adverse .. Patients with no recurrence of symptoms and none of the very high- outcome (Supplementary Figure 2). .. or high-risk criteria listed in the recommendation table regarding tim- .. .. ing of invasive strategy are to be considered at low risk of short-term In patients with transient ST-segment elevation and relief of symp- .. acute ischaemic events (Figure 9). These patients should be managed .. toms, an immediate invasive strategy did not reduce CMR-assessed .. according to the 2019 ESC Guidelines for the diagnosis and manage- infarct size compared to an early invasive strategy.273 .. ment of CCS.231 In this setting, stress echocardiography or stress ESC Guidelines 1325 .. CMR may be preferred over non-invasive anatomical testing.109 With .. most common presentation.292 There are three angiographic types routine use of hs-cTn and established diagnostic algorithms for .. of SCAD, which range from no obstruction to complete occlusion of .. NSTE-ACS assessment, ongoing myocardial injury even low level .. the affected coronaries. SCAD Type 1 (contrast dye staining of the can be identified. Therefore, patients previously regarded to be at .. arterial wall with multiple radiolucent lumen) and SCAD Type 2 .. intermediate risk (e.g. those with a history of revascularization or dia- .. (long diffuse and smooth narrowing) with non-obstructive coronary betes mellitus), but ruled out according to a diagnostic algorithm .. arteries (stenosis <50%) are described as possible causes of MI with .. using hs-cTn, should be regarded as low risk and follow a selective .. non-obstructive coronary arteries (MINOCA) (see section 7), while invasive strategy.1 .. SCAD Type 2 with severe coronary obstruction (>50%) and SCAD .. .. Type 3 (focal or tubular stenosis that mimics atherosclerosis) should .. be considered separately. As SCAD may be missed or not be detect- 6.1.3 Pattern of coronary artery disease in .. non-ST-segment elevation acute coronary syndrome .. able on CCTA, a negative CCTA should not exclude a diagnosis of .. SCAD.293 Intracoronary imaging [optical coherence tomography (Supplementary Data) .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 .. (OCT) and intravascular ultrasound (IVUS)] might be the most accu- .. rate options in unclear situations to prove the presence of intramural .. 6.1.4 How to identify the culprit lesion? (Supplementary .. haematoma or double lumen.294 This may be fundamental to making Data) .. a proper diagnosis.294 .. .. The optimal management of SCAD is still unclear, since no RCTs .. have compared medical therapy to revascularization strategies. 6.1.5 Spontaneous coronary artery dissection ... Spontaneous coronary artery dissection (SCAD) is defined as a .. According to available data, with the exception of very high-risk pro- non-atherosclerotic, non-traumatic, or iatrogenic separation of the .. file patients, a conservative approach should be the preferred strat- .. coronary arterial tunics secondary to vasa vasorum haemorrhage or .. egy.295297 The decision to treat either with a conservative medical intimal tear, which creates a false lumen, coronary compression, and .. approach or to perform PCI or CABG surgery must be individualized .. downstream myocardial ischaemia.288,289 .. and based on both clinical and angiographic factors. A possible treat- SCAD accounts for up to 4% of all ACS, but the incidence is .. ment algorithm is shown in Figure 11. Optimal medical treatment for .. reported to be much higher (2235% of ACS) in women <60 years .. patients with SCAD is still undetermined, but because hypertension of age, in pregnancy-related MI, and in patients with a history of fibro- .. is an independent predictor of recurrent SCAD,292,295,298 an aggres- .. muscular dysplasia, anxiety, depression, or previous neuropsychiatric .. sive anti-hypertensive therapy should be considered to ensure opti- disorders.290,291 Clinical presentations can vary considerably, but ele- .. mal blood pressure control. Beta-blockers, which have been .. vation of cardiac biomarkers associated with chest discomfort is the . reported to be significantly associated with a reduced risk of ©ESC 2020 Figure 11 Diagnosis and treatment of patients with non-ST-segment elevation acute coronary syndrome related to spontaneous coronary artery dis- section. CABG = coronary artery bypass graft(ing); CAD = coronary artery disease; CCTA = coronary computed tomography angiography; DAPT = dual antiplatelet therapy; ICA = invasive coronary angiography; IVUS = intravascular ultrasound; OCT = optical coherence tomography; OMT = optimal medi- cal therapy; PCI = percutaneous coronary intervention; SCAD = spontaneous coronary artery dissection. aSelection of revascularization strategy for high- risk anatomy according to local expertise. bBeta-blocker recommended while benefit of DAPT is questionable. cLeft main or proximal left anterior descendent or circumflex or right coronary artery, multivessel SCAD. Listen to the audio guide of this figure online. 1326 ESC Guidelines .. recurrent events, should be the preferred antihypertensive class in .. Clinically driven target lesion revascularization or definite stent this subset of patients.298 There is controversy regarding the benefit .. thrombosis was lower with the IVUS-guided strategy [1.2 vs. 2.6%, .. of antithrombotic therapy among these patients,292,298 however, .. relative risk (RR) 0.46, 95% CI 0.211.03, P¼0.05]. However, only among PCI-treated patients, the DAPT algorithms stated in section 5 .. 12% of the enrolled patients presented with STEMI or NSTE-ACS, .. should be used. Among SCAD patients treated medically and having .. limiting its validity in NSTE-ACS settings.313 persistent or recurrent symptoms, even in the absence of recurrent .. OCT-guided PCI is safe and results in a similar minimum stent area .. MI or ischaemia, CCTA might be considered for follow-up. .. to that of IVUS-guided PCI.314 In addition, OCT-guided PCI has been .. shown to lead to higher post-PCI FFR compared to angio-guided PCI .. .. among NSTE-ACS patients.315 Adequately powered trials for clinical 6.1.6 Fractional flow reserve, instantaneous wave-free .. endpoints, however, are lacking. Additionally, in patients with ratio, and other resting indices (Supplementary Data) .. .. MINOCA (see section 7), OCT is a diagnostic tool for evaluating 6.1.6.1 Fractional flow reserve .. SCAD, erosions, and plaque ruptures.312 .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Fractional flow reserve (FFR) is the current standard for the .. functional assessment of lesion severity in patients with intermediate- .. grade stenosis (4090%) without evidence of ischaemia in non- .. 6.2 Conservative treatment .. The established benefit associated with coronary revascularization in invasive testing, or in those with multivessel disease. Due to .. microvascular obstruction,299 the haemodynamic relevance of the .. NSTE-ACS patients has led to a significant reduction of medical man- .. agement alone, from 60% two decades ago down to 1030% in the culprit lesion in NSTE-ACS may be underestimated.300 However, it .. appears reliable for non-culprit lesion estimation when compared to .. contemporary era of PCI.170,225,316319 Medical management com- .. prises patients not undergoing coronary angiography, but also those postponed repeat FFR, CMR perfusion, or SPECT.301304 In ACS .. patients, deferred revascularization based on FFR or instantaneous .. with extensive CAD not amenable to revascularization or those .. without obstructive CAD (see MINOCA, section 7). wave-free ratio (iFR) is associated with worse clinical outcome com- .. pared to patients with stable CAD.305308 Persistent instability of .. .. non-haemodynamically significant stenoses or presence of more than .. 6.2.1 Patients who are not candidates for invasive one unstable lesion may account for the higher risk. .. .. coronary angiography The majority of the evidence relating to the value of FFR in NSTE- .. This group represents a small subgroup, where data indicating a ACS is derived from small subgroups of registries and randomized tri- .. .. hypothetical advantage of an invasive strategy are scarce. Depending als (Supplementary Table 5). In the small Fractional flow reserve versus .. on country and world region specific differences, advanced age, angiography in guiding management to optimize outcomes in non- .. .. female sex, chronic kidney disease (CKD), diabetes mellitus, prior ST-elevation myocardial infarction (FAMOUS-NSTEMI) randomized .. heart failure/revascularization, history of cancer, and frailty are the trial,309 significantly more NSTEMI patients were treated medically .. .. major reported reasons accounting for withholding diagnostic with FFR vs. an angio-guided PCI strategy (22.7 vs. 13.2%, P¼0.022). .. ICA.170,225,316,318,319 These features largely overlap with the predic- .. This strategy of functional revascularization seems to be safe without .. tors of bleeding and ischaemic adverse events320 and explain the any impact on clinical outcomes in NSTE-ACS. However, adequately .. poor prognosis of this population, with in-hospital mortality of 69% .. powered dedicated randomized trials are still lacking. .. that rises up to 20 and 50% at 6 months and 3 years, respectively.321 .. Medical management should be chosen after careful risk assessment, .. 6.1.6.2 Instantaneous wave-free ratio and other resting indices .. keeping in mind that ICA using the radial approach is a low-risk pro- There has been renewed interest in resting indices derived from rest- .. cedure, that impaired LV function increases mortality risk, and that .. ing gradients alone [distal coronary to aortic pressure ratio (Pd/Pa), .. coronary anatomy and presence of diabetes may refine the risk strati- iFR, coronary flow reserve (CFR), resting full-cycle ratio (RFR), or .. fication and the choice of pharmacological therapy (see Figures 57). .. the index of microcirculatory resistance (IMR)]. Two large-scale .. Advanced age or female sex alone, in the absence of severe comor- randomized trials showed broadly comparable results between FFR- .. bidities or frailty, should not be considered as a sufficient reason not .. guided and iFR-guided revascularization strategies in patients with .. to perform ICA and, likewise, ICA should not be denied for logistical intermediate-grade stenosis.310,311 In these trials, the proportion of .. 322,323 .. reasons. ACS patients was 1517%, the non-culprit lesions were investigated, .. and follow-up was limited to a 1-year duration. For resting indices .. .. 6.2.2 Patients with coronary artery disease not amenable other than iFR, randomized clinical outcome data are not available. .. .. to revascularization .. Patients diagnosed with severe CAD who are not amenable to any .. 6.1.7 Intracoronary imaging .. type of revascularization are at very high risk of recurrent ischaemic Both intracoronary imaging methods, IVUS and OCT, allow real-time .. events.324 Frequently, these patients are women, old and/or suffering .. tomographic assessment of vessel size, lumen area, plaque composi- .. from severe CKD, with multivessel CAD, and a history of MI or prior tion and volume, as well as stent coverage and expansion.312 .. revascularization. The decision not to perform PCI is an independent .. IVUS-guided PCI has been reported to reduce target vessel failure .. predictor of increased cardiovascular mortality, both in-hospital and 12 months after PCI compared to angio-guided PCI in the .. long-term.188,318 Accordingly, the decision not to perform revascula- .. Intravascular Ultrasound Guided Drug Eluting Stents Implantation in .. rization should be made in very selected patients only, where there is “All-Comers” Coronary Lesions (ULTIMATE) randomized trial: 2.9 .. consensus that risk outweighs the benefit for clinical or anatomical .. vs. 5.4%, respectively (HR 0.53, 95% CI 0.310.90, P¼0.019).313 . reasons. These patients should undergo an aggressive secondary ESC Guidelines 1327 .. prevention treatment with potent antiplatelet therapy (see .. stage complete revascularization can be reduced by staged complete Figures 58) and anti-anginal agents, taking their comorbidities into .. revascularization needs to be further evaluated. .. account.325,326 .. In contrast to the STEMI setting,342344 there is only one dedi- .. cated randomized trial examining the role of single vs. staged multi- .. 6.3 Technical aspects .. vessel PCI in NSTE-ACS patients [Impact of Different Treatment in .. Multivessel Non ST Elevation Myocardial Infarction Patients: One 6.3.1 Technical aspects and challenges .. The principal technical aspects of PCI in NSTE-ACS patients do not .. Stage Versus Multistaged Percutaneous Coronary Intervention .. (SMILE) trial].345 The complete single-stage coronary revasculariza- differ from the invasive assessment and revascularization strategies .. for other manifestations of CAD. In patients presenting with NSTE- .. tion resulted in less major adverse cardiovascular and cerebrovascu- .. lar events (defined as cardiac death, death, reinfarction, ACS who are deemed eligible for PCI in one or more vessels, implan- .. tation of new-generation DES is the standard of care,159,327,328 while .. rehospitalization for unstable angina, repeat coronary revasculariza- .. tion, and stroke at 1 year) compared to complete coronary revascu- routine thrombectomy has not been proven beneficial in this set- .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 ting.329,330 The combination and duration of antithrombotic treat- .. larization in multistage PCI during the index hospitalization (HR 0.55, .. 95% CI 0.360.83, P¼0.004).345 This benefit was largely determined ment are explained in section 5. .. .. by a significant reduction in repeat revascularization with single-stage .. multivessel PCI (HR 0.52, 95% CI 0.310.88, P¼0.01).345 However, 6.3.2 Vascular access .. .. since pursuing completeness of revascularization for some patients A timely performance of PCI and the use of potent antithrombotic .. with complex coronary anatomy may increase the risk of PCI or drugs have reduced ischaemic risk in patients with NSTE-ACS. .. .. require CABG, it is reasonable, in the absence of robust clinical data, However, this strategy is also invariably associated with an increased .. to tailor the need for, and timing of, complete revascularization to bleeding risk, which affects prognosis at least as much as ischaemic .. .. functional relevance of all stenoses, age, general patient condition and complications and is associated with impaired survival.331333 Among .. .. comorbidities, and LV function. Furthermore, selection of the revas- patients undergoing PCI, access-related bleeding accounts for .. cularization modality may rely on patient preference. For NSTE-ACS 3070% of total bleeding events.334 There is accumulative evidence .. .. patients presenting with CS, randomized evidence does not support showing that reducing access-site bleeding events with the use of .. routine immediate multivessel PCI (see details in section 8.1).346 radial access translates into significant clinical benefits. Two large .. .. randomized trials, the RadIal Vs femorAL access for coronary inter- .. vention (RIVAL) trial (n=7021 ACS patients) and the MATRIX trial .. 6.4 Coronary artery bypass grafting .. Approximately 510% of NSTE-ACS patients require CABG347 and (n=8404 ACS patients)335,336 have demonstrated significantly lower .. rates of access site-related bleeding, surgical access site repair, and .. these represent a challenging subgroup given their high-risk charac- .. teristics compared with patients undergoing elective CABG. In the blood transfusion with radial compared to femoral access. A pairwise .. meta-analysis comparing radial vs. femoral access in the whole spec- .. absence of randomized data, optimal timing for non-emergency .. CABG in NSTE-ACS patients should be determined individually.348 trum of patients with CAD, including 30-day follow-up of the .. MATRIX trial, showed a significant reduction in major bleeds; death, .. The risk of ischaemic events, possibly related to suboptimal antiplate- .. let therapy while awaiting surgery, is less than 0.1%, while periopera- MI, or stroke; and all-cause mortality favouring radial vs. femoral .. access.337 Although this effect was diluted at 1-year follow-up, net .. tive bleeding complications associated with platelet inhibitors is .. higher than 10%.349 In patients with ongoing ischaemia or haemody- clinical adverse events remained lower with a radial vs. femoral access .. site.336 Therefore, radial access is recommended as the preferred .. namic instability and with an indication for CABG, emergency surgery .. approach in NSTE-ACS patients undergoing invasive assessment with .. should be performed and not postponed as a consequence of antipla- or without PCI. However, dependent on their haemodynamic situa- .. telet treatment exposure. .. tion during index PCI and procedural technical aspects, femoral .. If CABG is to be performed, every effort should be made to mini- access might be selectively chosen instead of radial access. .. mize aortic manipulation, work off-pump if there is a calcified aorta .. .. or the patient is high risk, achieve complete revascularization, and use .. graft flow measurement. 6.3.3 Revascularization strategies .. .. Based on observational studies of patients with NSTE-ACS, the bene- .. fit of early intervention when compared to a conservative .. 6.5 Percutaneous coronary intervention .. approach may mandate a complete revascularization strategy, irre- .. vs. coronary artery bypass surgery spective of the possibility to identify and/or treat the culprit .. There is no randomized comparison of PCI vs. CABG surgery in the .. lesion.268,277,338340 Recently, data from the British Cardiac .. specific setting of NSTE-ACS. In the individual patient data analysis Intervention Society PCI database showed significantly lower cumula- .. from the Randomized Comparison of Coronary Artery Bypass .. tive mortality rates with single-stage complete revascularization com- .. Surgery and Everolimus-Eluting Stent Implantation in the Treatment pared to culprit-lesion-only PCI (22.5 vs. 25.9%, P=0.0005) at a .. of Patients with Multivessel Coronary Artery (BEST), Premier of .. median follow-up of 4.1 years (interquartile range 2.25.8) among .. Randomized Comparison of Bypass Surgery versus Angioplasty 21 857 NSTE-ACS patients with multivessel CAD undergoing PCI. .. Using Sirolimus-Eluting Stent in Patients with Left Main Coronary .. This long-term benefit was observed despite an initial increase in in- .. Artery Disease (PRECOMBAT), and Synergy between PCI with hospital mortality with single-stage complete revascularization (2.3 .. Taxus and cardiac surgery (SYNTAX) trials, which compared PCI .. vs. 1.5%, P¼0.002).341 Whether this initial increased risk with single- . with CABG, of the 3280 patients with multivessel CAD or left main 1328 ESC Guidelines .. disease, only 77 patients (2.2%) presented with NSTEMI and 1169 .. delayed invasive strategy, as recently shown in the randomized patients (35.7%) presented with unstable angina.350 Among NSTE- .. Coronary Angiography after Cardiac Arrest (COACT) trial.278 This .. ACS patients, at 5-year follow-up, the risk of death, MI, or stroke was .. trial enrolled 552 patients who had been successfully resuscitated significantly reduced with CABG compared to PCI (HR 0.74, 95% CI .. after out-of-hospital cardiac arrest and had no signs of STEMI. No dif- .. 0.560.98, P¼0.036). The difference was driven by a reduction in MI .. ference in 90-day survival was observed between these two strat- rates with CABG (3.8% vs. 7.5%, HR 0.50, 95% CI 0.310.82, .. egies, 64.5% in the immediate vs. 67.2% in the delayed angiography .. P¼0.006).350 In a population-based analysis, the benefit of CABG .. strategy (OR 0.89, 95% CI 0.621.27, P=0.51).358 Therefore, it over PCI was confirmed in patients with diabetes who presented .. appears reasonable to delay performance of ICA among NSTE-ACS .. with ACS. At 3-year follow-up, the combined incidence of all-cause .. patients.358 However, several ongoing trials will further define a pos- death, non-fatal MI, or non-fatal stroke was lower with CABG com- .. sible benefit of an early invasive approach.359 .. pared with PCI (20.8 vs. 33.4%, P<0.01).351 Taken together, evidence .. In comatose survivors, echocardiography should be performed is limited from these aforementioned RCTs to support one revascu- .. immediately for further evaluation of differential diagnoses. If aortic .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 larization strategy over the other, especially in NSTEMI patients. .. dissection or pulmonary embolism is suspected, CT is Thus, the currently available evidence indirectly suggests that the .. recommended.360,361 .. criteria applied in patients with stable CAD to guide the choice of .. revascularization modality (2018 ESC/EACTS Guidelines on myocar- .. .. 6.7 Recommendations for coronary dial revascularization)205 should also be applied to stabilized patients .. with NSTE-ACS, particularly for patients with diabetes.350354 .. revascularization .. For complex cases, Heart Team discussion and use of the . SYNTAX score are recommended, particularly given its ability to predict death, MI, and revascularization in multivessel CAD NSTE- Recommendations for coronary revascularization ACS patients undergoing PCI.355 Furthermore, calculation of a Recommendations Classa Levelb Society of Thoracic Surgeons (STS) score is recommended to assess in-hospital or 30-day mortality, and in-hospital morbidity after CABG Timing of invasive strategy among high-risk patients.356 Clinical and anatomical characteristics in An immediate invasive strategy (<2 h) is recom- favour of CABG are considered to be diabetes, reduced LV ejection mended in patients with at least one of the follow- fraction (LVEF) (<40%), contraindications to DAPT, recurrent diffuse ing very high-risk criteria: in-stent restenosis, anatomical and technical aspects likely resulting in • Haemodynamic instability or CS. incomplete revascularization with PCI, and the need for concomitant • Recurrent or refractory chest pain despite cardiovascular surgery. Those in favour of PCI are clinical and ana- medical treatment. tomical characteristics, such as presence of severe comorbidity (not I C • Life-threatening arrhythmias. reflected by scores), advanced age/frailty or reduced life expectancy, • Mechanical complications of MI. restricted mobility, conditions that affect the rehabilitation process, • Heart failure clearly related to NSTE-ACS. anatomical and technical aspects likely resulting in incomplete revas- • Presence of ST-segment depression >1 mm cularization with CABG surgery due to poor quality or missing con- in >_6 leads additional to ST-segment eleva- duits, severe chest deformation or scoliosis, sequelae of chest tion in aVR and/or V1. radiation, and porcelain aorta. An early invasive strategy within 24 h is recom- mended in patients with any of the following high- 6.6 Specific situations risk criteria: 6.6.1 Management of patients with ongoing myocardial • Diagnosis of NSTEMI suggested by the diag- ischaemia nostic algorithm recommended in section 3. I A These patients are characterized by an overwhelming risk of develop- • Dynamic or presumably new contiguous ing STEMI, onset of life-threatening arrhythmias, acute heart failure, ST/T-segment changes suggesting ongoing and CS. They should undergo coronary angiography within 2 h of ischaemia. hospital admission with intent to perform revascularization. Based on • Transient ST-segment elevation.273,362 published data, this approach reduces in-hospital mortality and mor- • GRACE risk score >140.271,272,277 tality at early and mid-term follow-up,281,357 as well as reducing the A selective invasive strategy after appropriate risk of new MI in the pre-catheterization period and the length of ischaemia testing or detection of obstructive CAD I A hospital stay.278 by CCTA is recommended in patients considered at low risk.267,268,363 Delayed as opposed to immediate angiography 6.6.2 Management of patients with cardiac arrest should be considered among haemodynamically The management of patients presenting with resuscitated cardiac stable patients without ST-segment elevation suc- IIa B arrest and concomitant NSTE-ACS needs to be individualized cessfully resuscitated after out-of-hospital cardiac according to their haemodynamic and neurological status. arrest.358,364 In out-of-hospital cardiac arrest and no ST-elevation without CS, Continued an unselected immediate invasive strategy is not superior over a ESC Guidelines 1329 .. Technical aspects .. pathological conditions, with the latter including cardiac and extra- .. cardiac disorders.370 Compared with patients with obstructive CAD, Radial access is recommended as the standard .. approach, unless there are overriding procedural I A .. NSTE-ACS patients diagnosed with MINOCA are more likely to be .. younger and female, and less likely diabetic, hypertensive, or dyslipi- considerations.336,337 .. .. daemic,371,372 suggesting a predominant role of non-atherosclerotic- DES are recommended over bare-metal stents for .. related aetiologies and of unusual or usual risk factors like psychoso- any PCI irrespective of: .. .. cial aspects, insulin-resistance, and inflammation.373 However, all • Clinical presentation. .. .. studies assessing prognosis in patients with MINOCA are consider- • Lesion type. I A .. ably heterogeneous in terms of inclusion criteria, outcomes measure- • Planned non-cardiac surgery. .. .. ments, and length of follow-up; some report the prevalence of hard • Anticipated duration of DAPT. .. endpoints like mortality or reinfarction,374,375 but few report out- • Concomitant anticoagulant therapy.354,365,366 .. .. comes for both MINOCA and CAD populations.376 Although associ- Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 It is recommended to base the revascularization .. ated with better prognosis compared to patients with ACS patients strategy (ad hoc culprit lesion PCI/multivessel PCI/ .. with obstructive CAD,371,372,376379 MINOCA patients have a lower CABG) on the patient’s clinical status and comor- .. .. survival rate than healthy individuals matched for age and bidities, as well as their disease severity [i.e. the .. sex.371,372,376379 Of importance, this excess of adverse events has distribution and angiographic lesion characteristics I B .. .. been reported at both early and late follow-up.371,372,376379 (e.g. SYNTAX score)], according to the principles .. The term MINOCA has been broadly used in the past and is often for stable CAD.350 However, the decision on .. .. misclassified, limiting all aspects of disease description, management, immediate PCI of the culprit stenosis does not .. and treatment. Despite having a contemporary position statement require Heart Team consultation. .. .. from the ESC and the AHA, great variability exists in the manner in Complete revascularization should be considered .. .. which patients with suspected MINOCA are evaluated and in NSTE-ACS patients without CS and with multi- IIa C .. treated.380,381 The extent of the diagnostic and therapeutic strategies vessel CAD. .. .. implemented often depends on local non-standardized practices and Intracoronary imaging should be considered to IIa C .. varies widely. diagnose SCAD if suspected. .. .. The ESC position statement on MINOCA proposed the following Complete revascularization during index PCI may .. MINOCA criteria:380 IIb B .. be considered in NSTE-ACS patients with multi- .. vessel disease.345 .. (1) AMI criteria as defined by the ‘Third universal definition of MI’.369 .. (2) Non-obstructive coronary arteries as per angiographic guidelines, FFR-guided revascularization of a non-culprit .. NSTE-ACS lesion may be used during index IIb B .. with no lesions >_50% in a major epicardial vessel. .. (3) No other clinically overt specific cause that can serve an alternative PCI.302 .. .. cause for the acute presentation. CABG = coronary artery bypass graft(ing); CAD = coronary artery disease; .. CCTA = coronary computed tomography angiography; CS = cardiogenic shock; .. Based on this ESC definition, myocarditis and Takotsubo syn- DAPT = dual antiplatelet therapy; DES = drug-eluting stent; FFR = fractional flow .. reserve; GRACE = Global Registry of Acute Coronary Events; MI = myocardial .. drome patients, among other non-ischaemic conditions, were .. labelled as MINOCA.380 infarction; NSTEMI = non-ST-segment elevation myocardial infarction; NSTE- .. ACS = non-ST-segment elevation acute coronary syndrome; PCI = percutaneous .. However, fundamental to the definition of MINOCA is the diagno- coronary intervention; SCAD = spontaneous coronary artery dissection; .. sis of MI with elevated cardiac biomarkers, typically cardiac troponin SYNTAX = Synergy between PCI with Taxus and cardiac surgery. .. a Class of recommendation. .. >99th percentile of the upper reference level with a rise or fall in the b Level of evidence. .. level on serial assessment. Although elevated troponin levels are indi- .. .. cative of myocyte injury with release of this intracellular protein into .. the systemic circulation, the process is not disease specific and can .. .. result from either ischaemic or non-ischaemic mechanisms. .. .. Therefore, the most recent scientific statement from the AHA 7 Myocardial infarction with .. provides a formal and updated definition for the broadly labelled .. non-obstructive coronary arteries .. term MINOCA incorporating the Fourth Universal Definition of .. Myocardial Infarction.381 Table 14 provides the current criteria for and alternative diagnoses .. .. the MINOCA definition, which by consensus now excludes myocar- Although the occurrence of an AMI without significant CAD was ini- .. ditis and Takotsubo syndrome from the final diagnosis of .. tially reported almost 80 years ago,367 and outcomes were definitely .. MINOCA.381 Interestingly, in some patients, Takotsubo syndrome described 13 years ago,368 the term MINOCA has only been used .. may be triggered by NSTEMI or STEMI.382 Furthermore, with regard .. recently to describe these patients.369 Accordingly, MINOCA is ini- .. to Takotsubo syndrome, there are no RCTs to support a specific tially considered at the time of angiography as a working diagnosis .. treatment and, therefore, all recommendations so far are based on .. until further assessment excludes other possible causes for troponin .. expert opinions.383 elevation. This incorporates a heterogeneous group of underlying .. It also provides a clinically useful framework and algorithms per- .. causes that may involve both coronary and non-coronary .. taining to the diagnostic evaluation and management of these . 1330 ESC Guidelines Table 14 Diagnostic criteria of myocardial infarction with non-obstructive coronary arteries The diagnosis of MINOCA is made in patients with AMI fulfilling the following criteria: 1. AMI (modified from the ‘Fourth Universal Definition of Myocardial Infarction’ criteria): • Detection of a rise or fall in cardiac troponin with at least one value above the 99th percentile upper reference limit and • Corroborative clinical evidence of infarction as shown by at least one of the following: a. Symptoms of myocardial ischaemia b. New ischaemic electrocardiographic changes c. Development of pathological Q waves d. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischae- mic cause e. Identification of a coronary thrombus by angiography or autopsy Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 2. Non-obstructive coronary arteries on angiography: • Defined as the absence of obstructive disease on angiography (i.e. no coronary artery stenosis >_50%) in any major epicardial vessela This includes patients with: • Normal coronary arteries (no angiographic stenosis) • Mild luminal irregularities (angiographic stenosis <30% stenoses) • Moderate coronary atherosclerotic lesions (stenoses >30% but <50%) 3. No specific alternate diagnosis for the clinical presentation: • Alternate diagnoses include, but are not limited to, non-ischaemic causes such as sepsis, pulmonary embolism, and myocarditis AMI = acute myocardial infarction; MINOCA = myocardial infarction with non-obstructive coronary arteries. a Note that additional review of the angiogram may be required to ensure the absence of obstructive disease. .. patients, which mainly includes a ‘traffic light’ clinical algorithm .. demand or elevation of cardiac troponin should be considered as (Figure 12). .. potential causes of myocardial injury, such as hypertensive crisis, .. Based on the initial working diagnosis, proper initial assessment of .. tachyarrhythmias, sepsis, severe anaemia, and cardiac contusion, LV wall motion should be promptly performed in the acute setting .. among others. .. using LV angiography, depending on renal function, or echocardiogra- .. Patients with an initial diagnosis of MINOCA, and an underlying phy. Regional wall motion abnormalities may indicate an epicardial .. cause identified during the diagnostic work-up, should be treated and .. cause of MINOCA or other specific causes, which may lead to the .. followed up according to the guidelines of the specific diagnosis. For exclusion of MINOCA. CMR is one of the key diagnostic tools in this .. example, MINOCA patients discharged with a final diagnosis of .. algorithm for the differential diagnosis of Takotsubo syndrome,384 .. NSTE-ACS or MINOCA of unknown cause should be followed up as myocarditis,385,386 or true MI.387 CMR has the ability to identify the .. ACS patients with obstructive CAD. .. underlying cause in as many as 87% of patients with MINOCA.388 In .. However, despite optimal work-up, the cause of MINOCA the sub-endocardium, late gadolinium enhancement may indicate an .. remains undetermined in 825% of patients.5,380,395 This condi- .. ischaemic cause, while sub-epicardial localization may indicate cardio- .. tion, identified as ‘myocardial infarction of unknown/unclear myopathies or myocarditis, and the absence of relevant late gadoli- .. causes’, represents a therapeutic dilemma. Treatment should tar- .. nium enhancement with oedema and associated specific wall motion .. get the most probable causes of MINOCA, with negative provoca- abnormalities is a hallmark of Takotsubo syndrome.387,388 In a meta- .. tive tests and CMR, namely vasospastic angina, coronary plaque .. analysis of five studies involving 556 patients with an initial diagnosis .. disruption, and thromboembolism. The benefit of DAPT (aspirin of MINOCA, CMR identified myocarditis as the primary cause in 33% .. þ P2Y12 receptor inhibitor) should be considered based on .. of patients.389 .. pathophysiological considerations. However, evidence is scarce. Intracoronary acetylcholine or ergonovine testing may be per- .. Pharmacological therapy with aspirin, statins, angiotensin- .. formed when coronary or microvascular spasm is suspected.390,391 .. converting enzyme (ACE) inhibitors/angiotensin receptor block- .. Intracoronary imaging with IVUS392 or OCT393,394 may also be valua- .. ers (ARBs), and calcium channel blockers (in case vasospasm is still ble for the detection of unrecognized causes at coronary angiogra- .. suspected) as routine treatment may be suggested.396 These medi- .. phy, especially when thrombus, plaque rupture or erosion, or SCAD .. cations have shown significant long-term beneficial effects in terms are suspected. .. of all-cause mortality (statins, beta-blockers), cardiovascular death .. Pulmonary embolism should also be considered as an alternative .. (statins), AMI (beta-blockers), stroke (statins), and MACE (statins, diagnosis as a possible cause of myocardial injury, and this diagnosis .. ACE inhibitor/ARB) at 12 months in a national registry.397 .. may be excluded with additional D-dimer testing, BNP, and/or CT .. However, this registry did not apply current MINOCA criteria,397 pulmonary angiography,361 as appropriate. Furthermore, other con- .. therefore, the conclusions drawn must be interpreted with .. ditions with an imbalance between myocardial oxygen supply and .. caution. . ESC Guidelines 1331 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Figure 12 Diagnostic algorithm for myocardial infarction with non-obstructive coronary arteries using a traffic light scheme. Red indicates immediate alternative diagnosis without further additional testing. Yellow indicates initial working diagnosis that may lead to the final MINOCA diagnosis or alternative diagnoses. Green indicates final MINOCA diagnosis. CAD = coronary artery disease; IVUS = intravascular ultrasound; MINOCA = myocardial infarction with non-obstructive coronary arteries; CMR = cardiac magnetic resonance; Echo = echocardiogram; LV = left ventricular; OCT = optical coherence tomography; SCAD = spontaneous coronary artery dissection; ULN = upper limit of normal. Listen to the audio guide of this figure online. Recommendations for myocardial infarction with non-obstructive coronary arteries Recommendations Classa Levelb In all patients with an initial working diagnosis of MINOCA, it is recommended to follow a diagnostic algorithm to differentiate true I C MINOCA from alternative diagnoses. It is recommended to perform CMR in all MINOCA patients without an obvious underlying cause.370 I B It is recommended to manage patients with an initial diagnosis of MINOCA and a final established underlying cause according to the I C disease-specific guidelines. Patients with a final diagnosis of MINOCA of unknown cause may be treated according to secondary prevention guidelines for athe- IIb C rosclerotic disease. CMR = cardiac magnetic resonance; MINOCA = myocardial infarction with non-obstructive coronary arteries. a Class of recommendation. b Level of evidence. .. 8 Special populations .. mortality compared with NSTE-ACS without acute heart .. failure.398401 .. 8.1 Heart failure and cardiogenic shock .. The diagnosis of NSTE-ACS in the context of acute heart failure Acute heart failure is a frequent complication of NSTE-ACS and is .. can be challenging because patients with acute heart failure may .. associated with a two to four-fold higher risk of in-hospital . present with chest discomfort, myocardial injury with troponin 1332 ESC Guidelines elevation can occur in the absence of obstructive CAD,3 and the .. Recommendations for non-ST-segment elevation acute ECG may not be interpretable (bundle branch block or paced .. coronary syndrome patients with heart failure or car- .. diogenic shock rhythm).402 Consequently, coronary angiography may be required to .. .. establish a diagnosis of NSTE-ACS. .. Recommendations Classa Levelb The management of acute heart failure should follow current .. .. Emergency coronary angiography is recom- guideline recommendations.403,404 Emergency echocardiography .. should be performed to gather information about the LVEF, regional .. mended in patients with CS complicating I B .. ACS.205,416,417 wall motion abnormalities, right ventricular function, presence of .. valvular heart disease, and volume loading.96,205,405 The revasculariza- .. Emergency PCI of the culprit lesion is recommended .. tion strategy should be based on the coronary anatomy, LV function, .. for patients with CS due to NSTE-ACS, independent I B comorbidities, functional relevance of stenoses, and estimated surgi- .. of the time delay from symptom onset, if the coro- .. cal risk according to a Heart Team consensus, and based upon cur- .. nary anatomy is amenable to PCI.205,417 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 rent recommendations.205 .. Emergency CABG is recommended for patients .. CS may occur in up to 4% of patients with NSTE-ACS.406,407 .. with CS if the coronary anatomy is not amenable I B Ischaemia-related heart failure, acute severe mitral regurgitation, and .. to PCI.205,417 .. mechanical complications are the major precipitating causes. These .. It is recommended to perform emergency echocar- patients should be transferred, as soon as possible, to a tertiary care .. .. diography without delay to assess LV and valvular I C centre where ICA can be performed. In hub centres, immediate cor- .. function and exclude mechanical complications. onary angiography is indicated and PCI should be performed. Nearly .. .. In cases of haemodynamic instability, emergency 80% of such patients have multivessel CAD. Based on the Culprit .. surgical or catheter-based repair of mechanical Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock .. I C .. complications of ACS is recommended, as (CULPRIT-SHOCK) trial,408 non-culprit lesions should not be rou- .. decided by the Heart Team. tinely treated immediately, and the immediate PCI strategy should be .. .. For NSTE-ACS-related mechanical complications, limited to the culprit lesion only. In CULPRIT-SHOCK, culprit-lesion- .. IIa C only PCI led to a significant reduction in all-cause death or renal- .. the use of IABP should be considered. .. In selected patients with ACS and CS, short-term replacement therapy at 30-day follow-up, favouring culprit-lesion- .. .. mechanical circulatory support may be consid- only PCI with possible staged revascularization [RR 0.83, (95% CI .. ered, depending on patient age, comorbidities, IIb C 0.710.96)].408 The risk of all-cause death in the culprit-lesion-only .. .. neurological function, and the prospects for long- PCI strategy was significantly lower compared to immediate multives- .. term survival and predicted quality of life. sel PCI at 30-day follow-up (RR 0.84, 95% CI 0.720.98, P¼0.03). .. .. Routine use of IABP in patients with CS and no Results for the composite endpoint were maintained at 1-year .. mechanical complications due to ACS is not III B follow-up, whereas the mortality difference was mainly confined to .. .. recommended.413,414,415 the first 30 days.346,408 .. In patients with a coronary anatomy not suitable for PCI, emer- .. Routine immediate revascularization of non-cul- .. prit lesions in NSTE-ACS patients with multivessel gency CABG is indicated. .. III B Percutaneous mechanical circulatory support devices and/or .. disease presenting with CS is not .. recommended.346,408 venoarterial extracorporeal membrane oxygenation may be consid- .. ered in selected patients, depending on age, comorbidities, neurologi- .. ACS = acute coronary syndromes; CABG = coronary artery bypass graft(ing); .. cal function, and severity of CS. Several RCTs are ongoing .. CS = cardiogenic shock; IABP = intra-aortic balloon pump; LV = left ventricular; (Supplementary Table 6). Currently, no survival benefit has been dem- .. NSTE-ACS = non-ST-segment elevation acute coronary syndrome; PCI = percu- .. taneous coronary intervention. onstrated for these devices compared with intra-aortic balloon a .. Class of recommendation. pump (IABP) use.409,410 Moreover, in a large retrospective registry of b .. Level of evidence. .. 48 306 haemodynamically unstable patients (44% NSTEMI) under- .. going PCI, higher mortality and bleeding rates were observed with .. .. Impella support compared to IABP.411 Similar results were observed .. 8.2 Diabetes mellitus .. in another registry confined to CS patients where Impella support .. Patients with diabetes more frequently present with non-typical was also associated with more complications and higher mortality, .. symptoms than patients without diabetes. They more frequently .. even after propensity matching.412 .. have multifocal CAD,418 less frequently receive guideline-indicated As shown in the Intraaortic Balloon Pump in cardiogenic shock .. care, and have worse clinical outcomes.419 Nonetheless, the selec- .. (IABP-SHOCK) II trial, IABP does not reduce 30-day, 1-year, or 6- .. tion of antithrombotics and an invasive strategy should not differ year mortality.413415 Therefore, IABP is not recommended on a .. from those without diabetes. Compared with clopidogrel, more .. routine basis, while its use in situations of ACS-related mechanical .. potent platelet inhibitors have higher absolute risk reductions in complications should be considered. .. patients with diabetes.420,421 .. For NSTE-ACS and stabilized heart failure, evidence-based phar- .. On admission to hospital, it is recommended that all patients with macotherapies including beta-blockers, ACE inhibitors or ARBs, and .. NSTE-ACS have their glycaemic status evaluated, regardless of a his- .. mineralocorticoid receptor antagonists (MRAs) should be offered in .. tory of diabetes, and for it to be monitored frequently in patients keeping with current guidelines.404 .. with diabetes or hyperglycaemia. Given that, during the acute phase ESC Guidelines 1333 .. of NSTEMI, there may be hyperglycaemia, there is the potential for a .. Hs-cTn assays maintain high diagnostic and prognostic accuracy false positive diagnosis of diabetes. Therefore, the diagnosis of diabe- .. and, therefore, clinical utility in patients with renal dysfunction.35,89,439 .. tes should be confirmed subsequent to the hospital stay. In critically .. A threshold of <5 ng/L may rule out myocardial injury in this popula- ill patients, there is a risk of hypoglycaemia-related events when using .. tion.89 Moreover, patients with troponin concentrations >99th per- .. intensive insulin therapy.422 It is not unreasonable to manage hyper- .. centile have a two-fold greater risk of cardiac events at 1 year, glycaemia in patients with NSTE-ACS by keeping their blood glucose .. irrespective of the diagnosis.89 .. concentration <11.0 mmol/L or <200 mg/dL) while avoiding hypogly- .. Patients with advanced kidney disease are less likely to receive an caemia, but intensive insulin therapy should not routinely be offered .. invasive strategy.440 Whilst the overall 1-year mortality is lower with .. unless clinically indicated. Intensive lipid modification is indicated for .. an invasive strategy, the benefit of such a strategy declines with secondary prevention.423 A multifactorial approach to diabetes melli- .. greater reductions in renal function, and with no impact on mortality .. tus management, with treatment targets, should be considered in .. among patients with eGFR <15 mL/min/1.73m2 and in those receiv- patients with diabetes mellitus and cardiovascular disease (CVD). .. ing dialysis. .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 .. When an invasive strategy is selected, measures should be taken .. to prevent contrast-induced nephropathy, for which adequate hydra- .. Recommendations for diabetes mellitus in non-ST-seg- .. tion is the main approach.441446 High-dose statins, irrespective of ment elevation acute coronary syndrome patients .. the risk of contrast-induced nephropathy, are indicated for secondary .. Classa Levelb .. prevention.442 For detailed recommendations for contrast-induced Recommendations .. .. nephropathy prevention, consult the 2018 ESC/EACTS Guidelines It is recommended to screen all patients with .. on myocardial revascularization, section 10.2.205 NSTE-ACS for diabetes and to monitor blood glu- .. I C .. The choice and dose of antithrombotic drugs should be carefully cose levels frequently in patients with known dia- .. considered in patients with CKD, as these patients have an betes or admission hyperglycaemia. .. .. increased risk of bleeding. While most anticoagulants need dose Avoidance of hypoglycaemia is .. adjustment in patients with renal insufficiency, this is not the case for I B .. recommended.424427 .. oral antiplatelet agents.447 However, for patients with stage 5 CKD Glucose-lowering therapy should be considered .. (i.e. eGFR <15 mL/min/1.73 m2), there are insufficient safety and effi- .. in ACS patients with blood glucose >10 mmol/L . cacy data for the use of P2Y12 receptor inhibitors. (>180 mg/dL), with the target adapted to comor- IIa B ... .. bidities, while episodes of hypoglycaemia should .. Recommendations for patients with chronic kidney dis- be avoided.422,428430 .. ease and non-ST-segment elevation acute coronary .. A multifactorial approach to diabetes mellitus man- .. syndrome agement, with treatment targets, should be consid- IIa B .. .. Recommendations Classa Levelb ered in patients with diabetes and CVD.431436 .. .. Less stringent glucose control should be consid- .. Risk stratification in CKD ered, both in the acute phase and at follow-up, in .. It is recommended to apply the same diagnostic IIa C .. patients with more advanced CVD, older age, lon- .. and therapeutic strategies in patients with CKD ger diabetes duration, and more comorbidities. .. (dose adjustment may be necessary) as for I C .. ACS = acute coronary syndromes; CVD = cardiovascular disease; NSTE-ACS = .. patients with normal renal function. .. non-ST-segment elevation acute coronary syndrome. .. It is recommended to assess kidney function by I C a Class of recommendation. .. eGFR in all patients. b Level of evidence. .. .. Myocardial revascularization in patients with CKD .. .. Use of low- or iso-osmolar contrast media (at 8.3 Chronic kidney disease .. lowest possible volume) are recommended in I A .. In all patients with NSTE-ACS, assessment of kidney function by .. invasive strategies.205,441,442,445,446 eGFR is recommended for prognostic reasons and to identify .. Pre- and post-hydration with isotonic saline .. patients at risk of contrast-induced nephropathy. Although individuals .. should be considered if the expected contrast vol- IIa C with CKD have a worse prognosis in the setting of NSTE-ACS than .. ume is >100 mL in invasive strategies. .. individuals with normal renal function, they less frequently receive .. As an alternative to the pre- and post-hydration .. IIb B evidence-based treatments such as antithrombotic agents and early .. regimen, tailored hydration regimens may be invasive strategy.437,438 .. considered.441,448 .. The diagnosis of NSTE-ACS in patients with CKD may be challeng- .. CABG should be considered over PCI in patients ing, as both mild elevations in cardiac troponin and ECG abnormalities .. with multivessel CAD whose surgical risk profile IIa B .. (e.g. associated with electrolyte disturbances or hypertensive heart dis- .. is acceptable and life expectancy is >1 year.449,450 ease) are frequent. Therefore, new ECG changes should be differenti- .. .. CABG = coronary artery bypass graft(ing); CAD = coronary artery disease; CKD ated from pre-existing abnormalities and absolute changes in cardiac .. = chronic kidney disease; eGFR = estimated glomerular filtration rate; PCI = per- troponin (i.e. increase and/or decrease) should be assessed to differen- .. cutaneous coronary intervention. .. a Class of recommendation. tiate MI from conditions associated with chronic cardiac injury. . b Level of evidence. 1334 ESC Guidelines .. endpoints. Furthermore, in the context of revascularization both 8.4 Anaemia .. .. PCI and CABG procedure-related complications are more fre- Anaemia is common in patients with NSTE-ACS.451 Persistent or .. quent in the older patient, including MI, heart failure, stroke, renal fail- worsening anaemia in patients with NSTE-ACS is associated with .. .. ure, and bleeding.457,465 increased mortality, recurrent MI, and major bleeding.452 However, it .. .. High-intensity lipid modification is indicated for secondary is uncertain whether anaemia itself is the determinant for poorer out- .. prevention.466 come or rather a marker of comorbidity. . Given that the treatment of NSTE-ACS includes antithrombotic ... .. therapy (which may exacerbate bleeding), it is important to identify .. Recommendations for older persons with non-ST-seg- the cause of anaemia and, in particular, occult bleeds in patients pre- .. ment elevation acute coronary syndrome .. senting with NSTE-ACS. The indication for ICA, access site choice .. (radial approach favoured), and the need for revascularization should .. Recommendations Classa Levelb .. be carefully considered to avoid further blood loss.453,454 Equally, the .. It is recommended to apply the same diagnos- Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 choice of antithrombotic agent requires evaluation of ischaemic and .. .. tic strategies in older patients as for younger I B bleeding risks, favouring the use of shorter half-life or reversible .. patients.458 agents. In the setting of anaemia related to an unknown/untreatable .. source, the use of DES should be limited to the new-generation devi- ... It is recommended to apply the same interven- .. tional strategies in older patients as for I B ces with proven safety profiles on short-term DAPT.455 Blood trans- .. fusion is discussed in section 5.4.9. .. younger patients.463,467 .. The choice of antithrombotic agent and dos- .. 8.5 Thrombocytopenia (Supplementary .. age, as well as secondary preventions, should .. be adapted to renal function, as well as specific I B Data) .. .. contraindications.461 8.5.1 Thrombocytopenia related to glycoprotein IIb/IIIa .. inhibitors (Supplementary Data) a .. Class of recommendation. b .. Level of evidence. .. .. 8.5.2 Heparin-induced thrombocytopenia (Supplementary .. Data) .. .. .. 8.7 Frailty 8.6 The older person .. Frailty is a syndrome characterized by reduced biological reserve, .. The clinical presentation of NSTE-ACS in the older person is more .. leading to a failure of homeostatic mechanisms following stressors often atypical. Among the atypical presentations, dyspnoea is the .. events.468,469 A combination of an aging population, improved disease .. leading symptom, while syncope, malaise, and confusion are less fre- .. survival, treatable conditions, and greater awareness has increased quently encountered.456 Electrocardiographic ST elevation is less fre- .. the prevalence of frailty.470 Frail patients with NSTE-ACS less fre- .. quently present in older than in younger patients.457Hs-cTn assays .. quently receive ACS pharmacotherapies and an invasive strategy, .. have more complex CAD,471,472 have longer lengths of hospital stay, have an excellent diagnostic performance for diagnosing early MI in .. the older person. However, the specificity of the test is lower than in .. and are at higher risk of death.459,473 Specifically, they are reported to .. have a higher rate of a composite of all-cause mortality, MI, stroke, younger patients, and elevated troponin levels are more commonly .. associated with conditions other than ACS.458 .. unplanned revascularization, and major bleeding at 1 year.474 In the .. For NSTE-ACS, age is a predictor of in-hospital and 6-month mor- .. absence of robust data to inform healthcare professionals about the tality.140,457 Decisions as to how to manage older patients should be .. management of frail people with NSTE-ACS,475 it is recommended .. based on ischaemic and bleeding risks, estimated life expectancy, .. that the risk of individual treatments is balanced against their risk of comorbidities, the need for non-cardiac surgery, quality of life, frailty, .. harm, whilst being mindful of potential for healthcare professional .. cognitive and functional impairment, patient values and preferences, .. aversion to treatment due to misperception of risk. Following risk and the estimated risks and benefits of revascularization.459,460 .. stratification, it would not be unreasonable to offer optimal medical .. The choice of antithrombotic agent and dosage should be adapted .. therapy plus an invasive strategy to frail patients at high risk of future to renal function, as well as specific contraindications.461 .. cardiovascular events and low risk of complications, and to offer opti- .. Despite the lower rate of revascularization in the older person, its .. mal medical therapy alone to those who are deemed at low risk of benefit appears to be maintained at older age.462,463 The effectiveness .. future events with a high risk of developing procedural complications. .. of an invasive strategy in the context of the older patient with NSTE- .. A systematic review by de Vries et al. identified a range of outcomes ACS is, however, the subject of ongoing research, including the .. instruments to measure frailty (Supplementary Table 7).476 .. SENIOR-RITA RCT (NCT03052036). Recent data have shown that, .. for patients aged 80 years and over with NSTE-ACS, an invasive strat- .. 8.8 Sex disparities .. egy was superior to a conservative strategy for the reduction of MI, .. Data from registries and studies demonstrate discrepant results with urgent revascularisation, stroke, and death, with no increase in bleed- .. respect to access to healthcare, the use of evidence-based therapy, .. ing complications.464 In this RCT, the primary composite endpoint .. and clinical outcome between men and women presenting with .. 477483 was predominantly driven by fewer MIs and urgent revascularisation .. ACS. Moreover, women are often under-represented in and was not sufficiently powered to test efficacy for individual . many RCTs. ESC Guidelines 1335 Although several non-invasive testing techniques exist, which may .. .. 9.2 Pharmacological management be more appropriate in the detection of microvascular CAD in .. (Supplementary Data) women,484 catheterization remains the reference standard for high- .. .. 9.2.1 Anti-ischaemic drugs risk NSTE-ACS and guidelines should be followed the same for .. both sexes. Specifically, women who present with NSTE-ACS should .. Often, patients do not continue to experience chest pain after .. NSTEMI and revascularization. For anti-ischaemic drug management, be provided with equal access to care, a prompt diagnosis, and treat- .. ments at the same rate and intensity as their male counterparts. It .. please refer to the 2019 ESC CCS Guidelines.231 .. should be noted that women with NSTEMI may receive higher antith- .. rombotic medication dosing than appropriate for their weight or renal .. 9.2.1.1 Beta-blockers (Supplementary Data) .. function (or both), and this is partly responsible for the higher risk of .. in-hospital bleeds and access-related complications after PCI in ... 9.2.2 Antithrombotic treatments .. Duration of antiplatelet treatment and/or anticoagulation are dis- women.485 For recommendations regarding the management of .. cussed in section 5.1.4. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 women who are pregnant and have NSTE-ACS, we refer the reader .. .. to the 2018 ESC Guidelines for the management of CVD during .. pregnancy.486 .. 9.2.3 Proton pump inhibitors (Supplementary Data) .. .. .. 9.2.4 Statins and other lipid-lowering agents .. Dyslipidaemia should be managed, according to lipid guidelines, with 9 Long-term management of .. .. pharmacological and lifestyle intervention.512 Patients with estab- non-ST-segment elevation acute .. .. lished CAD are regarded as being at very high risk for cardiovascular coronary syndrome .. events, and statin treatment must be considered, irrespective of low- .. 9.1 Lifestyle management .. density lipoprotein cholesterol (LDL-C) levels. The goal of treatment .. is to lower LDL-C to <1.4 mmol/L (<55 mg/dL) and to reduce it by (Supplementary Data) .. 9.1.1 Smoking (Supplementary Data) .. at least 50% if the baseline LDL-C level is 1.83.5 mmol/L (70135 .. mg/dL). When this level cannot be achieved, the addition of ezeti- 9.1.2 Diet and alcohol (Supplementary Data) .. .. mibe has been demonstrated to decrease cholesterol and cardiovas- 9.1.3 Weight management (Supplementary Data) .. cular events in post-ACS patients, and in patients with diabetes513 .. 9.1.3 Physical activity (Supplementary Data) .. with no further impact on mortality.514 In addition to exercise, diet, 9.1.4 Cardiac rehabilitation (Supplementary Data) .. and weight control, which should be recommended to all patients, .. 9.1.5 Psychosocial factors (Supplementary Data) .. dietary supplements including phytosterols may lower LDL-C to a .. lesser extent, but have not been shown to improve clinical out- 9.1.6 Environmental factors (Supplementary Data) .. .. comes.515 They may be considered (Class IIb) as an adjunct to phar- 9.1.7 Sexual activity (Supplementary Data) .. macological therapy in high- and very high-risk patients who fail to .. 9.1.8 Adherence and sustainability (Supplementary Data) .. achieve LDL-C goals on statins and those who cannot be treated 9.1.9 Influenza vaccination (Supplementary Data) .. with statins.516 Trials published since 2015 have demonstrated that .. . proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors Recommendations for lifestyle managements after non-ST-segment elevation acute coronary syndrome Recommendations Classa Levelb Improvement of lifestyle factors in addition to appropriate pharmacological management is recommended in order to reduce all- I A cause and cardiovascular mortality and morbidity and improve health-related quality of life.487497 Cognitive behavioural interventions are recommended to help individuals achieve a healthy lifestyle.498500 I A Multidisciplinary exercise-based cardiac rehabilitation is recommended as an effective means for patients with CAD to achieve a healthy lifestyle and manage risk factors in order to reduce all-cause and cardiovascular mortality and morbidity, and improve health- I A 487,497,501 related quality of life. Involvement of multidisciplinary healthcare professionals (cardiologists, general practitioners, nurses, dieticians, physiotherapists, psy- chologists, pharmacists) is recommended in order to reduce all-cause and cardiovascular mortality and morbidity, and improve I A health-related quality of life.492,499,502,503 Psychological interventions are recommended to improve symptoms of depression in patients with CAD in order to improve health- I B related quality of life.504,505 Annual influenza vaccination is recommended for patients with CAD, especially in the older person, in order to improve morbidity.505511 I B CAD = coronary artery disease. a Class of recommendation. b Level of evidence. 1336 ESC Guidelines (evolocumab517 and alirocumab518520) are very effective at Recommendations for pharmacological long-term man- reducing cholesterol, lowering LDL-C in a stable fashion to nearly agement after non-ST-segment elevation acute coro- nary syndrome (excluding antithrombotic treatments) 50 mg/dL (1.3 mmol/L) or less.521 In outcome trials, these agents have demonstrated a reduction of cardiovascular events, with little Recommendations Classa Levelb or no impact on mortality.522 Very low levels of cholesterol are gen- erally well tolerated and associated with fewer events,523 but the high Lipid-lowering drugs cost of PCSK9 inhibitors, unaffordable for many health systems,524 Statins are recommended in all NSTE-ACS patients. The aim is to reduce LDL-C by >_50% from baseline and unknown long-term safety have limited widespread use to date. I A and to achieve LDL-C <1.4 mmol/L (<55 mg/ LDL apheresis and new therapies, such as mipomersen and lomita- dL).533,534 pide, need further research. For patients undergoing PCI, high-dose If the LDL-C goalc is not achieved after 46 weeks with atorvastatin has been shown to reduce the frequency of periproce- I B the maximally tolerated statin dose, combination with dural events in both statin-naı̈ve patients and those receiving chronic ezetimibe is recommended.514,535 Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 statin therapy.525 The recent Reduction of Cardiovascular Events If the LDL-C goalc is not achieved after 46 weeks with Icosapent EthylIntervention Trial (REDUCE-IT),526 which despite maximally tolerated statin therapy and ezeti- I B included 8179 participants (70.7% for secondary prevention of cardi- mibe, the addition of a PCSK9 inhibitor is ovascular events) with a median follow-up of 4.9 years, demonstrated recommended.520,535 a significant effect of a pure prescription-grade eicosapentaenoic acid If the current NSTE-ACS episode is a recurrence omega-3 fatty acid, icosapent ethyl, on a composite of cardiovascular within less than 2 years of a first ACS, while taking death, non-fatal MI, non-fatal stroke, coronary revascularization, or maximally tolerated statin-based therapy, an LDL-C IIb B unstable angina in comparison to placebo (17.2 vs. 22.0%, HR 0.75, goal of <1.0 mmol/L (<40 mg/dL) may be 95% CI 0.680.83). Of note, very high doses of icosapent ethyl (two considered.520,535 times 2 g daily) were used.526 The 2019 ESC/EAS Guidelines for the ACE inhibitors or ARBs management of dyslipidaemias give icosapent ethyl a IIa ACE inhibitors (or ARBs in cases of intolerance to recommendation.512 ACE inhibitors) are recommended in patients with heart failure with reduced LVEF (<40%), diabetes, or CKD unless contraindicated (e.g. severe renal impair- I A 9.2.5 Glucose-lowering therapy in patients with diabetes ment, hyperkalaemia, etc.) in order to reduce all- This topic is beyond the scope of the present document and was dis- cause and cardiovascular mortality and cardiovascular cussed in recent guidelines.231 As a general rule, the more advanced morbidity.536538 the CVD, the older the patient, the longer the diabetes duration, and Beta-blockers the more comorbidities that are present, the less stringent the glu- Beta-blockers are recommended in patients with sys- cose control should be. tolic LV dysfunction or heart failure with reduced I A For the first time in the history of diabetes mellitus, there are data LVEF (<40%).539541 from several RCTs indicating cardiovascular benefits from the use of In patients with prior MI, long-term oral treatment glucose-lowering agents in patients with CVD or at very high/high with a beta-blocker should be considered in order to IIa B cardiovascular risk. The results obtained from these trials, using reduce all-cause and cardiovascular mortality and car- glucagon-like peptide-1-receptor antagonists527529 and sodium- diovascular morbidity.542547 glucose cotransporter-2 inhibitors,530532 strongly suggest that these MRAs agents should be recommended in patients with type 2 diabetes mel- MRAs are recommended in patients with heart failure with reduced LVEF (<40%) in order to reduce all- litus with prevalent atherosclerotic CVD. I A cause and cardiovascular mortality and cardiovascular morbidity.548,549 9.2.6 Renin-angiotensin-aldosterone system blockers Proton pump inhibitors (Supplementary Data) Concomitant use of a proton pump inhibitor is recom- mended in patients receiving aspirin monotherapy, 9.2.7 Mineralocorticoid receptor antagonist therapy DAPT, DAT, TAT, or OAC monotherapy who are at I A (Supplementary Data) high risk of gastrointestinal bleeding in order to reduce the risk of gastric bleeds.169 9.2.8 Antihypertensive therapy (Supplementary Data) ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; LDL-C = low-density 9.2.9 Hormone replacement therapy (Supplementary lipoprotein cholesterol; LV = left ventricular; LVEF = left ventricular ejection frac- tion; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; Data) NSTE-ACS = non-ST-segment elevation acute coronary syndrome; OAC = oral anticoagulation/anticoagulant; PCSK9 = proprotein convertase subtilisin kexin 9; TAT = triple antithrombotic therapy. a Class of recommendation. b Level of evidence. c For patients at very high cardiovascular risk (such as patients with ACS), an LDL- C reduction of at least 50% from baseline and an LDL-C goal <1.4 mmol/L (<55 mg/dL) are recommended.512 ESC Guidelines 1337 .. 10 Quality measures .. management of ACS in patients presenting without persistent ST- .. segment elevation, the QIs have been updated so that they align to Quality indicators (QIs) are sets of measures that enable the quantifi- .. the current recommendations, but also take into account the wider .. cation of adherence to guideline recommendations and provide a .. NSTE-ACS pathway of care. Briefly, the ESC ACVC QIs for AMI mechanism for measuring opportunities to improve cardiovascular .. comprise seven domains, which include the evaluation of: (1) centre .. care and outcomes.550 QIs are derived from evidence and should be .. organization, (2) the reperfusion/invasive strategy, (3) in-hospital risk feasible, concretely interpretable, and usable.551 They improve qual- .. assessment, (4) antithrombotic treatment during hospitalization, (5) .. ity by identifying practices that may lead to high-quality care and illus- .. secondary prevention discharge treatments, (6) patient satisfaction, trate how such care was delivered, and have been increasingly used .. and (7) composite QI risk-adjusted 30-day mortality. The composite .. by health authorities, professional organizations, healthcare payers, as .. QIs are combinations of individual indicators into a single number to well as the public.552555 .. summarize the multiple dimensions and facilitate comparisons and .. Typically, QIs are divided into structural, process, and outcome .. categorization of the centres and can be used by providers for deci- .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 indicators, depending on the aspect of care being measured.556 .. sion making and benchmarking. In this document, however, only the Although high-quality evidence tends to support process Qis,557 the .. QIs relevant to the management of NSTE-ACS are described and are inclusion of both outcome and process measures enables a more .. .. displayed in Table 15. comprehensive evaluation.558 Additionally, patient-reported out- .. The QIs defined here are intended for quality improvement and come measures (PROMs), which may not be underpinned by a .. .. performance measurement through meaningful surveillance, as well strong class of recommendation within guidelines, can be seen as hav- .. as for integration within registries that specifically aim to identify areas .. ing a complementary role alongside other Qis.559 .. for improvement in clinical practice. The main and secondary QIs In 2016, the ESC Association for Acute Cardiovascular Care .. represent major and complementary components of the quality of .. (ACVC), formerly the Acute Cardiovascular Care Association, devel- .. NSTE-ACS care, respectively, and are not intended for ranking oped a suite of QIs for the management of AMI with or without .. healthcare professionals/providers or payment incentives. .. ST-segment elevation.560 These QIs were externally validated in .. Continuous monitoring and update will be required for these QIs international clinical registries, and most demonstrated an inverse .. based on feedback and ‘downstream’ clinical registries data, as well as .. association with mortality.561563 For this 2020 Guidelines for the .. according to changes in evidence and guideline recommendations. . Table 15 Quality indicators in non-ST-segment elevation acute coronary syndrome care 1. Centre organization Classa Levelb Main QI: hospital use of hs-cTn. QI: hs-cTn is available in the centre for testing. Corresponding ESC CPG recommendation: it is recommended to measure cardiac troponins with high-sensitivity assays I B immediately after admission and obtain the results within 60 min of blood sampling. Secondary QI: the centre should participate in a regular registry or programme for quality assessment. QI: centres participating in a registry. Corresponding ESC CPG recommendation: no ESC CPG recommendation. NA NA 2. Invasive strategy Main QI (1): rate of NSTEMI patients who receive ICA within 24 h of their diagnosis. Numerator: number of NSTEMI patients who receive ICA within 24 h of their diagnosis. Denominator: all NSTEMI patients without contraindications. Corresponding ESC CPG recommendation: an early invasive strategy within 24 h is recommended in patients with any of I A high-risk criteria, including the diagnosis of NSTEMI suggested by a diagnostic algorithm. Main QI (2): use of radial access in case of invasive strategy. Numerator: number of NSTE-ACS patients who receive ICA via radial access. Denominator: number of NSTE-ACS patients who receive ICA without overriding procedural considerations against the use of radial access. Corresponding ESC CPG recommendation: radial access is recommended as the standard approach, unless there are overrid- I A ing procedural considerations. Continued 1338 ESC Guidelines 3. In-hospital risk assessment Main QI (1): the proportion of patients who have an assessment of LVEF before hospital discharge. LVEF should be assessed and the numerical value recorded for all patients admitted with NSTE-ACS. Numerator: number of NSTE-ACS patients who have their LVEF measured before hospital discharge. Denominator: number of NSTE-ACS patients. Corresponding ESC CPG recommendation: echocardiography is recommended to evaluate regional and global LV function I C and to rule in or rule out differential diagnoses. Main QI (2): LDL-C assessment should be performed during hospitalization. Numerator: number of NSTE-ACS patients who have their LDL-C measured during hospitalization. Denominator: number of NSTE-ACS patients. Corresponding ESC CPG recommendation: statins are recommended in all NSTE-ACS patients. The aim is to reduce LDL-C Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 I A by at least 50% from baseline and/or achieve LDL-C <1.4 mmol/L (<55 mg/dL). 4. Anti-thrombotic treatment during hospitalization Main QI: proportion of patients with ‘adequate P2Y12 receptor inhibition’. Numerator: number of NSTE-ACS patients prescribed adequate P2Y12 inhibitors at the time of hospital discharge. Denominator: NSTE-ACS patients alive at the time of hospital discharge with an indication for prasugrel, ticagrelor, or clopidogrel. Corresponding ESC CPG recommendation: a P2Y12 receptor inhibitor is recommended in addition to aspirin, to be main- I A tained over 12 months unless there are contraindications or an excessive risk of bleeding. 5. Secondary prevention discharge treatments Main QI: proportion of patients discharged from hospital on high-intensity statins (defined as atorvastatin >_40 mg or rosuvastatin >_20 mg) unless contraindicated. Numerator: number of NSTE-ACS patients who receive high-intensity statin therapy at the time of hospital discharge. Denominator: number of NSTE-ACS patients alive at the time of hospital discharge and without contraindications, refusal, side effects, allergy, or history of intolerance to high-intensity statin therapy. Corresponding ESC CPG recommendation: statins are recommended in all NSTE-ACS patients. The aim is to reduce LDL-C I A by at least 50% from baseline and/or achieve LDL-C <1.4 mmol/L (<55 mg/dL). Secondary QI (1): proportion of patients with LVEF <40% who are discharged from hospital on ACE inhibitor (or ARB if intolerant to ACE inhibitors). Numerator: number of NSTE-ACS patients with LVEF <40%, prescribed ACE inhibitor/ARB at the time of hospital discharge. Denominator: number of NSTE-ACS patients with LVEF<40% and alive at the time of hospital discharge who are eligible for ACE inhibitor/ARB (no severe renal impairment, hyperkalaemia, other contraindication, refusal, side effects, or allergy). Corresponding ESC CPG recommendation: ACE inhibitors (or ARB in cases of intolerance) are recommended in NSTE-ACS patients with co-existing hypertension, LVEF <40%, diabetes, or CKD, unless contraindicated (e.g. severe renal impairment, hyperka- I A laemia, etc.). Secondary QI (2): proportion of patients with LVEF <40% who are discharged from hospital on beta-blockers. Numerator: number of patients with LVEF <40% prescribed beta-blockers at the time of hospital discharge. Denominator: patients with LVEF<40% and alive at the time of hospital discharge who are eligible for beta-blockers. Corresponding ESC CPG recommendation: beta-blockers are recommended in patients with systolic LV dysfunction or heart I A failure with reduced LVEF (<40%). 6. Patient satisfaction Main QI: feedback regarding the patient’s experience should be systematically collected in an organized way from all patients. It should include the following points: Explanations provided by doctors and nurses (about the coronary disease, the benefit/risk of the discharge treatment, and medical follow-up). Discharge information regarding what to do in case of recurrence of symptoms and timing of visit. Numerator: number of NSTE-ACS patients alive at the time of discharge from hospital with feedback collected. Denominator: number of NSTE-ACS patients discharged from hospital alive. Corresponding ESC CPG recommendation (1): no ESC CPG recommendation. NA NA Continued ESC Guidelines 1339 Secondary QI: systematic assessment of health-related quality of life in all patients using a validated instrument. Numerator: number of NSTE-ACS patients alive at the time of hospital discharge who have their health-related quality of life assessed during hospitalization using a validated instrument. Denominator: number of NSTE-ACS patients discharged from hospital alive. Corresponding ESC CPG recommendation: no ESC CPG recommendation. NA NA 7. CQI Main CQI (opportunity based): with the following individual QIs (all indicators are weighted equally): The centre should participate in a regular registry or programme for quality assessment. Rate of NSTEMI patients who receive ICA within 24 h of their diagnosis. Proportion of patients who have an assessment of LVEF before hospital discharge. Proportion of patients with ‘adequate P2Y12 receptor inhibition’. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Proportion of patients discharged from hospital on high-intensity statins. Proportion of patients with LVEF <40% who are discharged from hospital on an ACE inhibitor/ARB. Proportion of patients with LVEF <40% who are discharged from hospital on beta-blockers. Feedback regarding the patient’s experience systematically collected in an organized way from all patients. Numerator: all NSTE-ACS patients discharged from hospital alive: sum of points (one point for each individual indicator). Denominator: all NSTE-ACS patients discharged from hospital alive: sum of points (one point for each applicable indicator, accord- ing to patient and centre characteristics). Corresponding ESC CPG recommendation: no ESC CPG recommendation. NA NA Secondary CQI (all or none): based on three or five components, according to LVEF: • Calculated on three individual QIs in patients with LVEF >_40%: (1) Rate of NSTEMI patients who receive ICA within 24 h of their diagnosis. (2) Proportion of patients with ‘adequate P2Y12 receptor inhibition’. (3) Proportion of patients discharged from hospital on high-intensity statins. • Calculated on five individual QIs in patients with LVEF <40%: (1) Rate of NSTEMI patients who receive ICA within 24 h of their diagnosis. (2) Proportion of patients with ‘adequate P2Y12 receptor inhibition’. (3) Proportion of patients discharged from hospital on high-intensity statins. (4) Proportion of patients with LVEF <40% who are discharged from hospital on an ACE inhibitor/ARB. (5) Proportion of patients with LVEF <40% who are discharged from hospital on beta-blockers. Numerator: all NSTE-ACS patients discharged from hospital alive: sum of points (one point for each individual indicator). Denominator: all NSTE-ACS patients discharged from hospital alive: sum of points (one point for each applicable indicator, accord- ing to patient and centre characteristics). 8. Outcome QI Secondary QI: risk adjusted 30-day mortality rate.c Numerator: all NSTE-ACS patients who died within 30 days after admission. Denominator: all NSTE-ACS patients at 30-day follow-up. Corresponding ESC CPG recommendation: no ESC CPG recommendation. NA NA ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CAD = coronary artery disease; CCS = chronic coronary syndromes; CKD = chronic kidney dis- ease; CPG = clinical practice guidelines; CQI = composite quality indicator; ESC = European Society of Cardiology; hs-cTn = high-sensitivity cardiac troponin; ICA = invasive coronary angiography; LDL-C = low-density lipoprotein cholesterol; LV = left ventricular; LVEF = left ventricular ejection fraction; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; NSTEMI = non-ST-segment elevation myocardial infarction; QI = quality indicator. a Class of recommendation. b Level of evidence. c Risk-adjusted 30-day mortality rates (i.e. using a logistic regression model adjusted for the risk score (by a validated risk score assessment), with 30-day mortality as the dependent variable. 1340 ESC Guidelines 11 Management strategy Figure 13 describes an overview and management pathway for NSTE-ACS patients. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Figure 13 Central illustration. Management strategy for non-ST-segment elevation acute coronary syndrome patients. BNP = B-type natriuretic pep- tide; CABG = coronary artery bypass graft(ing); CCU = coronary care unit; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; ECG = electrocar- diogram/electrocardiography; GP = glycoprotein; GRACE = Global Registry of Acute Coronary Events; hs-cTn = high-sensitivity cardiac troponin; NSTE- ACS = non-ST-segment elevation acute coronary syndrome; NSTEMI = non-ST-segment elevation myocardial infarction; NT-proBNP = N-terminal pro- B-type natriuretic peptide; PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin kexin 9; UFH = unfractionated heparin. Listen to the audio guide of this figure online. ESC Guidelines 1341 .. 12 Key messages .. .. predictive value for major bleeding. Their value in improving patient outcomes remains unclear. .. .. • Non-invasive imaging. Even after the rule-out of MI, elective • Diagnosis. Chest discomfort without persistent ST-segment .. non-invasive or invasive imaging may be indicated according to elevation (NSTE-ACS) is the leading symptom initiating the diag- .. nostic and therapeutic cascade. The pathological correlate at the .. clinical assessment. CCTA may be an option in patients with low- .. to-modest clinical likelihood of unstable angina as a normal scan myocardial level is cardiomyocyte necrosis, measured by tropo- .. nin release, or, less frequently, myocardial ischaemia without cell .. excludes CAD. CCTA has a high NPV to exclude ACS (by .. excluding CAD) and an excellent outcome in patients presenting damage (unstable angina). Individuals with unstable angina have a .. substantially lower risk of death and derive less benefit from an .. to the emergency department with low-to-intermediate pre-test .. probability for ACS and a normal CCTA. In addition, upfront aggressive pharmacological and invasive approach. .. • Troponin assays. High-sensitivity troponin assays measure- .. imaging with CCTA reduces the need for ICA in high risk .. patients. Stress imaging by cardiac magnetic resonance imaging, ments are recommended over less sensitive ones, as they .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 provide higher diagnostic accuracy at identical low cost. It should .. stress echocardiography, or nuclear imaging may also be an .. option based on risk assessment. be noted that many cardiac pathologies other than MI also result .. in cardiomyocyte injury and, therefore, cardiac troponin .. • Risk stratification for an invasive approach. An early rou- .. tine invasive approach within 24 h of admission is recommended elevations. .. • Other biomarkers. Other biomarkers may have clinical rele- .. for NSTEMI based on hs-cTn measurements, GRACE risk score .. >140, and dynamic new, or presumably new, ST-segment vance in specific clinical settings when used in combination with .. non hs-cTn T/I. CK-MB shows a more rapid decline after MI and .. changes as it improves major adverse cardiac events and possibly .. early survival. Immediate invasive angiography is required in highly may provide added value for detection of early reinfarction. The .. routine use of copeptin as an additional biomarker for the early .. unstable patients according to hemodynamic status, arrythmias, .. acute heart failure, or persistent chest pain. In all other clinical rule-out of MI should be considered in the increasingly uncom- .. mon setting where hs-cTn assays are not available. .. presentation, a selective invasive approach may be performed .. according to non-invasive testing or clinical risk assessment. • Rapid ‘rule-in’ and ‘rule-out’ algorithms. Due to the higher .. sensitivity and diagnostic accuracy for the detection of MI at pre- .. • Revascularization strategies. The principal technical aspects .. of PCI in NSTE-ACS patients do not differ from the invasive sentation, the time interval to the second cTn assessment can be .. shortened with the use of hs-cTn assays. It is recommended to .. assessment and revascularization strategies for other manifesta- .. tions of CAD. Radial access is recommended as the preferred use the 0 h/1 h algorithm (best option, blood draw at 0 h and 1 h) .. .. approach in NSTE-ACS patients undergoing invasive assessment or the 0 h/2 h algorithm (second-best option, blood draw at 0 h .. and 2 h). Optimal thresholds for rule-out and rule-in were .. with or without PCI. Multivessel disease is frequent in NSTE- .. ACS, timing and completeness of revascularization should be selected to allow for a minimal sensitivity and NPV of 99% and a .. minimal PPV of 70%. Used in conjunction with clinical and ECG .. decided according to functional relevance of all stenoses, age, .. general patient condition, comorbidities, and left ventricular findings, the 0 h/1 h and 0 h/2 h algorithm allows the identification .. of appropriate candidates for early discharge and outpatient .. function. .. • Myocardial infarction with non-obstructive coronary management. .. • Confounders of hs-cTn. Beyond the presence or absence of .. arteries. MINOCA incorporates a heterogeneous group of .. underlying causes that may involve both coronary and non- MI, four clinical variables affect hs-cTn concentrations. The effect .. of age (differences in concentration between healthy very young .. coronary pathological conditions, with the latter including cardiac .. and extra-cardiac disorders. It excludes by consensus myocarditis vs. ‘healthy’ very old individuals up to 300%), renal dysfunction .. (differences in concentration between otherwise healthy patients .. and Takotsubo syndrome. Cardiac magnetic resonance imaging is .. one of the key diagnostic tools as it identifies the underlying cause with very high vs. very low eGFR up to 300%), and chest pain .. onset (>300%) is substantial, and modest for sex (40%). .. in more than 85% of patients and the subsequent appropriate .. treatment. • Ischaemic risk assessment. Initial cTn levels add prognostic .. information in terms of short- and long-term mortality to clinical .. • Spontaneous coronary artery dissection. Defined as a .. non-atherosclerotic, non-traumatic, or iatrogenic separation of and ECG variables. The higher the hs-cTn levels, the greater the .. risk of death. Serum creatinine and eGFR should also be deter- .. the coronary arterial tunics secondary to vasa vasorum hemor- .. mined in all patients with NSTE-ACS because they affect progno- .. rhage or intimal tear, it accounts for up to 4% of all ACS, but the sis and are key elements of the GRACE risk score, which .. incidence is reported to be much higher (2235% of ACS) in .. assessment is superior to (subjective) physician assessment for .. women <60 years of age. Intracoronary imaging is very useful for the occurrence of death or MI. Natriuretic peptides may provide .. the diagnosis and treatment orientation. Medical treatment .. incremental prognostic information and may help in risk .. remains to be established. stratification. .. • Pre-treatment with P2Y12 receptor inhibitors. Routine .. • Bleeding risk assessment. ARC-HBR is a pragmatic approach .. pre-treatment with a P2Y12 receptor inhibitor in NSTE-ACS that includes the most recent trials performed in HBR patients, .. patients in whom coronary anatomy is not known and an early .. who were previously excluded from clinical trials of DAPT dura- .. invasive management is planned is not recommended given the tion or intensity. The PRECISE-DAPT score may be used to guide .. lack of established benefit. However, it may be considered in .. and inform decision making on DAPT duration with a modest . selected cases and according to the bleeding risk of the patient. 1342 ESC Guidelines • Post-treatment antiplatelet therapy. DAPT consisting of a .. • Triple antithrombotic therapy. In at least 68% of patients .. potent P2Y12 receptor inhibitor in addition to aspirin is generally .. undergoing PCI, long-term oral anticoagulation is indicated and recommended for 12 months, irrespective of the stent type, .. should be continued. NOACs are preferred over VKAs in terms .. unless there are contraindications. New scenarios have been .. of safety when patients are eligible. DAT with a NOAC at the implemented. DAPT duration can be shortened (<12 months), .. recommended dose for stroke prevention and SAPT (preferably .. extended (>12 months), or modified by switching DAPT or de- .. clopidogrel, chosen in more than 90% of cases in available trials) escalation. These decisions depend on individual clinical judgment .. is recommended as the default strategy up to 12 months after a .. being driven by the patient’s ischaemic and bleeding risk, the .. short period up to 1 week of TAT (with NOAC and DAPT). occurrence of adverse events, comorbidities, co-medications, .. TAT may be prolonged up to 1 month when the ischaemic risk .. and the availability of the respective drugs. .. outweighs the bleeding risk. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 13 Gaps in evidence for non-ST-segment elevation acute coronary syndrome care and future research Gaps in NSTE-ACS Care Needed RCTs RISK PREDICTION MODELLING Whether risk stratification of NSTE-ACS patients based on multivariable risk Patients randomized to treatment algorithms based on scores calculated at prediction models improves clinical outcomes remains unclear. point of care or to usual treatment. No dedicated RCT has evaluated the value of a management strategy based Patients randomized to management strategies based on risk prediction on a risk-prediction model (i.e. PRECISE-DAPT score, ARC-HBR criteria) models for DAPT duration vs. usual care. for DAPT duration following PCI for NSTE-ACS. MEDICAL TREATMENT STRATEGIES The efficacy and safety of pre-treatment NSTE-ACS patients with oral P2Y12 Dedicated RCTs for pre-treatment with ticagrelor (and separately, clopi- receptor inhibitors prior to ICA is unknown. dogrel) vs. placebo as opposed to loading after angiography in PCI patients. The efficacy and safety of early i.v. beta-blockers before an early or late inva- Patients randomized to i.v. beta-blockers or usual care before ICA. sive strategy in NSTE-ACS patients remain under question. The value of long-term therapy with beta-blockers in patients with LVEF Patients with LVEF>40% following 1 year of beta-blocker therapy after the >40% needs further evaluation. event randomized to long-term therapy or not. BIOMARKERS The role of platelet function testing or genetic testing to de-escalate oral Adequately powered RCTs of a strategy of platelet function testing- or P2Y12 receptor inhibitors after the first month of therapy following PCI for genetic testing-based de-escalation vs. usual guideline-based care. NSTE-ACS needs to be defined. What is the added value of biomarkers other than hs-cTn for rapid rule-out NSTE-ACS patients randomized to diagnostic pathways with or without of NSTE-ACS compared with usual care? biomarkers in addition to usual care. TIMING OF ANGIOGRAPHY AND REVASCULARIZATION STRATEGIES What is the optimal timing of invasive angiography in high-risk NSTE-ACS Further RCTs with different time intervals until angiography within the 72-h patients? window from presentation. Should low-risk NSTE-ACS patients undergo routine or selective invasive Appropriate risk-stratified patients randomized to routine or selective inva- assessment? sive strategy. The optimal invasive strategy for women presenting with NSTE-ACS is Adequately powered RCTs to identify potential sex differences in treatment unknown. strategies in patients presenting with NSTE-ACS. What is the role of CCTA- or other imaging-based stress testing strategies Diagnostic RCTs of routine non-invasive anatomy- or functional imaging- for low-risk NSTE-ACS patients or uncertain NSTEMI patients? based strategies prior to an ICA approach powered for clinical endpoints. What is the value of FFR-CT added to CCTA in evaluating the role of Diagnostic RCTs comparing the adding value of FFR-CT on a non-invasive adverse plaque characteristics and adverse haemodynamic characteristics in anatomical testing strategy (CCTA). the determination of ACS? The safety and effectiveness of routine vs. selective invasive assessment of Frail patients presenting with NSTE-ACS without ongoing ischaemia or hae- frail patients presenting with NSTE-ACS requires further evaluation. modynamic instability should be randomized to routine vs. selective ICA. Mainly due to difficulties in enrolment, older patients have been under-rep- Multicentre RCTs evaluating the safety and effectiveness of different treat- resented in clinical trials of invasive strategies for NSTE-ACS patients. ment strategies in sufficient numbers of older NSTE-ACS patients. Continued ESC Guidelines 1343 We do not know whether there are additional criteria for not waiting at all Risk stratification pathways to identify vulnerable populations having the in the NSTE-ACS population, apart from those currently listed in the imme- greatest benefit from an early invasive assessment (and perhaps also imme- diate invasive strategy. diate invasive assessment) deserve appropriate evaluation. It remains unclear whether coronary revascularization of the presumed cul- RCTs of PCI of the presumed culprit lesion only based on non-invasive prit lesion only or complete revascularization in NSTE-ACS patients should imaging and/or coronary angiography vs. complete revascularization with be attempted. PCI (or CABG). The value of haemodynamic assessment based on FFR of non-culprit lesions Patients presenting with NSTE-ACS and multivessel disease randomized to to guide complete revascularization in the NSTE-ACS setting remains PCI as indicated with vs. without FFR of non-culprit lesions. unclear. Should PCI or CABG be the preferred option in multivessel coronary dis- Dedicated trials focused on NSTE-ACS patients with multivessel coronary ease in NSTE-ACS? disease randomized to PCI vs. CABG including invasive and/or non-invasive Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 assessment. Should complete revascularization be achieved during the index intervention Immediate vs. staged complete revascularization should be evaluated in or as a staged approach? RCTs in patients with multivessel disease. The role and type of percutaneous mechanical circulatory support device in Strategies based on percutaneous mechanical circulatory support devices in patients presenting with NSTE-ACS and CS remains uncertain. NSTE-ACS patients presenting with CS should be evaluated compared to standard of care. LONG-TERM MANAGEMENT The optimal mode of training programmes following NSTE-ACS should be Patients randomized to different modes of rehabilitation programmes after determined. NSTE-ACS. It has to be determined whether neprilysin inhibitors in the specific group NSTE-ACS patients with systolic LV dysfunction should be randomized to of patients who have suffered NSTE-ACS with systolic LV dysfunction therapy with a neprilysin inhibitor vs. standard of care. improve clinical outcomes and reduce hospitalizations. What is the value of long-term beta-blocker and long-term ACE inhibitor/ RCTs comparing the long-term continuation of therapy with beta-blockers ARB in patients with normal LV function and no other indications for these and ACE inhibitor/ARB to withdrawal in patients with normal LV function in therapies? the absence of other indications following NSTE-ACS. What is the optimal long-term antithrombotic therapy in NSTE-ACS Dedicated RCTs comparing different combinations of potent antithrom- patients who have undergone percutaneous coronary revascularization? botic agents and examining the benefit-risk balance for ischaemic/bleeding events. The impact of heart valve disease in patients with CAD and NSTE-ACS is Strategies based on revascularization only vs. revascularization and heart unknown and needs to be investigated. valve disease treatment should be evaluated (non-severe valvular heart dis- ease including aortic stenosis and mitral regurgitation). ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; ARB = angiotensin receptor blocker; ARC-HBR = Academic Research Consortium - High Bleeding Risk; CABG = coronary artery bypass graft(ing); CAD = coronary artery disease; CCTA = coronary computed tomographic angiography; CS = cardiogenic shock; DAPT = dual antiplatelet therapy; FFR = fractional flow reserve; FFR-CT = fractional flow reserve-computed tomography; hs-cTn = high-sensitivity cardiac troponin ; ICA = invasive cor- onary angiography; i.v. = intravenous; LV = left ventricular; LVEF = left ventricular ejection fraction; NSTE-ACS = non-ST elevation acute coronary syndrome; NSTEMI = non- ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; RCT = randomized controlled trial. 14 ‘What to do’ and ‘what not to do’ messages Recommendations for diagnosis, risk stratification, imaging, and rhythm monitoring in patients with suspected Classa Levelb non-ST-segment elevation acute coronary syndrome Diagnosis and risk stratification It is recommended to base diagnosis and initial short-term risk stratification on a combination of clinical history, symptoms, vital signs, I B other physical findings, ECG, and laboratory results including hs-cTn.3 It is recommended to measure cardiac troponins with high-sensitivity assays immediately after admission and obtain the results within I B 60 min of blood sampling.3,1013,2931,34 It is recommended to obtain a 12-lead ECG within 10 min after first medical contact and to have it immediately interpreted by an I B experienced physician.21 It is recommended to obtain an additional 12-lead ECG in case of recurrent symptoms or diagnostic uncertainty. I C Continued 1344 ESC Guidelines The ESC 0 h/1 h algorithm with blood sampling at 0 h and 1 h is recommended if an hs-cTn test with a validated 0 h/1 h algorithm is I B available.30,33,35,36,39,68,69,75,76 Additional testing after 3 h is recommended if the first two cardiac troponin measurements of the 0 h/1 h algorithm are not conclu- I B sive and the clinical condition is still suggestive of ACS.85 As an alternative to the ESC 0 h/1 h algorithm, it is recommended to use the ESC 0 h/2 h algorithm with blood sampling at 0 h and 2 I B h, if an hs-cTn test with a validated 0 h/2 h algorithm is available.33,39,75,78,84 Additional ECG leads (V3R, V4R, V7V9) are recommended if ongoing ischaemia is suspected when standard leads are inconclusive. I C For initial diagnostic purposes, it is not recommended to routinely measure additional biomarkers such as h-FABP or copeptin, in III B addition to hs-cTn.47,48,51,52,54,118 Imaging In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin, echocardiography is recom- I C Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 mended and should be performed by trained physicians immediately following a 12-lead ECG. In patients with no recurrence of chest pain, normal ECG findings, and normal levels of cardiac troponin (preferably high sensitivity), but still with a suspected ACS, a non-invasive stress test (preferably with imaging) for inducible ischaemia or CCTA is recommended I B before deciding on an invasive approach.91,92,98,101,105108 Echocardiography is recommended to evaluate regional and global LV function and to rule in or rule out differential diagnoses.c I C CCTA is recommended as an alternative to ICA to exclude ACS when there is a low-to-intermediate likelihood of CAD and when I A cardiac troponin and/or ECG are normal or inconclusive.105,108,110114 Monitoring Continuous rhythm monitoring is recommended until the diagnosis of NSTEMI has been established or ruled out. I C It is recommended to admit NSTEMI patients to a monitored unit. I C Rhythm monitoring up to 24 h or to PCI (whichever comes first) is recommended in NSTEMI patients at low risk for cardiac I C arrhythmias.d Rhythm monitoring for >24 h is recommended in NSTEMI patients at increased risk for cardiac arrhythmias.e I C Recommendations on biomarker measurements for prognostic stratification Beyond its diagnostic role, it is recommended to measure hs-cTn serially for the estimation of prognosis.12,13,119,120 I B The measurement of additional biomarkers, such as mid-regional pro-A-type natriuretic peptide, high-sensitivity C-reactive protein, mid-regional pro-adrenomedullin, GDF-15, copeptin, and h-FABP is not recommended for routine risk or prognosis III B assessment.50,127,129 Recommendations for antithrombotic treatment in non-ST-segment elevation acute coronary syndrome patients undergoing percuta- neous coronary intervention Antiplatelet treatment Aspirin is recommended for all patients without contraindications at an initial oral LD of 150300 mg (or 75250 mg i.v.), and at a I A MD of 75100 mg o.d. for long-term treatment.179181 A P2Y12 receptor inhibitor is recommended in addition to aspirin, and maintained over 12 months unless there are contraindications or an excessive risk of bleeding.170,171,182 I A Options are: Prasugrel in P2Y12 receptor inhibitor-naı̈ve patients proceeding to PCI (60 mg LD, 10 mg/d as standard dose, 5 mg/d for patients I B aged >_75 years or with a body weight <60 kg).171 Ticagrelor irrespective of the planned treatment strategy (invasive or conservative) (180 mg LD, 90 mg b.i.d.).170 I B Clopidogrel (300600 mg LD, 75 mg daily dose), only when prasugrel or ticagrelor are not available, cannot be tolerated, or are I C contraindicated.182,183 Treatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known and is not recommended.188,189 III A It is not recommended to administer routine pre-treatment with a P2Y12 receptor inhibitor in patients in whom coronary anatomy is III A not known and an early invasive management is planned.174,177,190,191 Peri-interventional anticoagulant treatment Parenteral anticoagulation is recommended for all patients, in addition to antiplatelet treatment, at the time of diagnosis and, espe- I A cially, during revascularization procedures according to both ischaemic and bleeding risks.192,193 UFH (weight-adjusted i.v. bolus during PCI of 70100 IU/kg, or 5070 IU/kg in combination with a GP IIb/IIIa inhibitor; activated I A clotting time target range of 250350 s, or 200250 s if a GP IIb/IIIa inhibitor is given) is recommended in patients undergoing PCI. In cases of medical treatment or logistical constraints for transferring the patient to PCI within the required time frame, fondaparinux I B is recommended and, in such cases, a single bolus of UFH is recommended at the time of PCI.183 Continued ESC Guidelines 1345 It is recommended to select anticoagulation according to both ischaemic and bleeding risks, and according to the efficacysafety pro- I C file of the chosen agent. Crossover of UFH and LMWH is not recommended.196 III B Recommendations for post-interventional and maintenance treatment in patients with non-ST-segment elevation acute coronary syndrome In patients with NSTE-ACS treated with coronary stent implantation, DAPT with a P2Y12 receptor inhibitor on top of aspirin is rec- I A ommended for 12 months unless there are contraindications such as excessive risk of bleeding.170,171,225 Recommendations for anti-ischaemic drugs in the acute phase of non-ST-segment elevation acute coronary syndrome Sublingual or i.v. nitrates and early initiation of beta-blocker treatment are recommended in patients with ongoing ischaemic symp- I C toms and without contraindications. It is recommended to continue chronic beta-blocker therapy unless the patient is in overt heart failure. I C Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 i.v. nitrates are recommended in patients with uncontrolled hypertension or signs of heart failure. I C Recommendations for combining antiplatelet agents and anticoagulants in non-ST-segment elevation acute coronary syndrome patients requiring chronic oral anticoagulation Stroke prevention should be offered to AF patients with >_1 non-sex CHA2DS2-VASc stroke risk factors (score of >_1 in males or >_2 I A in females). For patients with >_2 non-sex stroke risk factors, OAC is recommended.255259 Patients undergoing coronary stenting Anticoagulation During PCI, additional parenteral anticoagulation is recommended, irrespective of the timing of the last dose of all NOACs and if INR I C is <2.5 in VKA-treated patients. Antiplatelet treatment In patients with AF and CHA2DS2-VASc score >_1 in men and >_2 in women, after a short period of TAT (up to 1 week from the acute event), DAT is recommended as the default strategy using a NOAC at the recommended dose for stroke prevention and a sin- I A gle oral antiplatelet agent (preferably clopidogrel).238241,244,245 Periprocedural DAPT administration consisting of aspirin and clopidogrel up to 1 week is recommended.238241,244,245 I A 236239,246 Discontinuation of antiplatelet treatment in patients treated with an OAC is recommended after 12 months. I B The use of ticagrelor or prasugrel as part of TAT is not recommended. III C Recommendations for coronary revascularization Timing of invasive strategy An immediate invasive strategy (<2 h) is recommended in patients with at least one of the following very high-risk criteria: • Haemodynamic instability or CS. • Recurrent or refractory chest pain despite medical treatment. • Life-threatening arrhythmias. I C • Mechanical complications of MI. • Heart failure clearly related to NSTE-ACS. • Presence of ST-segment depression >1 mm in >_6 leads additional to ST-segment elevation in aVR and/or V1. An early invasive strategy within 24 h is recommended in patients with any of the following high-risk criteria: • Diagnosis of NSTEMI suggested by the diagnostic algorithm recommended in section 3. • Dynamic or presumably new contiguous ST/T-segment changes suggesting ongoing ischaemia. I A • Transient ST-segment elevation.273,362 • GRACE risk score >140.271,272,277 A selective invasive strategy after appropriate ischaemia testing or detection of obstructive CAD by CCTA is recommended in I A patients considered at low risk.267,268,363 Technical aspects Radial access is recommended as the standard approach, unless there are overriding procedural considerations.336,337 I A DES are recommended over bare-metal stents for any PCI irrespective of: • Clinical presentation. • Lesion type. I A • Planned non-cardiac surgery. • Anticipated duration of DAPT. • Concomitant anticoagulant therapy.354,365,366 Continued 1346 ESC Guidelines It is recommended to base the revascularization strategy (ad hoc culprit lesion PCI/multivessel PCI/CABG) on the patient’s clinical status and comorbidities, as well as their disease severity [i.e. the distribution and angiographic lesion characteristics (e.g. SYNTAX I B score)], according to the principles for stable CAD.350 However, the decision on immediate PCI of the culprit stenosis does not require Heart Team consultation. Recommendations for myocardial infarction with non-obstructive coronary arteries In all patients with an initial working diagnosis of MINOCA, it is recommended to follow a diagnostic algorithm to differentiate true I C MINOCA from alternative diagnoses. It is recommended to perform CMR in all MINOCA patients without an obvious underlying cause.370 I B It is recommended to manage patients with an initial diagnosis of MINOCA and a final established underlying cause according to the I C disease-specific guidelines. Recommendations for non-ST-segment elevation acute coronary syndrome patients with heart failure or cardiogenic shock Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 Emergency coronary angiography is recommended in patients with CS complicating ACS.205,416,417 I B Emergency PCI of the culprit lesion is recommended for patients with CS due to NSTE-ACS, independent of the time delay from I B symptom onset, if the coronary anatomy is amenable to PCI.205,417 Emergency CABG is recommended for patients with CS if the coronary anatomy is not amenable to PCI.205,417 I B It is recommended to perform emergency echocardiography without delay to assess LV and valvular function and exclude mechanical I C complications. In cases of haemodynamic instability, emergency surgical or catheter-based repair of mechanical complications of ACS is recom- I C mended, as decided by the Heart Team. Routine use of IABP in patients with CS and no mechanical complications due to ACS is not recommended.413,414,415 III B Routine immediate revascularization of non-culprit lesions in NSTE-ACS patients with multivessel disease presenting with CS is not III B recommended.346,408 Recommendations for diabetes mellitus in non-ST-segment elevation acute coronary syndrome patients It is recommended to screen all patients with NSTE-ACS for diabetes and to monitor blood glucose levels frequently in patients with I C known diabetes or admission hyperglycaemia. Avoidance of hypoglycaemia is recommended.424427 I B Recommendations for patients with chronic kidney disease and non-ST-segment elevation acute coronary syndrome Risk stratification in CKD It is recommended to apply the same diagnostic and therapeutic strategies in patients with CKD (dose adjustment may be necessary) I C as for patients with normal renal function. It is recommended to assess kidney function by eGFR in all patients. I C Myocardial revascularization in patients with CKD Use of low- or iso-osmolar contrast media (at lowest possible volume) are recommended in invasive strategies.205,441,442,445,446 I A Recommendations for older persons with non-ST-segment elevation acute coronary syndrome It is recommended to apply the same diagnostic strategies in older patients as for younger patients.458 I B It is recommended to apply the same interventional strategies in older patients as for younger patients.463,467 I B The choice of antithrombotic agent and dosage, as well as secondary preventions, should be adapted to renal function, as well as spe- I B cific contraindications.461 Recommendations for lifestyle managements after non-ST-segment elevation acute coronary syndrome Improvement of lifestyle factors in addition to appropriate pharmacological management is recommended in order to reduce all- I A cause and cardiovascular mortality and morbidity and improve health-related quality of life.487497 Cognitive behavioural interventions are recommended to help individuals achieve a healthy lifestyle.498500 I A Multidisciplinary exercise-based cardiac rehabilitation is recommended as an effective means for patients with CAD to achieve a healthy lifestyle and manage risk factors in order to reduce all-cause and cardiovascular mortality and morbidity, and improve health- I A 487,497,501 related quality of life. Involvement of multidisciplinary healthcare professionals (cardiologists, general practitioners, nurses, dieticians, physiotherapists, psy- chologists, pharmacists) is recommended in order to reduce all-cause and cardiovascular mortality and morbidity, and improve I A health-related quality of life.492,499,502,503 Psychological interventions are recommended to improve symptoms of depression in patients with CAD in order to improve health- I B related quality of life.504,505 Annual influenza vaccination is recommended for patients with CAD, especially in the older person, in order to improve I B morbidity.505511 Continued ESC Guidelines 1347 Recommendations for pharmacological long-term management after non-ST-segment elevation acute coronary syndrome (excluding antithrombotic treatments) Lipid-lowering drugs Statins are recommended in all NSTE-ACS patients. The aim is to reduce LDL-C by >_50% from baseline and/or to achieve LDL-C I A <1.4 mmol/L (<55 mg/dL).533,534 If the LDL-C goalf is not achieved after 46 weeks with the maximally tolerated statin dose, combination with ezetimibe is I B recommended.514,535 If the LDL-C goalf is not achieved after 46 weeks despite maximally tolerated statin therapy and ezetimibe, the addition of a PCSK9 I B inhibitor is recommended.520,535 ACE inhibitors or ARBs ACE inhibitors (or ARBs in cases of intolerance to ACE inhibitors) are recommended in patients with heart failure with reduced Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 LVEF (<40%), diabetes, or CKD unless contraindicated (e.g. severe renal impairment, hyperkalaemia, etc.) in order to reduce all-cause I A and cardiovascular mortality and cardiovascular morbidity.536538 Beta-blockers Beta-blockers are recommended in patients with systolic LV dysfunction or heart failure with reduced LVEF (<40%).539541 I A MRAs MRAs are recommended in patients with heart failure with reduced LVEF (<40%) in order to reduce all-cause and cardiovascular I A mortality and cardiovascular morbidity.548,549 Proton pump inhibitors Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, DAT, TAT, or OAC I A monotherapy who are at high risk of gastrointestinal bleeding in order to reduce the risk of gastric bleeds.169 ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial fibrillation; ARB = angiotensin receptor blocker; b.i.d. = bis in die (twice a day); CABG = coronary artery bypass graft(ing); CAD = coronary artery disease; CCTA = coronary computed tomography angiography; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age >_75 years (2 points), Diabetes, Stroke (2 points)_Vascular disease, Age 65_74, Sex category (female); CKD = chronic kidney disease; CMR = cardiac mag- netic resonance; CS = cardiogenic shock; DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; DES = drug-eluting stent; ECG = electrocardiogram/electro- cardiography; eGFR = estimated glomerular filtration rate; ESC = European Society of Cardiology; FFR = fractional flow reserve; GDF-15 = growth differentiation factor 15; GP = glycoprotein; GRACE = Global Registry of Acute Coronary Events; h-FABP = heart-type fatty acid-binding protein; hs-cTn = high-sensitivity cardiac troponin; IABP = intra-aortic balloon pump; ICA = invasive coronary angiography; INR = international normalized ratio; i.v. = intravenous; LD = loading dose; LDL-C = low-density lipoprotein cholesterol; LMWH = low-molecular-weight heparin; LV = left ventricular; LVEF = left ventricular ejection fraction; MD = maintenance dose; MI = myocardial infarction; MINOCA = myocardial infarction with non-obstructive coronary arteries; MRA = mineralocorticoid receptor antagonist; NOAC = non-vitamin K antagonist oral anticoagulant; NSTEMI = non-ST-segment elevation myocardial infarction; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; OAC = oral anticoagulation/anticoagulant; o.d. = once daily; PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin kexin 9; TAT = triple antithrombotic therapy; UFH = unfractionated heparin; VKA = vitamin K antagonist. a Class of recommendation. b Level of evidence. c Does not apply to patients discharged the same day in whom NSTEMI has been ruled out d If none of the following criteria: haemodynamically unstable, major arrhythmias, LVEF <40%, failed reperfusion, additional critical coronary stenoses of major vessels, complica- tions related to percutaneous revascularization, or GRACE risk score >140 if assessed. e If one or more of the above criteria are present. f For patients at very high cardiovascular risk (such as patients with ACS), an LDL-C reduction of at least 50% from baseline and an LDL-C goal <1.4 mmol/L (<55 mg/dL) are recommended.512 15 Supplementary data .. .. Boston, United States of America; Paul Dendale, Faculty of Supplementary Data with additional Supplementary Figures, Tables, .. Medicine and Life Sciences, Hasselt University, Hasselt, Belgium; .. Maria Dorobantu, Cardiology, "Carol Davila" University of and text complementing the full text are available on the European .. Heart Journal website and via the ESC website at www.escardio.org/ .. Medicine and Pharmacy, Bucharest, Romania; Thor Edvardsen, .. Cardiology, Oslo University Hospital, Oslo, Norway; Thierry guidelines. ... Folliguet, UPEC, Cardiac surgery, Hôpital Henri Mondor .. .. (Assistance Publique Hôpitaux de Paris), Créteil, France; Chris P. .. 16 Appendix .. .. Gale, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom; Martine Gilard, Author/Task Force Member Affiliations: Emanuele .. .. Cardiology, CHU La Cavale Blanche, Brest, France; Alexander Barbato, Advanced Biomedical Sciences, University Federico II, .. Jobs, Department of Internal Medicine/Cardiology, Heart Center .. Napoli, Italy; Olivier Barthélémy, Sorbonne Université, ACTION .. Leipzig at University of Leipzig, Leipzig, Germany; Peter Jüni, Li Ka Study Group, Institut de Cardiologie, Hôpital Pitié-Salp^eetrière .. Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Canada; .. (Assistance Publique- Hôpitaux de Paris) (AP-HP), Paris, France; .. Ekaterini Lambrinou, Department of Nursing, School of Health Johann Bauersachs, Department of Cardiology and Angiology, .. Sciences, Cyprus University of Technology, Limassol, Cyprus; Basil .. Hannover Medical School, Hannover, Germany; Deepak L. Bhatt, .. S. Lewis, Cardiovascular Clinical Trials Institute, Lady Davis Carmel Brigham and Women’s Hospital and Harvard Medical School, .. Medical Center and the Ruth and Bruce Rappaport School of 1348 ESC Guidelines .. Medicine, Haifa, Israel; Julinda Mehilli, Munich University Clinic, .. Ingibjörg J. Guðmundsdottir; Ireland: Irish Cardiac Society, Aaron J. Ludwig-Maximilians University, Munich, Germany; Emanuele .. Peace; Israel: Israel Heart Society, Roy Beigel; Italy: Italian .. Meliga, Interventional Cardiology, AO Mauriziano Umberto I, Turin, .. Federation of Cardiology, Ciro Indolfi; Kazakhstan: Association of Italy; Béla Merkely, Heart and Vascular Center, Semmelweis .. Cardiologists of Kazakhstan, Nazipa Aidargaliyeva; Kosovo .. University, Budapest, Hungary; Christian Mueller, Cardiovascular .. (Republic of): Kosovo Society of Cardiology, Shpend Elezi; Research Institute Basel (CRIB) and Cardiology, University Hospital .. Kyrgyzstan: Kyrgyz Society of Cardiology, Medet Beishenkulov; .. Basel, University of Basel, Basel, Switzerland; Marco Roffi, Geneva .. Latvia: Latvian Society of Cardiology, Aija Maca; Lithuania: University Hospitals, Geneva, Switzerland; Frans H. Rutten, .. Lithuanian Society of Cardiology, Olivija Gustiene; Luxembourg: .. General Practice, Julius Center for Health Sciences and Primary Care, .. Luxembourg Society of Cardiology, Philippe Degrell; Malta: Maltese University Medical Center Utrecht, Utrecht University, Utrecht, .. Cardiac Society, Andrew Cassar Maempel; Moldova (Republic .. Netherlands; Dirk Sibbing, Privatklinik Lauterbacher Mühle am .. of): Moldavian Society of Cardiology, Victoria Ivanov; Netherlands: Ostersee, Munich, Germany; and Ludwig-Maximilians Universit€at .. Netherlands Society of Cardiology, Peter Damman; North .. Downloaded from https://academic.oup.com/eurheartj/article/42/14/1289/5898842 by guest on 08 February 2023 München, Munich, Germany; George C.M. Siontis, Department of .. Macedonia: North Macedonian Society of Cardiology, Sasko Cardiology, University Hospital of Bern, Inselspital, Bern, Switzerland. .. Kedev; Norway: Norwegian Society of Cardiology, Terje K. Steigen; .. .. Poland: Polish Cardiac Society, Jacek Legutko; Portugal: .. Portuguese Society of Cardiology, Jo~ao Morais; Romania: ESC Committee for Practice Guidelines (CPG): Stephan .. Windecker (Chairperson) (Switzerland), Victor Aboyans (France), .. Romanian Society of Cardiology, Dragos Vinereanu; Russian .. Federation: Russian Society of Cardiology, Dmitry Duplyakov; San Colin Baigent (United Kingdom), Jean-Philippe Collet (France), .. Veronica Dean (France), Victoria Delgado (Netherlands), Donna .. Marino: San Marino Society of Cardiology, Marco Zavatta; Serbia: .. Cardiology Society of Serbia, Milan Pavlovic; Slovakia: Slovak Fitzsimons (United Kingdom), Chris P. Gale (United Kingdom), .. Diederick E. Grobbee (Netherlands), Sigrun Halvorsen (Norway), .. Society of Cardiology, Marek Orban; Slovenia: Slovenian Society of .. Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni .. Cardiology, Matjaz Bunc; Spain: Spanish Society of Cardiology, Borja (Canada), Hugo A. Katus (Germany), Ulf Landmesser (Germany), .. Iba~nez; Sweden: Swedish Society of Cardiology, Robin Hofmann; .. Christophe Leclercq (France), Maddalena Lettino (Italy), Basil S. .. Switzerland: Swiss Society of Cardiology, Oliver Gaemperli; Lewis (Israel), Béla Merkely (Hungary), Christian Mueller .. Syrian Arab Republic: Syrian Cardiovascular Association, Yassin .. (Switzerland), Steffen E. Petersen (United Kingdom), Anna Sonia .. Bani Marjeh; Tunisia: Tunisian Society of Cardiology and Cardio- Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi .. Vascular Surgery, Faouzi Addad; Turkey: Turkish Society of .. (Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A. .. Cardiology, Eralp Tutar; Ukraine: Ukrainian Association of Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M. .. Cardiology, Alexander Parkhomenko; United Kingdom of Great .. Touyz (United Kingdom). .. Britain and Northern Ireland: British Cardiovascular Society, .. Nina Karia. .. 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Kahjustus võib ka müokard i i n fark t ireg ister on 1). Igapäevapraktikas on tarvis veel tekkida isegi intaktses südamelihases teinud aastaid tihedat koostööd meeles pidada, et cTn kontsentrat- erinevatel põhjustel, nagu füsioloogi- müokardiinfarkti (MI) diagnoosi- siooni suurenemiseks võivad olla line stress, apoptoos või müotsüütide mise juhendmaterjalide eestinda- üsna erinevad põhjused (vt tabel 2) membraani läbilaskvuse suurenemine misel (1–3), sel korral on töörühma ja ainult cTn sisalduse suurenemine (vt tabel 2). lisandunud Eesti Radioloogia Ühing. vereseerumis eraldiseisvana ei ole Kuna cTn vabanemine vererin- Juhendmaterjalide olemasolu on kardioloogi erakorralise konsultat- gesse sõltub olulisel määral süda- kogu riigis muutnud ühtlasemaks siooni tellimise põhjus. melihase verevoolust, erineb cTn müokardiinfarkti diagnoosimise, Joonised 1 ja 2 näitlikustavad 1. taseme tippväärtuse saabumine ja ühtlustunud on kasutusel olevate ja 2. tüüpi müokardiinfarkti puhust ülemise referentspiiri ületamine laboratoorsete meetodite valik ja koronaararterite leidu. patsientidel märkimisväärselt. cTn nende t u lemuste tõlgenda m i ne. taseme dünaamika sõltub ka proo- Erinevalt varasematest aastatest on 2. Müokardi kahjustuse vivõtmise ajastusest – liiga lühikese nüüd pööratud suuremat tähelepanu kindlakstegemise ajavahemiku järel võetud analüüside müokardi kahjustuse eristamisele laboratoorsed meetodid ja tulemustest võib olla raske leida müokardiinfarktist ja püütud paigu- tulemuste tõlgendamine dünaamilisi muutusi. tada kardiaalsete troponiinide (cTn) Eelistatud biomarkerid müokardi Oluline on teada, et cTn sisal- erinevaid väärtusi asjakohasesse kahjustuse diagnoosimiseks ning duse dünaamika hindamisel tuleb kliinilisse konteksti. v ä l i s t a m i s ek s on kõr g t u nd l i ke ar vestada n ii määra m ismeetod i Euroopa Kardioloogide Selts on meetoditega määratavad kardiaalsed analüütilist varieer uv ust k ui ka 2018. aastal avaldanud müokardiin- troponiinid I ja T (cTnI-hs, kard iaalne cTn enda bioloogilist varieeruvust. farkti diagnoosimise uue juhendma- troponiin I (kõrgtundlik) ja cTnT-hs, Kui cTn algväärtus jääb alla ülemise terjali (4), mille väljatöötamisel on k a r d i a a l n e t r o p o n i i n T ( kõr g- referentspiiri, siis on oluline ≥ 50% oma arvamust avaldanud ka Eesti tundlik)). suurenemine; kui aga algväärtus on Kardioloogide Seltsi esindaja, samuti Kreatiini kinaasi MB isoensüümi suurem kui ülemine referentspiir, on see dokument eri maades tunnus- mass (CK-MBm) on vähem tundlik on oluliseks ≥ 20% muutus. tatud igapäevakasutusse sobivaks. ja vähem spetsiifiline, kuid CK-MBm Uue (korduva) müokardiinfarkti Alljärgnevalt on avaldatud juhendi määramisest võib olla abi reinfarkti kahtluse korral tuleb vereanalüüs lühiversioon koos kommentaaridega, diagnoosimisel või keerukate diferent- kohe uuesti teha ja arvestada eelkir- et juhendis toodud põhimõtted oleks siaaldiagnostiliste olukordade korral. jeldatud cTn väärtuste tõlgendamise igapäevases kliinilises praktikas Tänapäeval ei kasutata müokardiin- soovitusi, diagnoosi kinnitamiseks mõistetud ja rakendatud ühetaoliselt farkti diagnoosimisel müoglobiini ja p eav ad esi nem a veel müok a r d i üle riigi. Märgime, et lisaks õigele transaminaase (ALAT, ASAT). i she e m i a le v i it a v a d k l i i n i l i s e d ravikäsitlusele tagab korrektne MI Ägeda MI (ÄMI) diagnoosi kinnita- tunnused. diagnoos ravijuhtude õige sisestamise miseks on vajalik cTn taseme tõus ja/ Mõnedel müoka rd i i n fa rk t iga müokardiinfarktiregistrisse ning see või langus koos müokardi isheemili- patsientidel võib esineda ebatüü- omakorda võimaldab ravikäsitluse ja sele kahjustusele viitava(te) tunnus(t) p i l i n e cTn t a s e m e d ü n a a m i k a . -tulemuste võrdlust eri ajaperioodidel, ega (vt tabel 1), kusjuures vähemalt Näiteks ei pruugigi cTn taseme tõusu samuti osalemist rahvusvahelistes üks cTn väärtus peab olema suurem tekkida, taseme muutus ei pruugi koostööprojektides. kui ülemine referentspiir. Tõusva ja/ vaatamata tüüpilisele kliinilisele või langeva dünaamika näitamine on pildile olla diagnostiliselt oluline, 1. Müokardi kahjustus ja vajalik, et eristada ägedat müokardi samuti võib arvestatav dünaamika müokardiinfarkt kahjustust kroonilisest (vt joonis 3). ilmneda alles 6 tundi pärast sümp- MI diagnoosimisel tuleb pöörata Kuigi cTn sisalduse suurenemine tomite algust. Kui patsient saabub t ä helepa nu sel lele, e t d iag noos veres peegeldab müokardi kahjustust, haiglasse 12–18 tundi pärast MI Eesti Arst 2019; 98(4):235–242 235 ravijuhend algust, siis nõuab langeva mustri niliselt oluline muutus cTn arvulises käsitluses tuleb aga ikkagi juhinduda tuvastamine pikemat jälgimist kui väärtuses jne. Enim soovitatakse eeskätt kliinilisest pildist. tavapäraselt. ägeda müokard i i n fark ti ka htlu- Mõnedes teadusuuringutes soovi- ÄMI diagnostilistes algoritmides sega patsiend i l võt ta vereproov t at ud 1–( 2) t u n n i a lgor it m i MI pole siiani üksmeelt, milliste ajava- cTn määramiseks kohe patsiendi välistamiseks Eestis ei soovitata, hem i ke järel a na lüüse määrata, ha iglasse saabu m isel ja kor rata kuna tulemuste tõlgendamist võivad milline on ÄMI diagnoosimisel klii- seda 3–6 tunni möödudes, patsiendi oluliselt häirida erinevate määra- Tabel 1. Müokardi kahjustuse ja müokardiinfarkti (MI) definitsioon Müokardi kahjustuse kriteeriumid Müokardi kahjustuse mõistet tuleb kasutada juhul, kui vähemalt üks kardiaalse troponiini (cTn) väärtustest ületab tervete referentsisikute 99. protsentiili (edaspidi ülemine referentspiir) (vt lisa 1 Eestis kasutatavate meetodite ja ülemiste referentspiiride kohta). Ägeda müokardi kahjustuse korral esineb cTn väärtuste suurenemine ja/või vähenemine. 1., 2. ja 3. tüüpi ägeda müokardiinfarkti (ÄMI) diagnoosimise kriteeriumid – Ägedat müokardiinfarkti saab diagnoosida, kui müokardi kahjustus koos cTn sisalduse iseloomuliku suurenemise ja/või vähenemisega esineb koos vähemalt ühe alltoodud kliinilise tunnusega, mis viitab müokardi isheemiale: • müokardi isheemia sümptomid; • EKG-l uus isheemiast tingitud muutus; • EKG-l uute patoloogiliste Q-sakkide tekkimine; • piltdiagnostikameetoditega tõendatud eluvõimelise müokardi uus kadu või uus segmentaarne kontraktsioonihäire, mis on seletatav müokardi isheemiaga; • koronarograafial või lahangul intrakoronaarne tromb (v.a 2. ja 3. tüüpi MI puhul). – Elupuhuselt aterosklerootilise naastu rebendi/erosiooniga seotud tromboos või lahanguleiuna infarkti põhjustanud koronaararteri äge tromboos vastab 1. tüüpi MI-le. – Koronaararteri ägeda aterotromboosiga mitteseotud müokardi hapnikuvarustuse ja hapnikuvajaduse düsbalanss vastab 2. tüüpi MI-le. – Kardiaalne äkksurm müokardi isheemiale viitavate sümptomitega ja arvatavalt EKG uue isheemilise muutusega, kui vereproovi cTn määramiseks pole võetud või selle väärtus pole veel jõudnud tõusta üle ülemise referentspiiri, vastab 3. tüüpi MI-le. Koronaarprotseduuriga seotud 4. ja 5. tüüpi ägeda müokardiinfarkti diagnoosimise kriteeriumid – Perkutaanse koronaarinterventsiooni (PKI) järgne MI on 4.a tüüpi MI. Ägeda MI-ga on tegemist, kui ≤ 48 tundi pärast PKI protseduuri leitakse normis cTn algväärtustega patsiendil enam kui 5kordne cTn-taseme tõus üle ülemise referentspiiri või eelnevalt tõusnud, kuid stabiilse või langeva cTn algväärtusega patsiendil enam kui 20% tõus algväärtusest. Lisaks peab esinema vähemalt üks müokardi isheemiale viitav kliiniline tunnus: • EKG-l uus isheemiast tingitud muutus; • EKG-l uute patoloogiliste Q-sakkide tekkimine; • piltdiagnostikameetoditega tõendatud uus segmentaarne kontraktsioonihäire või eluvõimelise müokardi uus kadu, mis on seletatav müokardi isheemiaga; • koronarograafial koronaarverevoolu takistav tüsistus, nt dissektsioon, koronaararteri või šundi oklusioon, külgharu oklusioon, kollateraalringe katkemine või distaalne embolisatsioon. – 4.b tüüpi MI-ga on tegemist stendi tromboosi korral, kui esinevad 1. tüüpi MI tunnused. 4.b tüüpi MI jagatakse alates protseduuri ajast järgmiselt: 0–24 tundi – äge; > 24 tundi kuni 30 päeva – alaäge; > 30 päeva kuni 1 aasta – hiline; > 1 aasta – väga hiline. – 4.c tüüpi MI-ga on tegemist südamelihase infarktialaga seotud stendi või ballooniga dilateeritud koronaararteri restenoosi korral, kui esinevad 1. tüüpi MI tunnused ja ei esine teisi olulisi stenoose või tromboosi teistes koronaararterites. Protseduurijärgne koronaartromboosi leid lahangul kinnitab 4.a tüüpi MI diagnoosi või stendi olemasolul 4.b tüüpi MI diagnoosi. – Aorto-koronaarse šunteerimise (AKŠ) järgne MI on 5. tüüpi MI. Ägeda MI-ga on tegemist, kui ≤ 48 tundi pärast AKŠd leitakse normis cTn algväärtusega patsiendil enam kui 10kordne cTn tõus üle ülemise referentspiiri või eelnevalt tõusnud, kuid stabiilse või langeva cTn algväärtusega patsiendil enam kui 20% tõus algväärtusest. Lisaks peab esinema vähemalt üks müokardi isheemiale viitav kliiniline tunnus: • EKG-l uute patoloogiliste Q-sakkide tekkimine; • piltdiagnostikameetoditega tõendatud uus segmentaarne kontraktsioonihäire või eluvõimelise müokardi uus kadu, mis on seletatav müokardi isheemiaga; • koronarograafial koronaarverevoolu takistav tüsistus, nt dissektsioon, koronaararteri või -šundi oklusioon, külgharu oklusioon, kollateraalringe katkemine või distaalne embolisatsioon. Läbipõetud MI diagnoosimise kriteeriumid Läbipõetud MI diagnoosimiseks on vajalik vähemalt ühe kriteeriumi olemasolu: – EKG-l uute patoloogiliste Q-sakkide teke (sümptomitega või ilma) mitteisheemiliste põhjuste puudumisel; – piltdiagnostikameetoditega tõendatud segmentaarne kontraktsioonihäire, mis on seletatav müokardi isheemiaga; – läbipõetud müokardiinfarkti leid lahangul. 236 Eesti Arst 2019; 98(4):235–242 ravijuhend mismeetodite täpsus, tegelik aeg Tabel 2. Näited müokardi kahjustuse ja kardiaalsete troponiinide (cTn) ataki algusest analüüsi võtmiseni taseme tõusu põhjuste kohta ja teistest põhjustest tulenev cTn Müokardi kahjustus, põhjustatud ägedast müokardi isheemiast väärtuste võimalik dünaamika. Alates 2012. aastast on enamikus Aterosklerootilise naastu ruptuur koronaararteri tromboosiga Eesti haiglates kasutusele võetud Müokardi kahjustus hapnikuvarustuse ja -vajaduse düsbalansist põhjustatud cTn-hs sisalduse määramise meetodid. ägedast müokardi isheemiast Tuleb arvestada, et erinevate määra- Müokardi vähenenud perfusioon mismeetoditega saadud cTn tule- Koronaarspasm, mikrovaskulaarne düsfunktsioon mused pole omavahel võrreldavad. Koronaaremboolia Koronaararteri dissektsioon Lisaks, mõnel pool kasutatavad point Bradüarütmia of care’ (POC) metoodikad pole nii Hüpotensioon või šokk tundlikud kui cTn-hs meetodid ja Hingamispuudulikkus Raske aneemia cTn taseme väikesed tõusud võivad Müokardi suurenenud hapnikuvajadus jääda avastamata. Ülevaade kasutusel Tahhüarütmia olevatest cTn määramismeetoditest Raske hüpertensioon koos vasema vatsakese müokardi hüpertroofiaga või ilma selleta ja referentspiiridest (vt lisa 1) on toodud ajakirja Eesti A rst, Eesti Müokardi kahjustuse teised põhjused Kardioloogide Seltsi, müokardiin- Kardiaalsed põhjused farktiregistri ja Eesti Laborimedit- Südamepuudulikkus Müokardiit siini Ühingu veebilehtedel, mida Kardiomüopaatia ajakohastatakse regulaarselt. Takotsubo sündroom Koronaararterite revaskulariseerimine Teised mitterevaskulariseerivad protseduurid südamel 3. Periprotseduuriline Kateeterablatsioon müokardiinfarkt Defibrillaatori šokid Pärgarterite revaskulariseerimise Südamepõrutus Süsteemsed põhjused (perkutaanne koronaarinterventsioon Sepsis, infektsioon (PKI) või aorto-koronaarne šuntimine Krooniline neerupuudulikkus (AKŠ)) käigus võib erinevate mehha- Insult, subarahnoidaalne hemorraagia Kopsuarteri trombemboolia, pulmonaalhüpertensioon nismide kaudu tekkida südamelihase Amüloidoos, sarkoidoos kahjustus, mis kajastub kardiaalsete Kemoterapeutikumid biomarkerite taseme tõusuna pärast Kriitilises seisus patsient Ülemäärane füüsiline koormus protseduuri. Patsiendi huvides on Skeletilihaste kahjustus (võib anda cTnT-hs taseme tõusu) alati sellise müokardikahjustuse ulatuse piiramine. cTnT-hs – kardiaalne troponiin T (kõrgtundlik) Per iprot seduu r i l i se MI d iag- nostilised kriteeriumid põhinevad konsensusel ning lisaks cTn taseme tõusule peavad esinema ka muud müoka rd i isheem ia le v i itav ad tunnused (vt tabel 1). Periprotse- duurilise MI diagnoosimiseks peab cTn olema määratud enne ja 6–24 tundi pärast protseduuri. Naastu ruptuur/erosioon okluseeriva trombiga Kui revaskulariseerimise järel tek k iv cTn taseme tõus ei ü leta periprotseduurilise müokardiin- farkti diagnostilist kriteeriumit (PKI korral cTn tõus > 5 korda) või esineb cTn tõus > 5 korda ilma müokardi isheemia tunnusteta, ei ole õige Naastu ruptuur/erosioon mitteokluseeriva trombiga diagnoosida periprotseduurilist müokardiinfarkti, vaid diagnoos on sel juhul „müokardi kahjustus“. St e n d i t r om b o o s i s t t e k k i v a Joonis 1. 1. tüüpi müokardiinfarkt, lähtudes koronaararterite müokardiinfarkti diagnoosimiseks seisundist. Eesti Arst 2019; 98(4):235–242 237 ravijuhend peab tromboos olema tõestatud AKŠga seotud müokardiinfarkti esinema normis cTn algväärtusega kas angiograafiliselt või lahangul. korral on harvem tegemist lokaalse patsiendil > 10kordne cTn taseme Erinevate patofüsioloogiliste mehha- kahjustusega ja sagedamini esineb tõus üle ülemise referentspiiri või nismide rõhutamiseks soovitatakse d i f u u s s e t s u b e n d o k a r d i a a ls e t eelnevalt tõusnud, kuid stabiilse või klassifitseerida stendi tromboosid i sheem i at , m i s on p õhju s t at ud langeva cTn algväärtusega patsiendil tekkeaja järgi pärast protseduuri ot sesest oper at sioon it r au m a st, > 20% tõus alg väärtusest. Lisaks järgmiselt: 0–24 tundi – äge; > 24 ebapiisavast kardiopleegiast või peab esinema vähemalt 1 tabelis 1 tundi kuni 30 päeva – alaäge; > 30 reperfusioonikahjustusest. AKŠga toodud müokardi isheemiale viita- päeva kuni 1 aasta – hiline; > 1 aasta – seotud müokardiinfarkti diagnoosi- vatest tunnustest. väga hiline. miseks peab ≤ 48 tundi pärast AKŠd 4. Mitteobstruktiivsete koronaararteritega müokardiinfarkt (MINOCA) L i g i k au d u 6 –8% -l ä ge d a M I-g a patsientidest ei leita angiograafilise Ateroskleroos ja hapniku juurdevoolu/ uuringu käigus koronaararterites vajaduse düsbalanss obstruktiivseid muutusi (≥ 50%-lisi stenoose). Sellisel juhul kasutatakse seisundi kohta kok k uleppeliselt terminit MINOCA (ingl myocardial Vasospasm või koronaararteri infarction with non-obstructive coro- mikrovaskulaarne düsfunktsioon nary arteries). Müokardi kahjustuse mehhanismiks on isheemia, mis võib olla põhjustatud nii naastu ruptuu- rist ja tromboosist (1. tüüpi MI) kui ka koronaarspasmist või spontaan- Mitteaterosklerootiline koronaararteri dissektsioon sest koronaararteri dissektsioonist (2. tüüpi MI). Lisaks on oluline välis- tada mitteisheemilised põhjused, näiteks müokardiit, ning veenduda, e t koron aa r a r ter ite k a hju st u se Hapniku juurdevoolu/vajaduse düsbalanss u lat u st ei ole v ää r it i h i n nat ud. MINOCA diagnoosi kinnitamiseks ja isheemia põhjuse kindlakstege- Joonis 2. 2. tüüpi müokardiinfarkt, lähtudes koronaararterite miseks võib olla vaja rakendada seisundist. teisi pi ltd iag nost i k a meetodeid, Väga millega saab hinnata koronaarar- varane Varane Hilisem Väga hiline terite seisundit. analüüs analüüs analüüs analüüs 5. Takotsubo sündroom Ta kot subo sü nd room ( TS ) võib matkida ägedat MI-d ning see esineb Äge 1–2%-l STEMI-kahtlusega patsien- müokardi- tidest. Sellele eelneb sageli tugev infarkt emotsionaalne stress ja üle 90% cTn Krooniline patsientidest on postmenopausis müokardi naised. Kardiovaskulaarsed komp- kahjustus likatsioonid ( kardiogeenne šokk, vasaku vatsakese ruptuur ja maliigsed Referentspiir arütmiad) esinevad umbes pooltel juhtudest ning haiglasisene suremus on sarnane STEMI-patsientide omaga. Aeg ataki algusest (tundides) TSi peaks kahtlustama, kui klii- nilised sümptomid ja EKG muutused Joonis 3. Kardiaalse troponiini (cTn) sisalduse dünaamika ägeda p o l e k o o s k õ l a s cTn v ä ä r t u s t e müokardiinfarkti ja kroonilise müokardikahjustuse korral. kasvuga ning kui vasaku vatsakese 238 Eesti Arst 2019; 98(4):235–242 ravijuhend regionaalse kontraktiilsuse häired ei ei esine koronaararterite kahjus- eriti kui esineb koronaarhaig us. korreleeru ühe üksiku koronaarar- tust, või isegi kui seda esineb (u Takotsubo sündroomi diagnoosi teri varustusalaga. TSi kliiniline pilt 15%-l juhtudest), siis ei seostu see kood RHK-10 järgi on Eestis kokku- sarnaneb sageli ägeda koronaarsünd- regionaalse kontrak tsioonihäire leppeliselt I42.8. roomi omaga ja EKG-l võib esineda lokalisatsiooniga. Vasaku vatsakese ST-segmendi elevatsioone, enamasti kont r a k t sioon i v i sua l i seer iv ate 6. Elektrokardiogramm ja laialdasemalt kui ainult prekordiaal uuringutega võib täheldada erine- selle tõlgendamine setes lülitustes. ST-segmendi depres- v a id s ü d a me l i h a s e s eg me nt ide E KG o n ä g e d a k o r o n a a r s ü n d - sioon on umbes 10%-l patsientidest liik uv use häireid, sh apikaalset, room i ka htluse kor ra l rav id iag- ning 12–24 tunni järel esineb sageli ke sk ve nt r i k u l a a r s e t , b a s a a l s e t nostiliste otsuste nurgakivi. Selle sümmeetrilist T-sakkide inversiooni või fokaalset ringjat hüpo- ja/või lihtsa meetodi kiire kättesaadavus ja QTc-aja pi kenem ist. Üldju hu l akineesi, mis on ulatuslikum kui peab olema tagatud kõikjal Eestis. esineb katehoolamiinidest tingitud ainult ühe koronaararteri varustus- EKG t u leb teha n i ng seda peab sekundaarne mööduv cTn taseme alale vastav häire. Kardiaalse funkt- tõlgendama 10 minuti jooksul nii tõus, kuid tippväärtused on taga- siooni normaliseerumise kiirus võib haiglaeelses etapis kui ka haiglate sihoidlikud ja vastuolus ulatuslike varieeruda tundidest nädalateni, vastuvõtuosakondades alates haige muutustega EKG-l või vasaku vatsa- k u id u mbes 10–15%-l ju ht udest kont a k t i st med it si i n itööt ajag a. kese düsfunktsiooni leiuga. võib tä heldada püsiv a id hä ireid Heameel on tõdeda, et tasapisi on Diag noosi k i n n it a m i sek s on diastoolses funktsioonis, müokardi hakanud juurduma EKG ülekanne tavaliselt vaja teha koronaaran- kontraktiilses reservis koormusel vastuvõtvasse haiglasse ja konsul- giog raaf ia ja eh hokard iog raaf ia või rütmihäireid. Ägeda MI ja TSi teer i m i ne sea lse ka rd ioloog iga. või ventrik ulog raaf ia. Enamasti er i st a m i ne võib ol la keer u l i ne, See võimaldab parandada raviot- suse kvaliteeti ja samal ajal vähen- d ad a a sjat ut pr ot seduu r ieel se t ajakulu koronaarsekkumisi tegevas haiglas. Tuleb märkida, et kvaliteetse EKG jaoks on ülioluline elektroodide õige asetus (vt joonis 4). Asetust tuleb kindlasti jälgida korduvate EKGde tegemisel ja tõlgendamisel kliini- liselt ebamäärastes olukordades. EKG leiu tõlgendamise meelespea on esitatud tabelis 3 ja 4. 7. Piltdiagnostika meetodid Müokardiinfarkti saab diagnoosida, 1 2 kui troponiini tõusule või langusele 3 kaasub piltdiagnostikameetoditega tõendatud uus segmentaarne kont- 4 5 6 raktsioonihäire või uus eluvõimelise müokardi kadu, mis on seletatav müokardi isheemiaga. V1 V2 V 3 V4 V5 V6 Ehhokardiograafia on kõige kiirem, k ät tes a ad av a m ja o d av a m pi lt- diagnostika meetod MI diagnoosi- Joonis 4. EKG elektroodide standardsed asetused. V 1 – neljas misel. Ehhokardiograafiliselt saab roidevahemik paremal rinnaku äärel; V 2 – neljas roidevahemik vasemal h i n nat a n i i süda me st r u k t uu re rinnaku äärel; V 3 –V 2 ja V4 vahel; V4 – viies või kuues roidevahemik kui ka funktsioone. MI kontekstis (tiputõuke juures) keskmisel klavikulaarjoonel; V 5 – eesmisel aksillaarjoonel, samal kõrgusel kui V4; V6 – keskmisel aksillaarjoonel V4 h i n nat a k se v atsa keste suu r u st, ja V 5 kõrgusel. üldist süstoolset funktsiooni, seina Jäsemetele asetatavad elektroodid on tähistatud järgmiselt: paksust, seina ehitust ning regio- RA – parem käsi (punane); LA – vasem käsi (kollane); LL – vasem naa l se t sü stool se t f u n k t sioon i: jalg (roheline); RL – parem jalg / maandus (must). Parempoolsed sei n a pa k senem i s t, õhenem i s t, rinnalülitused asetatakse rindkerele joonisel esitatuga peegelpildis. liikumist. Regionaalne kontraktsioo- Eesti Arst 2019; 98(4):235–242 239 ravijuhend nihäire tekib isheemia tõttu kohe, Tabel 3. Müokardi isheemiale viitavad muutused EKGs (vasaku kui isheemiast on haaratud üle 20% vatsakese hüpertroofia ja Hisi kimbu blokaadi puudumise korral) seinapaksusest. Tuleb aga meeles ST-segmendi elevatsioon pidada, et regionaalse kontraktsioo- nihäire puudumine ei välista kind- Uus ST-segmendi elevatsioon J-punktis ≥ 0,1 mV (1 mm) kahes järjestikuses sama piirkonda kajastavas lülituses nii meestel kui ka naistel, välja arvatud lülitustes V2 ja V3. lalt MI-d ning mittekoronarogeense Lülitustes V2 ja V3 on järgmised ST-segmendi elevatsiooni kriteeriumid: ≥ 0,2 mV uue regionaalse kontraktsioonihäire (2 mm) meestel vanuses ≥ 40 aastat ja ≥ 0,25 mV (2,5 mm) meestel vanuses < 40 põhjusteks võivad olla põletikulised aastat ning ≥ 0,15 mV (1,5 mm) naistel olenemata vanusest. või infiltratiivsed haigused ning ST-segmendi depressioon ja T-saki muutused kardiomüopaatiad, sh TS. E h hok a r d iog r a a f i l i s e lt s a ab Uus horisontaalne või destsendeeruv ST-segmendi depressioon ≥ 0,05 mV (0,5 mm) kahes järjestikuses sama piirkonda kajastavas lülituses ja/või d i ag no osid a te i si r i nd ke r e v a lu põhjuseks olevaid südamehaigusi T-saki inversioon ≥ 0,1 mV (1 mm) kahes järjestikuses lülituses promineeruva R-sakiga või R/S suhtega > 1. nag u per i kard i it, aord i d issek t- sioon, aord i k lapi r aske stenoos Tabel 4. EKG muutused seoses läbipõetud müokardiinfarktiga (vasaku j a hüp e r t r o of i l i n e k a r d iomü o - vatsakese hüpertroofia ja Hisi kimbu blokaadi puudumise korral) paatia. Ehhokardiograafia on kiirelt Q-sakk ≥ 0,02 s või QS-kompleks lülitustes V2 ja V3. rakendatav ka raske hemodünaa- m i k a h ä i r e ( k a r d iogeen se šok i ) Q-sakk ≥ 0,03 s ja ≥ 0,1 mV (1 mm) sügavusega või QS-kompleks vähemalt kahes sama piirkonda kajastavas lülituses (I, aVL; V1–V6; II, III ja aVF). p õhj u s t e s e l g i t a m i s e l , n ä i t e k s M I meh a a n i l i s te t ü si s t u s te või R-sakk ≥ 0,04 s lülitustes V1-V2 ja R/S ≥ 1 koos samaaegse positiivse T-sakiga ülejuhtehäire puudumisel. mittekoronarogeensete haiguste (kopsuarteri trombemboolia, aordi dissektsioon) kahtluse korral. kardiaalse müokardi kahjustus ning koronaararteri kahjustust ei leita Uutest ehhokardiograafia meeto- MI ala ulatus subendokardiaalsetest (nä itek s võib ol la teg u ok lusee- d itest on MI d iagnostikas k ind- kiududest epikardi suunas. Mitte runud koronaararteri haru mittelei- lasti kasu kontrastehhokardiograa- isheemilise kahjustusmustri korral tava köndiga). Uueks arendatavaks f iast – see võimaldab endokardi domineerib subepikardiaalsete ja meetodiks on müokardi perfusiooni paremat visualiseerimist kujutise mesokardiaalsete müokardi kiudude ja isheemilise kahjustuse hindamine kehva kvaliteedi korral. Müokardi k a hjust us n i ng m it mekoldel i ne KT-l, selle meetodi kohta kliinilises per f usioon i uu r i m i ne kont r ast müokardi haaratus. praktikas näeme tulevikus. ehhokardiograafiaga ei ole meil veel MRT on näidustatud rindkerevalu kliinilisse kasutusse jõudnud. Uueks ja troponiini muutustega patsiendil, 8. Diagnoosi vormistamine meetodiks on ka vasema vatsakese kui koronaararterite angiograafilisel Rahv usvahelise haiguste klassifi- üldise ja regionaalse deformatsiooni uuringul ei leita pärgarteri kliinili- katsiooni 10. versiooni ( RHK-10) hindamine ( global strain, longitu- selt olulist stenoosi või oklusiooni alusel (5) kodeeritakse esmane äge dinal strain, GLS), mida Eestis juba (MINOCA). müokardiinfark t k ui I21.0–I21.9 rakendatakse. MRT võimaldab eristada, kas juhul, kui sümptomite algusest on tegem i s t on M I-s t p õhju s t at ud möödunud ≤ 28 päeva. Koodi I21 Mag ne t resona nt stomog raa f ia l müokardi kahjustusega või teiste kasutatakse patsiendi elu jooksul (MRT) on MI korral võimalik hinnata ägedate müokardi haigustega nagu ainult esimese müokardiinfarkti südamelihase funktsiooni, kahjus- müokardiit, perikardiit, Takotsubo korral. Korduva ägeda müokardi- tuse ulatust (subendokardiaalne, sündroom. infark ti kood on I22.0–I22.9 iga t r a n smu r aa l ne i n fa rk t), sa mut i Enne planeeritavat müokardi järgneva müokardiinfarkti puhul mikrovaskulaarse obstruktsiooni, revask ulariseerimist ( PKI, A KŠ) ( ha ig use kest us a lates sü mpto- verdumise ja turse olemasolu ning võib olla vaja hinnata müokardi mite algusest ≤ 28 päeva). Euroopa ulatust. eluvõimelisust revaskulariseerimise Ka rd ioloog ide Seltsi ju hend ma- Tu r s e ole m a s olu h i nd a m i ne vajaduse ja ulatuse otsustamiseks. terjalis tähistatakse vähem kui 28 või ma ldab er istada ägedat MI-d päeva jooksul tekkinud uut müokar- kroonilisest kahjustusest. MI kahjus- Kompuutertomograafiline ( KT ) diinfarkti terminiga re-infarction tusala diagnoosimise aluseks on angiograafia koronaararteritest ja alates 28 päevast tekkinud MI-d ek st r atsel lu laa rse kont r ast a i ne tuleb ÄMI-haigel arvesse, kui MRT-l terminiga recurrent infarction. visualiseerumine müokardi hilise on t üüpi l i ne äged a i sheem i l i se Märkus. Korduva müokardiin- kontrasteerumise seerial (LGE – late müoka rd i ka hjust use leid, k u id farkti diagnoos tuleb vormistada gadolinium enhancement). Isheemi- koronaararterite angiograafilisel ka nendel juhtudel, kui eelmisest lisele MI-le on iseloomulik subendo- uuringul infarkti põhjuseks olevat müok a r d i i n f a rk t i s t on möö d a s 240 Eesti Arst 2019; 98(4):235–242 ravijuhend vähem kui 28 päeva, kuid esinevad I22.8 Mu u d e p a i k m e t e k o r d u v Infarctus myocardii acutus ( I, tabelis 1 kirjeldatud kriteeriumid. müokardiinfarkt 12.01.2019, inferioorne, NSTEMI, Koodi I25.2 kasutatakse vara- I22.9 Täpsustamata paikme korduv 1. tüüp). AKŠ (16.01.2019; 3 šunti: sema müokardiinfarkti või para- müokardiinfarkt LIMA → A; Di; OM), RHK kood I21.1. nenud müokardiinfarkti korral, kui I25.2 Varasem müokardiinfarkt Infarctus myocardii recurrens (II, ägeda müokardiinfarkti sümptomite 12.01.2019, anterioorne, STEMI, 1. algusest on möödunud üle 28 päeva. Ägeda müokardiinfarkti lõplik diag- tüüp). Trombolüüs (12.01.2019, tenek- Takotsubo sündroomi diagnoosi noos peab sisaldama järgmist infot: teplaas). Päästev PKI (12.01.2019, koodina kasutatakse I42.8 (muud - Mitmenda ÄMI-ga on tegemist? A6 → 1, 2 DES), RHK kood I22.0. kardio(müo)paatiad). - ÄMI kuupäev. Erand! Kui äge MI on seotud koro- - ÄMI lokalisatsioon. naarangiograafiaga või PKI-ga, siis RHK-10 koodide laiendid täpsustavad - Kas tegemist on ST-segmendi lisada sulgudes periprotseduuriline. müokardiinfarkti järgmiselt: ele v atsioon iga (ST EMI ), Kui ÄMI on seotud AKŠga, siis lisada I21.0 Äge seinaläbine [ehk trans- S T- s e g m e n d i e l e v a t s i o o n i t a perioperatiivne. muraalne] müokardi eesseina müokardiinfarktiga ( NSTEMI ) Infarctus myocardii recurrens (II, infarkt või periprotseduurilise/periope- 12.01.2019, inferioorne, NSTEMI, I21.1 Äge seinaläbine [ehk trans- ratiivse müokardiinfarktiga. periprotseduuriline, 4.a tüüp). PKI muraalne] müokardi allseina - Kui patsiendil on tehtud trom- (12.01.2019, D4 → 1+1 DES), RHK infarkt bolüüs, siis teave trombolüüsi kood I22.1. I21.2 Muude paikmete äge seinalä- kohta (k.a kuupäev). Infarc tus myocardii pristinus bine müokardiinfarkt - Kui patsiendil on tehtud PKI ja/ (1998, i n fe r io or ne; 2018, a nte- I21.3 Äge seinaläbine täpsustamata või AKŠ, siis info nende kohta. rioorne). PKI (1998, D). AKŠ (2014, paikme müokardiinfarkt - Ä M I t ü ü p (uus kohus t usl i k 2: LIMA → DIP; OM) RHK kood I25.2. I21.4 Ä g e s u b e n d o k a r d i a a l n e tunnus alates 2019 aastast, vt müokardiinfarkt tabel 5). 9. Müokardiinfarktiregister I21.9 Täpsustamata äge müokardi- Oluline on sisestada andmed müokar- infarkt Näited diinfarktijuhu kohta müokardiin- Märkus. Korduva müokardiin- Äge müokardiinfark t / Infarctus farktiregistrisse tähtaegselt ja täie- farkti puhul ei kasutata koodi I21.x. myocardii acutus (mitmes, kuupäev, likult, nii saame kõik kaasa aidata lok a l i s at sioon , ST EM I/ NST EM I, kvaliteetsete aruannete õigeaegsele I22.0 Korduv müokardi eesseina t ü ü p) . Tr o m b o l ü ü s ( k u u p ä e v, valmimisele ja müokardiinfarktire- infarkt millega). PKI ( kuupäev, koronaar gistri tegevuse eesmärkide täitmisele. I22.1 Korduv müokard i a l lsei na arterid, stendid ). AKŠ ( kuupäev, infarkt šundid). K IRJA NDUS 1. Müokardiinfarkti diagnoosimise uuendatud kri- teeriumid 2010. Eesti Arst 2010;89:375–7. 2. Müokardiinfarkti kolmas universaalne definitsioon. Tabel 5. Müokardiinfarkti tüübid Eesti Arst 2013;92:231–5. 3. Uuenenud müokardiinfarkti kolmas universaalne 1. tüüp – müokardiinfarkt, mis on seotud aterosklerootilise naastu rebendi/ definitsioon. Eesti Arst 2017;96:113–4. erosiooniga, mille tulemusena käivitub aterotrombootiline protsess 4. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth uni- versal definition of myocardial infarction (2018). 2. tüüp – müokardiinfarkt, mis on tekkinud koronaararteri ägeda aterotromboosiga Eur Heart J 2019;40:237–69. mitteseotud müokardi hapnikuvarustuse ja hapnikuvajaduse düsbalansi 5. Diagnoosikoodid RHK järgi. http://rhk.sm.ee/. tõttu (nt koronaararterite spasm, embol, tahhü-braduarütmia, aneemia, hingamispuudulikkus, hüpertensiivne kriis) Euroopa Kardioloogide Seltsi juhendmaterjali eestin- damisel osalesid Toomas Marandi (töörühma juht), Tiia 3. tüüp – kardiaalne äkksurm müokardi isheemiale viitavate sümptomitega ja Ainla, Mai Blöndal, Ruth Brand, Jaan Eha, Märt Elmet, arvatavalt EKG uue isheemilise muutusega, kui vereproovi cTn määramiseks pole Jaanus Laanoja, Peep Laanmets, Anita Liiver, Ants võetud või selle väärtus pole veel jõudnud tõusta üle ülemise referentspiiri Paapstel, Margus Peeba, Julia Reinmets, Katrin Reimand, Aet Saar, Tarmo Serka, Andrei Šamarin, Karel Tomberg, 4.a tüüp – perkutaanse koronaarinterventsiooniga (PKI) seotud müokardiinfarkt, Kaja Vaagen, Gudrun Veldre, Galina Zemtsovskaja. mis tekib ≤ 48 tunni jooksul (pärast PKI protseduuri leitakse normis cTn algväärtustega patsiendil > 5kordne cTn tõus üle ülemise referentspiiri või Käesoleva dokumendi on heaks kiitnud Eesti Kardio- eelnevalt tõusnud, kuid stabiilse või langeva cTn algväärtusega patsiendil > 20% loogide Selts 15.03.2019, Eesti Laborimeditsiini Ühing 25.02.2019 ja Eesti Radioloogia Ühing 25.02.2019. tõus algväärtusest ja lisaks esineb vähemalt üks müokardi isheemiale viitav kliiniline tunnus) 4.b tüüp – stendi tromboosiga seotud müokardiinfarkt TÄ NUAVA LDUS 4.c tüüp – stendi restenoosiga seotud müokardiinfarkt Juhendmaterjali koostamist on finantseerinud Eesti 5. tüüp – aortokoronaarse šunteerimisega (AKŠ) seotud müokardiinfarkt, mis tekib Kardioloogide Selts ja Eesti Teadusagentuur (PRG 435) ≤ 48 tunni jooksul (pärast AKŠd leitakse normis cTn algväärtustega patsiendil > 10kordne cTn taseme tõus üle ülemise referentspiiri või eelnevalt tõusnud, kuid Kirjavahetajaautor: stabiilse või langeva cTn algväärtusega patsiendil > 20% tõus algväärtusest ja Toomas Marandi lisaks esineb vähemalt üks müokardi isheemiale viitav kliiniline tunnus) [email protected] Eesti Arst 2019; 98(4):235–242 241 ravijuhend Lisa 1. Eestis kasutusel olevad kardiaalse troponiini (cTn) määramise meetodid (ajakohastatud 16.04.2019) Ülemine referentspiir (referentsisikute Haigla Tootja/analüsaator cTnT või cTnI 99. protsentiil) Piirkondlikud haiglad Põhja-Eesti Regionaalhaigla Roche / cobas e 601 cTnT-hs 14 ng/l Tartu Ülikooli Kliinikum Roche / cobas e 601 cTnT-hs 14 ng/l Keskhaiglad Ida-Tallinna Keskhaigla Roche / cobas e 601 cTnT-hs 14 ng/l Lääne-Tallinna Keskhaigla Roche / cobas e 411 cTnT-hs 14 ng/l Ida-Viru Keskhaigla Roche / cobas e 601 / e 411 cTnT-hs 14 ng/l Pärnu Haigla Abbott/Architect / i1000sr/i2000sr cTnI-hs 26 ng/l Üldhaiglad Järvamaa Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Kuressaare Haigla Roche / cobas e 601 / e 411 cTnT-hs 14 ng/l Läänemaa Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Rakvere Haigla Beckman Coulter / ACCESS 2 cTnI-hs 40 ng/l Lõuna-Eesti Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Narva Haigla Abbott / Architect i1000sr cTnI-hs 26 ng/l Viljandi Haigla Roche / cobas e 601 / e 411 cTnT-hs 14 ng/l Valga Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Hiiumaa Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Põlva Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Raplamaa Haigla Roche / cobas e 411 cTnT-hs (kl 8.00–18.00) 14 ng/l Roche / cobas h232 (EMO POC)* cTnT (kl 18.00–8.00) Pole rakendatav Kohalik haigla Jõgeva Haigla Roche / cobas e 411 cTnT-hs 14 ng/l Labor Eralabor Siemens / ADVIA Centaur XPT cTnI-hs 47 ng/l EMO – erakorralise meditsiini osakonnas tehtud analüüs cTnT – kardiaalne troponiin T cTnI – kardiaalne troponiin I cTnT-hs – kardiaalne troponiin T (kõrgtundlik) cTnI-hs – kardiaalne troponiin I (kõrgtundlik) * POC troponiini tulemusele ei saa toetuda müokardiinfarkti välistamisel, sest POC analüsaatori väikseim määratav tulemus on 40 ng/l. POC – point of care 242 Eesti Arst 2019; 98(4):235–242 08.02.23 11:25 Kõrgtundliku troponiin T ja I kasu: kas nad on samaväärsed? – American College of Cardiology Kasu kõrgtundliku troponiin T ja I määramisest: kas nad on samaväärsed? 21.11.2019 | Paul Welsh. PhD: David Preiss. MB ChB. PhD: Naveed Sattar, MD Ekspertanalüüs Sarkomeeri ja troponiini taust Troponiin T ja I osas teadaoleva info konteksti paigutamiseks tasub üle vaadata troponiini ekspressiooni ja bioloogilise toime põhialused. Keskkooli bioloogias õpetatakse õpilastele, et lihaste kokkutõmbed ilmnevad sarkomeerides, mis on üksteise järel asuvad mikromeetri mõõdus struktuuriüksused, ja need määravad nii südame kui ka skeleti vöötlihaste anatoomia. Jämedad (müosiini) ja peened (aktiini) filamendid asuvad sakromeeris nii, et iga jäme filament on ümbritsetud kuue peenega. Sarkomeeride kogumid koonduvad lineaarselt lihaskiududesse ja kaltsiumivoog põhjustab lihaskiudude kokkutõmbe. Tropomüosiin on pikk kokkukeerdunud valk, kus sisaldub enamik aktiinfilamendist, olulisest lihaste kokkutõmmete reguleerijast, mis takistab müosiini kinnitumist (ja seega takistab lihaste kokkutõmmet). Igas tropomüosiinvalgus on heterotrimeerse troponiini kompleksid. Need koosnevad troponiini alaühikutest: troponiin T (TnT), troponiin I (Tnl) ja troponiin C (TnC) (vt joonis 1). TnC seob kaltsiumivoo ajal kaltsiumiioone. See protsess põhjustab vastavad muutused Tnl-s, mis omakorda tekitab aktiinfilamendi kokkupuute müosiiniga ja võimaldab lihastel kokku tõmbuda. TnT sisuliselt kinnitab troponiini kompleksi tropomüosiini struktuurile. Silelihased troponiini ei sisalda. Joonis 1. Joonis heterotrimeerse troponiini asukoht vöötlihase sarkomeeris Roosa värviga tähistatud troponiini alaühik on TnT, sinine alaühik Tnl ja kollane alaühik TnC. Kohandatud allikast Servier Medical Art https://smart.servier.com/ Creative Commons Attribution 3.0 Unported litsentsi alusel. Tnl esineb konkreetsetes isovormides, mida kodeerivad kolm erinevat geeni: aeglastes skeletilihastes, kiiretes skeletilihastes ja südamelihases. Ka TnT esineb konkreetsetes isovormides, mida kodeerivad kolm erinevat geeni: aeglastes skeletilihastes, kiiretes skeletilihastes ja südamelihases.1 Konkreetsed südamelihases esinevad ja hukkumise. Tropomüosiin Heterotrimeerne troponiin Müosiin Aktiin Troponiini praegune kliiniline kasutamine: Ägeda müokardiinfarkti diagnoosimine Kuigi skeletilihaste müotsüüdid võivad hukkuda ja uuesti diferentseeruda, peetakse südamekude suures osas mitoosivõimetuks, misttõttu tõlgendatakse valgu väljasurumist kardiomüotsüütidest kahjustuse ja/või nekroosi nähuks. Kliiniline hindamine, 12 lülituseline elektrokardiograafia ja cTnl või cTnT määramine on ootamatult äkiliselt algava rindkerevalu diagnostilised alustalad. Südamekoe kahjustuse eelistatud markerina kasutatakse juba ammu vereproovist teostatavaid kardiaalsete troponiinide analüüse, mis asendavad varem kasutatud analüüse, nagu kreatiini kinaas, kreatiini kinaasi südamelihasega seotud isoensüüm, laktaadi dehüdrogenaas ja aspartaadi aminotransferaas.2 Ajalooliselt andsid vähetundlikud troponiini analüüsid tulemusi, mida tõlgendati positiivsete või negatiivsetena. National Institute for Health and Care Excellence ja European Society of Cardiology on andnud soovitusi, mis toetavad uue põlvkonna kõrgtundlike kardiaalse troponiini (hs-cTn) https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 1/6 08.02.23 11:25 Kõrgtundliku troponiin T ja I kasu: kas nad on samaväärsed? – American College of Cardiology analüüside kasutamist.3, 4 Kuigi USA toidu- ja ravimiamet ei ole nendele analüüsidele veel ametlikku kasutusluba andnud, on need oluliselt parendanud ägeda müokardiinfarkti välistamise kiirust.5, 6 International Federation of Clinical Chemistry soovitab ägeda müokardiinfarkti diagnoosimise läveks määrata ülemise võrdluspiiri 99. protsentiili. Need soovitused on selgelt pragmaatilised ja mitte bioloogiliselt samaväärsed määramispiirid, arvestades erinevate analüüside erinevusi.5 Hs-cTnl ja hs- cTnT analüüside võrdlemine võib osutuda keeruliseks, kuna üldrahvastikus kasutatakse erinevaid referentsväärtusi ja analüüsieelseid ning analüütilisi muutujaid. Valepositiivsed ja valenegatiivsed tulemused võivad olla tingitud analüüsipõhistest mittekorratavatest faktoritest või segavad õige tulemuse saamist loomulikud antikehad. Huvitav on see, et valik, kas ägeda seisundi korral mõõta hs-cTnT või hs-cTnl väärtust, ei ole tavaliselt iseenesest kliiniline otsus. Patendiõiguste tõttu on hs-cTnT analüüsid saadaval ainult ühelt tootjalt (Roche Diagnostics). Seevastu hs-cTnl analüüse turustavad mitmed tootjad (sealhulgas Abbott, Siemens ja Beckman Coulter). Seetõttu määrab sageli kohaliku biokeemia labori peamine tarnija, kas patsientide raviks määratakse hs-cTnl või hs-cTnT analüüs. Harva mõõdetakse ühes ja samas uuringukohordis nii hs-cTnT-d kui ka hs-cTnl-d, ning sageli on arstidel kogemusi ühe, kuid mitte mõlema hs-cTn analüüsi tulemuste kliinilises tõlgendamises. cTnl ja cTnT võrdlus ägeda müokardiinfarkti diagnoosimisel Olemasolevad andmed näitavad, et ägeda seisundi korral toimivad hs-cTn analüüsid kliinilises ravis väga sarnaselt. Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) uurimisrühm püstitas hüpoteesi, et hs-cTnT ja hs-cTnl analüüsi kahe biokeemilise signaali kombineerimine võib kaotada biomarkerite vahelised eelanalüütilised, analüütilised ja patofüsioloogilised erinevused ning tõhustada kliinilist otsustamist. Nad hõlmasid uuringusse 2256 ägeda müokardiinfarkti kahtlusega patsienti (välja arvatud ST-segmendi elevatsiooniga müokardiinfarktiga patsiendid), kellest 18%-le määrati ägeda müokardiinfarkti diagnoos. Nii hs-cTnT (Roche Diagnostics) kui hs-cTnl (Abbott) analüüs määrati kogu kohordil haiglasse sissekirjutamisel, ja korrelatsioonikordaja nende mõõtmiste vahel oli r = 0,89. Mõlema analüüsi kõvera alune pindala (diagnostiline täpsus) haiglasse sissekirjutamisel oli 0,93 (95% usaldusvahemik, 0,92–0,94). hs-cTnl analüüsi lisamine hs-cTnT analüüsile parandas eristamistvõimet ägeda müokardiinfarkti diagnoosimisel ainult vähesel määral, ilma et oleks tõendeid selle kohta, et hs-cTnT lisamine parandas hs-cTnl analüüsi suutlikkust.7 Mõlema troponiini väärtuse (koos vastavate piirväärtustega) kombineerimine parandas vähesel määral negatiivseid ennustusväärtusi. Siemensi hs-cTnl analüüsi lisauuring näitas sarnast diagnostilist toimivust. 8 Analüüside kliinilise rakendamise peamine probleem on referentsväärtuste määramine. Üldiselt toimivad analüüsid sarnaselt, mis viitab sellele, et äge müokardi kahjustus põhjustab mõlema troponiini ringlemist organismis. hs-cTnl ja hs-cTnT võrdlus üldrahvastikus Vaatamata troponiini analüüside ilmsele suurele kooskõlale ägeda seisundi korral, viitavad üldrahvastikus esiletulevad tugevad tõendid sellele, et cTnT ja cTnl erinevad oluliselt oma seoste poolest haiguse ravitulemitega. Kõrgtundlike analüüside turuletulek tähendab, et määratluse kohaselt peaks analüüs suutma tuvastada troponiini vähemalt 50% elanikkonna verest. See on kaasa toonud huvi troponiini analüüside kasutamise vastu mitte ainult ägeda seisundi korral, vaid ka südame-veresoonkonna haiguste (SVH) riski ennustamisel. Varasemates kohortuuringutes mõõdeti kas hs-cTnl-d või hs-cTnT-d (kuid harva mõlemat), mis eeldatavasti tulenes analüüside oletatavast samaväärsusest ägeda seisundi korral. Seetõttu on tekkinud tõendusbaas, milles puuduvad otsesed tõendid selle kohta, millist biomarkerit võiks eelistada. See kajastub meie hiljutises uuringutaseme metaanalüüsis, kus 13 uuringus mõõdeti cTnl-d ja 7 uuringus mõõdeti cTnT-d; üheski uuringus ei mõõdetud mõlemat. Jaotuskõvera ülemises ja https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 2/6 08.02.23 11:25 Kõrgtundliku troponiin T ja I kasu: kas nad on samaväärsed? – American College of Cardiology alumises kolmandikus oli tulevikus tekkivate SVH juhtude riskisuhe cTnT korral nominaalselt kõrgem kui cTnl korral (riskisuhe = 1,60 vs. 1,36; p = 0,171), kusjuures cTnT oli tugevamalt seotud surmaga lõppenud SVH-ga (p = 0,027).9 Siiski on selliseid cTn-analüüside otseseid võrdlusi raske tõlgendada, arvestades uuritud kohortide omaduste erinevusi. Läbilõikeline Maastrichti uuring annab esialgseid tõendeid selle kohta, et troponiini analüüsid ei pruugi olla üldrahvastikus omavahel asendatavad.10 1540 keskealisel isikul, kellel puudus oluline põhihaigus, oli korrelatsioonikordaja hs-cTnl (Abbott) ja hs-cTnT (Roche) vahel ainult r = 0,54. On selge, et enamiku bioloogiliste seisundite korral on selline korrelatsioonikordaja märkimisväärne, kuid selle põhjal ei saa sama biomarkerit mõõtvaid analüüse omavahel kaugeltki asendatavaks pidada. Võtsime endale ülesande võrrelda ja vastandada hs-cTnl (Abbott) ja hs-cTnT (Roche) prospektiivses kohortuuringus Generation Scottish Family Health Study, milles osales 19 501 täiskasvanut kogu elanikkonnast. Läbilõikeandmetes olid hs-cTnT ja hs-cTnl tuvastatavad vastavalt 53,3%-l ja 74,8%-l osalejatest ning kohandamata analüüsides olid need analüüsid ainult mõõdukalt korrelatsioonis (r = 0,46), mis on üldjoontes kooskõlas Maastrichti uuringu andmetega (vt joonis 2). Joonis 2. cTnT ja cTnl jaotumise hajusdiagramm uuringust Generation Scotland Scottish Family Health Study Punane punktiirjoon näitab soovituslikku (soost sõltumatut) 99. sentiili (n = 19 501). Reprodutseeritud Welsh et al loal (2018).11 Kahe troponiini vaheline korrelatsioon oli pärast vanusele ja soole kohandamist veelgi nõrgem (r = 0,31).11 Mõlema troponiini seos tavapäraste SVH riskiteguritega oli samuti erinev, kusjuures hs-cTnl näitas tugevamaid seoseid vanuse, meessoo, kehamassiindeksi ja süstoolse vererõhuga, ning cTnT näitas tugevamaid seoseid suhkurtõve esinemisega. Seejärel uurisime seoseid SVH ja SVH-ga mitteseotud tulemitega. Mõlemal troponiinil oli tugev muutumatu seos SVH tulemitega, mis näitab, et veres ringlevate troponiidide tasemed olid tõenäoliselt mingil määral seotud müokardi kahjustusega (vt joonis 3, vasakpoolsed alamaknad). Pärast tavapärastele SVH riskiteguritele kohandamist nõrgenes seose tugevus mõlema troponiini osas (vt joonis 3, parempoolsed alamaknad), nii et logaritmitud troponiini ühe standardhälbe võrra suurenemise riskisuhe oli 1,24 (95% usaldusvahemik, 1,17–1,32), mis võimaldab kindlaks teha võimalikud troponiini vereringesse paiskamise põhjused hs-cTnl-st ülesvoolu asuvates geenides. Konkreetsete alleelivariantide pärimine on rahvastiku tasandil juhuslik (ja seetõttu ei ole eluviisist tingitud risk ja muud asjaolud siinkohal segavateks teguriteks) ja seda ei mõjuta vastupidine põhjuslikkus. 13 Generation Scotland Scottish Family Health Study uuring näitas, et hsTnT-ga ja hsTnl- iga seotud üksiku nukleotiidi polümorfismide seaduspärad on erinevad. Näiteks seostati cTnl-i üksiku nukleotiidi polümorfismidega KLKB1 ja F12 geenides. Need geenid kodeerivad valke, mis on mõlemad osa kallikreiini-kiniini teljest, millel on seosed teiste vasoaktiivsete peptiididega, näiteks B-tüüpi natriureetilise peptiidiga. Aga need geenisignaalid ei olnud seotud hs-cTnT-ga. See annab vähemalt mõned tõendid selle kohta, et cTn geneetiliselt määratavad tegurid ei pruugi kattuda, kuigi selle küsimuse üksikasjalikumaks käsitlemiseks on vaja ulatuslikumaid metaanalüüse. https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 3/6 08.02.23 11:25 Kõrgtundliku troponiin T ja I kasu: kas nad on samaväärsed? – American College of Cardiology cTnl, ng/l SVH riskisuhe (kohandamata) SVH riskisuhe (kohandamata) SVH riskisuhe (kohandamata) SVH riskisuhe (kohandamata) cTnl (ng/l) cTnl (ng/l) cTnT (ng/l) cTnT (ng/l) Mistahes signaal, mis ei ole seotud ägedaloomulise kardiomüotsüütide hukkumise või kahjustumisega, muutub käimasoleva juhtumi ülekaaluka signaali tõttu nõrgemaks. Seetõttu võib enamiku vereringes olevast cTn-st (I või T) seostada kardiomüotsüütide kahjustusega. Isegi siis on troponiinide vabanemise kineetika erinev ja mõlemad neist kipuvad ringlema nii eriomaste komplektide kui ka vaba vormina.14 Esineb ka heterofiilseid antikehi, mis võivad mõjutada mõlemat analüüsi. Seetõttu ei ole analüüsitulemused alati ühtivad. Selle üle on pikka aega vaieldud, kas cTnT (kuid mitte cTnl) võib mõnes olukorras väljenduda skeletilihastes.15 CTnT on väljendunud loote skeletilihastes.16 Hiljutine 74 päriliku ja omandatud skeletilihaste müopaatiaga patsiendi uuring näitas, et 69%-l patsientidest oli hs-cTnT näit suurenenud üle 99. tsentiili, kuid cTnl näit ainult 4%-l. Ka rakkude värvimise uuringutes leiti tõendeid, et skeleti lihaskude on veres ringleva cTnT allikaks.17 Teised uuringud on lisanud sarnaseid andmeid.18, 19 Kooskõlas selle leiuga on liikumisuuringutes juba ammu leitud, et intensiivsed aeroobsed harjutused võivad tõsta nii cTnT ja cTnl taset20. Kuna mõju võib cTnT puhul olla suurem, viitab see , et troponiin võib pärineda ka mujalt kui südamelihasest.21 See narratiiv võib sobida Generation Scottish Family Health Study uuringu andmetega, mis näitab, et hs-cTnT on enam seotud SVH-ga mitteseotud suremusega. Inimestel, kellel on väike lihasmass, võib toimuda kataboolne lihaste kärbumine ja nad surevad tõenäolisemalt SVH-ga seotud ja mitteseotud põhjustesse.22 See hüpotees vajab täpsustamist. Järeldused Hs-cTnT ja hs-cTnl taseme tõus on ägedate kliiniliste seisundite korral oluline diagnostiline vahend ning enamik tõendeid viitab sellele, et mõlemad analüüsid toimivad patsientidel selle eesmärgi täitmiseks sarnaselt. Kuid praegu tuntakse üha suuremat huvi nende analüüside võimaliku kasutamise osas üldrahvastikus tulevaste haigusseisundite ennustamisel. Optimaalne lähenemine troponiini analüüsi mõistlikuks kasutamiseks teadaolevalt tervete patsientide ravi parandamisel ei ole veel selge. Siiski viitavad uued tõendid sellele, et konkreetse troponiini analüüsi valimine konkreetse kliinilise ülesande jaoks võib olla tulevikus kliinilise otsustamise oluline osa. Viited 1. Sheng JJ, Jin JP. TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structurefunction relationships. Gene 2016; 576: 385–94. 2. Lippi G. Biomarkers: Novel troponin immunoassay for early ACS rule-out. Nat Rev Cardiol 2016; 13: 9–10. 3. Myocardial infarction (acute): Early rule out using high-sensitivity troponin tests (Elecsys Troponin T high-sensitive, ARCHITECT STAT High Sensitive Troponin-I and AccuTnl+3 assays) Diagnostic guidance (DG)15 (National Institute for Health and Care Excellence website). Oktoober 2014. Kättesaadav veebilehel https://www.nice.org.uk/guidance/dg15. Vaadatud https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 4/6 08.02.23 11:25 Kõrgtundliku troponiin T ja I kasu: kas nad on samaväärsed? – American College of Cardiology 5. septembril 2019. 4. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST- Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267–315. 5. Apple FS, Sandoval Y, Jaffe AS, Ordonez-Llanos J. Cardiac Troponin Assays: Guide to Understanding Analytical Characteristics and Their Impact on Clinical Care. Clin Chem 2017; 63: 73–81. 6. Shah AS, Anand A, Sandoval Y, et al. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet 2015; 386: 2481–8. 7. van der Linden N, Wildi K, Twerenbold R, et al. Combining High-Sensitivity Cardiac Troponin I and Cardiac Troponin T in the Early Diagnosis of Acute Myocardial Infarction. Circulation 2018; 138: 989–99. 8. Boeddinghaus J, Twerenbold R, Nestelberger T, et al. Clinical Validation of a Novel High- Sensitivity Cardiac Troponin I Assay for Early Diagnosis of Acute Myocardial Infarction. Clin Chem 2018; 64: 1347–60. 9. Willeit P, Welsh P, Evans JDW, et al. High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants. J An? Coll Cardiol 2017; 70: 558–68. 10. Kimenai DM, Henry RM, van der Kallen CJ, et al. Direct comparison of clinical decision limits for cardiac troponin T and I. Heart 2016; 102: 610–6. 11. Welsh P, Preiss D, Shah ASV, et al. Comparison between High-Sensitivity Cardiac Troponin T and Cardiac Troponin I in a Large General Population Cohort. Clin Chem 2018; 64: 1607–16. 12. Welsh P, Preiss D, Hayward C, et al. Cardiac Troponin T and Troponin I in the General Population. Circulation 2019; 139: 2754–64. 13. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 2018; 362: k601. 14. Park KC, Gaze DC, Collinson PO, Marber MS. Cardiac troponins: from myocardial infarction to chronic disease. Cardiovasc Res 2017; 113: 1708–18. 15. Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T.J Am Coll Cardiol 2011; 58: 1819–24. 16. Anderson PA, Malouf NN, Oakeley AE, Pagani ED, Allen PD. Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ Res 1991; 69: 1226–33. 17. Schmid J, Liesinger L, Birner-Gruenberger R, et al. Elevated Cardiac Troponin T in Patients With Skeletal Myopathies. J An? Coll Cardiol 2018; 71: 1540–9. 18. Rittoo D, Jones A, Lecky B, Neithercut D. Elevation of cardiac troponin T, but not cardiac troponin I, in patients with neuromuscular diseases: implications for the diagnosis of myocardial infarction. J An? Coll Cardiol 2014; 63: 2411–20. 19. Wens SC, Schaaf GJ, Michels M, et al. Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease. Circ Cardiovasc Genet 2016; 9: 6–13. 20. Klinkenberg LJ, Luyten P, van der Linden N, et al. Cardiac Troponin T and I Release After a 30-km Run. Am J Cardiol 2016; 118: 281–7. 21. Skadberg Ø, Kleiven Ø, Ørn S, et al. The cardiac troponin response following physical exercise in relation to biomarker criteria for acute myocardial infarction; the North Sea Race Endurance Exercise Study (NEEDED) 2013. Clin Chim Acta 2018; 479: 155–9. 22. Srikanthan P, Horwich TB, Tseng CH. Relation of Muscle Mass and Fat Mass to Cardiovascular Disease Mortality. Am J Cardiol 2016; 117: 1355–60. Jagamine: Kliinilised teemad: Äge koronaarsündroom, südame-veresoonkonna haiguste ravimeeskond, https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 5/6 08.02.23 11:25 Kõrgtundliku troponiin T ja I kasu: kas nad on samaväärsed? – American College of Cardiology düslipideemia, ennetus, äge koronaarsündroom ja südame biomarkerid, lipiidide metabolism, uued ained, treening Märksõnad aktiin tsütoskeletis, äge koronaarsündroom, alleelid, kehamassiindeks, aspartaat- aminotransferaasid, keemia, kliiniline, vererõhk, kaltsium, südame-veresoonkonna haigused, kohortuuringud, rindkerevalu, usaldusvahemikud, usaldusvahemikud, kreatiini kinaas, isovorm südamelihases, läbilõikeuuringud, suhkurtõbi, liikumisravi, peretervishoid, hematoloogilised testid, immuunanalüüsid, elektrokardiograafia, antikehad, heterofiil, kineetika, laktaadi dehüdrogenaasid, kiniinid, kallikreiinid, eluviis, ioonid, lihas, sile, lihaskokkutõmme, müokard, müokardiinfarkt, müotsüüdid, südame, lihashaigused, müosiinid, natriureetiline peptiid, aju, patsientide ravi, lihas, skeleti, prospektiivsed uuringud, valu isovormid, riskitegurid, referentsväärtused, polümorfism, üksik nukleotiid, sarkomeerid, müokardi infarkt, värvimine ja märgistamine, tropomüosiin, troponiin C, troponiin I, troponiin T, Ameerika Ühendriikide Toidu- ja Ravimiamet © 2023 American College of Cardiology Foundation. Kõik õigused kaitstud. https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 6/6 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology Utility of High-Sensitivity Troponin T and I: Are They the Same? Nov 21, 2019 | Paul Welsh, PhD; David Preiss, MB ChB, PhD; Naveed Sattar, MD Expert Analysis Background to the Sarcomere and Troponin In order to place what we know about troponin T and I in context, it is worth reviewing the fundamentals of troponin expression and biological action. High school biology teaches students that the basic structure of muscle contraction is the sarcomere, a repeating micrometer-sized unit that dictates the anatomy of both cardiac and skeletal striated muscle. The thick (myosin) and thin (actin) filaments within the sarcomere interlock, such that each thick filament is surrounded by six thin ones. Aggregates of https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 1/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology sarcomeres assemble linearly into myofibers, and calcium flux causes contraction of the structure. Tropomyosin is a long, coiled protein that spans most of the actin filament and is an important regulator of muscle contraction, preventing myosin adherence (and hence preventing contraction). Within each tropomyosin protein are complexes of heterotrimeric troponin. These comprise troponin subunits troponin T (TnT), troponin I (TnI), and troponin C (TnC) (Figure 1). TnC binds calcium ions during calcium flux, and this process causes a conformational change in TnI, which in turn exposes the actin filament to myosin and allows muscle contraction. TnT essentially anchors the troponin complex to the tropomoysin structure. Smooth muscle does not contain troponin. Figure 1. Illustration of the Location of the Troponin Heterotrimer in the Sarcomere of Striated Muscle Pink troponin subunit is TnT, blue subunit is TnI, and yellow subunit is TnC. Adapted from Servier Medical Art https://smart.servier.com/ under Creative Commons Attribution 3.0 Unported license. TnI is expressed in specific isoforms encoded by three distinct genes: slow skeletal, fast skeletal, and cardiac muscle. TnT also exists as specific isoforms encoded by three distinct genes: slow skeletal, fast skeletal, and cardiac.1 It is the presence of distinct cardiac https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 2/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology isoforms that have allowed development of TnI and TnT immunoassays that are specific for the detection of cardiomyocyte injury and death using a blood test (cTnI and cTnT). https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 3/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology Current Clinical Use of Troponin: Diagnosis of AMI Although skeletal myocytes can die and re-differentiate, the cardiac tissue is largely viewed as post-mitotic; therefore, protein extrusion from cardiomyocytes is interpreted as a sign of injury and/or necrosis. Clinical assessment, 12-lead electrocardiography and cardiac cTnI or cTnT form the diagnostic cornerstones of patients with acute-onset chest pain. Blood-based cardiac troponin assays have now long been used as the preferred marker of cardiac tissue injury, replacing older assays such as total creatine kinase, creatine kinase-myocardial band, lactate dehydrogenase, and aspartate aminotransferase.2 Historically, low-sensitivity troponin assays yielded results that were interpreted as positive or negative. The National Institute for Health and Care Excellence and the European Society of Cardiology have issued recommendations supporting the use of a new generation of high-sensitivity cardiac troponin (hs-cTn) assays.3,4 Although yet to be formally endorsed by the Food and Drug Administration, these assays have vastly improved the speed of ruling out acute myocardial infarction (AMI).5,6 The International Federation of Clinical Chemistry recommends determination of the 99th percentile upper reference limit as diagnostic thresholds for AMI. These recommendations are clearly pragmatic and not biologically equivalent cutoffs given the variation between different assays.5 Comparing hs-cTnI and hs-cTnT assays can be challenging due to different https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 4/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology reference ranges applied in the general population and different assay-specific pre- analytical and analytical variables. False positives and false negatives can be due to non- repeatable "flyers" or native antibody interference that are assay specific. Interestingly, the decision regarding whether to measure either hs-cTnT or hs-cTnI in the acute setting is not typically a clinical decision per se. Due to patent, hs-cTnT assays are available from only one manufacturer (Roche Diagnostics). In contrast, several manufacturers market hs-cTnI assays (including Abbott, Siemens, and Beckman Coulter). Therefore, the primary supplier to the local biochemistry laboratory often dictates which of hs-cTnI or hs-cTnT is measured for patient care. It is rare for both hs-cTnT and hs-cTnI to be measured in the same study cohort, and clinicians are often experienced in the clinical interpretation of either hs-cTn assay result but not both. Comparison of cTnI and cTnT in the Diagnosis of AMI In the acute setting, the available data suggest that hs-cTn assays perform very similarly in clinical care. The Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) study group hypothesized that combining the two biochemical signals from hs- cTnT and hs-cTnI might overcome preanalytical, analytical, and pathophysiological differences between the biomarkers and improve clinical decision-making. They recruited 2,256 patients with suspected AMI (after excluding those with ST-segment elevation myocardial infarction), and 18% were diagnosed with AMI by adjudication. Both hs-cTnT https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 5/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology (Roche Diagnostics) and hs-cTnI (Abbott) were measured in the whole cohort at admission, and the correlation between these measures was r = 0.89. The area under the curve (diagnostic accuracy) for both assays at presentation was 0.93 (95% confidence interval, 0.92-0.94). Addition of hs-cTnI to hs-cTnT only marginally improved discrimination for diagnosing AMI, with no evidence that addition of hs-cTnT improved the performance of hs-cTnI.7 Combining both troponin measurements (with their respective cutoffs) marginally improved negative predictive values. Further study of the Siemens hs-cTnI assay showed similar diagnostic performance.8 The main issue for clinical implementation of the assays is therefore where to draw the diagnostic threshold. Overall, the assays perform similarly, suggesting that acute myocardial injury drives circulating concentrations of both cTn in this setting. Comparison of hs-cTnI and hs-cTnT in the General Population Despite apparent broad concordance between troponin assays in the acute setting, strong emerging evidence in the general population suggests that cTnT and cTnI differ meaningfully in their association with disease outcomes. The advent of high-sensitivity assays means that, by definition, the assay should detect troponin in the circulation of at least 50% of the general population. This has led to interest in use of the troponin assays not just in the acute setting but also for cardiovascular disease (CVD) risk prediction. https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 6/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology In previous cohort studies, one of hs-cTnI or hs-cTnT (but rarely both) had been measured, presumably led by a presumed inter-changeability of assays in the acute setting. This has yielded an evidence base lacking direct evidence as to which biomarker might actually be preferable. This is reflected in our recent study-level meta-analysis, where 13 studies measured cTnI and 7 studies measured cTnT; none measured both. In the top versus bottom third of the distribution, the hazard ratio for future CVD events was nominally stronger for cTnT than cTnI (hazard ratio =1.60 versus 1.36; p = 0.171), and cTnT was more strongly associated with fatal CVD (p = 0.027).9 However, such direct comparisons of cTn assays are difficult to interpret given the differences in the characteristics of the cohorts between studies. The cross-sectional Maastricht study provides preliminary evidence that troponin assays may not be interchangeable in the general population.10 In 1,540 middle-aged individuals from the general population without significant baseline disease, the correlation between hs-cTnI (Abbott) and hs-cTnT (Roche) was only r = 0.54. Clearly, in most biological situations this is a notable correlation, but it is a long way from being considered interchangeable for assays supposedly measuring the same biomarker. We undertook to compare and contrast hs-cTnI (Abbott) and hs-cTnT (Roche) in the Generation Scotland Scottish Family Health Study prospective cohort study of 19,501 adults from the general population. In cross-sectional data, hs-cTnT and hs-cTnI were https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 7/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology detectable in 53.3% and 74.8% of participants, respectively, and were only modestly correlated in unadjusted analyses (r = 0.46), broadly in line with the Maastricht study data (Figure 2). Figure 2. Scatter Graph of the Distributions of cTnT and cTnI in the Generation Scotland Scottish Family Health Study Red dotted line indicates the recommended (non-sex-specific) 99th centile (n = 19,501). Reproduced with permission from Welsh et al. (2018).11 However, the correlation between the two troponins was even weaker after adjusting for age and sex (r = 0.31).11 The association of each troponin with traditional CVD risk factors was also distinct, with hs-cTnI showing stronger associations with age, male sex, body mass index, and systolic blood pressure and cTnT showing stronger associations with the presence of diabetes. We then investigated associations with CVD and non-CVD outcomes. Both troponins had strong univariable associations with CVD outcomes, indicating that circulating levels were probably to some degree related to myocardial injury (Figure 3, left panels). However, after adjusting for traditional CVD risk factors, the strength of the association attenuated for both troponins (Figure 3, right panels) such that the hazard ratio for a 1 standard deviation increase in log troponin was 1.24 (95% confidence interval, 1.17-1.32) for hs-cTnI https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 8/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 9/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology and 1.11 (1.04-1.19) for hs-cTnT. Both troponins had stronger associations with CVD death than the composite CVD outcome. Of interest, hs-cTnT (but not hs-cTnI) showed an association with non-CVD death.12 Figure 3. Association of hs-cTnI and hs-cTnT Unadjusted and Adjusted With Composite Fatal/Non-Fatal CVD Outcome Over Median 7.8 Years (n = 1,177 events) Reproduced with permission from Welsh et al. (2019).12 As a final examination of the possible distinct natures of hs-cTnT and hs-cTnI, we can use genetics to identify potential upstream causes of troponin extrusion into the circulation. Inheritance of specific allelic variants is random at a population level (and therefore not confounded by lifestyle risk factors and circumstance) and is not subject to reverse causality.13 The Generation Scotland Scottish Family Health Study indicated distinct patterns of single nucleotide polymorphisms related to hsTnT and hsTnI. For instance, cTnI was associated with single nucleotide polymorphisms in the KLKB1 and F12 genes. These genes encode proteins that are both part of the kallikrein-kinin axis and have shown associations with other vasoactive peptides such as B-type natriuretic peptide. However, these genetic signals were not associated with hs-cTnT. This provides at least some evidence that the genetic determinants of the cTn might not overlap, although larger-scale meta-analyses are required to look at this issue in more detail. https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 10/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 11/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology Why Are hs-cTnI and hs-cTnT Signals Different? The simplest explanation as to why the two cTn appear very similar in the acute setting is that any signal not related to acute cardiomyocyte death or injury is diluted by the overpowering signal derived from the ongoing event. Therefore, most of the cTn (I or T) in the circulation can be attributed to the cardiomyocyte injury. Even then, release kinetics are distinct, and both troponins tend to circulate in distinctive complexes, as well as free forms.14 There are also heterophilic antibodies that might interfere with either assay. Therefore, the assays will not always be entirely concordant. It has long been debated that skeletal muscle may in some circumstances express cTnT (but not cTnI).15 Fetal skeletal muscle expresses cTnT.16 A recent study in 74 patients with hereditary and acquired skeletal myopathies showed elevations beyond the 99th centile in hs-cTnT in 69% of patients but elevation in cTnI in only 4%. There was also evidence from staining studies that the skeletal muscle tissue itself was the source of circulating cTnT.17 Other studies have reported similar data.18,19 In line with this, exercise studies have long reported that intensive aerobic exercise interventions can raise both cTnT and cTnI levels,20 although the effect may be greater for cTnT, suggesting there may also be a non-cardiac source.21 This narrative might fit with the data from the Generation Scotland Scottish Family Health Study showing that hs-cTnT is more closely associated with non- CVD death; people with low muscle mass may be undergoing catabolic wasting and are https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 12/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology more likely to die of CVD and non-CVD causes.22 This hypothesis requires further elaboration. Conclusions Elevations in hs-cTnT and hs-cTnI are important diagnostic tools in the acute clinical setting, and most evidence suggests the tests perform similarly in patients for this purpose. However, there is now growing interest in the potential use of these assays in the general population for prediction of future events. The optimal approach in judicious use of the troponin assay to improve care for apparently healthy patients is not yet clear. However, emerging evidence suggests that selection of a particular troponin assay for a particular clinical task may be an important component of future clinical decision-making. References 1. Sheng JJ, Jin JP. TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure- function relationships. Gene 2016;576:385-94. 2. Lippi G. Biomarkers: Novel troponin immunoassay for early ACS rule-out. Nat Rev Cardiol 2016;13:9-10. 3. Myocardial infarction (acute): Early rule out using high-sensitivity troponin tests (Elecsys Troponin T high-sensitive, ARCHITECT STAT High Sensitive Troponin-I and AccuTnI+3 assays) Diagnostic guidance (DG)15 (National Institute for Health and Care https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 13/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology Excellence website). October 2014. Available at https://www.nice.org.uk/guidance/dg15. Accessed September 5, 2019. 4. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315. 5. Apple FS, Sandoval Y, Jaffe AS, Ordonez-Llanos J. Cardiac Troponin Assays: Guide to Understanding Analytical Characteristics and Their Impact on Clinical Care. Clin Chem 2017;63:73-81. 6. Shah AS, Anand A, Sandoval Y, et al. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet 2015;386:2481-8. 7. van der Linden N, Wildi K, Twerenbold R, et al. Combining High-Sensitivity Cardiac Troponin I and Cardiac Troponin T in the Early Diagnosis of Acute Myocardial Infarction. Circulation 2018;138:989-99. 8. Boeddinghaus J, Twerenbold R, Nestelberger T, et al. Clinical Validation of a Novel High-Sensitivity Cardiac Troponin I Assay for Early Diagnosis of Acute Myocardial Infarction. Clin Chem 2018;64:1347-60. 9. Willeit P, Welsh P, Evans JDW, et al. High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants. J Am Coll https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 14/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology Cardiol 2017;70:558-68. 10. Kimenai DM, Henry RM, van der Kallen CJ, et al. Direct comparison of clinical decision limits for cardiac troponin T and I. Heart 2016;102:610-6. 11. Welsh P, Preiss D, Shah ASV, et al. Comparison between High-Sensitivity Cardiac Troponin T and Cardiac Troponin I in a Large General Population Cohort. Clin Chem 2018;64:1607-16. 12. Welsh P, Preiss D, Hayward C, et al. Cardiac Troponin T and Troponin I in the General Population. Circulation 2019;139:2754-64. 13. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 2018;362:k601. 14. Park KC, Gaze DC, Collinson PO, Marber MS. Cardiac troponins: from myocardial infarction to chronic disease. Cardiovasc Res 2017;113:1708-18. 15. Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T. J Am Coll Cardiol 2011;58:1819-24. 16. Anderson PA, Malouf NN, Oakeley AE, Pagani ED, Allen PD. Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ Res 1991;69:1226-33. 17. Schmid J, Liesinger L, Birner-Gruenberger R, et al. Elevated Cardiac Troponin T in Patients With Skeletal Myopathies. J Am Coll Cardiol 2018;71:1540-9. https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 15/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology 18. Rittoo D, Jones A, Lecky B, Neithercut D. Elevation of cardiac troponin T, but not cardiac troponin I, in patients with neuromuscular diseases: implications for the diagnosis of myocardial infarction. J Am Coll Cardiol 2014;63:2411-20. 19. Wens SC, Schaaf GJ, Michels M, et al. Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease. Circ Cardiovasc Genet 2016;9:6- 13. 20. Klinkenberg LJ, Luyten P, van der Linden N, et al. Cardiac Troponin T and I Release After a 30-km Run. Am J Cardiol 2016;118:281-7. 21. Skadberg Ø, Kleiven Ø, Ørn S, et al. The cardiac troponin response following physical exercise in relation to biomarker criteria for acute myocardial infarction; the North Sea Race Endurance Exercise Study (NEEDED) 2013. Clin Chim Acta 2018;479:155-9. 22. Srikanthan P, Horwich TB, Tseng CH. Relation of Muscle Mass and Fat Mass to Cardiovascular Disease Mortality. Am J Cardiol 2016;117:1355-60. Share via: 59 Clinical Topics: Acute Coronary Syndromes, Cardiovascular Care Team, Dyslipidemia, Prevention, ACS and Cardiac Biomarkers, Lipid Metabolism, Novel Agents, Exercise Keywords: Actin Cytoskeleton, Acute Coronary Syndrome, Alleles, Body Mass Index, Aspartate Aminotransferases, Chemistry, Clinical, Blood Pressure, Calcium, Cardiovascular Diseases, Cohort Studies, Chest Pain, Confidence Intervals, Confidence Intervals, Creatine Kinase, MB Form, Cross- https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 16/17 08.02.23 11:25 Utility of High-Sensitivity Troponin T and I: Are They the Same? - American College of Cardiology Sectional Studies, Diabetes Mellitus, Exercise Therapy, Family Health, Hematologic Tests, Immunoassay, Electrocardiography, Antibodies, Heterophile, Kinetics, Lactate Dehydrogenases, Kinins, Kallikreins, Life Style, Ions, Muscle, Smooth, Muscle Contraction, Myocardium, Myocardial Infarction, Myocytes, Cardiac, Muscular Diseases, Myosins, Natriuretic Peptide, Brain, Patient Care, Muscle, Skeletal, Prospective Studies, Protein Isoforms, Risk Factors, Reference Values, Polymorphism, Single Nucleotide, Sarcomeres, Myocardial Infarction, Staining and Labeling, Tropomyosin, Troponin C, Troponin I, Troponin T, United States Food and Drug Administration © 2023 American College of Cardiology Foundation. All rights reserved. https://www.acc.org/latest-in-cardiology/articles/2019/11/21/07/26/utility-of-high-sensitivity-troponin-t-and-I 17/17 MAKSEKORRALDUS NR 12061 MAKSJA / REMITTER / ПЛАТЕЛЬЩИК KUUPÄEV / DATE / ЧИСЛО ISIS MEDICAL OÜ 27.02.2023 MAKSJA KONTO NR / REMITTER´S ACC. / № СЧЕТА ПЛАТЕЛЬЩИКА REG. NR / REG. 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ПОДПИСАНИЕМ НАСТОЯЩЕГО ПЛАТЕЖНОГО ПОРУЧЕНИЯ ПОДТВЕРЖДАЮ, ЧТО Я ОЗНАКОМИЛСЯ/ОЗНАКОМИЛАСЬ И СОГЛАСЕН/СОГЛАСНА С ДЕЙСТВУЮЩИМИ В SWEDBANK AS ПРЕЙСКУРАНТОМ И УСЛОВИЯМИ ОСУЩЕСТВЛЕНИЯ ПЛАТЕЖНЫХ ОПЕРАЦИЙ. BY SIGNING THIS PAYMENT ORDER I WARRANT AND REPRESENT THAT I HAVE EXAMINED AND CONSENT TO THE EFFECTIVE PRICE LIST AND CONDITIONS FOR MAKING PAYMENT TRANSACTIONS OF SWEDBANK AS. Kokkuvõte Taustteave Kardiaalset troponiini T (cTnT) ja kardiaalset troponiini I (cTnI) loetakse spetsiifilisteks südamehaiguste markeriteks, mis on ägeda müokardiinfarkti diagnoosimisel samaväärsed. Varasemad uuringud viitasid, et cTnT väärtuste suurenemine võib olla põhjustatud ka harvaesinevatest skeletilihaste müopaatiatest. Meie eesmärk oli kindlaks teha cTnT usaldusväärsus/spetsiifilisus südamehaiguste osas erinevate skeletilihaste haigustega patsientidel. Metoodika Uuringusse kaasati prospektiivselt kahe riigi neljas haiglas viibivad lihaskaebustega patsiendid (≥ 2 nädala kestnud kaebustega). Pärast südameuuringuid määrati patsiendid kolme eelnevalt määratletud südamehaiguste kategooriasse. cTnT/I kontsentratsiooni ja sellest tulenevaid cTnT/I omavahelisi erinevusi hinnati kõrgtundliku cTnT (hs-cTnT Roche Elecsys) ning kolme hs-cTnI analüüsi abil (hs-cTnI Abbott Architect, hs-cTnI Beckman-Coultier Access, hs-cTnI Siemens -Vista) ja võrreldi kontrollrühmaga, kellel skeletilihaste häired puudusid ning kes pöördusid erakorralise meditsiini osakonda kindlaks tehtud südamega mitteseotud rindkerevaluga (n = 3508, keskmine vanus 55 aastat, 37% naised). Saadaolevate skeletilihaste biopsiatega patsientide TNNT/I1-3 mRNA diferentseeritud geeniekspressiooni võrreldi skeletilihaste häireteta kontrollrühma patsientidelt võetud biopsiatega. Järeldused Aktiivse kroonilise skeletilihaste häiretega patsientidel on cTnT kontsentratsiooni tõus sage ja enamasti pole see põhjustatud südamehaigustest. Seda ei täheldatud cTnI osas, ja see võib osaliselt olla seletatav cTnT taasekspressiooniga skeletilihastes. Järeldused Kokkuvõtteks võib öelda, et hs-cTnT tõus on sage patsientidel, kellel on aktiivne krooniline mittepõletikuline müopaatia ja müosiit, kuid mitte teiste skeletilihaste häiretega patsientidel, ning see on osaliselt põhjustatud TNNT2 aktiveerumisest ja seeläbi taasekspressioonist haigetes skeletilihastes. Seevastu ei leitud tõendeid, et TNNT2 aktiveerumine ja sellest põhjustatud taasekspressioon haigetes skeletilihastes suurendaks cTnI väärtust. Seetõttu on aktiivse kroonilise mittepõletikulise müopaatia ja müosiidiga patsientidel cTnI eelistatud analüüt südame tervise üldhindamiseks ja ägeda müokardiinfarkti korral. 10.1161/CIRCULATIONAHA.121.058489 Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T Running Title: Mueller et al.; Cardiac Troponins and Skeletal Muscle Disease Jeanne du Fay de Lavallaz, MD-PhD* ; Alexandra Prepoudis, MD*1; Maria Janina Wendebourg MD2; Eva Kesenheimer MD2; Diego Kyburz, MD3,4; Thomas Daikeler, MD3; Philip Haaf, MD1; Julia Wanschitz, MD5; Wolfgang N. Löscher, MD PhD5; Bettina Schreiner, MD6; Mira Katan, MD, MSc6; Hans H. Jung, MD6; Britta Maurer, MD7,8; Angelika Hammerer-Lercher MD9; Agnes Mayr, MD10; Danielle M. Gualandro, MD PhD1; Annemarie Acket, MD1; Christian Puelacher, MD PhD1; Jasper Boeddinghaus, MD1; Thomas Nestelberger, MD1, ; Pedro Lopez- Ayala, MD1; Noemi Glarner, MD1; Samyut Shrestha, MD1; Robert Manka, MD; Joanna Gawinecka, PhD13; Salvatore Piscuoglio, PhD14; John Gallon, PhD14; Sophia Wiedemann, MD- PhD14; Michael Sinnreich MD, PhD2,4; Christian Mueller, MD1,4, for the BASEL XII Investigators# 1 Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Downloaded from http://ahajournals.org by on April 19, 2022 Basel, Basel, Switzerland; 2Neurology Clinic and Policlinic, University Hospital of Basel, Basel, Switzerland; 3Department of Rheumatology, University Hospital of Basel, Basel, Switzerland; 4 University of Basel, Basel, Switzerland; 5Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; 6Department of Neurology, University Hospital of Zürich, Zürich, Switzerland; 7Department of Rheumatology and Immunology, Inselspital Bern, Bern, Switzerland; 8Department of Rheumatology, University Hospital of Zürich, Zürich, Switzerland; 9 Department of Laboratory Medicine, Cantonal Hospital of Aarau, Aarau, Switzerland; 10 Department of Radiology, Medical University Innsbruck, Innsbruck, Austria; 11Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada; 12Department of Cardiology, University Hospital of Zürich, Zürich, Switzerland; 13Institute of Clinical Chemistry, University of Zürich, Zürich, Switzerland; 14 Department of Biomedicine, University Hospital of Basel, Basel, Switzerland *Both authors contributed equally and should be considered first authors 1 10.1161/CIRCULATIONAHA.121.058489 Address for Correspondence: Prof. Dr. Christian Mueller, MD Department of Cardiology and Cardiovascular Research Institute Basel (CRIB) University Hospital Basel Petersgraben 4, CH-4031 Basel, Switzerland Phone Number: +41 61 328 65 49 Fax number: +41 61 265 53 53 E-mail: [email protected] *This article is published in its accepted form, it has not been copyedited and has not appeared in an issue of the journal. Preparation for inclusion in an issue of Circulation involves copyediting, typesetting, proofreading, and author review, which may lead to differences between this accepted version of the manuscript and the final, published version. Downloaded from http://ahajournals.org by on April 19, 2022 2 10.1161/CIRCULATIONAHA.121.058489 Abstract Background: Cardiac troponin T (cTnT) and cTnI are considered cardiac-specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a non-cardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMD). Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in four hospitals in two countries. After cardiac work-up, patients were adjudicated into three predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed using high-sensitivity cTnT (hs-cTnT-Elecsys) and three hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista), and compared to controls without SMD presenting with adjudicated non-cardiac chest pain to the emergency department (n=3508, mean age 55y, 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared to biopsies obtained in controls without SMD. Results: Among 211 patients (mean age 57y, 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) mild and 59 (28%) severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no versus mild versus severe cardiac disease for all assays (all p<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus controls (median 16ng/L (IQR 7-32.5) versus 5ng/L (IQR 3-9), p<0.001) while hs-cTnI concentrations were mostly similar (hs-cTnI-Architect 2.5ng/L (IQR 1.2-6.2) versus 2.9ng/L (IQR 1.8-5.0), hs-cTnI-Access 3.3ng/L (IQR 2.4-6.1) versus 2.7ng/L (IQR 1.6-5.0) and hs-cTnI-Vista 7.4ng/L (IQR 5.2-13.4) versus 7.5ng/L (IQR 6-10)). hs-cTnT- Elecsys concentrations were above the upper-limit of normal (ULN) in 55% of patients with Downloaded from http://ahajournals.org by on April 19, 2022 SMD vs 13% of controls (p<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from non-inflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI); versus controls (n=16, pWald <0.001), the expression correlated with pathological disease activity (R=0.59, pt-statistic <0.001) and circulating hs-cTnT concentrations (R=0.26, pt-statistic =0.031). Conclusion: In patients with active chronic SMD, elevations in cTnT concentrations are common and not due to cardiac disease in the majority. This was not observed for cTnI, and may in part be explained by re-expression of cTnT in skeletal muscle. Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03660969. Key Words: High-sensitivity; Troponin; Myocardial Infarction; Myopathy; Skeletal Non-standard Abbreviations and Acronyms: AMI, Acute myocardial infarction; CAD, Coronary artery disease; CK, Creatine kinase; CMR, cardiac magnetic resonance imaging; cTnT, Cardiac troponin T; cTnI, Cardiac troponin I; CV, Coefficient of variation; DGE, Differential gene expression; ECG, Electrocardiogram; ED, Emergency department; ESC, European Society of Cardiology; hs-cTnT, High-sensitivity cardiac troponin T; hs-cTnI, High-sensitivity cardiac troponin I; IQR, Interquartile range; LoD, Limit of Detection; NT-proBNP, N-terminal pro-B- type natriuretic peptide; SD, Standard deviation; SMD, Skeletal muscle disease; ULN, Upper limit of normal 3 10.1161/CIRCULATIONAHA.121.058489 Clinical Perspective What is new? • hs-cTnT-Elecsys concentrations were above the upper-limit of normal (ULN) in >50% of patients with active chronic skeletal muscle disease and significantly higher versus controls. • Hs-cTnI concentrations measured with three different were above the biologic-equivalent ULN in <25% of patients and comparable to controls, thereby leading to hs-cTnT/hs- cTnI mismatches in up to 50% of patients. • hs-cTnT-Elecsys elevations in patients without cardiac disease were largely restricted to patients with active non-inflammatory myopathy and myositis. • mRNA analyses in skeletal muscle biopsies showed 8-fold upregulation of TNNT2, encoding cTnT versus controls and the expression correlated with circulating hs-cTnT concentrations. Downloaded from http://ahajournals.org by on April 19, 2022 What are the clinical implications? • In patients presenting with suspected AMI, the presence of active chronic non- inflammatory myopathy and myositis, should be considered as a major confounder of hs- cTnT-concentration, but not hs-cTnI-concentrations. • These patients are at risk of erroneous AMI diagnosis with hs-cTn, where hs-cTnI is the preferred analyte. • In patients with other skeletal muscle disease, hs-cTnT seemed to retain cardiac specificity. 4 10.1161/CIRCULATIONAHA.121.058489 Introduction The troponin complex is composed of three isoforms (T, I and C) and is essential for contraction of striated muscle.1,2 While the function of troponins is very similar, their amino acid sequences and configuration in cardiac and skeletal muscle differ.1,2 Cardiac troponins (cTn) are rapidly released when, for example, cardiomyocytes experience ischemic damage and have become a central component in the early diagnosis of acute myocardial infarction (AMI).3 The development and clinical implementation of high-sensitivity cTn (hs-cTn) assays has enabled precise discrimination of mild cTn elevations from normal cTn concentrations.4 In addition, high-sensitivity cTn-based rapid algorithms have substantially accelerated and facilitated the early diagnosis of AMI.5,6 Specificity issues with early iterations of the cTnT assays had appeared and were believed to be due to a cross-reactivity between the cTnT assay and skeletal muscle epitopes.7,8 Downloaded from http://ahajournals.org by on April 19, 2022 However, falsely elevated concentrations of cTnT were considered a problem solved when using the latest version of the cTnT assay.9–15 The specificity deficit of earlier versions of the assay have been highlighted for instance by Ricchuti et al.7, who found evidence of cTnT in the skeletal muscle of patients with chronic renal disease. Given the epitopes recognized by the antibodies of the commercial cTnT assay used by Ricchuti et al. in 1998 and the variable presence of these cTnT isoforms in skeletal muscle, these same authors postulated that the modified, second-generation cTnT assay would not detect these isoforms if they are released from skeletal muscle into the circulation.7 Therefore, current clinical practice guidelines consider cTnT and cTnI cardiac-specific, equivalent, and interchangeable in the diagnosis of AMI.6 This concept has been again challenged by recent studies using the latest generation of the hs-cTnT assay showing evidence 5 10.1161/CIRCULATIONAHA.121.058489 of re-expressed cTnT in diseased skeletal muscle of patients with neuromuscular disorders, commonly resulting in cTnT-, but only rarely in cTnI-elevations in the systemic circulation. 11,12 While previously documented, the clinical implications of these translational findings for patients presenting with skeletal muscle disorders (SMD), as well as the overall population presenting with suspected AMI are incompletely understood. 16 There are, for example, uncertainties related to the fact that out of all studies, only three used the hs-cTnT assay, previous studies often had a small sample size and mostly investigated selected patients with rare neuromuscular disorders, some with cardiac involvement that possibly contributed to systemic cTnT concentrations. Furthermore, some studies had selection bias enrolling exclusively patients with cTnT-elevations instead of consecutive unselected patients, and used only one cTnI assay as comparator.9,11,12,17 Downloaded from http://ahajournals.org by on April 19, 2022 Therefore, we performed a prospective international multicenter study to address these uncertainties using four hs-cTnT/I assays in a broad population of patients presenting with muscular complaints. Materials and Methods The data, code, and study material that support the findings of this study are available from the corresponding author on reasonable request. Study Design, Setting, and Patient Population This is the primary analysis of the Heart & Muscle BASEL XII Study (NCT03660969), an ongoing prospective international multicenter diagnostic study enrolling patients presenting with active chronic muscular complaints for elective ambulatory or in-patient evaluation in a 6 10.1161/CIRCULATIONAHA.121.058489 neuromuscular, rheumatology, or medical service in four hospitals in two countries (Basel, Aarau and Zürich in Switzerland and Innsbruck in Austria). Active chronic muscular complaints were defined as any symptom related to muscle disease lasting for at least 2 weeks. The study was designed to contribute to a better understanding of the reliability of cTnT and cTnI for the diagnosis of AMI in the presence of SMD. Adult patients presenting with a broad spectrum of muscular complaints e.g. muscle pain, weakness (defined as scoring ≤ 4 on the Medical Research Council scale for muscle strength18), atrophy, stiffness, and fasciculations were recruited. Patients were excluded if they had acute trauma, acute medical disease such as sepsis, AMI, stroke, or other acute cardiac diseases, or terminal kidney failure requiring dialysis. The study was conducted according to the principles of the Declaration of Helsinki and approved by the local ethic committees. Written informed consent was obtained from all patients. The authors designed the study, gathered and analyzed the data according to the STROBE guidelines for Downloaded from http://ahajournals.org by on April 19, 2022 observational studies (Table S1),19 vouched for the data and analysis, wrote the paper, and made the decision to submit the manuscript for publication. Data was entered in a dedicated RedCap database20. Clinical Assessment Work-up for skeletal muscle disease was performed according to local standard operating procedures. The diagnosis of SMD was established by the treating clinicians (neurologists, rheumatologists and internists) at the recruiting centers. All patients went through a thorough muscular and neurologic diagnostic process including laboratory testing (such as antibody screens), chest imaging, electro(neuro)myography, muscle MRIs, genetic testing and muscle biopsies analyses, as clinically indicated. After work-up was completed, final diagnoses were adjudicated in conjunction with a neurologist into six groups: non-inflammatory myopathies, 7 10.1161/CIRCULATIONAHA.121.058489 neuropathies, myasthenic syndromes, myositis (primary, secondary and overlap syndromes), auto-immune diseases with muscular symptoms and muscle symptoms of unknown origin (Table S2). Non-inflammatory myopathies included myotonic dystrophy, facioscapulohumeral muscular dystrophy, limb–girdle muscular dystrophy, mitochondrial disease and glycogen storage disease. Myositis included dermatomyositis, polymyositis, sporadic inclusion body myositis, hereditary inclusion body myositis, Immune mediated necrotizing myositis, myositis with overlap with collagenous disease, statin-induced myositis and vasculitis. Standardized cardiac assessment included a structured questionnaire for history of cardiovascular disease and cardiovascular risk factors, physical examination, 12-lead electrocardiogram (ECG), measurement of N-terminal pro-B-type natriuretic peptide (NT- proBNP) as a quantitative marker of hemodynamic cardiac stress21, cTnT, cTnI, and cardiac imaging including echocardiography and cardiac magnetic resonance imaging (CMR) whenever Downloaded from http://ahajournals.org by on April 19, 2022 indicated by clinical uncertainty regarding the underlying cardiac disease including cTnT/I elevations. Classification According to Cardiac Disease Using predefined criteria, patients were centrally adjudicated into three categories according to the presence and extent of cardiac disease (no cardiac disease, mild cardiac disease, severe cardiac disease) by investigators blinded to cTnT/I results. According to current guidelines6, cTnT and cTnI are quantitative markers of ongoing cardiomyocyte damage, elevations in cTnT or cTnI as a reflection of true cardiac disease may be present in a relevant proportion of patients with severe cardiac disease, are unlikely in patients with mild cardiac disease, and very unlikely in patients with no cardiac disease. 8 10.1161/CIRCULATIONAHA.121.058489 Patients with prior AMI, chronic heart failure (NYHA class ≥ II), severe valvular disease, left ventricular ejection fraction below 40%, CMR showing late gadolinium enhancement, or NT-proBNP concentrations above 400 ng/L21 were classified as having severe cardiac disease. In the absence of these criteria, patients with coronary artery disease (CAD), atrial fibrillation/flutter, left or right bundle branch block on ECG, left ventricular hypertrophy, mild- to-moderate valvular disease or any other structural or functional abnormality (abnormal motility, dilation) detected in echocardiography or CMR, or NT-proBNP concentrations 125-400 ng/L21 were classified as having mild cardiac disease. All other patients were classified as having no cardiac disease. Endpoints The primary clinical endpoints were systemic hs-cTnT/I concentrations, the prevalence of cTnT/I elevations in the overall cohort as well as in patients with no cardiac disease, and the resulting Downloaded from http://ahajournals.org by on April 19, 2022 cTnT/I mismatches. Secondary endpoints were the patient-specific correlation of cTnT/I and creatine kinase (CK) as a quantitative marker of skeletal muscle injury. The translational endpoints for mRNA analyses were the gene expression in the six TnT/I genes in cases versus controls and the correlation of the three TnT genes with circulating hs-cTnT concentrations among cases. Control Cohorts hs-cTnT/I concentrations and the prevalence of hs-cTnT/I mismatches were compared to a control cohort of patients presenting to the emergency department (ED) with acute chest pain and adjudicated non-cardiac cause (n=3508, mean age 55 years, 37% women, Table S3) within an 9 10.1161/CIRCULATIONAHA.121.058489 international multicenter study (APACE, ClinicalTrials.gov registry number NCT00470587, Supplemental methods). mRNA analyses were compared to a control cohort of consecutive patients free from known SMD undergoing hip replacement surgery at the University Hospital of Basel, who were asked for consent to perform an intra-operative skeletal muscle biopsy (n=16, mean age 68 years, 44% women). No other exclusion criteria applied. Thus, patients had cardiac and non-cardiac comorbidities. Skeletal muscle tissue samples were processed by the Pathology Department of the University of Basel similarly to the skeletal muscle tissue samples obtained from patients with SMD to allow for mRNA extraction and analysis. No matching was performed between the SMD patients and patients from the control cohorts. Downloaded from http://ahajournals.org by on April 19, 2022 Laboratory Measurements One set of venous blood samples were drawn at enrolment via a peripheral intravenous line and heparin plasma was then immediately processed for the measurement using the most widely applied high-sensitivity cTnT assay (Roche hs-cTnT-Elecsys) and Abbott-hs-cTnI-Architect assays, or frozen at -80°C until assayed for measurement using Siemens-hs-cTnI-Dimension Vista or Beckman-hs-cTnI-Access assays. Additionally, plasma CK, CK-MB isoenzyme as measured by immunoassay and plasma creatinine (Cobas automated analyzer, Roche Diagnostics) and NT-proBNP (Elecsys proBNP assay, Roche Diagnostics22) were measured. The hs-cTnT-Elecsys assay (Elecsys 2010 hs-cTnT, Roche Diagnostics) has a 99th-percentile concentration (upper limit of normal, ULN) of 14 ng/L with a coefficient of variation (CV) of 10% at 13 ng/L. Limit of blank and limit of detection (LoD) have been determined to be 3 ng/L 10 10.1161/CIRCULATIONAHA.121.058489 and 5 ng/L. Sex-specific ULNs were determined at 15.5 ng/L for men and 9 ng/L for women.23 The hs-cTnI-Architect assay (ARCHITECT STAT high-sensitivity troponin I, Abbott Laboratories) has a 99th-percentile concentration of 26 ng/L with a CV of < 5%, a limit of blank of 1.3 ng/L and a LoD of 1.9 ng/L. Sex-specific ULNs were defined at 34.2 ng/L for men and 15.6 ng/L for women.24,25 The hs-cTnI-Access assay (ACCESS hs-cTnI, Beckman Coulter) has an overall 99th- percentile concentration of 18.2 ng/L with a CV of < 10%. Limit of blank and LoD have been determined to be 1.7 ng/L and 2.3 ng/L, respectively. Sex-specific ULNs were defined at 20.9ng/L for men and 9.6ng/L for women.26 The hs-cTnI-Dimension Vista has an overall 99th- percentile concentration of 58.9 ng/L with a CV of < 5%, a limit of blank of 1ng/L and a LoD of 2 ng/L. Sex-specific ULNs were defined at 68ng/L for men and 44ng/L for women.27 The uniform and sex-specific ULNs used in the current analysis are consistent with the ULNs Downloaded from http://ahajournals.org by on April 19, 2022 provided by the IFCC Committee on Clinical Applications of Cardiac Biomarkers.28 The different hs-cTnI assays examined use different antibody combinations, are not standardized and thus the ratios of T/I will differ between assay.29 Therefore, we expected varying rates of hs-cTnT/I mismatches depending on the hs-cTnI assay used. mRNA Analysis Muscle tissue samples were obtained during patient work-up whenever clinically indicated. RNA extraction was performed by CEGAT (Tübingen, Germany) using the RNeasy Mini Kit (Qiagen, Netherlands) or RNeasy Fibrous Tissue Mini kit (Qiagen, Netherlands) after sample randomization. Libraries were prepared and RNA sequenced as detailed in the supplemental. After mapping, pre-processing and quality control, differential gene expression (DGE) analysis 11 10.1161/CIRCULATIONAHA.121.058489 was conducted on all sequenced samples using the summarized gene counts with DESeq2 v1.28.0.30 The DGE analysis of cases was compared to controls. In total, six troponin genes were tested for DGE (TNNT2, TnT cardiac type, TNNT1, TnT slow skeletal type, TNNT3, TnT fast skeletal type, TNNI3, TnI cardiac type, TNNI1, TnI slow skeletal type, TNNI2, TnI fast skeletal type). Importantly, the entire process of RNA extraction and analysis was conducted blinded to the blood concentrations of hs-cTnT/I for all cases and controls. To correlate TNNT2 expression with disease activity, a score was derived based on 18 marker variables resulting from visual biopsies analysis by specialized pathologists at the respective centers. (Supplemental methods, Figure S1 and S2). Determination of Sample Size Based on prior literature,11,12 we estimated the proportion of patients to present an elevated hs- cTnT in the overall cohort to be 67% and the proportion of patients presenting an elevated hs- Downloaded from http://ahajournals.org by on April 19, 2022 cTnI to be 10%. Based on initial preliminary data, we conservatively predicted the proportion of patients without cardiac disease to be 25% in our cohort. We estimated at 10% of the patients lacking at least one of the three hs-cTnI measurement. For a selected power of 90% and a two- sided type I error of 0.05 which was then adjusted for multiple testing (three comparison with each hs-cTnI assay), a minimal sample size of 176 patients was calculated to detect a difference in proportion of hs-cTn between the two assays using a McNemar test and to allow sufficient power the population with no cardiac disease. Further details to the derivation of the sample size are given in the supplemental. 12 10.1161/CIRCULATIONAHA.121.058489 Statistical Analysis As recent studies have reported that approved uniform 99th-percentiles ULN are not biologically equivalent,31 biologically equivalent ULN derived from a large prospective diagnostic study with parallel measurement of the respective hs-cTnT/I assays was used for the primary analysis (Supplemental methods, Figures S3 and S4) for the hs-cTnI-Architect and hs-cTnI-Access assays. In brief, the biologically equivalent ULNs for hs-cTnI-Architect and hs-cTnI-Access to the ULN of 14 ng/L for hs-cTnT were derived in APACE32 and found to be 6.6 ng/L and 6.9 ng/L, respectively31,33. For the hs-cTnI-Vista assay, the biologically equivalent ULN of 42 ng/L to the ULN of 14 ng/L for hs-cTnT was derived in a recent study of healthy individuals.27 Secondary analyses used the manufacturer-recommended and regulatory authorities approved 99th-percentiles ULN described above as well as sex-specific cut-offs.25,26,31,34,35 To further assess the clinical implications for the early diagnosis of AMI in patients presenting with acute Downloaded from http://ahajournals.org by on April 19, 2022 chest pain, the proportion of patients with hs-cTnT elevations above the rule-in cut-off of the European Society of Cardiology (ESC) 0/1h-algorithm (52 ng/L) was calculated.5,6,33 Continuous variables are presented as mean ± standard deviation (SD) when normally distributed and median with interquartile ranges (IQR) when non-normally distributed. Categorical variables are expressed as numbers and percentages. Independent t-tests, Mann- Whitney-U or Kruskall Wallis tests were applied for comparison of continuous variables and the Fisher’s exact test was used for the comparison of categorical variables. Comparisons of proportions were made using a 2-sample test for equality of proportions with continuity correction. A subgroup analysis was performed to evaluate whether the prevalence of cTnT/I elevations differed among the different underlying etiologies of muscular complaints. When hs- 13 10.1161/CIRCULATIONAHA.121.058489 cTnT/I concentrations were used in statistical modelling or analyses, concentrations were transformed on the logarithmic scale to approximate normal distribution. Correlations were assessed using the Kendall rank correlation coefficient, the coefficient of determination (R-squared) and p-values provided by linear regressions. The Benjamini and Hochberg (BH) method was used to correct for multiple testing where appropriate36. Statistical analyses were performed using the R statistical package (Vienna, Austria). For mRNA analyses, resulting P-values attained by the Wald test were also corrected for multiple testing using the BH method. An adjusted P-value <0.05 was considered significant. A subgroup analysis on the major gene of interest, TNNT2 (cardiac type) was conducted by correlating a SMD activity score with TNNT2 gene expression while correcting for SMD etiology (myopathy, myositis or other SMD). Downloaded from http://ahajournals.org by on April 19, 2022 Results Patient Characteristics and Assessment of Cardiac Health From August 2018 to October 2020, 223 patients were enrolled and 211 patients were eligible for this analysis (Figure S5). The mean age was 57 years, 88 (42%) were women, 23 (11%) had known CAD, 16 (8%) prior AMI, 15 (7%) a history of atrial fibrillation, 81 (38%) arterial hypertension, and 33 (16%) diabetes mellitus (Table 1). Patients were mainly recruited during ambulatory evaluation of their muscle disorder (188, 89%). Most patients presented with muscle weakness (n=129, 61%) and/or muscle pain (n=87, 41%). Functional limitations such as dysphagia, dyspnea, incontinence, digestive symptoms or falls were present in 2 to 14% of the patients. Echocardiography was performed in 56% of the patients and CMR in 22% (Table S4). 14 10.1161/CIRCULATIONAHA.121.058489 Non-inflammatory myopathy, myositis, and myasthenic syndrome were the most common final diagnosis after work-up (Table S2). Cardiac characterization classified 59 patients (28%) as having severe cardiac disease, 44 (21%) mild cardiac disease, and 108 patients (51%) no cardiac disease (Table 2). hs-cTnT/I Concentration and hs-cTnT/I Mismatches hs-cTnT/I concentrations increased significantly from patients with no cardiac disease versus patients with mild cardiac disease versus patients with severe cardiac disease for all assays (all pMann-Whitney<0.001). In the overall group, hs-cTnT-Elecsys concentrations were above the uniform approved ULN in 55%, and significantly higher versus controls (median 16ng/L (IQR 7- 32.5) versus 5ng/L (IQR 3-9), pMann-Whitney<0.001, Figure 1, Table S5). Elevations in hs- cTnT were even above the rule-in cut-off of the ESC 0/1h-algorithm and of the ESC 0/2h- algorithm (52ng/L) in 34 patients (16.1%, Table S6). In contrast, hs-cTnI-Architect, hs-cTnI- Downloaded from http://ahajournals.org by on April 19, 2022 Access, and hs-cTnI-Vista concentrations were above the biologic-equivalent ULN in 23%, 23%, and 8%, and overall comparable to controls (hs-cTnI-Architect 2.5ng/L (IQR 1.2-6.2) versus 2.9ng/L (IQR 1.8-5.0), hs-cTnI-Access 3.3ng/L (IQR 2.4-6.1) versus 2.7ng/L (IQR 1.6-5.0) and hs-cTnI-Vista 7.4ng/L (IQR 5.2-13.4) versus 7.5ng/L (IQR 6-10), Table S5). This resulted in hs- cTnT/hs-cTnI-mismatches in 36-50% in the overall cohort and in 33-37% in patients without cardiac disease (Figure 2, Table S7). These findings were confirmed using uniform approved and sex-specific ULN (Supplemental Figures 6-9). In the control cohort, hs-cTnT/hs-cTnI mismatches were uncommon (4 to 5% using biologically equivalent ULN, Figure S10, Table S8). 15 10.1161/CIRCULATIONAHA.121.058489 Impact of Underlying Etiology on CK and hs-cTnT/I Concentrations When the different etiologies of muscle disorders were analyzed separately, relevant differences among the etiologies emerged in CK and hs-cTnT concentrations, which were not observed with the hs-cTnI Architect, hs-cTnI-Access, and hs-cTnI-Vista assays (Figure 3A). Non-inflammatory myopathies and myositis had the highest CK and hs-cTnT concentrations, both in the overall cohort and in the subgroup of patients without cardiac disease (Figure 3B). hs-cTnT elevations in patients without cardiac disease were largely restricted to patients with non-inflammatory myopathies and myositis. Within this subgroup of non-inflammatory myopathies and myositis, 77% (in the overall cohort) and 68% (in the subgroup with no cardiac disease) presented hs- cTnT concentrations > uniform approved ULN, while only a few of these patients also showed a hs-cTnI elevation (pz-test<0.001, Table S9; Figure 3, Figures S11 and S12). In contrast, the vast majority of patients with neuropathies, myasthenic syndromes and auto-immune diseases had Downloaded from http://ahajournals.org by on April 19, 2022 normal hs-cTnT concentrations. Correlation between hs-cTnT/I and CK as Quantitative Indicator of Muscle Damage In the overall cohort, hs-cTnI concentrations did not correlate with CK or CK-MB concentrations, while hs-cTnT concentrations showed a positive significant correlation with CK and CK-MB concentrations (e.g. with CK R=0.33, and R=0.43 in subgroup of patients without cardiac disease, both ptau-statistic<0.001, Figure 4A,B; Figure S13, Table S10 and S11). Muscle Tissue mRNA Analysis Muscle biopsies from diseased skeletal muscle were available for 33 patients, mean age 59 years, 39% women (Table S12). DGE analysis showed significant upregulation of the gene TNNT2 coding for cTnT (Top 96 differentially expressed gene, 8-fold change as compared with controls, 16 10.1161/CIRCULATIONAHA.121.058489 pt-statistic<0.001), fast skeletal muscle TNNT3 and TNNI2 genes (Figure 5A and B). Both the cardiac TNNT2 and TNNI3 genes were expressed at low levels in control muscle biopsies, but the level of expression stayed largely below the expression of skeletal muscle troponin genes (Figure 5C). There was a significant positive correlation between the TNNT2 gene and a SMD activity score based on pathological features of the diseased skeletal muscle biopsies, independently of disease etiology, with higher disease activity score showing higher TNNT2 upregulation (R=0.59, pt-statistic<0.001, Figure 5D). Correlation between Normalized Count of TnT Gene Expression and Circulating hs-cTnT Among the 33 patients providing muscle tissue, circulating hs-cTnT concentrations significantly positively correlated with normalized TNNT2 (R=0.26, pt-statistic =0.032, Figure 6, Table S15) expression, but not with TNNT1 or TNNT3. Discussion Downloaded from http://ahajournals.org by on April 19, 2022 This prospective multicenter study evaluated cTnT and cTnI concentrations using four widely applied hs-cTnT/I assays in a broad population of patients presenting with skeletal muscle symptoms. Those were compared to a large control cohort of patients adjudicated to have non- cardiac causes of acute chest pain, to assess possible implications for the diagnosis of AMI or other cardiac diseases, and cardiovascular risk-stratification. We report eight major findings. First, about 50% of patients with SMD had mild or severe cardiac disease. Most of the cardiac abnormalities were related to common cardiac disorders such as CAD, which are associated with an increased risk of future AMI, further documenting the clinical relevance of reliable AMI diagnosis in this population. Second, hs-cTnT/I serum concentrations significantly increased from patients with no cardiac disease versus mild cardiac disease versus severe cardiac disease for all assays. Accordingly, cardiomyocyte injury due to cardiac disease was a major 17 10.1161/CIRCULATIONAHA.121.058489 contributor to hs-cTnI and hs-cTnT concentrations also in patients with SMD. Third, hs-cTnT- Elecsys concentrations were above the uniform approved ULN in 55% and significantly higher versus controls (median 16ng/L versus 5ng/L, p<0.001). In contrast, hs-cTnI-Architect, hs-cTnI- Access and hs-cTnI-Vista concentrations were above the biologic-equivalent ULN in 23%, 23%, and 8%, and overall comparable to controls. These findings were confirmed using uniform approved and sex-specific ULN. Fourth, elevations in hs-cTnT/I concentrations were most often mild. However, 16.1% of patients in the overall cohort and 12.9% in the subgroup without cardiac disease had hs-cTnT concentrations above the rule-in cut-off of the ESC 0/1h-algorithm and ESC 0/2h-algorithm (52 ng/L).5,6,33 Therefore, the proportion of SMD patients possibly misclassified by the rule-in cut-off of the ESC 0/1h-algorithm or ESC 0/2h-algorithm seemed even higher compared to more common populations with increased baseline hs-cTnT/I concentrations such as patients with renal dysfunction and the elderly.37,38 Fifth, hs-cTnT Downloaded from http://ahajournals.org by on April 19, 2022 elevations in patients without cardiac disease were largely restricted to patients with non- inflammatory myopathy and myositis, whereas the vast majority of patients with neuropathies, myasthenic syndromes, auto-immune diseases, or other causes of skeletal muscle symptoms had hs-cTnT concentrations within the normal range. Sixth, hs-cTnT, but not hs-cTnI, showed a significant positive correlation with CK, a biomarker of skeletal muscle damage, providing further support for the concept that damaged skeletal muscle is the origin of some of the systemic hs-cTnT concentration.9,11,12 Seventh, in the subgroup of patients with skeletal muscle biopsies available, mRNA analyses in diseased skeletal muscle showed 8-fold upregulation of TNNT2, encoding cTnT, versus controls without SMD undergoing hip replacement. The expression strongly correlated with pathological disease activity, thereby suggesting active chronic SMD as a significant contributor to the systemic hs-cTnT concentration. This assumption was further 18 10.1161/CIRCULATIONAHA.121.058489 strengthened by a positive and significant correlation between TNNT2 gene expression and circulating hs-cTnT concentrations. Eight, in contrast, no evidence of upregulation/re-expression in diseased skeletal muscle was found for cTnI. These findings extend and corroborate results from prior studies, including three studies using the hs-cTnT assay.9,12,17 Among 27 ambulatory patients with skeletal myopathies and muscle dystrophies, hs-cTnT concentrations were elevated in 18 patients (67%), with a median of 21 ng/l (IQR 11 to 38 ng/l), while cTnI was elevated in only one patient (4%).11 Among 74 patients with hereditary and acquired skeletal myopathies, hs-cTnT concentrations were elevated in 69%, with a median of 24 ng/l (IQR 11 to 54 ng/l), while hs-cTnI was elevated in 4% of patients.12 In 122 patients with Pompe disease, hs-cTnT concentrations were elevated in 82% of patients (median 27 ng/L), while hs-cTnI concentrations were normal in all patients. All three studies found elevated systemic concentration of hs-cTnT, but not hs-cTnI, and, in part also, Downloaded from http://ahajournals.org by on April 19, 2022 evidence for some RNA and/or protein expression on skeletal muscular tissue level. Based on these consistent findings, the following insights emerge: first, in the presence of active chronic SMD from two categories, non-inflammatory myopathy and myositis, including statin-induced myopathy, hs-cTnT loses cardiac specificity as diseased skeletal muscle contributes to the systemic hs-cTnT concentration. Second, based on mRNA analysis, re- expression of cTnT during chronic repair mechanisms in the diseased skeletal muscle appears to be the underlying pathophysiology.7,9–13,39,40 Third, re-expression of cTnT during skeletal muscle repair mechanisms seems to be time-dependent. It was present in this study of patients with active chronic SMD with ongoing skeletal muscle damage and repair lasting for weeks to months. In contrast, no evidence was found in patients with acute rhabdomyolysis, an in vivo model of acute skeletal muscle damage of several days duration, as no correlation was observed 19 10.1161/CIRCULATIONAHA.121.058489 between hs-cTnT and CK concentrations. Accordingly, hs-cTnT/I mismatches were uncommon in acute rhabdomyolysis.41,42 Fourth, other SMD categories including neuropathies, myasthenic syndromes, auto-immune diseases, or other causes of skeletal muscle symptoms do not seem to be relevant sources of systemic hs-cTnT concentration. Fourth, while a small number of patients with SMD also showed elevations in hs-cTnI, the absence of an increase in cTnI mRNA at the tissue level and the absence of correlation with CK highlighted both in this and previous studies clearly argue against a skeletal muscle origin.7,17 Alternative explanations need to be considered in these patients, such as analytical interference e.g. due to heterophilic antibodies, autoantibodies, or the formation of macro-troponin complexes, which seem to be affect hs-cTnI more commonly than hs-cTnT.43–47 The interpretation of CK-MB is difficult, as it has cardiac and skeletal muscle sources and is re-expressed in diseased skeletal muscle.3 Contrary to what was expected, the prevalence of hs-cTnT/I mismatch was higher in the Downloaded from http://ahajournals.org by on April 19, 2022 overall group with about half having documented cardiac disease versus the subgroup without cardiac disease (36-50% versus 33-37%). This indicates that to some degree preferential release of cTnT versus cTnI from cardiomyocytes due to chronic cardiac disease may have also contributed to hs-cTnT/I mismatch. The exact pathophysiology underlying this differential release is largely unknown.48 Alternatively, differences in renal function between the overall group and patients with no cardiac disease could have led to differences in clearance between the hs-cTnT and hs-cTnI circulating concentrations. These findings have clinical implications. In patients presenting with suspected AMI and without ST-segment elevation, the presence of active chronic non-inflammatory myopathy or myositis as a possible important confounder of hs-cTnT concentrations must be actively assessed in institutions using hs-cTnT as their standard of care in the ED, as the risk of erroneous AMI 20 10.1161/CIRCULATIONAHA.121.058489 diagnosis is increased in these patients. If no SMD or SMD other than these two categories are present, no change in their standard of care seems necessary. If patient history reveals active chronic non-inflammatory myopathy or myositis, hs-cTnI rather than hs-cTnT should be measured as an alternative, if available. If hs-cTnI is not available, resampling at 1h or 2h would be mandatory to differentiate AMI with its rise within 1h or 2h versus non-cardiac causes of chest pain with usually stable hs-cTnT concentrations5,6,33. A similar change in management should also be considered in other acute disorders, in which an elevated hs-cTnT concentration is associated with a change in management, such as for instance rhythm monitoring and/or escalation of therapy as in peri-/myocarditis and in patients with acute pulmonary embolism. Although the prevalence of patients with active chronic non-inflammatory myopathy or myositis in previous diagnostic studies deriving rapid hs-cTnI-based triage algorithms likely was very small, our findings provide further support for the more sophisticated methodology of using two Downloaded from http://ahajournals.org by on April 19, 2022 adjudicated final diagnoses: one using serial measurements of hs-cTnT, and one of hs-cTnI.49,50 Finally, our results highlight the need for future hs-cTnT assays to ensure that their antibodies do not cross react to the troponin T form found in diseased skeletal muscle. Several limitations of the present study merit consideration. First, while being the largest study performed to date, the sample size of some etiologies was only modest. Second, this study included three widely applied hs-cTnI assays. Although the findings were quite consistent among the different hs-cTnI assays, studies including other clinically used hs-cTnI assays seem warranted to explore their reliability in patients with SMD. Given the relevant differences in the antibody combination used in these different immunoassays27,35, different findings may emerge. Third, we may have misclassified a small number of patients as having no cardiac disease, as symptoms, signs, ECG, and NT-proBNP concentrations were available in all of these 21 10.1161/CIRCULATIONAHA.121.058489 patients, but cardiac imaging only in a subset. Fourth, over the span of their lifetime, 10-20% of patients with non-inflammatory myopathies and myositis seem to develop clinically apparent cardiac involvement(51–53). Therefore, in a small proportion of patients with these underlying etiologies, despite normal findings in cardiac imaging, subtle microscopic cardiomyocyte injury may have already been present and contributed to the high prevalence of hs-cTnT elevation. Future studies including long-term follow-up are necessary to provide an additional domain assessing the biological significance of elevated hs-cTnT concentrations in these patients. Fifth, it is impossible to precisely quantify the proportion of the systemic hs-cTnT concentration that was contributed by the diseased skeletal muscle versus cardiomyocyte injury in the two affected SMD categories. The modest correlation between TNNT2 gene expression and circulating hs- cTnT concentrations and the persistent association between the extent of cardiac disease and hs- cTnT concentration suggest that cardiomyocyte injury remained the dominant source. Sixth, due Downloaded from http://ahajournals.org by on April 19, 2022 to the absence of serial assessments, we cannot comment on the exact timepoint at which cTnT start to be re-expressed in non-inflammatory myopathies and myositis. Longitudinal studies are required to quantify the time to re-expression. Conclusions In conclusion, hs-cTnT elevations are common in patients with active chronic non-inflammatory myopathy and myositis, but not with other SMD, and in part due to upregulation and thereby re- expression of TNNT2 in diseased skeletal muscle. In contrast, no evidence of upregulation/re- expression in diseased skeletal muscle was found for cTnI. Therefore, in patients with active chronic non-inflammatory myopathy and myositis, cTnI is the preferred analyte for assessing cardiac health in general and the presence of AMI. 22 10.1161/CIRCULATIONAHA.121.058489 Sources of Funding The study was supported by research grants from the Swiss Heart Foundation, University of Basel, University Hospital of Basel, and Abbott, Roche, and Siemens. Disclosures We disclose that Dr. Jeanne du Fay de Lavallaz has received research support from the Swiss Heart Foundation. We disclose that Dr. Nestelberger has received research support from the Swiss National Science Foundation (P400PM_191037/1), the Prof. Dr. Max Cloëtta Foundation, the Margarete und Walter Lichtenstein-Stiftung (3MS1038), and the University Hospital Basel as well as speaker honoraria/consulting honoraria from Siemens, Beckman Coulter, Bayer, Ortho Clinical Diagnostics and Orion Pharma, outside the submitted work. Dr. Boeddinghaus has received research grants from the University of Basel and the Division of Internal Medicine, the Downloaded from http://ahajournals.org by on April 19, 2022 Swiss Academy of Medical Sciences, the Gottfried and Julia Bangerter-Rhyner-Foundation, and speaker honoraria from Siemens, Roche, Ortho Clinical Diagnostics, and Quidel Corporation, outside the submitted work. Dr. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the University Hospital Basel, the University of Basel, Abbott, Beckman Coulter, Idorsia, Novartis, Ortho Clinical Diagnostics, Quidel, Roche, Siemens, as well as speaker honoraria/consulting honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Idorsia, Novartis, Osler, Roche, and Sanofi, outside the submitted work. Dr. Maurer has grant/research support from Prof. Max Cloetta Foundation, AbbVie, Protagen, Novartis Biomedical Research, received speaker fees from Boehringer-Ingelheim as well as congress support from Pfizer, Roche, Actelion, Mepha, and MSD. In addition, Dr. Maurer has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143), all outside the submitted work. Dr. Gualandro received 23 10.1161/CIRCULATIONAHA.121.058489 research grants from FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brasil) and consulting honoraria from Roche, outside the submitted work. Dr. Lopez-Ayala has received research support from the Swiss Heart Foundation (FF20079). Dr. Puelacher reports research funding from Roche Diagnostics, the University of Basel, the University Hospital Basel, outside of the submitted work. Dr. Sinnreich has received financial support from Roche from 2015 to 2019 for a research collaboration unrelated to the current work. All other authors declare that they have no conflict of interest with this study. The hs-cTn assays investigated were donated by the manufacturers, who had no role in the design of the study, the analysis of the data, the preparation of the manuscript, or the decision to submit the manuscript for publication. Appendix #Additional BASEL XII Investigators to be listed as collaborators in PUBMED: Downloaded from http://ahajournals.org by on April 19, 2022 Tibor Zehntner MD , Raoul Giger MD14, Thomas Stoll MD14, Hadrien Schöpfer MD14, Fabian Jordan MS14, Michael Carigiet, MD14, Nicola Haeni MD14, Vincent Gysin MD14, Michele Sara Gafner, MD14, Desiree Wussler, MD14; Luca Koechlin, MD14; Michael Freese, RN14; Christian Ruiz , PhD; Olivia Strauch MS14, Tobias Zimmermann, MD14; Ivo Strebel, PhD14; Ulrich A. Walker, MD ; Thomas Vogt, MD16; Martina Hartmann MD ; Timo Kahles17, MD; Paul Hasler , MD; Funda Seidel MD ; Xenia Zavtsyea, MD19; Katharina Rentsch, PhD , Sandra Mitrovic, PhD20; Arnold von Eckardstein, MD , Johannes Mair, MD , Michael Schreinlechner, MD ; Wijstke Wallimann, MD23, Manuel Dietrich , Tania Carrillo Roah24, Markus Knoll24, Alexander Fuchs, PhD ; Ellen Bruske, PhD25; Matthias Munz, PhD24, Stefan Kunzelmann, PhD24; Gesa Albert, PhD24; Tobias Becher, MD24; Peter Kastner, PhD24; Samuel Katsuyuki Shinjo, PhD . 24 10.1161/CIRCULATIONAHA.121.058489 Supplemental Material List Expanded Methods 1) Supplemental data regarding the APACE control cohort Cohort details Derivation of bioequivalent cut-offs in the control cohort Sample size calculation 2) RNA-seq experiment Sample randomization RNA extraction Library preparation and RNA sequencing 3) RNA-seq computational analysis Mapping and pre-processing Downloaded from http://ahajournals.org by on April 19, 2022 Quality control Differential gene expression TNNT2 vs disease activity correlation analysis Figures S1-S13 Tables S1-S13 Appendix and contributing authors References (49, 50, 3, 32) 25 10.1161/CIRCULATIONAHA.121.058489 References 1. 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High-Sensitivity* Cardiac Troponin I and T Assay Analytical Characteristics Designated by Manufacturer IFCC Committee on Clinical Applications of Cardiac Bio-Markers (C-CB) V082318.; 2019. http://www.ifcc.org/media/477441/high-sensitivity-cardiac-troponin-i-and-t-assay-analytical- characteristics-designated-by-manufacturer-v08232018.pdf Downloaded from http://ahajournals.org by on April 19, 2022 29. Ungerer JPJ, Marquart L, O’Rourke PK, Wilgen U, Pretorius CJ. Concordance, variance, and outliers in 4 contemporary cardiac troponin assays: Implications for harmonization. Clin Chem. 2012;58(1):274-283. doi:10.1373/clinchem.2011.175059 30. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi:10.1186/s13059-014-0550-8 31. Wildi K, Gimenez MR, Twerenbold R, Reichlin T, Jaeger C, Heinzelmann A, Arnold C, Nelles B, Druey S, Haaf P, et al. Misdiagnosis of Myocardial Infarction Related to Limitations of the Current Regulatory Approach to Define Clinical Decision Values for Cardiac Troponin. Circulation. 2015;131(23):2032-2040. doi:10.1161/CIRCULATIONAHA.114.014129 32. Steyerberg EW. FRANK E. HARRELL, Jr., Regression Modeling Strategies: With Applications, to Linear Models, Logistic and Ordinal Regression, and Survival Analysis, 2nd ed. Heidelberg: Springer. Biometrics. 2016;72(3):1006-1007. doi:10.1111/biom.12569 33. Twerenbold R, Costabel JP, Nestelberger T, Campos R, Wussler D, Arbucci R, Cortes M, Boeddinghaus J, Baumgartner B, Nickel CH, et al. Outcome of Applying the ESC 0/1-hour Algorithm in Patients With Suspected Myocardial Infarction. J Am Coll Cardiol. 2019;74(4):483-494. doi:10.1016/j.jacc.2019.05.046 34. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56(2):254-261. doi:10.1373/clinchem.2009.132654 28 10.1161/CIRCULATIONAHA.121.058489 35. Apple FS, Sandoval Y, Jaffe AS, Ordonez-Llanos J. Cardiac troponin assays: Guide to understanding analytical characteristics and their impact on clinical care. Clin Chem. 2017;63(1):73-81. doi:10.1373/clinchem.2016.255109 36. Noble WS. How does multiple testing correction work? Nat Biotechnol. 2009;27(12):1135-1137. doi:10.1038/nbt1209-1135 37. Boeddinghaus J, Nestelberger T, Twerenbold R, Neumann JT, Lindahl B, Giannitsis E, Sörensen NA, Badertscher P, Jann JE, Wussler D, et al. Impact of age on the performance of the ESC 0/1h-algorithms for early diagnosis of myocardial infarction. Eur Heart J. 2018;39(42):3780-3794. doi:10.1093/eurheartj/ehy514 38. Twerenbold R, Badertscher P, Boeddinghaus J, Nestelberger T, Wildi K, Puelacher C, Sabti Z, Rubini Gimenez M, Tschirky S, Du Fay De Lavallaz J, et al. 0/1-Hour Triage Algorithm for Myocardial Infarction in Patients with Renal Dysfunction. Circulation. 2018;137(5):436-451. doi:10.1161/CIRCULATIONAHA.117.028901 39. Messner B, Baum H, Fischer P, Quasthoff S, Neumeier D. Expression of messenger RNA of the cardiac isoforms of troponin T and I in myopathic skeletal muscle. Am J Clin Pathol. 2000;114(4):544-549. 40. Fisher C, Agrawal S, Wong WM, Fahie-Wilson M, Dasgupta B. Clinical observations on the significance of raised cardiac troponin-T in patients with myositis of varying etiologies seen in rheumatology practice. Clin Rheumatol. 2010;29(10):1107-1111. doi:10.1007/s10067-010- 1511-6 41. du Fay de Lavallaz J, Zehntner T, Puelacher C, Walter J, Strebel I, Rentsch K, Downloaded from http://ahajournals.org by on April 19, 2022 Boeddinghaus J, Nestelberger T, Twerenbold R, Mueller C. Rhabdomyolysis: A Noncardiac Source of Increased Circulating Concentrations of Cardiac Troponin T? J Am Coll Cardiol. 2018;72(23):2936-2937. doi:10.1016/j.jacc.2018.09.050 42. Giger RD, du Fay de Lavallaz J, Prepoudis A, Stoll T, Lopez-Ayala P, Glarner N, Boeddinghaus J, Puelacher C, Nestelberger T, Mueller C. Rhabdomyolysis: A Noncardiac Source of Increased Circulating Concentrations of Cardiac Troponin T? J Am Coll Cardiol. 2020;76(22):2685-2687. doi:10.1016/j.jacc.2020.08.088 43. Lewis JG, Connolly AJL, Ploeg H, Phillips IJ, King RI, Elder PA, Florkowski CM. Grossly Elevated False-Positive High-Sensitivity Troponin I Due to Heterophilic Antimouse IgG1 Antibodies. J Appl Lab Med. 2020;5(4):815-817. doi:10.1093/jalm/jfaa024 44. Strasser B, Tomasits J, Fellner A, Lambert T. Troponin interference with special regard to macrocomplex formation. Clin Chem Lab Med. 2022;60(2):162-168. doi:10.1515/cclm-2021- 0841 45. Herman DS, Kavsak PA, Greene DN. Variability and error in cardiac troponin testing: An ACLPS critical review. Am J Clin Pathol. 2017;148(4):281-295. doi:10.1093/AJCP/AQX066 46. Lam L, Aspin L, Heron RC, Ha L, Kyle C. Discrepancy between Cardiac Troponin Assays Due to Endogenous Antibodies. Clin Chem. 2020;66(3):445-454. doi:10.1093/clinchem/hvz032 29 10.1161/CIRCULATIONAHA.121.058489 47. Leuschner F, Li J, Göser S, Reinhardt L, Öttl R, Bride P, Zehelein J, Pfitzer G, Remppis A, Giannitsis E, et al. Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction. Eur Heart J. 2008;29(16):1949-1955. doi:10.1093/eurheartj/ehn268 48. Mair J, Lindahl B, Hammarsten O, Müller C, Giannitsis E, Huber K, Möckel M, Plebani M, Thygesen K, Jaffe AS. How is cardiac troponin released from injured myocardium? Eur Hear journal Acute Cardiovasc care. 2018;7(6):553-560. doi:10.1177/2048872617748553 49. Boeddinghaus J, Nestelberger T, Koechlin L, Wussler D, Lopez-Ayala P, Walter JE, Troester V, Ratmann PD, Seidel F, Zimmermann T, et al. Early Diagnosis of Myocardial Infarction With Point-of-Care High-Sensitivity Cardiac Troponin I. J Am Coll Cardiol. 2020;75(10):1111-1124. doi:10.1016/j.jacc.2019.12.065 50. Koechlin L, Boeddinghaus J, Nestelberger T, Lopez-Ayala P, Wussler D, Shrestha S, Resa T, Wildi K, Bakula A, Frey S, et al. Performance of the ESC 0/2h-algorithm using high- sensitivity cardiac troponin I in the early diagnosis of myocardial infarction. Am Heart J. 2021;242:132-137. doi:10.1016/j.ahj.2021.08.008 51. Gupta R, Wayangankar SA, Targoff IN, Hennebry TA. Clinical cardiac involvement in idiopathic inflammatory myopathies: A systematic review. Int J Cardiol. 2011;148(3):261-270. doi:10.1016/j.ijcard.2010.08.013 52. Lilleker JB, Vencovsky J, Wang G, Wedderburn LR, Diederichsen LP, Schmidt J, Oakley P, Benveniste O, Danieli MG, Danko K, et al. The EuroMyositis registry: An international collaborative tool to facilitate myositis research. Ann Rheum Dis. 2018;77(1):30- Downloaded from http://ahajournals.org by on April 19, 2022 39. doi:10.1136/annrheumdis-2017-211868 53. Lundberg IE. The heart in dermatomyositis and polymyositis. Rheumatology. 2006;45(SUPPL. 4):18-21. doi:10.1093/rheumatology/kel311 30 10.1161/CIRCULATIONAHA.121.058489 Table 1. Severe Mild No Overall Variable cardiac cardiac cardiac p cohort disease disease disease n 211 59 44 108 Sex : Female (%) 88 (42) 22 (37) 17 (39) 49 (45) 0.566 Age (mean (SD)) 56.8 (17.4) 66.6 (15.2) 63.2 (14.9) 48.9 (15.7) <0.001 Hospitalized (%) 23 (11) 11 (19) 2 (5) 10 (9) 0.063 Coronary artery disease (%) 23 (11) 16 (27) 7 (16) 0 (0) <0.001 Previous AMI (%) 16 (8) 16 (27) 0 (0) 0 (0) <0.001 Hypertension (%) 81 (38) 34 (58) 23 (52) 24 (22) <0.001 Hypercholesterolemia (%) 49 (23) 24 (41) 12 (27) 13 (12) <0.001 Diabetes Mellitus (%) 33 (16) 15 (25) 8 (18) 10 (9) 0.018 History of atrial fibrillation (%) 15 (7) 14 (24) 1 (2) 0 (0) <0.001 Previous DVT or PE (%) 11 (5) 4 (7) 4 (9) 3 (3) 0.225 Heart failure (%) <0.001 Downloaded from http://ahajournals.org by on April 19, 2022 None 192 (93) 44 (77) 42 (98) 106 (100) NYHA I 5 (2) 4 (7) 1 (2) 0 (0) NYHA II 5 (2) 5 (9) 0 (0) 0 (0) NYHA III 2 (1) 2 (4) 0 (0) 0 (0) NYHA IV 2 (1) 2 (4) 0 (0) 0 (0) Chronic kidney disease (%) 14 (7) 8 (14) 4 (9) 2 (2) 0.007 91.8 102.7 96.0 82.0 eGFR (median [IQR]) [67.3, [90.4, <0.001 [76.6, 114.6] [69.2, 105.6] 107.0] 118.1] Pacemaker (%) 6 (3) 4 (7) 2 (5) 0 (0) 0.014 ICD (%) 2 (1) 1 (2) 1 (2) 0 (0) 0.237 Stroke (%) 9 (4) 5 (8) 2 (5) 2 (2) 0.141 Muscle manifestations: Upper or 0.675 lower body (%) 31 10.1161/CIRCULATIONAHA.121.058489 Severe Mild No Overall Variable cardiac cardiac cardiac p cohort disease disease disease Lower body 30 (14) 7 (12) 7 (16) 16 (15) Upper body 20 (9) 7 (12) 2 (5) 11 (10) Lower and upper body 57 (27) 15 (25) 16 (36) 26 (24) Not localized 104 (49) 30 (51) 19 (43) 55 (51) Muscle manifestations : proximal 0.179 or distal (%) proximal 10 (5) 4 (7) 3 (7) 3 (3) distal 39 (18) 7 (12) 6 (14) 26 (24) proximal and distal 58 (27) 18 (31) 16 (36) 24 (22) Not localized 104 (49) 30 (51) 19 (43) 55 (51) Begin of symptoms (%) 0.214 2-4 weeks 15 (8) 8 (15) 3 (7) 4 (4) >1 month, up to 12 months 43 (22) 13 (24) 9 (21) 21 (21) Downloaded from http://ahajournals.org by on April 19, 2022 >1 year 138 (70) 34 (62) 30 (71) 74 (75) Muscle pain (%) 87 (41) 25 (42) 15 (34) 47 (44) 0.526 Muscle cramps (%) 25 (12) 7 (12) 7 (16) 11 (10) 0.565 Muscle atrophy (%) 54 (26) 14 (24) 11 (25) 29 (27) 0.935 Muscle stiffness (%) 19 (9) 3 (5) 4 (9) 12 (11) 0.437 Muscle weakness (%) 129 (61) 41 (69) 26 (59) 62 (57) 0.305 Skin manifestations present (%) 14 (7) 6 (10) 2 (5) 6 (6) 0.540 Joint manifestations present (%) 42 (20) 13 (22) 7 (16) 22 (21) 0.744 Clinical evaluation (%) 0.617 Planned follow-up visit 174 (82) 46 (78) 39 (89) 89 (82) First evaluation 30 (14) 10 (17) 5 (11) 15 (14) Relapse 7 (3) 3 (5) 0 (0) 4 (4) Symptom activity (%) 0.375 Worsening 74 (35) 23 (39) 11 (25) 40 (37) 32 10.1161/CIRCULATIONAHA.121.058489 Severe Mild No Overall Variable cardiac cardiac cardiac p cohort disease disease disease Improving 15 (7) 6 (10) 3 (7) 6 (6) Stable 122 (58) 30 (51) 30 (68) 62 (57) Dysphagia (%) 29 (14) 11 (19) 3 (7) 15 (14) 0.216 Dyspnea (%) 24 (11) 9 (15) 5 (11) 10 (9) 0.509 Incontinence (%) 5 (2) 3 (5) 0 (0) 2 (2) 0.288 Digestive symptoms (%) 10 (5) 3 (5) 0 (0) 7 (7) 0.221 Falls (%) 13 (6) 3 (5) 3 (7) 7 (7) 1.000 Any cardiac medication (%)a* 96 (45) 45 (76) 27 (61) 24 (22) <0.001 Final diagnosis NA Non-inflammatory myopathyb† 51 (24) 11 (19) 14 (32) 26 (24) Muscle symptoms 20 (9) 3 (5) 2 (5) 15 (14) Neuropathy 21 (10) 5 (8) 3 (7) 13 (12) Myasthenic syndrome 43 (20) 11 (19) 11 (25) 21 (19) Downloaded from http://ahajournals.org by on April 19, 2022 Myositis c ‡ 53 (25) 21 (36) 7 (16) 25 (23) Autoimmune disease with 23 (11) 8 (14) 7 (16) 8 (7) muscle symptoms a*Cardiac medications: Any of cardiac aspirin, anti-platelet agent, beta-blocker, Angiotensin converting enzyme inhibitor or aldosteron-receptor antagonist, calcium channel antagonist, nitrates, alpha-blockers, diuretics, anti- arrhythmics or digitalis. b† Non-inflammatory myopathy: Myotonic dystrophy, Facioscapulohumeral muscular dystrophy, Limb–girdle muscular dystrophy, Mitochondrial disease, Glycogen storage disease. c‡ Myositis: Dermatomyositis, Polymyositis, Sporadic inclusion body myositis, Hereditary inclusion body myositis, Immune mediated necrotizing myositis, Myositis with overlap with collagenous disease, Statin induced myositis, Vasculitis. AMI=Acute myocardial infarction, DVT = Deep venous thrombosis, eGFR = estimated Glomerular filtration rate, ICD = Implantable cardiac defibrillator, NYHA = New York Heart Association, SD = Standard deviation, PE = Pulmonary embolism estimated Glomerular filtration rate was calculated using the CKD-EPI formula p-values comparing the three groups with different prevalence of cardiac diseases (no, mild, severe) and are derived using following tests : Chi-square tests with continuity correction for categorical variables, ANOVA for normally-distributed variables (presented with mean ± sd) and Kruskal-Wallis tests for non-normally distributed variables (presented with median [IQR]) 33 10.1161/CIRCULATIONAHA.121.058489 Table 2. Number Overall n 211 Cardiac disease (%) No cardiac disease 108 (51) Mild cardiac disease 44 (21) Severe cardiac disease 59 (28) Severe cardiac disease (%) Cardiomyopathie 1 (2) History of HF (NYHA II-IV) 4 (7) LGE 7 (12) LVEF ≤40% 1 (2) NTproBNP>400pg/mL 24 (41) previous AMI 11 (19) Mild cardiac disease (%) ECG: complete bundle branch block 13 (15) ECG: LVH 2 (2) History of atrial fibrillation 11 (13) Downloaded from http://ahajournals.org by on April 19, 2022 History of CAD 11 (13) NTproBNP 125-400pg/mL 35 (42) TTE or CMR: Dilation of LV or RV 1 (1) TTE or CMR: LVH 4 (5) TTE or CMR: Reduced Motility of LV or RV 7 (8) AMI = Acute myocardial infarction, CAD = Coronary artery disease, CMR = Cardiovascular magnetic resonance imaging, ECG = electrocardiogram, HF = Heart failure, LGE = Late gadolinium enhancement, LV = Left ventricle, LVEF = Left ventricular ejection fraction, LVH = Left ventricular hypertrophy, NTproBNP = N-terminal pro-B-type natriuretic peptide, NYHA = New York Heart Association, RV = Right ventricle, TTE = Transthoracic echocardiogram. 34 10.1161/CIRCULATIONAHA.121.058489 Figure Legends Figure 1: Violine Plots Representing the Distribution of hs-cTnT/I Concentrations for the Four Tested Assays and across Categories of Cardiac Disease. A single comparison using a Mann-Whitney-U test was conducted between the controls of the APACE cohort and the overall cohort of patients with skeletal muscle disease. Bioequivalent and overall approved Upper Limit of Normal (ULN) are represented as broken lines. hs-cTnT-Elecsys and hs-cTnI-Architect concentrations were available in all 211 patients, hs-cTnI-Access concentrations in 187 patients, and hs-cTnI-Vista concentrations in 194 patients. The p-values were calculating using a Wilcoxon-test comparing the overall group with the control group and have been corrected for multiple testing (4 tests) using the Benjamini and Hochberg method. Figure 2: Inter-assay hs-cTnT/I Mismatches Using Biologically-equivalent Upper Limits of Downloaded from http://ahajournals.org by on April 19, 2022 Normal (ULN). For each subpanel, two hs-cTnT/I assay are represented with their biologically- equivalent assay-specific 99th-percentile Upper Limit of Normal (ULN). In each panel, the four quadrants represent the percentage of patients with the following constellations: green when both hs-cTnT/I assays were below the ULN, grey when both were above the ULN, and red when there was a hs-cTnT/I mismatch (with one of the assay above and one of the assay below the ULN). A) overall cohort, B) Subgroup without cardiac disease. Figure 3: The Different Etiologies of the Skeletal Muscle Disorders are Represented on the X-Axis and the Concentrations of the Biomarkers are Represented on the Y-axis Using a Logarithmic Scale. Boxplots represents the interquartile range (IQR) and whiskers ± 1.5*IQR. Bioequivalent and overall approved Upper Limit of Normal (ULN) are represented as broken lines. 35 10.1161/CIRCULATIONAHA.121.058489 A) in the overall cohort, B) in the cohort without cardiac disease. AD = Autoimmune disease. The p-values have been corrected for multiple testing using the Benjamini and Hochberg method. Figure 4: Correlation between Creatine Kinase (CK) and hs-cTn in A) the Overall Cohort and in B) Patients with No Cardiac Disease. Biomarkers have been log-transformed to approximate normal distribution. Figure 5: A. Differential Gene Expression (DGE) Results from a Case/Control Study Comparing Skeletal Muscle Biopsies from Patients with (33 cases) and without (16 controls) Skeletal Muscle Disease (SMD). After correcting for multiple testing using Benjamini and Hochbert, 847 of 17,124 protein coding genes were upregulated and 966 were downregulated at a significance Downloaded from http://ahajournals.org by on April 19, 2022 level of 𝛼𝛼 = 0.05. Three of six genes of the Troponin gene family show a significant upregulation (TNNT2, top 96 differentially expressed gene [DEG]; TNNT3, top 881 DEG; TNNI2, top 1,821 DEG). B. Detailed DGE Results for Six Genes of the Troponin Gene Family. Fold changes and significance levels are concordant among the slow (TNNT3 and TNNI2) and fast (TNNT1, TNNI1) skeletal muscle gene pairs but not for the cardiac gene pair (TNNT2 and TNNI3). C. Base Level Expression of the Troponin Gene Family in Skeletal Muscle. Cardiac genes TNNT2 and TNNI3 exhibit an expression of 6 and 6.3 TPM (transcripts per million), ranking among top 39% and 38% expressed protein coding genes in the DGE analysis. Fast and slow skeletal muscle genes TNNT1, TNNI1, TNNT3, TNNI2 exhibit a mean expression of 6,848, 3,614, 1,590 and 1,418 TPM (all top 0.1%). 36 10.1161/CIRCULATIONAHA.121.058489 D. Variation of TNNT2 Expression in the Case Samples (n = 28 after Filtering for Missingness in Marker Variables for Disease Activity) Can Be Explained by Biopsy-specific Disease Activity. Linear regression shows a significant positive correlation (R = 0.59, p <0.001) between a disease activity score derived from 14 disease activity markers and normalized counts. The score remains significant (p = 0.001) after adjusting for disease class (“Myopathy” [n = 7], “Myositis” [n = 13], “Other SMD” [n = 8]). Conversely, the case subset showed borderline significant differences between disease classes after adjusting for disease activity score in a likelihood ratio test (p = 0.069). A detailed description of the score calculation is available in the supplements. Figure 6: Correlation between Normalized Gene Expression of the Three TnT Genes and Circulating hs-cTnT Concentrations. hs-cTnT concentrations and normalized gene expression Downloaded from http://ahajournals.org by on April 19, 2022 have been log-transformed to approximate normal distribution. 37 Downloaded from http://ahajournals.org by on April 19, 2022 Downloaded from http://ahajournals.org by on April 19, 2022 Downloaded from http://ahajournals.org by on April 19, 2022 Downloaded from http://ahajournals.org by on April 19, 2022 Downloaded from http://ahajournals.org by on April 19, 2022 Downloaded from http://ahajournals.org by on April 19, 2022 KOKKUVÕTE See ülevaade annab olulist harivat teavet cTnI ja cTnT analüüside ja nende 99. protsentiili sooliselt eristatud ülemiste võrdluspiiride kohta ning käsitleb neid just madalate kontsentratsioonide mõõtmiseks kasutatavate kõrgtundlike analüüside kontekstis. Antakse soovitusi, et aidata selgitada kõrgtundlike analüüside nomenklatuuri ning nende analüütilisi ja kliinilisi omadusi. Ülevaates näidatakse ka probleeme, mis on seotud kõrgtundlike analüüside üha levinuma kasutamisega kliinilises praktikas. Loodame, et nende ideede kasutuselevõtuga saavad laborandid, arstid ja teadlased kujundada ühtsema vaate sellest, kuidas selliseid analüüse tuleks kõikjal maailmas kasutada. © 2016 American Association for Clinical Chemistry Kardiaalse troponiin I (cTnI)5 ja troponiin T (cTnT) määramine on ägeda müokardiinfarkti diagnoosimise standard ning on kõrgtundlike analüüsiversioonide kasutuselevõtuga saavutanud heakskiidu selle seisundi varajasel välistamisel (1–7). Kardiaalne troponiin on olnud oluline nii ägeda koronaarsündroomiga seotud kui ka mitteseotud südamelihase kahjustusega patsientide riskipõhisel eristamisel ja raviootuste hindamisel ning võib olla kasutatav esmases ennetuses (8). Selgub, et cTnI ja cTnT analüüside sisu mõistetakse ebapiisavalt. Eelretsenseeritud uuringute metoodikaid lugedes selgub, et nii cTnI kui ka cTnT analüüside analüütilised omadused kipuvad olema valesti esitatud, ning õiged piirväärtused ehk 99. protsentiili ülemised referentsväärtused pole uuringust uuringusse õigesti määratletud (9). cTnI ja cTnT analüüsid on asendanud kreatiini kinaasi analüüsi, kuna need on südame lihaskoele spetsiifilisemad (1, 10). Kuigi cTnI jääb sellele kontseptsioonile truuks, on hiljutised uuringud näidanud, et immuunreaktiivsed valgud – kas cTnT isovormid või muud valgud – paistavad uuritud neuromuskulaarsete haiguste patoloogiate väikeses alarühmas ristreageerivat Roche poolt turustatavate cTnT analüüsidega (11, 12). Arstid peavad olema teadlikud, et cTnT väärtus võib tõusta ka südamega mitteseotud põhjustel (sellise tõusu praegune levimus on tõenäoliselt väike, aga see pole selge) ja võib skeletilihaste patoloogiate puhul põhjustada südamekahjustuse võimalikku valepositiivset diagnoosi. Clinical Chemistry 63:1 73–81 (2017) Mini-Reviews Cardiac Troponin Assays: Guide to Understanding Analytical Characteristics and Their Impact on Clinical Care Fred S. Apple,1* Yader Sandoval,2 Allan S. Jaffe,3 and Jordi Ordonez-Llanos,4 for the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 BACKGROUND: Cardiac troponin I (cTnI) and cardiac introduction of these concepts, laboratorians, clinicians troponin T (cTnT) determinations are fixtures in clinical and researchers can develop a more unified view of how practice and research. Cardiac troponin testing has been these assays should be used worldwide. the standard of practice for the diagnosis of acute myo- © 2016 American Association for Clinical Chemistry cardial infarction (AMI), early rule-out, risk stratifica- tion, and outcomes assessment in patients presenting with acute coronary syndrome (ACS) and non-ACS Cardiac troponin I (cTnI)5 troponin T (cTnT) determi- myocardial injury. We recognize from reading the liter- nations are the standard of practice for the diagnosis of ature over the past several years how poorly understood acute myocardial infarction (AMI) and have been gaining the analytical characteristics are for cTnI and cTnT assays acceptance for early rule-out when using high-sensitivity by laboratorians, clinicians, and scientists who use (hs)-assays (1–7 ). Cardiac troponin also has been impor- these assays. tant for risk stratification and outcomes assessment in patients presenting with acute coronary syndrome (ACS) CONTENT: The purposes of this mini-review are (a) to and non-ACS myocardial injury, and may have potential define limit of blank, limit of detection, limit of quanti- in primary prevention (8 ). What has become apparent is fication, and imprecision, (b) overview the analytical how poorly understood cTnI and cTnT assays are by characteristics of the existing cardiac troponin assays, (c) those who use these assays. This is evident by reading the recommend approaches to define a healthy (normal) ref- methods sections of peer-reviewed studies, recognizing erence population for determining the 99th percentile that the analytical characteristics of both cTnI and cTnT and the appropriate statistic to use for this calculation, assays tend to be misrepresented along with how appro- (d ) clarify how an assay becomes designated as “high priate cutoffs, 99th percentile upper reference limits sensitivity,” and (e) provide guidance on determining (URLs), are defined from study to study (9 ). delta (⌬) change values. cTnI and cTnT assays have replaced creatine kinase SUMMARY: This review raises important educational in- (CK) MB because of their myocardial tissue specificity formation regarding cTnI and cTnT assays, their 99th (1, 10 ). While cTnI remains true to this concept, studies percentile upper reference limits (URL) differentiated by have recently demonstrated that immuno-reactive pro- sex, and specifically addresses high-sensitivity (hs)-assays teins, whether cTnT isoforms or other proteins, do ap- used to measure low concentrations. Recommendations pear to cross-react with the cTnT assays that are mar- are made to help clarify the nomenclature and analytical keted by Roche in a small subset of neuromuscular and clinical characteristics to define hs-assays. The review disease pathologies that have been studied (11, 12 ). Cli- also identifies challenges for the evolving implementation nicians need to be aware of the possibility that noncardiac of hs-assays into clinical practice. It is hoped that with the increases in cTnT may occur (the current prevalence of such increases is likely small but not clear), and may lead to possible false-positive diagnosis of cardiac injury when skeletal muscle pathology is present. Both cTnI and 1 Department of Laboratory Medicine and Pathology, Hennepin County Medical Center, cTnT assays demonstrate a lack of standardization (13 ). and University of Minnesota, Minneapolis, MN; 2 Division of Cardiology, Department of Medicine, Hennepin County Medical Center and Minneapolis Heart Institute, Abbott- Northwestern Hospital, Minneapolis, MN; 3 Mayo Clinic and Mayo College of Medicine, Rochester, MN; 4 Servei Bioquimica, IBB-Hospital de la Santa Creu i Sant Pau and De- partment de Bioquimica i Biologia Molecular, Universitat Autònoma, Barcelona, Spain. 5 * Address correspondence to this author at: Hennepin County Medical Center, Clinical Nonstandard abbreviations: cTnT, cardiac troponin T; cTnI, cardiac troponin I; AMI, acute Labs P4, 701 Park Ave, Minneapolis MN 55415. Fax 612-904-4229; e-mail myocardial infarction; hs, high-sensitivity; ACS, acute coronary syndrome; CK, creatine [email protected]. kinase, POC, point of care; FAB, fragment antigen binding; URL, upper reference limits; Received July 22, 2016; accepted August 17, 2016. LoQ, limit of quantiﬁcation; LoB, limit of blank; LoD, limit of detection; NPV, negative Previously published online at DOI: 10.1373/clinchem.2016.255109 predictive value; TF-CB, Task Force on Clinical Applications of Cardiac Biomarkers; MI, © 2016 American Association for Clinical Chemistry myocardial infarction; RCV, reference change values. 73 Mini-Reviews While hs-cTn assays are starting to receive in- tion, phosphorylation, and complexing with cTnC, hep- creasing usage worldwide, in the US they have not yet arin, heterophile or human antimouse antibodies, and been cleared by the FDA (14 ). It is important that cTnI-specific autoantibodies (15 ). MAbs are often se- cardiac troponin users do not lose sight of the under- lected in such a way that if one of the MAbs (capture or standing that contemporary and point of care (POC) detection) is sensitive to the presence of an antigen in the assays still maintain a large market share in clinical sample, then the other MAb should be insensitive to the practice (15 ). The purpose of this mini-review is to same antigen. cTnI has been shown to be cleaved by address important characteristics of cTnI and cTnT endogenous proteases during incubation of necrotic assays. This review does not supplant present guide- myocardial muscle after an AMI (15 ). The vast majority lines but does offer recommendations in several areas (⬎95%) of cTnI in blood occurs as a binary cTnI– cTnC pertaining to the optimal utilization (16 ) of cardiac complex. Consideration of assays including an anti- Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 troponin testing based on assay characteristics. cTnC antibody may be useful in improving the analytical sensitivity. Antibodies used in assays should recognize all Cardiac Troponin Assays circulating cardiac troponin forms on an equimolar basis. CARDIAC TROPONIN T Deﬁnitions: Limits of Blank, Detection, and The hs-cTnT (fifth generation) assay (Roche Diagnos- Quantiﬁcation tics) uses fragment antigen binding (FAB) portions of 2 cTnT-specific mouse monoclonal antibodies (MAbs) di- With the advent of hs-assays and the emphasis on impre- rected against epitopes in the central region of human cision (% CV) of assays at the 99th percentile URL and cTnT. The capture antibody (M7) is biotinylated and the limit of quantification (LoQ), along with the increas- directed against an epitope at amino acid residues 125– ing role of using the limit of blank (LoB) and the limit of 131 identical to that in the previous, fourth-generation detection (LoD) as cutoffs for early rule-out of AMI, assay. The detection antibody is directed against an understanding what these values mean is important (19 ); epitope at amino acid residues 136 –147. The original all are analytical parameters used to describe the low con- antibody (M11.7) has been reengineered, with the con- centrations of cardiac troponin measurements. Under- stant C1 region of the FAB being replaced by a human standing these terms is related to the emerging clinical IgG C1 region to produce a mouse– human chimeric evidence suggesting that at “undetectable levels,” concen- detection antibody (15 ). The assay is calibrated against trations less than either LoB or LoD, clinicians can po- recombinant human cTnT produced in Escherichia coli tentially safely rule-out AMI, using a single cardiac tro- cell culture (15 ). Assay calibration is not identical to that ponin, based on very high negative predictive value of the fourth-generation assay, so identical samples mea- (NPV) and high clinical sensitivity (1–7 ). The LoB is the sured with the fourth-generation and hs-cTnT assays will highest cardiac troponin concentration expected to be give different results. The 99th percentile upper reference found when replicates of a sample containing the zero limit (URL) of 10 ng/L with the fourth-generation cTnT calibrator for a cardiac troponin assay are tested. Statisti- assay corresponds to 30 ng/L with the hs-cTnT assay cally, it is often represented as: LoB ⫽ mean (zero cali- (17 ). brator) ⫹ 1.645 ⫻ SD (zero calibrator). In the US, the LoB is not clinically reportable, as high imprecision (% CARDIAC TROPONIN I CV ⬎20%) makes a result at this concentration unreli- MAbs specific to different epitopes of cTnI are able to able and one that should not be used. The clinical utili- recognize multiple modifications circulating in the zation of the LoB concentration is not clear at present. blood. Different forms of the cTnI antigen used as stan- LoD, a concentration greater than the LoB, is the lowest dards or calibrators have helped to improve correlations detectable cardiac troponin concentration reliably distin- between different commercial assays by more than 10- guished from the LoB in a sample containing a low car- fold, but standardization is unlikely (15 ). An IFCC diac troponin concentration that can confidently be re- working group is addressing whether cTnI harmoniza- ported for clinical use. In the US, laboratories often may tion can be achieved, predicated on a pooled serum-based not be able to report cardiac troponin at the LoD because secondary reference material (18 ). Even with the use of a available contemporary (generation of assays pre-hs as- mathematical formula, harmonization between assays re- says) and POC cardiac troponin assays have imprecisions mains elusive. The most common reason for the discrep- ⬎20% at this concentration, and the FDA only allows ancy in cTnI measurements is the difference in epitope manufacturers to report cardiac troponin assay results at specificity of antibodies used in different assays. Even for concentrations less than the lowest concentration that assays that employ similar antibodies, different numeric has a %CV (total imprecision) of ⱕ20%. Thus, the low- concentrations are found. cTnI measurements are influ- est cardiac troponin concentration that demonstrates a enced by multiple factors, including proteolytic degrada- 20% CV is defined as the LoQ. 74 Clinical Chemistry 63:1 (2017) Cardiac Troponin Assay Analytics Mini-Reviews Total Imprecision (% CV) at 99th Percentile factor influencing the 99th percentile, and sex-specific 99th percentiles are recommended to be reported for Day-to-day imprecision of cardiac troponin assays is de- clinical use when using hs-assays. Contemporary and fined by the % CV and is determined using multiple lots POC (24 ) assays do not have the analytical sensitivity to of both reagents and calibrators over multiple days (19 ). adequately differentiate 99th percentiles by sex, and thus The CLSI EP5-A2 document details the evaluation pro- only require a single over-all (men plus women) 99th tocol that spans 20 days, 2 repeats a day, with 2 different percentile. The use of a single diagnostic cardiac troponin lots used for reagents and calibration materials. For clin- threshold for hs-cTnI assays, as studies for hs-cTnT are ical use, cardiac troponin assays have been deemed limited, has been shown to contribute to the under diag- “guideline acceptable” if they have a % CV of ⱕ10% at nosis of AMI in women, whereas with sex-specific cutoffs the 99th percentile, “clinically usable” if the % CV is the proportion of men and women with the diagnosis of Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 ⬎10% to ⱕ20%, and “not clinically acceptable” if the % AMI is similar (22, 25 ). For hs assays, cardiac troponin CV is ⬎20% (20, 21 ). The hs-assays have less analytical results should be reported in whole numbers in nano- noise and meet the highest standard of clinical-practice grams per liter (ng/L) to distinguish them from contem- guideline precision recommendations (% CV ⱕ10%) at porary and POC assays. While globally endorsed, the the 99th percentile, whereas contemporary and POC car- 99th percentile is still not uniformly applied in clinical diac troponin assays have a % CV between 10% and 20% practice. Only 30% to 50% of laboratories have reported at the 99th percentile. Using hs-cTn assays decreases an- using the 99th percentile, thereby compromising the di- alytical noise, allowing reporting of real cardiac troponin agnosis of AMI in practice as well as myocardial infarc- increases above the 99th percentile indicative of myocar- tion (MI) endpoints in clinical trials (26 ). Although con- dial injury, rather than increases in cardiac troponin re- centrations with hs-cTn assays increase with age, this is sulting from analytical imprecision, thereby improving likely due to comorbidities, and changing URLs with age diagnostic accuracy. The Third Universal Definition of for clinical use would add complexity and disadvantage MI guidelines recommends preferential use of assays that the more healthy elderly. demonstrate a total CV of ⱕ10% at the 99th percentile (1 ), but also supports the use of assays with a CV of Deﬁning Healthy Reference Populations for ⱕ20%, because a 20% CV does not lead to misclassifi- Determining 99th Percentile cation of patients in diagnostic or risk-assessment man- agement (20 ). 99th Percentiles for contemporary, POC, and hs-assays Table 1 shows that all hs-cTn assays attain a CV at are shown in Table 1. There is poor consistency in the the 99th percentile ⱕ10%. Such information is useful to composition or numbers of individuals enrolled for de- laboratorians and clinicians because it allows them to termining the 99th percentile. Defining what constitutes confidently report hs-cTn values and serial changes in a healthy reference individual is a topic of debate (21 ). cardiac troponin results over time that are unaffected by Should individuals be apparently healthy, young individ- analytical noise. The true test of how well the % CV of uals, or should they be age-matched patients hospitalized assays will hold up is when assays are used daily in clinical without known cardiovascular disease, similar to the de- practice and QC materials are evaluated over weeks. Pres- mographics of patients who rule in for an AMI, with ages ently, only the Abbott hs-cTnI and the Roche hs-cTnT of 30 –90 years? How does one determine who is healthy? assays are used in clinical practice, and appear to have Should individuals be selected: (a) via personal interview maintained the ⬍10% CV quality characteristic at the with questions addressing known cardiac medications, 99th percentile (22, 23 ). Contemporary assays often re- such as statins; (b) after obtaining information about ported in the manufacturers’ package insert as being able known diseases associated with cardiovascular disease, to achieve a 10% CV at the 99th percentile are rarely able such as renal disease or diabetes; or (c) via definitive phy- to do so in clinical laboratory practice. sician evaluation of an individual after taking a history and physical examination, including an electrocardio- 99th Percentile gram, echocardiogram or imaging? The third option, while ideal, is cost-prohibitive. Sequential selection of a The cardiac troponin 99th percentile URL corresponds reference population on this basis has been shown to shift to the clinical-practice guideline concentration for the the derived 99th percentile to lower values (27 ). We diagnosis of AMI (21 ). This URL is typically derived recommend a 2-fold approach in which both younger from apparently healthy individuals enrolled in studies (⬍30 years) and older (⬎30 years, with median age of by manufacturers or investigators (9 ). For hs-cTn assays, 60 – 65 years to be representative of cardiac patients), the IFCC Task Force on Clinical Applications of Cardiac apparently healthy reference groups are recruited. Inclu- Biomarkers (TF-CB) has proposed recommendations for sion criteria should be based on data obtained from a determining 99th percentiles (21 ). Sex is an important history of medications (not on cardiac drugs), known Clinical Chemistry 63:1 (2017) 75 76 Table 1. Analytical characteristics of commercial and research contemporary, POC, and hs-cTnI and hs-cTnT assays.a LoD, 99th, % CV 10% CV, Company/platform/assay μg/L μg/L at 99th μg/L Epitopes/antibodiesb Detection tag Contemporary assays Abbott ARCHITECT <0.01 0.028 15 0.032 C: 87–91, 24–40; D: 41–49 Acridinium Beckman Access 2 0.01 0.02 14 0.040 C: 41–49; D: 24–40 ALP Beckman Coulter DxI 0.01 0.03 14 0.040 C:41–49; D:28–80 ALP Ortho-Clinical Diagnostics Vitros 0.012 0.034 10 0.034 C: 24–40, 41–49; D: 87–91 HRP Siemens Centaur Ultra 0.006 0.04 10 0.030 C: 41–49, 87–91; D: 27–40 Acridinium Mini-Reviews Siemens Dimension RxL 0.04 0.07 20 0.140 C: 27–32; D: 41–56 ALP Siemens VISTA 0.015 0.045 10 0.040 C: 27–32; D: 41–56 Chemiluminescent Clinical Chemistry 63:1 (2017) Tosoh AIA 0.06 <0.06 8.5 0.090 C: 41–49; D: 87–91 ALP Roche 4th generation cTnT 0.01 0.01 18 0.03 C: 125–131; D: 136–147 Ruthenium POC assays Abbott i-STAT 0.02 0.08 16 0.10 C: 41–49, 88–91; D: 28–39,62–78 ALP Alere Triage 0.05 <0.05 NA NA C: NA; D: 27–40 Fluorophor bioMérieux Vidas 0.01 0.01 27 0.11 C: 41–49, 22–29; D: 87–91, 7B9 ALP LSI Medience PATHFAST 0.008 0.029 5.1 0014 C: 41–49; D:71–116, 163–209 ALP Radiometer AQT90 cTnI 0.0095 0.023 17 0.039 C: 41–49, 190–196; D: 137–149 Europium Radiometer AQT90 cTnT 0.01 0.017 20 0.03 C: 125–131; D:136–147 Europium Response Biomedical RAMP 0.03 <0.1 18 0.21 C: 85–92; D: 26–38 Flourophor Roche Cardiac Reader <0.05 <0.05 NA NA C: 125–131; D:136–147 Gold particules Siemens Stratus CS 0.03 0.07 10 0.06 C: 27–32; D: 41–56 ALP Trinity Meritas 0.019 0.036 17 NA C: 24–40; 41–49, D: 88–90, Fluorophor 137–148,190–196 ET Health 0.1 0.2 NA 0.42 C: 87–91:D: 27–40 ALP Nanomix 0.15 NA NA 0.64 C: 87–91:D: 27–40 ALP M/F, % CV 10% CV, hs-Assays ng/L ng/L at 99th ng/L Epitopes/antibodies Detection tag Abbott ARCHITECT hs-cTnI 1.2/1.9 34/16 5 3 C: 24–40; D: 41–49 Acridinium Beckman Coulter Access hs-cTnI 2.5 52/23 <10 8 C: 41–49; D: 24–40 ALP Ortho-Clinical Diagnostics hs-cTnI 1.0 19/16 <10 3 C:24–40, 41–49; D: 87–91 HRP Roche E170 hs-cTnT 5 20/13 8 13 D: 125–131; C: 136–147 Ruthenium Siemens Vista hs-cTnI 0.5 55/33 5 3 C: 30–35; D: 41–56,171–8 Luminescence Singulex Errena hs-cTnI 0.09 36/30 5 0.9 C: 41–49; D: 27–41 Fluorescence a Assays not designated as cTnT are cTnI. b C, capture antibody; D, detection antibody; NA, not available. Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 Cardiac Troponin Assay Analytics Mini-Reviews Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 Fig. 1. Comparison of both 99th percentile values (circles) and percent measurable concentrations (boxes) in a presumably healthy population for 19 cardiac troponin assays designated by hs (left), sensitive-contemporary (middle), and POC (right). mod-sens, modiﬁed-sensitive [used with permission from Apple et al. (28 )]. underlying diseases, and blood measurements, using a temporary, POC, and hs-assays, the ability of the various natriuretic peptide concentration (assay dependent) that assays to measure concentrations below the 99th percen- would provide a high NPV for ruling out heart failure to tile ranged from 1% to 98% of samples (Fig. 1). The 99th serve as a surrogate biomarker for underlying myocardial percentile variability between assays was substantial, dysfunction, and an estimated glomerular filtration rate exemplifying the lack of cTnI and cTnT assay stan- (eGFR) ⬎60 mL 䡠 min⫺1 m⫺2 for defining underlying dardization. The hs-cTn assays with an ability to mea- renal insufficiency. At present, no definitive peer- sure concentrations in all or nearly all reference indi- reviewed surrogate biomarker recommendations have viduals demonstrated nearly gaussian distributions of been published. Men and women should be equally rep- cardiac troponin results. resented, with a diverse racial and ethnic mix. The num- ber of individuals for determining a 99th percentile has Analytical Designation for hs-Assay been defined by the IFCC TF-CB to be a minimum of 300 for men and 300 for women. No study has compared It is important to understand that the term “high- all contemporary sensitive assays and/or hs-assays within sensitivity” reflects the assay’s characteristics and does not the same reference or disease population (28 ). At the refer to a difference in the form of cardiac troponin being 2016 national AACC meeting, a reference interval blood measured. There is a need for a consensus on defining draw study was performed that allowed manufacturers to what nomenclature should be used for an hs-assay. The purchase 535 plasma or serum samples for use in deter- term “high-sensitivity” has uniformly been used for pub- mination of a 99th percentile. lication in Clinical Chemistry and more frequently To solve the conundrum of assay-to-assay differ- throughout the scientific/medical literature. This term, ences, direct comparisons of contemporary assays used in however, begs the question: how does one define an hs- clinical practice with hs-cTn assays already in the mar- assay? The IFCC TF-CB has proposed that for an assay to ketplace are needed. In 1 study examining multiple con- be defined as hs, 2 analytical criteria need to be met (21 ). Clinical Chemistry 63:1 (2017) 77 Mini-Reviews Table 2. Measurable values among hs-cardiac troponin assays using sex-speciﬁc cutoffs. No. of LoD, Measurable values Proportion of undetectable Manufacturer—analyzer—assay results ng/L ≥LoD values (<LOD) Abbott ARCHITECT hs-cTnI F: 252a 1.9 F: 67% (170/252) F: 33% (82/252) M: 272 M: 80% (217/272) M: 20% (55/272) Beckman Coulter Access hs-cTnI F: 252 2.5 F: 74% (187/252) F: 27% (65/252) M: 272 M: 87.5% (238/272) M: 13% (34/272) Roche Cobas e601 hs-cTnT F: 252 5 F: 7% (18/252) F: 93% (234/252) Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 M: 272 M: 43% (117/272) M: 57% (155/272) Siemens Dimension Vista hs-cTnI F: 239 0.5 F: 82% (196/239) F: 18% (43/239) M: 264 M: 90% (237/264) M: 10% (27/264) Singulex Erenna hs-cTnI F: 252 0.09 F: 100% (252/252) F: 0% (0/0) M: 272 M: 100% (272/272) M: 0% (0/0) a F, female; M, male. First, the % CV at the 99th percentile value should be Sex-Derived 99th Percentiles ⱕ10%. Second, measurable concentrations should be at- tainable with at a concentration above the assay’s LoD for For hs-cTn assays, sex-specific 99th percentiles are rec- at least 50% of healthy individuals. As shown in Table 2 ommended (21 ). Numerous studies have demonstrated and Fig. 1, the hs-cTnT assay showed lower than recom- distinct 99th percentiles according to sex, with men hav- mended rates of measurable concentrations when using ing higher concentrations than women, justified by men the IFCC recommendation. None of the currently FDA having larger left ventricular mass than women (25, 29 ). cleared assays for either contemporary or POC testing In a large, healthy population cohort study in which hs- met the 2-fold criteria for an hs designation. One com- cTn was measured using 5 hs-assays (28 ), men had a mercial hs-cTnI assay (Abbott) is available worldwide higher proportion of measurable cardiac troponin con- (except in the US, where it is not yet FDA cleared). For centrations than women (Table 3). The hs-cTnI assays hs-assays all journals, manufacturers, and laboratories demonstrated a heterogeneous ability to measure values should adopt the ng/L unit of measure to avoid confusion above the LoD, but all above 50%. The proportion of and decimal points followed by unnecessary zeros as used undetectable cardiac troponin values varied substantially for contemporary and POC assays. Thus, a concentra- across assays with women having a higher proportion of tion of 0.0015 ␮g/L (contemporary assay) would need to undetectable values as compared with men. By using the be reported as 2 ng/L (hs-assay). hs-cTnT assay, marked differences were observed be- Table 3. Short-term analytical and biological variation of hs-cTn assays.a Abbott Beckman Roche (E170) Siemens Singulex b CV-A, % 13.8 14.5 7.8 13.0 8.3 CV-I, % 15.2 6.1 15.0 12.9 9.7 CV-G, % 70.5 34.8 NA 12.3 57 Index of individuality 0.22 0.46 NA 0.11 0.21 RCV, %b NA NA 47.0 NA NA RCV increase, %c 69.3 63.8 NA 57.5 46.0 RCV decrease, %c −40.9 −38.9 NA −36.5 −32 Within-individual mean, ng/L 3.5 4.9 NA 5.5 2.8 a Adapted with permission from Apple and Collinson (15 ). b CV-A, analytical CV; CV-I, within-individual CV; CV-G, between-individual CV; NA, not available. c RCV percentage applies to the parametric data. d RCV increase and decrease percentages refer to nonparametric data and are log transformed. 78 Clinical Chemistry 63:1 (2017) Cardiac Troponin Assay Analytics Mini-Reviews tween men and women in both the proportion of mea- ng/L and 5 ng/L for both cTnI and cTnT, respectively, surable (F, 7%, vs M, 43%) and undetectable (F, 93%, vs and reference change values (RCV) ranged from ⫾32% M, 57%) values. to ⫾69.3%. For hs-cTnT differences in RCVs have also From a clinical perspective these data are informa- been found between different analyzers used for the same tive owing to the emergent interest in using undetectable assay. cardiac troponin values to expedite the rule-out of AMI with a single measurement at presentation, which if un- Characterizing hs-Assays by Using Clinical der the LoD, safely identifies a subset of patients at very Criteria low risk for adverse events (3–7, 30, 31 ). A balance needs to be struck between using this rule-out strategy in the While criteria has been provided by the IFCC TF-CB for highest proportion of patients possible vs the interest in Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 defining hs-cTn assays using analytical characteristics using assays with high analytical sensitivity that facilitate (21 ), investigators have opined that clinical criteria may the use of following serial concentration changes, partic- also be of importance in defining hs-assays. The IFCC ularly at low concentrations, to rule in/out acute MI. TF-CB is currently evaluating whether the following Again, it must be acknowledged that different assays will clinical criteria would provide hs-assay clarity. First, use a have different LoD concentrations (15 ). rule-out MI criterion predicated on an hs-cTn measure- ment ⬍LoD concentration that coincides with a NPV at Statistical Approach to Deﬁne 99th Percentile baseline sample ⬎99.0% and a clinical sensitivity at base- line sample ⬎99.0%. Second, use a risk outcomes crite- There is a need for a uniform, standardized statistical rion predicated on a NPV of ⬎99% for major adverse approach to calculate cardiac troponin 99th percentiles. cardiac events or all-cause death at 30 days using either a A recently published study (32 ) is the first to demon- concentration ⬍LoD or a 0 –1 h or 0 –2 h absolute con- strate and support the use of the nonparametric method centration ⌬ (assay dependent). Additional studies will and not the Harrell–Davis Bootstrap Method (or non- be needed to determine whether these risk criteria can parametric Bootstrap Method) or the Robust method. also be used with contemporary assays. The nonparametric method is a distribution-free method using ranks of observed values to determine percentiles Implementing Δ Cardiac Troponin Values for a given reference interval/cutoff. It is simple to calcu- late and easy to determine a sample size. For a 99th per- There is no universal ⌬ value for cTnI or cTnT values to centile and 90% CI, n ⱖ299 study participants are re- best optimize clinical specificity (21 ). Deltas will be assay quired, as recommended by the IFCC TF-CB. The dependent and vary between a percentage change for Harrell-Davis Bootstrap method uses a linear combina- contemporary and POC assays (33 ) as compared to ab- tion of order statistics to estimate a percentile/reference interval and weights observed values using the incomplete ␤ solute concentration changes for hs-assays (5 ). Further, distribution. However, it involves a more complicated cal- the calculation of ⌬ values will vary depending on the culation. It can provide similar results obtained by the tra- timing between serial samples, i.e., 0 –1, 2 or 3 h (hs- ditional nonparametric method, but the extra effort is not assays) vs 0 to 6 h (contemporary assays), as well as seen as worthwhile. This method also can be highly influ- whether the initial cardiac troponin concentration is enced by outliers. The robust method uses estimates of lo- within the reference range below the 99th percentile (at cation and scale, iteratively weights-observed values, and the time of the disease evolution) or above the 99th per- smooths/down-weights observations the further they are centile. Small concentration changes may also result from from the center. It minimizes effect of outlying/extreme ob- poor analytical imprecision for contemporary and POC servations, requires data to be symmetric and is computa- assays that tend to have poor imprecision at low cardiac tionally intensive. troponin concentrations, particularly those near the 99th percentile. Defining a consistent period of time for anal- Biological Variability of hs-cTn Assays ysis is also important for the development of an accurate approach to this analysis if different assays are to be com- Determining biological variation is not possible for both pared. A recommendation has been made for hs-cTnT to cTnI and cTnT with contemporary and POC assays in use a 50% change near the 99th percentile URL and a clinical practice today, because these assays cannot reli- 20% change when the baseline value is increased above ably measure concentrations in healthy individuals where the 99th percentile within a 3 h interval (34 ). Shorter they detect measurable values in ⬍25% of healthy individ- time intervals (ⱕ3 h) will be required with hs-cTn assays uals (15 ). In contrast, Table 3 demonstrates the biological- to assist in ruling out AMI. Consideration must always be variation characteristics of 5 hs-assays. Within-individual given to late presenting MIs, which may confound the mean cardiac troponin concentrations ranged between 2 use of both absolute and percentage ⌬ values (35 ). Clinical Chemistry 63:1 (2017) 79 Mini-Reviews Preparing for Implementation of hs-Assays an increased cardiac troponin is reflective of MI it does not mean there was an MI, as each patient’s cardiovascu- As global change occurs, laboratories need to start pre- lar history must be reviewed in this context (39 ). Tenth, paring their services for the eventuality of going live with work on assuring good preanalytical sampling as the hs- hs-assays (36, 37 ). The following draft check-list, de- assays are so sensitive that poor sample quality can be a rived from the evidence based literature, will help educate problem. laboratories currently using and prepare laboratories not using hs-assays for the conversion from contemporary and POC assays to hs-assays. First, education of labora- Author Contributions: All authors confirmed they have contributed to tory medicine and clinical staff on relevant literature per- the intellectual content of this paper and have met the following 3 require- taining to the manufacturers’ assay being implemented ments: (a) significant contributions to the conception and design, acquisi- Downloaded from https://academic.oup.com/clinchem/article/63/1/73/5612819 by guest on 10 February 2023 will be necessary. Distribute analytical, diagnostic and tion of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published risk assessment outcomes studies to your clinical col- article. leagues, and present information on the new hs-assay at Authors’ Disclosures or Potential Conflicts of Interest: Upon man- their staff meetings and clinical conferences. Second, de- uscript submission, all authors completed the author disclosure form. velop understanding among users of the new hs-assay Disclosures and/or potential conflicts of interest: that the concentration numbers are going to change, and Employment or Leadership: F.S. Apple, Clinical Chemistry, AACC. that they should not expect a conversion factor. Third, a Consultant or Advisory Role: F.S. Apple, HyTest, Philips Healthcare URL at the 99th percentile will need to be established, Incubator, and Metanomics Health; Y. Sandoval, Roche Clinical Di- agnostics; A. Jaffe, Beckman Coulter, Alere, Abbott, Roche, Siemens, following the IFCC TK-LB educational materials. ET Healthcare, NeuorgenomiX, Lpath, Singluex, and Novartis; Fourth, preparation will be needed for changing from a J.Ordonez-llanos, Roche Diagnostics, Singulex, bioMerieux, and Stat single to sex-specific 99th percentile, recognizing that Diagnostics. this value for women will be less than for men. Fifth, Stock Ownership: None declared. conversion to reporting only whole numbers in ng/L will Honoraria: F.S. Apple, Instrumentation Laboratory and Abbott POC; J.Ordonez-llanos, bioMérieux and Roche Diagnostics. be needed. Sixth, define a QC material at the 99th per- Research Funding: Roche Diagnostics and Singulex, Inc. F.S. Apple, centile to monitor % CV. Seventh, consider using cardiac Abbott Diagnostics, Siemens Healthcare, Singulex, Roche Diagnostics, troponin values ⬍LoD of the hs- assay as a potential and Beckman Coulter. rule-out characteristic. Work closely with your emer- Expert Testimony: None declared. gency medicine colleagues to explore this financial sav- Patents: None declared. ings utilization. Eighth, provide serial testing protocols Acknowledgments: Justin L Rogers, PhD, Abbott Diagnostics; IFCC that consider earlier measurements such as at baseline, Task Force on Clinical Applications of Cardiac Biomarkers committee 1.5h and 3h for diagnostic determinations (38 ). Work members: Paul Collinson, Mario Plebani, Martin Than, Judd Hol- lander, Bertil Lindahl, and Martin Mockel; and numerous representa- conjointly with emergency department physicians and tives of the in vitro diagnostic industry that manufacture high sensitiv- cardiologists to define clinical protocols to facilitate op- ity contemporary and POC cardiac troponin assays who serve as timal use. Ninth, educate your clinicians that although consultants to the TF. References 1. Thygesen K, Alpert JS, Jaffe AS, Simooons ML, Chait- 5. Mueller C, Giannitsis E, Christ M, Ordóñez-Llanos J, de- ponin. Clin Chem 2014;60:455– 62. man BR White HD, the writing group on behalf of the Filippi C, McCord J, et al. 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National Academy of Clinical Bio- a pragmatic randomized controlled trial embedded 12. Wens SC, Schaaf GJ, Michels M, Kruijshaar ME, van chemistry practice guidelines: clinical characteristics within practice. Ann Emerg Med 2016;68:93–102. Gestel T, Groen S, et al. Elevated plasma cardiac tro- and utilization of biomarkers in acute coronary syn- 7. Shah ASV, Anand A, Sandoval Y, Lee KK, Smith SW, Ad- ponin T levels caused by skeletal muscle damage in dromes. Clin Chem 2007;53:552–74. amson PD, et al, on behalf of the High-STEACS investi- Pompe disease. Circ Cardiovasc Genet 2016;9:6 –13. 3. Cullen L, Aldous S, Than M, Greenslade JH, Tate JR, gators. High-sensitivity cardiac troponin I at presenta- 13. Apple FS. Standardization of cardiac troponin I as- George PM, et al. Comparison of high sensitivity tro- tion in patients with suspected acute coronary says will not occur in my lifetime. Clin Chem 2012; ponin T and I assays in the diagnosis of non-ST elevation syndrome: a cohort. Lancet 2015;386:2481– 8. 58:169 –71. acute myocardial infarction in emergency patients with 8. Apple FS, Steffen LM, Pearce LA, Murakami MM, Luep- 14. Apple FS, Hollander J, Wu AHB, Jaffe AS. Improving the chest pain. Clin Biochem 2014;47:321– 6. ker RV. Increased cardiac troponin I as measured by a 510k FDA process for cardiac troponin assays: in search 4. Than M, Cullen L, Aldous S, Parsonage WA, Reid CM, high-sensitivity assay is associated with high odds of of common ground. Clin Chem; 2014;60:1273–5. Greenslade J, et al. 2-hour accelerated diagnostic pro- cardiovascular death: the Minnesota Heart Survey. Clin 15. Apple FS, Collinson PO, for the IFCC Task Force on Clin- tocol to assess patients with chest pain symptoms using Chem 2012;58:930 –5. ical Applications of Cardiac Bio-Markers. Analytical contemporary troponins as the only biomarker. J Am 9. Sandoval Y, Apple FS. The global need to deﬁne characteristics of high-sensitivity cardiac troponin as- Coll Cardiol 2012;59:2091– 8. normality: the 99th percentile value of cardiac tro- says. Clin Chem 2012;58:54 – 61. 80 Clinical Chemistry 63:1 (2017) Cardiac Troponin Assay Analytics Mini-Reviews 16. Love SA, McKinney ZJ, Sandoval Y, Smith SW, Kohler R, 24. Amundson BE, Apple FS. Cardiac troponin assays: a re- tile of cardiac troponin I. Clin Biochem 2016;49:1109 – Murakami MM, Apple FS. Electronic health record- view of quantitative point-of-care devices and their efﬁ- 12. based performance improvement project to document cacy in the diagnosis of myocardial infarction. Clin 33. Apple FS, Smith SW, Pearce LA, Murakami MM. Delta and reduce excessive cardiac troponin testing. Clin Chem Lab Med 2015;53:665–76. changes for optimizing clinical speciﬁcity and 60-day Chem 2015;61:498 –504. 25. Shah A, Grifﬁths M, Lee KK, McAllister MA, Hunter AL, risk of adverse events in patients presenting with symp- 17. Apple FS. Jaffe AS. Clinical implications of a recent ad- Cruikshank A, et al. High sensitivity cardiac troponin toms suggestive of acute coronary syndrome utilizing justment to the high sensitivity cardiac troponin T and the under-diagnosis of myocardial infarction in the ADVIA Centaur TnI-Ultra assay. Clin Biochem 2012; assay: user beware. Clin Chem 2012;58:1599 – 600. women. BMJ 2015;350:g7873. 45:711–3. 18. Tate JR, Bunk DM, Christenson RH, Barth JH, Katrukha 26. Hammerer-Lercher A, Suvisaari J, Apple FS, Christen- 34. Thygesen K, Mair J, Giannitsis E, Mueller C, Lindahl B, A, Noble JE, et al. Evaluation of standardization capabil- son RC, Pulkki K, van Dieijeb-Visser P, et al. How well do Blankenberg S, et al. How to use high-sensitivity car- ity of current cardiac troponin I assays by a correlation laboratories adhere to recommended clinical guide- diac troponins in acute cardiac care. Eur Heart J 2012; study: results of an IFCC pilot project. 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Clin Chem 2012;58:219 –25. diovascular Cares Association. Eur Heart J Acute Cardio- 55:1303– 6. 28. Apple FS, Ler R, Murakami MM. Determination of 19 vasc Care 2014;4:313– 6. 21. Apple FS, Jaffe AS, Collinson P, Mockel M, Ordonez- cardiac troponin I and T assay 99th percentile values 36. Kavsak P, Beattie J, Pickersgill R, Ford, Caruso, Clark L. A Llanos J, Lindahl B, et al., IFCC Task Force on Clinical from a common presumably healthy population. Clin practical approach for the validation and clinical imple- Applications of Cardiac Bio-Markers. IFCC educational Chem 2012;58:1574 – 81. mentation of a high-sensitivity cardiac troponin assay materials on selected analytical and clinical applica- 29. Gore MO, Seliger SL, deFilippi CR, Nambi V, Christen- tions of high-sensitivity cardiac troponin assays. Clin son RH, Hashim IA, et al. Age- and sex-dependent up- across a North American city. Prac Lab Med 2015;1:28 – Biochem 2015: 2015;48:201–3. per reference limits for the high-sensitivity cardiac tro- 34. 22. Sandoval Y, Smith SW, Schulz KM, Murakami MM, Love ponin T assay. J Am Coll Cardiol 2014;63:1441– 8. 37. Sandoval Y, Smith SW, Apple FS. Present and future of SA, Nicholson J, Apple FS. Diagnosis of type 1 and type 30. Januzzi JL Jr., Bamberg F, Lee H, Truong QA, Nichols cardiac troponin clinical practice: a paradigm shift to 2 myocardial infarction using a high-sensitivity cardiac JH, Karakas M, et al. High-sensitivity troponin T concen- high-sensitivity assays. Am J Med 2016;4:354 – 65. troponin I assay with gender-speciﬁc 99th percentiles trations in acute chest pain patients evaluated with car- 38. Love S, Sandoval Y, Apple FS. Incorporating high sensi- based on the Third Universal Deﬁnition of Myocardial diac computed tomography. Circulation 2010;121: tivity cardiac troponin assays into clinical practice: these Infarction Classiﬁcation System. Clin Chem 2015;61: 1227–34. assays are your friend. Heart Metab 2015;67:9 –14. 657– 63. 31. Bandstein N, Ljung R, Johansson M, Holzmann MJ. Un- 39. Love SA, Sandoval Y, Smith SW, Nicholson J, Cao J, Ler 23. Rubini Giménez M, Hoeller R, Reichlin T, Zellweger C, detectable high-sensitivity cardiac troponin T level in R, Schulz K, Apple FS. Incidence of undetectable. Mea- Twerenbold R, Reiter M. Rapid rule out of acute myocar- the emergency department and risk of myocardial in- sureable, and increased cardiac troponin I concentra- dial infarction using undetectable levels of high- farction. J Am Coll Cardiol 2014;63:2569 –78. tions above the 99th percentile using a high-sensitivity sensitivity cardiac troponins. Int J Cardiol 2013;168: 32. Eggers KM, Apple FS, Lind L, Lindahl B. The applied vs a contemporary assay in patients presenting to the 3896 –901. statistical approach highly inﬂuences the 99th percen- emergency department. Clin Chem 2016;62:1115–9. Clinical Chemistry 63:1 (2017) 81 Kõrgtundlike kardiaalsete troponiinide I ja T otsene võrdlus ägeda müokardiinfarkti varajases diagnostikas Maria Rubini Gimenez1, 2†, Raphael Twerenbold1, 3†, Tobias Reichlin1, 4, Karin Wildi1, Philip Haaf1, Miriam Schaefer1, Christa Zellweger1, Berit Moehring1, Fabio Stallone1, Seoung Mann Sou1, Mira Mueller1, Kris Denhaerynck1, Tamina Mosimann1, Miriam Reiter1, Bernadette Meller1, Michael Freese1, Claudia Stelzig1, Irina Klimmeck1, Janine Voegele1, Beate Hartmann1, Katharina Rentsch5, Stefan Osswald1 ja Christian Mueller1* Probleem Me ei tea, kas ST-segmendi elevatsioonita müokardiinfarkti varajasel diagnoosimisel tuleks biomarkerina eelistada kardiaalset troponiini I või troponiini T. Meetodid ja Prospektiivses mitmekeskuselises uuringus mõõtsime cTnI ja cTnT väärtusi, kasutades tulemused kliiniliselt kättesaadavaid kõrgtundlikke analüüse (hs-cTnI Abbott ja hs-cTnT Roche), ja võrdlesime nende diagnostilist ning prognostilist täpsust järjest patsientidel, kes saabusid erakorralise meditsiini osakonda ägeda rindkerevaluga. Lõpliku diagnoosi määrasid kaks sõltumatut kardioloogi, kasutades selleks kogu konkreetsete patsientide kohta olemasolevat teavet. Keskmine jälgimisperioodi pikkus oli 24 päeva. 2226-st järjestikku saabunud patsiendist 18%-le määrati lõplikuks diagnoosiks ST-segmendi elevatsioonita müokardiinfarkt. ST-segmendi elevatsioonita müokardiinfarkti korral oli diagnoosi täpsus /määratuna haiglasse saabumisel ROC-kõvera aluse pindalana (AUC)), väga hea ja sarnane nii hs-cTnI [AUC: 0,93, 95% usaldusvahemik (CI) 0,92–0,94] kui hs- cTnT analüüsi korral (0,94, 95% CI: 0,92–0,94) p = 0,62. Kiiremini haiglasse pöördujatel (alla kolme tunni jooksul alates rindkerevalu tekkimisest) näitas hs-cTnI suuremat diagnostilist täpsust (AUC: 0,92; 95% CI: 0,89–0,94) kui hs-cTnT analüüs (AUC: 0,89, 95% CI: 0,86–0,91) (p = 0,019), samal ajal kui hs-cTnT oli hilisematel pöördujatel täpsem [AUC hs-cTnT 0,96 (95% CI: 0,94–0,96) kui hs-cTnI analüüs (AUC 0,94, 95% CI: 0,93– 0,95); p = 0,007]. Üldsuremuse prognostiline täpsus oli AUC-i põhjal määratuna hs-cTnT analüüsi korral oluliselt suurem (AUC: 0,80; 95% CI: 0,78-0,82) kui hs-cTnI analüüsiga (AUC: 0,75; 95% CI: 0,73–0,77; p < 0,001). Järeldus Nii hs-cTnI kui ka hs-cTnT analüüs tagasid kõrge diagnostilise ja prognostilise täpsuse. Otsene võrdlus näitas väikesi, kuid potentsiaalselt olulisi erinevusi, mis võivad aidata hs-cTn analüüside kliinilist kasutamist veelgi tõhustada. Arutelu Kuigi hs-cTn analüüsid ootavad veel USA-s kliinilise kasutamise luba, muutusid Euroopas ja paljudes teistes riikides 2010. aastal (hs-cTnT, Roche) ja 2013. aastal (hs-cTnI, Abbott) kliiniliseks kasutamiseks kättesaadavaks kaks täielikult välja töötatud hs-cTn-i analüüsi. Käesolevas suures prospektiivses mitmekeskuselises uuringus võrreldi just nende kliiniliseks kasutamiseks kättesaadavate hs-cTn analüüside diagnostilist ja prognostilist täpsust patsientidel, kes pöördusid erakorralisse meditsiini osakonda ägeda rindkerevaluga. Kajastame kuute olulist leidu. Esiteks, meie analüüsis näitasid nii hs-cTnI kui ka hs-cTnT väärtused juba haiglasse pöördumisel väga suurt diagnostilist täpsust ST-segmendi elevatsioonita müokardiinfarkti osas (AUC 0,93 ja 0,94), kinnitades ja täiendades sarnaseid varasemaid leide nii kliiniliselt kättesaadavate kui ka turustamiseelses seisus olevate s-cTn ja hs-cTn analüüside osas.7, 8, 29 Teiseks oli mõlema analüüsi korral ST-segmendi elevatsioonita müokardiinfarkti diagnostiline täpsus kogu uuritava rühma kohta haiglasse pöördumisel sarnane. Sellel on suur kliiniline tähtsus arstide, laboriekspertide ja haiglajuhtide jaoks, sest see aitab neil otsustajatena kavandada oma asutuse laborite tulevasi tegevuskavasid. Kuid meie andmed viitasid ka sellele, et sümptomite tekkimisest möödunud aeg võib mõjutada kummagi analüüsi diagnostilist eelist võrreldes teisega: hs-cTnI analüüs näis olevat täpsem varajastel haiglasse pöördujatel, hs-cTnT analüüs aga hilisematel pöördujatel. Oluline on rõhutada, et hs-cTn I analüüsi diagnostiline eelis on varajaste pöördujate korral metoodiliselt väga usaldusväärne, sest meie metoodika tõi diagnostilise täpsuse osas kaasa väikese, kuid vältimatu nihke hs-cTnT eelistamiseks. Kuigi diagnostikaks kasutati nii cTnI kui ka cTnT analüüside kohapeal määratud tulemusi, olid nn. ägeda mikroinfarkti täiendavaks diagnostikaks kättesaadavad ainult hs-cTnT väärtused, mistõttu rohkem patsiente kaasati pigem (hs-)cTnT analüüsi kasutanud uuringukeskustesse (võrreldes cTnI analüüsi kasutavate keskustega). Lisaks sellele toetavad hs-cTnI diagnostilist eelist varajastel haiglasse pöördujatel sarnased hiljutised s-cTnI leiud kriitilistes alarühmades, nagu eakad ja juba avaldunud koronaararterite haigusega patsiendid11, 12, mistõttu on meie järeldus suure tõenäosusega äärmiselt tõene. Kuigi võib eeldada, et varasemad haiglasse pöördujad saavad varajasest revaskularisatsioonist enim kasu, ei ole teada, kas see erinevus on kliinilise olulisuse saavutamiseks piisav. Varasematel haiglasse pöördujatel võivad isegi väikesed erinevused ägeda müokardiinfarkti diagnostilises täpsuses avaldada piisavat mõju nended esmasele ravile. Lisaks võivad need erinevused mõjutada ka näiteks teatavate välistamisalgoritmide negatiivset diagnostilist väärtust.14 Nende aktsepteerimiseks ja kasutuselevõtmiseks võivad arstid vaadata erinevust algoritmi vahel, mille negatiivne ennustusväärtus on 99,9%, võrreldes algoritmiga, mille negatiivne ennustusväärtus on 99,5%. Kolmandaks suurenes järjestikuse proovide võtmisega nii hs-cTnI kui ka hs-cTnT diagnostiline täpsus veelgi. Kui hs-cTnI ja hs- cTnT otsene võrdlemine konkreetsetel hilisematel aegadel näitasid mõlema osas sarnast täpsust, siis vastavate väärtuste kombinatsioonide võrdlemine haiglasse saabumisel ja jhilisematel mõõtmistel näitas hs-cTnT väga väikest, kuid statistiliselt nähtavat paremat diagnostilist täpsust võrreldes hs-cTnI- ga. Neljandaks, kui võrrelda mõlema analüüsi diagnostilist võimekust ebastabiilse stenokardia eristamisel südamega mitteseotud rindkerevalust, oli hs-cTnI analüüs veidi parem kui hs-cTnT analüüs. Siiski on oluline rõhutada, et üldiselt oli hs-cTn analüüsi diagnostiline täpsus ebastabiilse stenokardia korral ainult mõõdukas, mida kinnitavad ka varasemate, ainult tavatundlikkusega cTn analüüsidel põhinevate diagnostiliste uuringute põhjal avaldatud andmed.7 On vaja edasisi uuringuid, et määratleda hs-cTn analüüsi parim võimalik kliiniline kasutamine koos kõigi muude kliiniliste andmetega ebastabiilse stenokardia eristamisel südamega mitteseotud rindkerevalust. Viiendaks oli üldsuremuse prognostiline täpsus 24 kuud kestnud jälgimisaja jooksul kõrge nii hs-cTnI kui ka T osas, kuigi faktiliselt oli hs-cTnT analüüsi täpsus oluliselt parem kui hs-cTnI. Meie andmed kinnitavad ja täiendavad hiljutisi uuringuid, milles võrreldi hs-cTnT analüüsi s-cTnI ja turustamiseelses faasis hs-cTnI analüüsidega, milles näidati, et esimene on prognostiliselt parem.9, 10, 30–32 Kuna järelkontroll viidi läbi nii hs-cTnT kui ka hs-cTnI väärtuste suhtes „pimedalt“ ja see hõlmas märkimisväärset surmade arvu, ning see nähtus jäi püsima kolmes erinevas prognostilise täpsuse mõõtmise statistilises mudelis, tundub ka hs-cTnT prognostiline paremus võrreldes hs-cTnI analüüsiga metodoloogiliselt väga usaldusväärne. Täheldatud erinevus prognostilises täpsuses (∆AUC 0,05) oli stabiilne ST-segmendi elevatsioonita müokardiinfarkti ja selle seisundita rühmas, mis tundub selgelt kliiniliselt oluline.33 Kuuendaks, mõlema biomarkeri prognostiline täpsus surmaga mittelõppenud ägeda müokardiinfarkti ennustamisel 24-kuulise jälgimisaja jooksul oli müokardiinfarktita rühma patsientide hulgas mõlema biomarkeri korral madal kuni mõõdukas, kuid hs-cTnI analüüs oli võrreldes hs-cTnT analüüsiga veidi täpsem. Seda leidu toetab sarnane tähelepanek teises rindkerevalu kohordis 34, mis rõhutab asjaolu, et erinevad patofüsioloogilised nähud võivad olla abiks surma vs. ägeda naasturebendi (mis põhjustab surmaga mittelõppeva ägeda müokardiinfarkti) ennustamisel. Võime ainult oletada, millised patofüsioloogilised erinevused cTnI, cTnT ja konkreetsete hs-cTn analüüside vahel võisid olla täheldatud erinevuste peamised mõjutegurid. Esiteks, cTn vabanemine toimub esmalt raku põhiainest ja seejärel raku organellidest.6, 35–37 Troponiini vabanemine organellidest on kliiniliselt täheldatud püsiva cTn väärtuse tõusu põhjus ägeda müokardiinfarkti korral, ja see näitab sarkomeervalkude pöördumatut lagunemist.6 Võib eeldada, et raku põhiainest esmaselt vabanev troponiin sisaldab suuremaid koguseid cTnI-d võrreldes cTnT-ga, mis selgitaks asjaolu, et varaste haiglasse pöördujate jaoks tundub cTnI olevat parem biomarker. Teisest küljest, kui cTnT tuleneb suuremal määral sarkomeervalkude pöördumatust lagunemisest, võib seda suuremat kahjustust arusaadavalt paremini seostada suremusega - seda võrreldes biomarkeriga, mille taseme tõus võib olla põhjustatud ka kergemast kahjustusest. Seda hüpoteesi toetavad hiljutised tähelepanekud kehalisest koormusest tingitud müokardi isheemia uuringutes. 38 Asümptomaatiline pärgarterite naastude rebend koos hilisema mikrotrombiga võib olla põhjus, mis seob hs-cTn analüüsi ägeda müokardiinfarkti tulevikuriskiga.39–41 Kuna mikrotromb kujutab endast kerget kahjustust, võib see põhjustada cTn varast vabanemist eeskätt raku põhiainest, misõttu võib see paremini kajastuda hs-cTnI tasemetes. Patsientidel, kellel esineb mikrotrombiga asümptomaatiline naasturebend, võib olla suurem risk järgnevate naasturebendite tekkeks, mis ei pruugi iseeneslikult paraneda ja mille tagajärjeks võib olla kliiniliselt sümptomaatiline äge müokardiinfarkt. Teiseks, me arvame, et on ebatõenäoline, et ühe analüüsi eelanalüütilised või analüütilised probleemid mängisid olulist rolli, kuna iga analüüs osutus teistest vähemalt ühes kategoorias võimekamaks. hs-cTnT mõõtmised teostati kahte tüüpi proovidest (seerum ja EDTA-plasma), hs-cTnI mõõdeti ainult ühte tüüpi proovidest (seerum). Kuigi need proovitüübid on näidanud väga kõrget korrellatsioonikordajat 1 lähedal6, 9, võis kahte tüüpi proovide kasutamine põhjustada hs-cTnT analüüsi mõnevõrra väiksema võimekuse. Täheldatud erinevused ei tohiks tähelepanu kõrvale juhtida hs-cTnI ja hs-cTnT äärmisest sarnasusest, samuti ei tohiks seda valesti tõlgendada, kui soovitust kasutada paralleelselt kahte hs-cTn analüüsi.5, 29 Lisaks on oluline rõhutada, et hs-cTn analüüsi tuleb alati kasutada ja tõlgendada koos kogu muu kliinilise teabega. Toome välja mõned selle uuringu puudujäägid. Esmalt analüüsisime cTnI ja cTnT diagnostilist ja prognostilist toimivust, kasutades kahte kliiniliselt kättesaadavat hs-cTn analüüsi. Tulevased uuringud peavad hindama, kas meie leiud kehtivad ka teiste hs-cTnI analüüside kohta, kui need muutuvad kliiniliselt kättesaadavaks. Teiseks, kuna meie uuring oli prospektiivne ja vaatluslik, ei saa me täpselt määrata kliinilist kasu, mis on seotud kas hs-cTnI või hs-cTnT analüüsi kasutamisega. Kolmandaks, kuna dialüüsi vajavad terminaalse neerupuudulikkusega patsiendid jäeti sellest uuringust välja, ei saa me kommenteerida cTnI või cTnT analüüsi diagnostilist ja prognostilist toimivust nendel patsientidel. Neljandaks, meie andmekogum ei võimalda käsitleda küsimust, kas ja mil määral aitas meie leidudele kaasa cTnI ja cTnT molekulmassi erinevus (23 vs. 35 kDa). Kokkuvõttes tagasid nii hs-cTnI kui ka hs-cTnT analüüs suure diagnostilise ja prognostilise täpsuse. Otsene võrdlus näitas väikesi, kuid võimalik, et olulisi erinevusi cTnI molekuli ja cTnT molekuli toimivuse vahel, mis võivad aidata veelgi parandada hs-cTn kliinilist kasutamist ägeda müokardiinfarktiga patsientide ravis.

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