European Heart Journal (2016) 37, 267315 ESC GUIDELINES

doi:10.1093/eurheartj/ehv320

2015ESCGuidelinesforthemanagement
ofacutecoronarysyndromesinpatients
presentingwithoutpersistentST-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)
Authors/Task Force Members: Marco Rof* (Chairperson) (Switzerland),
Carlo Patrono* (Co-Chairperson) (Italy), Jean-Philippe Collet (France),
Christian Mueller (Switzerland), Marco Valgimigli (The Netherlands),
Felicita Andreotti (Italy), Jeroen J. Bax (The Netherlands), Michael A. Borger
(Germany), Carlos Brotons (Spain), Derek P. Chew (Australia), Baris Gencer
(Switzerland), Gerd Hasenfuss (Germany), Keld Kjeldsen (Denmark),
Patrizio Lancellotti (Belgium), Ulf Landmesser (Germany), Julinda Mehilli (Germany),
Debabrata Mukherjee (USA), Robert F. Storey (UK), and Stephan Windecker
(Switzerland)
Document Reviewers: Helmut Baumgartner (CPG Review Coordinator) (Germany), Oliver Gaemperli (CPG Review
Coordinator) (Switzerland), Stephan Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon (Spain),
Colin Baigent (UK), He ctor Bueno (Spain), Raffaele Bugiardini (Italy), Scipione Carerj (Italy), Filip Casselman
(Belgium), Thomas Cuisset (France), etin Erol (Turkey), Donna Fitzsimons (UK), Martin Halle (Germany),

*Correspondingauthors:MarcoRof,DivisionofCardiology,University Hospital,Rue GabriellePerret-Gentil4,1211Geneva14,Switzerland,Tel: +41223723743,Fax:

+412237
27 229, E-mail: Marco.Rof@hcuge.ch
Carlo Patrono, Istituto di Farmacologia, Universita ` Cattolica del Sacro Cuore, Largo F. Vito 1, IT-00168 Rome, Italy, Tel: +39 06 30154253, Fax: +39 06 3050159,
E-mail:
Sectioncarlo.
Coordinators afliations listed in the Appendix.
patrono@rm.unicatt.it
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association
of Cardiovas-
cular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council for Cardiology Practice (CCP), Council on Cardiovascular Primary Care (CCPC).
Working Groups: Working Group on Cardiovascular Pharmacotherapy, Working Group on Cardiovascular Surgery, Working Group on Coronary Pathophysiology and
Microcir-
culation, Working Group on 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.
Disclaimer: The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientic and medical knowledge and the
evidence available 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 ofcial recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health
professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive,
diagnostic or
therapeutic medical
& Thestrategies;
European however,
Society ofthe ESC Guidelines
Cardiology dorights
2015. All not override,
reserved.in For
anypermissions
way whatsoever,
pleasethe individual responsibility of health professionals to make
email:
appropriate andjournals.permissions@oup.com.
accurate decisions in consideration of each patients health condition and in consultation with that patient and, where appropriate and/or necessary, the patients
caregiver. Nor
dotheESCGuidelines exempthealth professionalsfromtakinginto fullandcarefulconsiderationtherelevantofcialupdatedrecommendationsorguidelines issued
bythecompetent
public health authorities, in order to manage each patients case in light of the scientically accepted data pursuant to their respective ethical and professional
obligations. It is also the
health professionals responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
 268 ESC Guidelines

Christian Hamm (Germany), David Hildick-Smith (UK), Kurt Huber (Austria), Efstathios Iliodromitis (Greece),
Stefan James (Sweden), Basil S. Lewis (Israel), Gregory Y. H. Lip (UK), Massimo F. Piepoli (Italy), Dimitrios Richter
(Greece), Thomas Rosemann (Switzerland), Udo Sechtem (Germany), Ph. Gabriel Steg (France), Christian Vrints
(Belgium), and Jose Luis Zamorano (Spain)

The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines

Online publish-ahead-of-print 29 August 2015

-----------------------------------------------------------------------------------------------------------------
-------------------------------------
Keywords Acute cardiac care Acute coronary syndromes Angioplasty Anticoagulation Apixaban Aspirin
Atherothrombosis Beta-blockers Bivalirudin Bypass surgery Cangrelor Chest pain unit
Clopidogrel Dabigatran Diabetes Early invasive strategy Enoxaparin European Society of
Cardiology Fondaparinux Glycoprotein IIb/IIIa inhibitors Guidelines Heparin High-sensitivity
troponin Myocardial ischaemia Nitrates Non-ST-elevationmyocardial infarction Plateletinhibition
Prasugrel Recommendations Revascularization Rhythmmonitoring Rivaroxaban Statin Stent
Ticagrelor Unstable angina Vorapaxar

5.1.1 General supportive measures . . . . . . . . . . . . . . . 281

5.1.2 Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
5.1.3 Beta-blockers. . . . . . . . . . . . . . . . . . . . . . . . . . 281
Table of Contents 5.1.4 Other drug classes (see Web addenda) . . . . . . . . . 282
5.1.5 Recommendations for anti-ischaemic drugs in
the acute phase of non-ST-elevation acute coronary
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . 270
syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
5.2 Platelet inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.2.1 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1 Denitions, pathophysiology and epidemiology . . . . . . . 273
5.2.2 P2Y12 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.1 Universal denition of myocardial infarction . . . . . . 273
5.2.2.1 Clopidogrel . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.1.1 Type 1 MI . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.2.2.2 Prasugrel . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.1.2 Type 2 MI . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.2.2.3 Ticagrelor . . . . . . . . . . . . . . . . . . . . . . . . . 283
2.1.2 Unstable angina in the era of high-sensitivity cardiac
5.2.2.4 Cangrelor . . . . . . . . . . . . . . . . . . . . . . . . . 284
troponin assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.2.3 Timing of P2Y12 inhibitor administration . . . . . . . . 285
2.1.3 Pathophysiology and epidemiology
5.2.4 Monitoring of P2Y12 inhibitors
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 273
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 285
3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.2.5 Premature discontinuation of oral antiplatelet
3.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . 273
therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
3.2 Physical examination . . . . . . . . . . . . . . . . . . . . . . . . 274
5.2.6 Duration of dual antiplatelet therapy. . . . . . . . . . . 285
3.3 Diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
5.2.7 Glycoprotein IIb/IIIa inhibitors . . . . . . . . . . . . . . . 286
3.3.1 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 274
5.2.7.1 Upstream versus procedural initiation
3.3.2 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
3.3.3 Rule-in and rule-out algorithms . . . . . . . . . . . . . 276
5.2.7.2 Combination with P2Y12 inhibitors
3.3.4 Non-invasive imaging . . . . . . . . . . . . . . . . . . . . . 277
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
3.3.4.1 Functional evaluation . . . . . . . . . . . . . . . . . . 277
5.2.7.3 Adjunctive anticoagulant therapy
3.3.4.2 Anatomical evaluation . . . . . . . . . . . . . . . . . 277
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
3.4 Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 278
5.2.8 Vorapaxar (see Web addenda) . . . . . . . . . . . . . . 286
4. Risk assessment and outcomes . . . . . . . . . . . . . . . . . . . . . 278
5.2.9 Recommendations for platelet inhibition in
4.1 Clinical presentation, electrocardiogram and biomarkers 278
non-ST-elevation acute coronary syndromes . . . . . . . . . 286
4.1.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . 278
5.3 Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
4.1.2 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 278
5.3.1 Anticoagulation during the acute phase . . . . . . . . . 287
4.1.3 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
5.3.1.1 Unfractionated heparin . . . . . . . . . . . . . . . . 287
4.2 Ischaemic risk assessment. . . . . . . . . . . . . . . . . . . . . 279
5.3.1.2 Low molecular weight heparin . . . . . . . . . . . . 288
4.2.1 Acute risk assessment . . . . . . . . . . . . . . . . . . . . 279
5.3.1.3 Fondaparinux . . . . . . . . . . . . . . . . . . . . . . . 288
4.2.2 Cardiac rhythm monitoring . . . . . . . . . . . . . . . . . 279
5.3.1.4 Bivalirudin . . . . . . . . . . . . . . . . . . . . . . . . . 288
4.2.3 Long-term risk . . . . . . . . . . . . . . . . . . . . . . . . . 280
5.3.2 Anticoagulation following the acute phase . . . . . . . 289
4.3 Bleeding risk assessment . . . . . . . . . . . . . . . . . . . . . 280
4.4 Recommendationsfordiagnosis,riskstratication,imaging
and rhythm monitoring in patients with suspected non-ST-
elevation acute coronary syndromes . . . . . . . . . . . . . . . . 280
5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
5.1 Pharmacological treatment of ischaemia . . . . . . . . . . . 281
ESC Guidelines 269

5.3.3 Recommendations for anticoagulation

acute coronaryinsyndrome patients requiring coronary
non-ST-elevation acute coronary arterysyndromes
bypass surgery . . . . . . . . . 289 . . . . . . . . . . . . . . . . . . . . 299
5.4 Managing oral antiplatelet agents 5.6.6.3 in Technical
patientsaspects requiring and outcomes
long-term oral anticoagulants . (see . . . .Web
. . . .addenda)
. . . . . . . .......... 290 . . . . . . . . . . . . . . . . . . . 299
5.4.1 Patients undergoing percutaneous 5.6.7 Percutaneous coronarycoronary intervention vs. coronary
intervention. . . . . . . . . . . . . .artery
. . . . . bypass
. . . . . . surgery
. . . . . . 290 . . . . . . . . . . . . . . . . . . . . . . . . 299
5.4.2 Patients medically managed 5.6.8 or Management
requiring coronary of patients with cardiogenic shock . . . 300
artery bypass surgery . . . . . .5.6.9 . . . . Recommendations
. . . . . . . . . . . . . . 292 for invasive coronary angiography
5.4.3 Recommendations for combining and revascularization
antiplatelet in agents
non-ST-elevation acute coronary
and anticoagulants in non-ST-elevation syndromesacute . . . . coronary
. . . . . . . . . . . . . . . . . . . . . . . . . . . 300
syndrome patients requiring5.7 chronic
Gender oralspecicities
anticoagulation (see Web . 292addenda) . . . . . . . . . . . 301
5.5 Management of acute bleeding 5.8 Specialevents populations and conditions (see Web addenda) . 301
(see Web addenda) . . . . . . . . .5.8.1 . . . . The
. . . .elderly
. . . . . .and . . .frail
. 293 patients (see Web addenda) . . 301
5.5.1 General supportive measures 5.8.1.1(see Recommendations
Web addenda) . for . 293the management of
5.5.2 Bleeding events on antiplatelet elderly patients
agents with non-ST-elevation acute coronary
(see Web addenda) . . . . . . . . syndromes
. . . . . . . . . . . . . . . . . .293 . . . . . . . . . . . . . . . . . . . . . 301
5.5.3 Bleeding events on vitamin 5.8.2KDiabetes
antagonists mellitus (see Web addenda) . . . . . . . . . . 301
(see Web addenda) . . . . . . . . 5.8.2.1
. . . . . . Recommendations
. . . . . . . . . . . 293 for the management of
5.5.4 Bleeding events on non-vitamin diabetic Kpatients antagonist withoral non-ST-elevation acute coronary
anticoagulants (see Web addenda) syndromes . . . . . .. .. .. .. .. .. .. .. .. .. .. .293
. . . . . . . . . . . . . . . . . . 301
5.5.5 Non-access-related bleeding 5.8.3 events
Chronic kidney disease (see Web addenda) . . . . . . 302
(see Web addenda) . . . . . . . . 5.8.3.1
. . . . . . Dose
. . . . .adjustment
. . . . . . 293of antithrombotic agents
5.5.6 Bleeding events related (see to percutaneous
Web addenda) coronary
. . . . . . . . . . . . . . . . . . . . . . . . 302
intervention (see Web addenda) 5.8.3.2
. . . . Recommendations
. . . . . . . . . . . . . 293 for the management of
5.5.7 Bleeding events related patients to coronary withartery
chronic bypasskidney disease and non-ST-
surgery (see Web addenda) . .elevation . . . . . . . .acute
. . . . coronary
. . . . . . 293 systems . . . . . . . . . . . . . . . 302
5.5.8 Transfusion therapy (see 5.8.4
WebLeft addenda)
ventricular . . . . dysfunction
. . . . 293 and heart failure (see
5.5.9 Recommendations for bleeding Web addenda) management . . . . . . and . . . . . . . . . . . . . . . . . . . . . . . 302
blood transfusion in non-ST-elevation 5.8.4.1 Recommendations
acute coronary for the management of
syndromes . . . . . . . . . . . . . . .patients
. . . . . . .with
. . . .acute
. . . . .heart
293 failure in the setting of non-ST-
5.6 Invasive coronary angiography elevation
and revascularization
acute coronary syndromes . . . 294 . . . . . . . . . . . . . 302
5.6.1 Invasive coronary angiography 5.8.4.2 .Recommendations
. . . . . . . . . . . . . . 294 for the management of
5.6.1.1 Pattern of coronary artery patients diseasewith heart
. . . . . failure
. . . . 294 following non-ST-elevation
5.6.1.2 Identication of the culprit acutelesioncoronary . . . .syndromes
. . . . . . 294. . . . . . . . . . . . . . . . . . . 303
5.6.1.3 Fractional ow reserve 5.8.5
. . . .Atrial
. . . . brillation
. . . . . . . .(see . 295 Web addenda) . . . . . . . . . . 303
5.6.2 Routine invasive vs. selective 5.8.5.1invasive
Recommendationsapproach . . for . . 295
the management of atrial
5.6.3 Timing of invasive strategy brillation
. . . . . in. .patients
. . . . . . .with . . . 295 non-ST-elevation acute
5.6.3.1 Immediate invasive strategy coronary(,2 syndromes
h) . . . . . .. .. .. .. 295 . . . . . . . . . . . . . . . . . . . 303
5.6.3.2 Early invasive strategy 5.8.6 (,24Anaemia
h) . . . . (see . . . . Web. . . 295 addenda) . . . . . . . . . . . . . . . 304
5.6.3.3 Invasive strategy (,72 5.8.7
h) . Thrombocytopenia
. . . . . . . . . . . . . . 296 (see Web addenda) . . . . . . . . 304
5.6.3.4 Selective invasive strategy 5.8.7.1. Thrombocytopenia
. . . . . . . . . . . . . . 297 related to GPIIb/IIIa
5.6.4 Conservative treatment inhibitors . . . . . . . . (Web. . . . .addenda)
. . . . . . 297 . . . . . . . . . . . . . . . . . . . . 304
5.6.4.1 In patients with coronary 5.8.7.2 artery
Heparin-induced
disease . . . . .thrombocytopenia
. 297 (Web
5.6.4.1.1 Non-obstructive CAD addenda)
. . . . . . . . . . . . . . 297 . . . . . . . . . . . . . . . . . . . . . . 304
5.6.4.1.2 CAD not amenable5.8.7.3 to revascularization
Recommendations . . . 297 for the management of
5.6.4.2 In patients with normal thrombocytopenia
coronary angiogram in non-ST-elevation acute coronary
(see Web addenda) . . . . . . . syndromes
. . . . . . . . . . . . . . . . . .297 . . . . . . . . . . . . . . . . . . . . . 304
5.6.5 Percutaneous coronary 5.8.8 intervention
Patients. .requiring. . . . . . . chronic
. . 297 analgesic or anti-
5.6.5.1 Technical aspects and inammatory
challengestreatment . . . . . . . . (see . . 297 Web addenda) . . . . . . . . . 304
5.6.5.2 Vascular access . . . .5.8.9 . . . . Non-cardiac
. . . . . . . . . .surgery. . . . 298 (see Web addenda) . . . . . . . . 304
5.6.5.3 Revascularization strategies
5.9 Long-term and outcomes
management . . . .. 298 . . . . . . . . . . . . . . . . . . . . . 304
5.6.6 Coronary artery bypass5.9.1 surgery Medical. . . . .therapy
. . . . . . for . . .secondary
298 prevention . . . . . . . 304
5.6.6.1 Timing of surgery and5.9.1.1 antithrombotic
Lipid-lowering drug treatment . . . . . . . . . . . . . . . 304
discontinuation (see Web addenda) 5.9.1.2 .Antithrombotic
. . . . . . . . . . . .therapy 299 . . . . . . . . . . . . . . . . 304
5.6.6.2 Recommendations for5.9.1.3 perioperative
ACE inhibition . . . . . . . . . . . . . . . . . . . . . . 304
management of antiplatelet 5.9.1.4 therapyBeta-blockers
in non-ST-elevation . . . . . . . . . . . . . . . . . . . . . . . 304
 270 ESC Guidelines

5.9.1.5 Mineralocorticoid receptor antagonist therapy . 304 CKD chronic kidney disease
5.9.1.6 Antihypertensive therapy . . . . . . . . . . . . . . . 304 CK-MB
creatine kinase myocardial band
5.9.1.7 Glucose-lowering therapy in diabetic patients . . 304
COX
cyclooxygenase
5.9.2 Lifestyle changes and cardiac rehabilitation . . . . . . . 305
5.9.3 Recommendations for long-term management after CMR
cardiac magnetic resonance
non-ST-elevation acute coronary syndromes . . . . . . . . . 305 CPG Committee for Practice Guidelines
6. Performance measures . . . . . . . . . . . . . . . . . . . . . . . . . . 305 CREDO
Clopidogrel for the Reduction of Events
During Observation
7. Summary of management strategy . . . . . . . . . . . . . . . . . . . 306
8. Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 CRUSADE
Can Rapid risk stratication of Unstable an-
9. To do and not to do messages from the guidelines . . . . . . . . 308 gina patients Suppress ADverse outcomes
10. Web addenda and companion documents. . . . . . . . . . . . . 309 with Early implementation of the ACC/AHA
11. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
guidelines
12. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
CT
computed tomography
13. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
CURE Clopidogrel in Unstable Angina to Prevent
Recurrent Events
CURRENT-OASIS
7
Clopidogrel and Aspirin Optimal Dose Usage
Abbreviations and acronyms to Reduce Recurrent EventsSeventhOrgan-
ization to Assess Strategies in Ischaemic
Syndromes
ACC American College of Cardiology CV cardiovascular
ACCOAST Comparison of Prasugrel at the Time of CYP cytochrome P450
Percutaneous Coronary Intervention or as DAPT dual(oral) antiplatelet therapy
Pretreatment at the Time of Diagnosis in DES drug-eluting stent
Patients with Non-ST Elevation Myocardial EARLY-ACS Early Glycoprotein IIb/IIIa Inhibition in
Infarction Non-ST-Segment Elevation Acute Coronary
ACE angiotensin-converting enzyme Syndrome
ACS acute coronary syndromes ECG electrocardiogram
ACT activated clotting time eGFR estimated glomerular ltration rate
ACTION Acute Coronary Treatment and Intervention EMA European Medicines Agency
Outcomes Network ESC European Society of Cardiology
ACUITY Acute Catheterization and Urgent Interven- FDA Food and Drug Administration
tion Triage strategY FFR fractional ow reserve
ADAPT-DES AssessmentofDualAntiPlateletTherapywith FREEDOM Future Revascularization Evaluation in
Drug-Eluting Stents Patients with Diabetes Mellitus: Optimal
ADP adenosine diphosphate Management of Multivessel Disease
AHA American Heart Association GPIIb/IIIa glycoprotein IIb/IIIa
APPRAISE Apixaban for Prevention of Acute IschaemicGRACE 2.0 Global Registry of Acute Coronary Events 2.0
Events GUSTO Global Utilization of Streptokinase and TPA
aPTT activated partial thromboplastin time for Occluded Arteries
ARB angiotensin receptor blocker GWTG Get With The Guidelines
ATLAS ACS HAS-BLED hypertension, abnormal renal and liver func-
2-TIMI 51 tion (1 point each), stroke, bleeding history
or predisposition, labile INR, elderly (.65
years), drugs and alcohol (1 point each)
HIT heparin-induced thrombocytopenia
Anti-Xa Therapy to Lower Cardiovascular
HORIZONS Harmonizing Outcomes with Revasculariza-
Events in Addition to Aspirin With or With-
tiON and Stents in Acute Myocardial Infarction
out Thienopyridine Therapy in Subjects with
HR hazard ratio
Acute Coronary SyndromeThrombolysis
IABP-Shock II Intra-Aortic Balloon Pump in Cardiogenic
in Myocardial Infarction 51
Shock II
ATP adenosine triphosphate
IMPROVE-IT IMProved Reduction of Outcomes: Vytorin
BARC Bleeding Academic Research Consortium
Efcacy International Trial
BMS bare-metal stent
INR international normalized ratio
CABG coronary artery bypass graft
ISAR-CLOSURE Instrumental Sealing of ARterial puncture
CAD coronary artery disease
siteCLOSURE device versus manual
CHA2DS2-VASc Cardiac failure, Hypertension, Age e75
compression
(2 points), Diabetes, Stroke (2 points)
ISAR-REACT Intracoronary stenting and Antithrombotic
Vascular disease, Age 6574, Sex category
RegimenRapid Early Action for Coronary
CHAMPION Cangrelor versus Standard Therapy to
Treatment
Achieve Optimal Management of Platelet
Inhibition
CI condence interval
CK creatine kinase
ESC Guidelines 271

ISAR-TRIPLE Triple Therapy in Patients on Oral Anticoagula-

TIA transient ischaemic attack
tion After Drug Eluting Stent Implantation TIMACS Timing of Intervention in Patients with Acute
i.v. intravenous Coronary Syndromes
LDL low-density lipoprotein TIMI Thrombolysis In Myocardial Infarction
LMWH low molecular weight heparin TRA 2P-TIMI 50 Thrombin Receptor Antagonist in Secondary
LV left ventricular Prevention of Atherothrombotic Ischemic
LVEF left ventricular ejection fraction EventsThrombolysis in Myocardial Infarc-
MACE major adverse cardiovascular event tion 50
MATRIX Minimizing Adverse Haemorrhagic Events TRACER
by Thrombin Receptor Antagonist for Clinical
TRansradial Access Site and Systemic Imple- Event Reduction in Acute Coronary
mentation of angioX Syndrome
MDCT multidetector computed tomography TRILOGY ACS Targeted Platelet Inhibition to Clarify the Op-
MERLIN Metabolic Efciency With Ranolazine for Less timal Strategy to Medically Manage Acute
Ischaemia in Non-ST-Elevation Acute Coron- Coronary Syndromes
ary Syndromes TRITON-TIMI 38 TRial to Assess Improvement in Therapeutic
MI myocardial infarction Outcomes by Optimizing Platelet InhibitioN
MINAP Myocardial Infarction National Audit Project with PrasugrelThrombolysis In Myocardial
NOAC non-vitamin K antagonist oral anticoagulant Infarction 38
NSAID non-steroidal anti-inammatory drug TVR target vessel revascularization
NSTE-ACS non-ST-elevation acute coronary syndromes
UFH unfractionated heparin
NSTEMI non-ST-elevation myocardial infarction VKA vitamin K antagonist
NYHA New York Heart Association WOEST What is the Optimal antiplatElet and anti-
OAC oral anticoagulation/anticoagulant coagulant therapy in patients with OAC and
OASIS Organization to Assess Strategies for Ischae- coronary StenTing
mic Syndromes ZEUS Zotarolimus-eluting Endeavor Sprint Stent in
OR odds ratio Uncertain DES Candidates
PARADIGM-HF Prospective comparison of ARNI with ACEI
to Determine Impact on Global Mortality
and morbidity in Heart Failure
PCI percutaneous coronary intervention 1.Preamble
PEGASUS-TIMI 54 Prevention of Cardiovascular EventsGuidelines
in Pa- summarize and evaluate all available evidence on a
tients with Prior Heart Attack Using Ticagre-par-
lor Compared to Placebo on a Background of ticular issue atthe time ofthewriting process,withthe aimof assist-
Aspirin-ThrombolysisinMyocardialInfarction ing health professionals in selecting the best management
54 strategies
PLATO PLATelet inhibition and patient Outcomesfor an individual patient with a given condition, taking into
POISE PeriOperative ISchemic Evaluation account
RCT randomized controlled trial the impact on outcome, as well as the riskbenet ratio of particu-
RIVAL RadIal Vs femorAL access for coronary lar diagnostic or therapeutic means. Guidelines and recommenda-
intervention tions should help health professionals to make decisions in their
RR relative risk daily practice. However, the nal decisions concerning an
RRR relative risk reduction individual
SAFE-PCI Study of Access Site for Enhancement of PCI must be made by the responsible health professional(s) in
patient
for Women consultation with the patient and caregiver as appropriate.
s.c. subcutaneous A great numberof Guidelines havebeen issued in recent years by
STEMI ST-segment elevation myocardial infarction the European Society of Cardiology (ESC) as well as by other soci-
SWEDEHEART Swedish Web-system for Enhancement andand organisations. Because of the impact on clinical
eties
Development of Evidence-based care in practice,
HeartdiseaseEvaluatedAccordingtoRecom- quality criteria for the development of guidelines have been
mended Therapies estab-
SYNERGY Superior Yield of the New Strategy of Enoxa-
lished in order to makeall decisionstransparentto the user. The re-
parin, Revascularization and Glycoprotein IIb/ commendations for formulating and issuing ESC Guidelines can
IIIa Inhibitors trial be
SYNTAX SYNergy between percutaneous coronary found on the ESC website (http://www.escardio.org/Guidelines-
intervention with TAXus and cardiac surgery &-Education/Clinical-Practice-Guidelines/Guidelines-development/
TACTICS Treat angina with Aggrastat and determineWriting-ESC-Guidelines).ESCGuidelinesrepresenttheofcialpos-
Cost of Therapy with an Invasive or Conser-ition of the ESC on a given topic and are regularly updated.
vative Strategy Members of this Task Force were selected by the ESC to re-
present professionals involved with the medical care of patients
with this pathology. Selected experts in the eld undertook a com-
prehensive review of the published evidence for management
(including diagnosis, treatment, prevention and rehabilitation) of
a
given condition according to ESC Committee for Practice Guide-
lines(CPG)policy.Acriticalevaluationofdiagnosticandtherapeutic
procedures was performed, including assessment of the
 272 ESC Guidelines

Table 1 Classes of recommendations

Classes of Suggested wording to use

recommend
ations
Is recommended/is
Class I Evidence and/or indicated
general
agreement that a given treatment
or procedure is beneficial, useful,
effective.
Conflicting evidence
Class II and/or a
divergence of opinion about the
treatment or procedure. of
usefulness/efficacy
Class IIa Weight of evidence/opinion is in
the given Should be
considered

May be considered
Class IIb
favourby
established ofevidence/opinion.
usefulness/efficacy. Is not
Class III Evidence or general agreement recommended
that the given treatment or
Usefulness/efficacy
procedure is
is not useful/effective,
less well
and in some cases may be harmful.

riskbenetratio.Estimatesofexpectedhealthoutcomesforlarger
Table 2 Levels of evidence
populations were included, where data exist. The level of evidence
and the strength of the recommendation of particular management
optionswereweighedandgradedaccordingto predenedscales,asLevel of Data derived from multiple
outlined in Tables 1 and 2. evidenc
randomized
The experts of the writing and reviewing panels provided declar- eA clinical trials or meta-analyses.
Data derived from a single
ationofinterestformsforallrelationshipsthatmightbeperceivedas
randomized
real or potential sources of conicts of interest. These forms were Level of
clinical trial or large non-randomized
compiled into one le and can be found on the ESC website (http:// evidence B
studies.
www.escardio.org/guidelines). Any changes in declarations of Consensus of opinion of the
interest that arise during the writing period must be notied to Level of experts and/
the ESC and updated. The Task Force received its entire nancial or small studies, retrospective
evidence Cstudies,
support fromthe ESC without any involvementfrom the healthcare
registries.
industry.
TheESCCPGsupervisesandcoordinatesthepreparationofnew
Guidelinesproducedbytaskforces,expertgroupsorconsensuspa-
nels. The Committee is also responsible for the endorsementThe National
pro- Societies of the ESC are encouraged to endorse,
translate and implement all ESC Guidelines. Implementation pro-
cess of these Guidelines. The ESC Guidelines undergo extensive
review by the CPG and external experts. After appropriate grammes
revi- are needed because it has been shown that the
outcome
sions the Guidelines are approved by all the experts involved in
the Task Force. The nalized document is approved by the of CPG
disease may be favourably inuenced by the thorough applica-
tion
for publication in the European Heart Journal. The Guidelines of clinical recommendations.
were developed after careful consideration of the scientic Surveysandregistriesareneededtoverifythatreal-lifedailyprac-
and medical knowledge and the evidence available at the ticetime
is in of
keeping with what is recommended in the guidelines,
their dating. thus
The task of developing ESC Guidelines covers not onlycompleting the loop between clinical research, writing of
guidelines,
integration of the most recent research, but also the creation of
educational tools and implementation programmes for disseminating
the recom- them and implementing them into clinical practice.
mendations. To implement the guidelines, condensed pocket Health professionals are encouraged to take the ESC Guidelines
fully into
guidelines versions, summary slides, booklets with essential mes- account when exercising their clinical judgment, as well
as
sages, summary cards for non-specialists and an electronic version
for digital applications (smartphones, etc.) are produced. inthedeterminationandtheimplementationofpreventive,diagnos-
These
tic or therapeutic
versions are abridged and thus, if needed, one should always refer medical strategies. However, the ESC
Guidelines
to the full text version which is freely available on the ESC website.
do not override in any way whatsoever the individual
responsibility
of health professionals to make appropriate and accurate
decisions
in consideration of each patients health condition and in consult-
ationwiththatpatientandthepatientscaregiverwhereappropriate
and/or necessary. It is also the health professionals responsibility
to
verifytherulesandregulationsapplicabletodrugsanddevicesatthe
time of prescription.
ESC Guidelines 273

myocardial blood ow and/or distal embolization and subsequent

2.Introduction myocardialnecrosis.Thepatientmayhaveunderlyingseverecoron-
ary artery disease (CAD) but, on occasion (i.e. 520% of cases),
theremaybenon-obstructivecoronaryatherosclerosisornoangio-
2.1Denitions, pathophysiology and graphic evidence of CAD, particularly in women.25
epidemiology
The leading symptom that initiates the diagnostic and therapeutic
cascade in patients with suspected acute coronary syndromes
2.1.1.2 Type 2 MI
(ACS) is chest pain. Based on the electrocardiogram (ECG), two
Type2MIismyocardialnecrosisinwhichaconditionotherthancor-
groups of patients should be differentiated: onary plaque instability contributes to an imbalance between myo-
cardial oxygen supply and demand.2 Mechanisms include coronary
(1) Patients with acute chest pain and persistent (.20artery
min) spasm, coronary endothelial dysfunction, tachyarrhythmias,
ST-segment elevation. bradyarrhythmias, anaemia, respiratory failure, hypotension and
This condition is termed ST-elevation ACS and generally
se- re-
ects anacutetotal coronaryocclusion. Most patientsvere
will ultim-
hypertension. In addition, in critically ill patients and in
atelydevelopanST-elevationmyocardialinfarction(STEMI).The
patients
mainstay of treatment in these patients is immediate reperfusion
undergoing major non-cardiac surgery, myocardial necrosis may
by primary angioplasty or brinolytic therapy. 1 be
(2) Patients with acute chest pain but no persistent ST-segment
related to injurious effects of pharmacological agents and toxins. 6
elevation. The universaldenition ofMI alsoincludestype3 MI(MIresulting
ECG changes may include transient ST-segment elevation,
in death when biomarkers are not available) and type 4 and 5 MI
persistent or transient ST-segment depression, T-wave inver-
(related to percutaneous coronary intervention [PCI] and coronary
sion, at T waves or pseudo-normalization of T waves or
arterythe
bypass grafting [CABG], respectively).
ECG may be normal.
2.1.2 Unstable angina in the era of high-sensitivity cardiac
The clinical spectrum of non-ST-elevation ACS (NSTE-ACS)
troponinmayassays
range from patients free of symptoms at presentation to individuals
Unstable angina is dened as myocardial ischaemia at rest or
with ongoing ischaemia, electrical or haemodynamicminimal
instability or
cardiac arrest. The pathological correlate at the myocardial
exertion level is absence of cardiomyocyte necrosis. Among unse-
in the
cardiomyocyte necrosis [NSTE-myocardial infarction (NSTEMI)]
lected patients presenting with suspected NSTE-ACS to the emer-
or, less frequently, myocardial ischaemia without cellgency
loss (unstable
department, the introduction of high-sensitivity cardiac
angina). A small proportion of patients may present with ongoing
troponin measurements in place of standard troponin assays
myocardial ischaemia, characterized by one or more resulted
of the follow-
ing: recurrent or ongoing chest pain, marked ST depression on
in an increase in the detection of MI (4% absolute and 20% relative
12-lead ECG, heart failure and haemodynamic or electrical instabil-
increase) and a reciprocal decrease in the diagnosis of unstable
ity. Due to the amount of myocardium in jeopardy and an-the risk of
malignant ventricular arrhythmias, immediate coronary gina.710 Compared with NSTEMI patients, individuals with unstable
angiography angina do not experience myocardial necrosis, have a
and, if appropriate, revascularization are indicated. substantially
2.1.1 Universal denition of myocardial infarction lower risk of death and appear to derive less benet from intensied
Acute myocardial infarction (MI) denes cardiomyocyte necrosis intherapy as well as early invasive strategy. 24,613
antiplatelet
a clinical setting consistent with acute myocardial ischaemia. 2
A combination of criteria is required to meet the diagnosis of acute
MI, namely the detection of an increase and/or decrease of
2.1.3 Pathophysiology and epidemiology
acardiac
(see Web addenda)
biomarker, preferably high-sensitivity cardiac troponin, with at least
onevalueabovethe99thpercentileoftheupperreferencelimitand
at least one of the following: 3.Diagnosis
(1) Symptoms of ischaemia.
(2) New or presumed new signicant ST-T wave changes 3.1Clinical
or left presentation
bundle branch block on 12-lead ECG. Anginal pain in NSTE-ACS patients may have the following
(3) Development of pathological Q waves on ECG. presentations:
(4) Imaging evidence of new or presumed new loss of Prolonged
viable myo- (.20 min) anginal pain at rest;
cardium or regional wall motion abnormality. New onset (de novo) angina (class II or III of the Canadian Car-
(5) Intracoronary thrombus detected on angiography or autopsy. Society classication);21
diovascular
Recent destabilization of previously stable angina with at least
2.1.1.1 Type 1 MI Canadian Cardiovascular Society Class III angina characteristics
(crescendo
Type 1 MI is characterized by atherosclerotic plaque rupture, ulcer-angina); or
Post-MI
ation, ssure, erosion or dissection with resulting intraluminal angina.
thrombus in one or more coronary arteries leading toProlonged
decreasedand de novo/crescendo angina are observed in 80%
and 20% of patients, respectively. Typical chest pain is character-
ized by a retrosternal sensation of pressure or heaviness (angina)
radiating to the left arm (less frequently to both arms or to the
right
arm), neck or jaw, which may be intermittent (usually lasting
several
minutes) or persistent. Additional symptoms such as sweating,
nau-
sea,abdominalpain,dyspnoeaandsyncopemaybepresent.Atypical
 274 ESC Guidelines

presentations include epigastric pain, indigestion-like symptoms

stenosis(mimickingACS). 25Rarely,asystolicmurmurmayindicatea
and mechanicalcomplication(i.e.papillarymuscleruptureorventricular
isolated dyspnoea. Atypical complaints are more often observed
septal defect) of a subacute and possibly undetected MI. Physical
in examination may identify signs of non-coronary causes of chest
the elderly, in women and in patients with diabetes, chronic
pain (e.g.
renalpulmonary embolism, acute aortic syndromes,
disease or dementia.2224 The exacerbation of symptomsmyoperi-by phys-
ical exertion and their relief at rest increase the probability
carditis,
of aortic stenosis) or extracardiac pathologies (e.g.
myo- pneumo-
cardial ischaemia. The relief of symptoms after nitratesthorax, pneumonia or musculoskeletal diseases). In this setting,
administration is not specic for anginal pain as it is reported
the presence
also of a chest pain that can be reproduced by exerting
inothercausesofacutechestpain. 24Inpatientspresentingwithsus-
pressure on the chest wall has a relatively high negative
pectedMItotheemergencydepartment,overall,thediagnosticper-predictive
formance of chest pain characteristics for MI is limited.24
value
Olderfor NSTE-ACS.24,26 According to the presentation,
age, abdominal
male gender, family history of CAD, diabetes, hyperlipidaemia,
disorders(e.g.oesophagealspasm,oesophagitis,gastriculcer,chole-
hypertension, renal insufciency, previous manifestationcystitis,
of CAD pancreatitis) may also be considered in the differential
aswellasperipheralorcarotidarterydiseaseincreasethelikelihood
diag-
of NSTE-ACS. Conditions that may exacerbate or precipitatenosis. Differences in blood pressure between the upper and lower
NSTE-ACS include anaemia, infection, inammation, fever, limbs
andor between the arms, irregular pulse, jugular vein
metabolic or endocrine (in particular thyroid) disorders.distension,
heart murmurs, friction rub and pain reproduced by chest or ab-
dominal palpation are ndings suggestive of alternative
3.2Physical examination diagnoses.
Physical examination is frequently unremarkable in patients
Pallor,with
sweating or tremor may point towards precipitating condi-
suspected NSTE-ACS. Signs of heart failure or haemodynamic or as anaemia and thyrotoxicosis.27
tions such
electrical instability mandate a quick diagnosis and treatment.
Car-
diac auscultation may reveal a systolic murmur due to ischaemic
mi- 3.3Diagnostic tools
tral regurgitation, which is associated with poor prognosis,
3.3.1 orElectrocardiogram
aortic The resting 12-lead ECG is the rst-line diagnostic tool in the
Low Likelihood High
assess- Likelihood
mentofpatientswithsuspectedACS(Figure1).Itisrecommendedto

1. Presentation

2.
ECG

3.
Troponin

4. Non- UA Other NSTE STE

Diagnos Cardi
cardiac MI MI
ac
is
STEMI = ST-elevation myocardial infarction; NSTEMI = non-ST-elevation myocardial infarction; UA = unstable angina.

Figure 1 Initial assessment of patients with suspected acute coronary syndromes. The initial assessment is based on the integration of low-
likelihoodand/orhigh-likelihoodfeaturesderivedfromclinical presentation(i.e.,symptoms,vital signs), 12-leadECG,andcardiactroponin. Thepro-
portion of the nal diagnoses derived from the integration of these parameters is visualized by the size of the respective boxes. Other cardiac
includes,amongother,myocarditis,Tako-Tsubocardiomyopathy,ortachyarrhythmias.Non-cardiacreferstothoracicdiseasessuchaspneumonia
orpneumothorax.Cardiactroponinshouldbeinterpretedasaquantitativemarker:thehigherthelevel,thehigherthelikelihoodforthepresenceof
myocardial infarction. In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin,
echocardiography
should be performed/interpreted by trained physicians immediately following a 12-lead ECG. If the initial evaluation suggests aortic dissection or
pulmonary embolism, D-dimers and multi-detector computed tomography angiography are recommended according to dedicated
algorithms.42,43
ESC Guidelines 275

Table 3 Clinical implications of high-sensitivity Table 4 Conditions other than acute myocardial
cardiac troponin assays infarction type 1 associated with cardiac troponin
elevation
Compared with standard cardiac troponin assays, high-sensitivity
assays:
" Have higher negative predictive value for acute MI. Tachyarrhythmias
" Reduce the troponin-blind interval leading to earlier detection of acute MI. Heart failure
" Result in a ~4% absolute and ~20% relative increase in the detection of Hypertensive emergencies
type 1 MI and a Critical illness (e.g. shock/ sepsis/ burns)
corresponding decrease in the diagnosis of unstable angina. Myocarditisa
" Are associated with a 2-fold increase in the detection of type 2 MI. Tako-Tsubo cardiomyopathy
Levels of high-sensitivity cardiac troponin should be interpreted Structural heart disease (e.g. aortic stenosis)
as quantitative Aortic dissection
markers of cardiomyocyte damage (i.e. the higher the level, the Pulmonary embolism, pulmonary hypertension
greater the Renal dysfunction and associated cardiac disease
likelihood of MI):
" Elevations beyond 5-fold the upper reference limit have high (>90%) Acute neurological event (e.g. stroke or subarachnoid
positive predictive
haemorrhage)
value for acute type 1 MI. Cardiac contusion or cardiac procedures (CABG, PCI, ablation,
" Elevations up to 3-fold the upper reference limit have only limited
pacing,
Coronarycardioversion,
spasm or
(5060%) positive endomyocardial biopsy)
predictive value for acute MI and may be associated with a broad
Hypo- and hyperthyroidism
spectrum of conditions.
" It is common to detect circulating levels of cardiac troponin in healthy
individuals.
Rising and/or falling cardiac troponin levels differentiate acute
from chronic
cardiomyocyte damage (the more pronounced the change, the
higher the
likelihood of acute MI).
obtain it within 10 min of the patients arrival in the emergency venoms)
Extreme endurance efforts
room Rhabdomyolysis
or,ideally,atrstcontactwithemergencymedicalservicesinthepre-
MI myocardial infarction.
hospital setting and to have it immediately interpreted by a
qualied
Bold = most frequent conditions; CABG coronaryartery bypass
physician.28 While the ECG in the setting of NSTE-ACS may be nor- PCI
surgery;
mal in more than one-third of patients, characteristic percutaneous coronary intervention.
abnormalities aincludes myocardial extension of endocarditis or pericarditis.

includeSTdepression,transientSTelevationandT-wavechanges.the vast1,18
majority of cardiac troponin assays run on automated
If the standard leads are inconclusive and the patient plat-
has signs or
symptoms suggestive of ongoing myocardial ischaemia, formsandaresensitive(i.e.allowfordetectionofcardiactroponinin
additional 2050% of healthy individuals) or high-sensitivity (detection in
leads should be recorded; left circumex artery occlusion or right
5090% of healthy individuals) assays. High-sensitivity assays are
ventricular MI may be detected only in V7V9 and V3R and V4R, re-
recommendedoverlesssensitiveones. 2,6,8Themajorityofcurrently
spectively.2 In patients with suggestive signs and symptoms, the
used point-of-care assays cannot be considered sensitive or high-
nding of persistent STelevation indicates STEMI, whichsensitivity
mandatesassays.8,35 Therefore the obvious advantage of
immediate reperfusion.1 Comparison with previous tracings is
point-of-care tests, namely the shorter turnaround time, is
valuable, particularly in patients with pre-existing ECGcounter-
abnormal-
ities. It is recommended to obtain additional 12-lead ECGs in the
balanced by lower sensitivity, lower diagnostic accuracy and
case of persistent or recurrent symptoms or diagnostic uncer-
lower
tainty. In patients with bundle branch block or paced rhythm,
negative predictive value. Overall, automated assays have been
ECG is of no help for the diagnosis of NSTE-ACS. morethoroughlyevaluatedascomparedwithpoint-of-caretests.2,6,8
As these techniques continue to improve and performance
charac-
3.3.2 Biomarkers teristics are bothassayandhospital dependent,norecommendation
Biomarkers complement clinical assessment and 12-lead regarding
ECG inthe site of measurement (central laboratory vs.
the bedside)
diagnosis, risk straticationand treatment ofpatients withsuspected
can be given.2,6,8,38 Data from large multicentre studies have
NSTE-ACS. Measurement of a biomarker of cardiomyocyte consist-
injury,
preferably high-sensitivity cardiac troponin, is mandatoryentlyinshown
all that sensitive and high-sensitivity cardiac troponin
pa- as-
tients with suspected NSTE-ACS.2,6,8 Cardiac troponinssays are more
increase diagnostic accuracy for MI at the time of
sensitive and specic markers of cardiomyocyte injury presentation
than
creatine ascomparedwithconventionalassays,especiallyinpatientspresent-
kinase (CK), its MB isoenzyme (CK-MB) and myoglobin.ing 6 Ifearly
the clin-
after chest pain onset, and allow for a more rapid rule-in
ical presentation is compatible with myocardial ischaemia,and rule-out
then a of MI (see section 3.3.3 and Table 3).2,6,8,2934
dy- Inmostpatientswithrenaldysfunction,elevationsincardiactropo-
namic elevation of cardiac troponin above the 99th percentile
nin should of not be primarilyattributed to impaired clearance and
healthy individuals indicates MI.2 In patients with MI, levels
con- of
cardiac sidered harmless, as cardiac conditions such as chronic coronary
troponin rise rapidly(i.e. usually within 1 h if using high-
or
sensitivityas- hypertensive heart disease seem to be the most important
says) after symptom onset and remain elevated for a contribu-
variable
period tor to troponin elevation in this setting.41 Other life-threatening
oftime(usuallyseveraldays).2,6Advancesintechnologyhaveledtoa
con-
renement in cardiac troponin assays and have improved ditions
the presenting with chest pain, such as aortic dissection and
ability pulmonary embolism, may also result in elevated troponin levels
to detect and quantify cardiomyocyte injury.2,6,8,10,2937and
In Europe,
should be considered as differential diagnoses (Table 4).
 H

276 ESC Guidelines

Acute Chest
Pain

hs-cTn
hs-cTn <ULN hs-cTn >ULN hs-cTn
<ULN >ULN

Pain
Pain Pain
Pain
>6h
>6h <6h
<6h

Re-test hs-
cTn: 3h

hs-cTn
hs-cTnno
no change
changeaa
hs-cTn
hs-cTnno
no
change
change (1
(1value
value>>
change
change
ULN)
ULN)
Painfree,
Painfree,GRACE
GRACE<140,
<140,
differential
differentialdiagnoses
diagnosesexcluded
excluded Work-up
Work-updifferential
differential
diagnoses
diagnoses

Discharge/Stress
Discharge/Stress Invasive
Invasive
testing
testing management
management
GRACE = Global Registry of Acute Coronary Events score; hs-cTn = high sensitivity cardiac troponin; ULN = upper limit of normal, 99th
percentile of healthy controls.
a

Figure 2 0 h/3 h rule-out algorithm of non-ST-elevation acute coronary syndromes using high-sensitivity cardiac troponin assays.

Among the multitude of additional biomarkers evaluated for the

diagnosis of NSTE-ACS, only CK-MB and copeptin seem to have
clinical relevance.2,6,8,10,4450 CK-MB shows a more rapid decline Suspected
after MI as compared with cardiac troponin and may provide added NSTEMI
value for the timing of myocardial injury and the detection of early
reinfarction.2,6,8,10 Assessment of copeptin, the C-terminal part of B ng/l 0h
D ng/l
the vasopressin prohormone, may quantify the endogenous stress 0h or 0h
and Other or
level in multiple medical conditions including MI. As the level of <A
en-*ng/l 0-1hC ng/l 0-1hE ng/l

dogenous stress appearsto be invariably high at the onset of MI, the

added value of copeptin to conventional (less sensitive) cardiac Rule- Obser Rule-
troponin assays is substantial.4450 Therefore the routine use of out ve in
copeptin as an additional biomarker for the early rule-out of MI
A B C D E
is recommended whenever sensitive or high-sensitivity cardiachs-cTnT (Elecsys) 5 12 3 52 5
troponin assays are not available. Copeptin may have some added hs-cTnl (Architect) 2 5 2 52 6
hs-cTnl (Dimension Vista)+ 0.5 5 2 107 19
value even over high-sensitivity cardiac troponin in the early rule-
out of MI.4448

Figure 3 0 h/1 h rule-in and rule-out algorithms using high-

sensitivity cardiac troponins (hs-cTn) assays in patients presenting
3.3.3 Rule-in and rule-out algorithms
with suspected non-ST-elevation myocardial infarction (NSTEMI)
Due to the higher sensitivity and diagnostic accuracy for the detec-
to the emergency department. 0 h and 1 h refer to the time from
tion of acute MI at presentation, the time interval to the second car-test. NSTEMI can be ruled-out already at presentation,
rst blood
diac troponin assessment can be shortened with the use ofif the hs-cTn concentration is verylow. NSTEMI can also be ruled-
high-sensitivity assays. This may reduce substantially the delay to
outbythecombinationoflowbaselinelevelsandthelackofarele-
diagnosis, translating into shorter stays in the emergency depart-
vantincreasewithin1 h.PatientshaveahighlikelihoodforNSTEMI
if the hs-cTn concentration at presentation is at least moderately
ment and lower costs.2,6,8,10,2936 It is recommended to use the
elevatedorhs-cTnconcentrationsshowaclearrisewithintherst
0 h/3 h algorithm (Figure 2). As an alternative, 0 h/1 h assessments
are recommended when high-sensitivity cardiac troponin assayshour. Cut-off levels are assay-specic. Cut-off levels for other
hs-cTn assays are in development. *Only applicable if chest pain
with a validated algorithm are available (Figure 3). The 0 h/1 h algo-
onset .3h, +At the time of the publication of the guideline not
rithmsrelyontwoconcepts:rst,high-sensitivitycardiactroponinisyet commercially available.
a continuous variable and the probability of MI increases with in-
creasing high-sensitivity cardiac troponin values;39 second, early ab-
solute changes of the levels within 1 h can be used as surrogates
for
valuetothecardiactroponinassessmentatpresentation. 39Thecut-
absolutechangesover3 hor6 handprovideincrementaldiagnostic
off levels within the 0 h/1 h algorithm are assay specic.36,39,5155
Those algorithms should always be integrated with a detailed
ESC Guidelines 277

clinical assessment and 12-lead ECG and repeat blood NSTE-ACS.

sampling This is imaging modality is useful to identify
mandatory in case of ongoing or recurrent chest painabnormalities
(Table 5,
see Web addenda). suggestive of myocardial ischaemia or necrosis (i.e. segmental
Table 5 (see Web addenda) Characteristics of the 0 h/3 hypo- h
and 0 h/1 h algorithms kinesia or akinesia). In the absence of signicant wall motion abnor-
The negativepredictivevaluefor MIin patientsassignedrule-out
malities, impaired myocardial perfusion detected by contrast
exceeded 98% in several large validation cohorts. 3034,36,39,5155
echocardiography or reduced regional function using strain and
Used in conjunction with clinical and ECG ndings, the strain
0 h/1 h rate imaging might improve the diagnostic and prognostic
algorithm may allow the identication of candidates for va-early dis-
charge and outpatient management. The positive predictivelue of conventional
value echocardiography. 60,61 Moreover, echocardiog-
for MI in those patients meeting the rule-in criteria wasraphy
75 can help in detecting alternative pathologies associated
80%.3034,39,5355Mostoftherule-inpatientswithdiagnosesother
with
than MI did have conditions that usually require inpatient
chestpain,suchasacuteaorticdissection,pericardialeffusion,aortic
coronary
angiography for accurate diagnosis, including TakoTsubo valve cardio-
stenosis, hypertrophic cardiomyopathy or right ventricular
myopathy and myocarditis.39,5355 Patients who do notdilatation
qualify forsuggestive of acute pulmonary embolism. Similarly,
rule-out or rule-in represent a heterogeneous group that echo- may re-
quire further investigations if no alternative explanation
cardiography
for the is the diagnostic tool of choice for patients with
car- haemodynamic instability of suspected cardiac origin.62 Evaluation
diac troponin elevation is identied. A large proportionof ofleft
theseventricular (LV) systolic function, at the latest by the time
patients may require a further high-sensitivity cardiacoftroponin
hospitalas- discharge, is important to estimate prognosis, and
sessment (e.g. at 3 h). Coronary angiography should echo-be
considered cardiography (as well as other imaging modalities) can provide
in patients for whom there is a high degree of clinicalthis
suspicion of
NSTE-ACS, while in patients with low to intermediate information.
likelihood
for this condition, computed tomography (CT) coronaryInpatientswithout
angiog- ischaemicchangeson12-leadECGsandnega-
raphy should be considered. No further diagnostic testingtive cardiac
in the troponins (preferably high-sensitivity) who are free of
emergency department is indicated when alternativechestpain
conditionsfor severalhours, stressimaging can be performed
such as rapid ventricular rate response to atrial brillation
during or hyper-
tensive emergency have been identied. admissionorshortlyafterdischarge.Stressimagingispreferredover
For rapid rule-out, two alternative approaches to theexercise
0 h/1 h ECG due to its greater diagnostic accuracy. 63 Various
or 0 h/3 h algorithms have been adequately validatedstud- and may be
considered.First,a2 hrule-outprotocolcombiningtheThromboly-
ies have shown that normal exercise, dobutamine or dipyridamole
sis in Myocardial Infarction (TIMI) risk score with ECG stress
and high- echocardiograms havehighnegativepredictivevaluefor
sensitivity cardiac troponin at presentation allowed a ischae-
safe rule-out
in up to 40% of patients.5658 Second, a dual-marker strategy
mia andcom- are associated with excellent patient outcomes. 64,65 More-
bining normal levels of cardiac troponin together withover,low levels
stressof echocardiography demonstrated superior prognostic
copeptin (,10 pmol/L) at presentation showed very high valuenegative
over exercise ECG.64,66 The addition of contrast may
predictive value for MI, obviating the need for serial testing
improve in se-
lected patients.4450 When using any algorithm, three mainendocardial
caveatsborder detection, which may facilitate detection of
apply:(i)algorithmsshouldonlybeusedinconjunctionwithallavail-
ischaemia.67
able clinical information, including detailed assessment Cardiac
of chest magnetic resonance (CMR) can assess both perfusion
pain and wall motion abnormalities, and patients presenting with acute
characteristics and ECG; (ii) in patients presenting verychest
early pain
(e.g.
with a normal stress CMR have an excellent short- and
within 1 h from chest pain onset), the second cardiacmidterm
troponin prognosis.68 CMR also permits detection of scar tissue
level (using late gadolinium enhancement) and can differentiate this
should be obtained at 3 h, due to the time dependency fromrecentinfarction(usingT2-weightedimagingtodelineatemyo-
of troponin
release; (iii) as late increases in cardiac troponin havecardial
been de- oedema).69,70 Moreover, CMR can facilitate the differential
scribed in 1% of patients, serial cardiac troponin testing
diagnosis
should between infarction and myocarditis or TakoTsubo car-
bepursuediftheclinicalsuspicionremainshighorwheneverthepa-
diomyopathy.71 Similarly, nuclear myocardial perfusion imaging
tient develops recurrent chest pain.52,54 High-sensitivity
hascardiac
troponin assays also maintain high diagnostic accuracy beenin patients
shown to be useful for risk stratication of patients with acute
with renal dysfunction. To ensure the best possible clinical
chest use,pain suggestive for ACS. Resting myocardial scintigraphy, by
assay-specic optimal cut-off levels, which are higher in detecting
patientsxed perfusion defects suggestive of myocardial necrosis,
with renal dysfunction, should be used.59 can be helpful for initial triage of patients presenting with chest
pain
without ECG changes or elevated cardiac troponins. 72 Combined
3.3.4 Non-invasive imaging stressrest imaging may further enhance assessment of ischaemia,
3.3.4.1 Functional evaluation while a normal study is associated with excellent outcome. 73,74
Stressrest
Transthoracic echocardiography should be routinely available inimaging modalities are usually not widely available on
24
emergency rooms and chest pain units and performed/interpretedh service.
by trained physicians in all patients during hospitalization for
3.3.4.2 Anatomical evaluation
Multidetector computed tomography (MDCT) allows for visualiza-
tion of the coronary arteries and a normal scan excludes CAD. A
meta-analysisofninestudies(n 1349patients)hasreportedover-
all high negative predictive values to exclude ACS (by excluding
CAD) and excellent outcome in patients presenting to the emer-
gency department with low to intermediate pre-test probability
for ACS and a normal coronary CT angiogram.75 Four randomized
controlled trials (RCTs) have tested MDCT (n 1869 patients) vs.
 278 ESC Guidelines

usual care (n 1397) in the triage of low- to intermediate-risk

and coronary pa- artery spasm are briey described in section 5.6.4.2,
tients presenting with acute chest pain to emergency departments
Web addenda. Stroke may be accompanied by ECG changes, myo-
without signs of ischaemia on ECG and/or inconclusivecardial cardiacwall tro-motion abnormalities and an increase in cardiac
ponins.7679 At a follow-up of 16 months, there were no troponin
deaths,
and a meta-analysis demonstrated comparable outcomes with
levels. the majority of patients presenting with acute chest pain
2,6 The
two approaches (i.e. no difference in the incidence of MI, to post-
discharge emergency department visits or rehospitalizations) and
the emergency department have non-cardiac conditions causing
showedthatMDCTwasassociatedwithareductioninemergencyde- the
partment costs and length of stay.80 However, none of chest thesediscomfort.
studies In many instances the pain is musculoskeletal,
used high-sensitivity cardiac troponin assays, which also and may
reduce therefore benign, self-limiting and does not require hospitalization.
hospital stay. It was also noted that MDCT was associated Chest with
pain ancharacteristics help to some extent in the early
in- identica-
crease in the use of invasive angiography {8.4% vs. 6.3%; tion ofodds
those patients.24
ratio
[OR] 1.36 [95% condence interval (CI) 1.03, 1.80], P 0.030}. 80 Ac-
cordingly, MDCT coronary angiography canbe used to exclude CAD
(and MDCT is thus not useful in patients with known CAD). Other
factors limiting MDCT coronary angiography include severe calcica-
tions (high calcium score) and elevated or irregular heart rate; in
4.Risk assessment and outcomes
add-
4.1Clinical
ition, a sufcient level of expertise is needed and 24 h service is presentation,
currentlynotwidelyavailable.Finally,theuseofMDCTcoronaryangi-
electrocardiogram and biomarkers
ography in the acute setting in patients with stents or previous
4.1.1 Clinical presentation
CABG
In addition to some universal clinical markers of risk, such as ad-
hasnotbeenvalidated.Importantly,CTimagingcaneffectivelyexclude
vanced age, diabetes and renal insufciency, the initial clinical
other causes of acute chest pain that, if untreated, are associated
pres-
with
entation is highly predictive of early prognosis. 82 Chest pain at rest
highmortality,namelypulmonaryembolism,aorticdissectionandten-
carries a worse prognosis than symptoms elicited during physical
sion pneumothorax.81
exertion. In patients with intermittent symptoms, an increasing
numberof episodes preceding the indexeventalso adverselyaffects
prognosis. Tachycardia, hypotension, heart failure and new mitral
3.4Differential diagnosis regurgitation at presentation predict poor prognosis and call for
Among unselected patients presenting with acute chest ra-pain to the
emergency department, disease prevalence can be expected pid diagnosis
to be and management.25,8284
the following: 510% STEMI, 1520% NSTEMI, 10% unstable an-
gina, 15% other cardiac conditions and 50% non-cardiac dis-
eases.48,51,52,5658 Several cardiac and non-cardiac conditions may
4.1.2 Electrocardiogram
mimic NSTE-ACS (Table 6). The initial ECG is predictive of early risk.18 Patients with ST depres-
Conditions that should always be considered in the differential
sion have a worse prognosis than patients with a normal ECG. 85,86
diagnosis of NSTE-ACS, because they are potentially life- The number of leads showing ST depression and the magnitude of
threatening but also treatable, include aortic dissection, pulmonary
STdepressionareindicativeoftheextentofischaemiaandcorrelate
embolism and tension pneumothorax. Echocardiography withshould
prognosisbe on the one hand, and benet from an invasive treat-
performed urgently in all patients with haemodynamicment instability
strategy of on the other.87 ST depression e0.05 mV in two or
suspected cardiovascular (CV) origin.62 more contiguous leads, in the appropriate clinical context, is sug-
ChestX-ray is recommendedinall patients in whom NSTE-ACSis gestive of NSTE-ACS and linked to adverse prognosis. 85 ST depres-
consideredunlikelyinordertodetectpneumonia,pneumothorax,rib sion combined with transient ST elevation identies a high-risk
fractures or other thoracic disorders. TakoTsubo cardiomyopathy
subgroup,88 while associated T-wave inversion does not alter the
Table 6 Differential diagnoses of acute coronary syndromes prognosticin the setting
value of depression.
of ST acute chestWhile
pain isolated T-wave inversion
on admission has not been associated with worse prognosis com-
Cardiac Pulmonary Vascular pared with the absence
Gastro-intestinal of ECG abnormalities,
Orthopaedic Other it frequently
Myopericarditis triggers
Pulmonary embolism Aortic dissection Oesophagitis, reflus or spasm Musculoskeletal disorders Anxiety
Cardiomyopathiesa disorders
a more rapid diagnosis and treatment.86
Tachyarrhythmias Peptic ulcer, gastritis Chest trauma Herpes zoster
(Tension)-Pneumothorax
Symptomatic Pancreatitis
aortic aneurysm Peptic ulcer, gastritis Chest trauma Herpes zoster
Acute heart failure
Bronchitis, pneumonia Anaemia Anaemia
Hypertensive
Pleuritis
Stroke Pancreatitis Cholecystitis Cholecystitis
Costochondritis Costochondritis
emergencies
Cervical spine pathologies
Cervical spine pathologies
Aortic valve stenosis
Tako-Tsubo
cardiomyopathy
Coronary spasm
Cardiac trauma

Bold common and/or important differential diagnoses.

aDilated, hypertrophic and restrictive cardiomyopathies may cause angina or chest
discomfort.
ESC Guidelines 279

4.1.3 Biomarkers out. The greatest challenge is the integration of clinical

Beyond diagnostic utility, cardiac troponin levels addpresentation
prognostic in-
formation in terms of short- and long-term mortality to withinformationderivedfromECG,
clinical and troponin assessmentandimaging
ECG variables. While high-sensitivity cardiac troponinmodalities
T and I seeminto a standardised management strategy. 97
to have comparable diagnostic accuracy, high-sensitivityAssessment
cardiac of
troponin T has greater prognostic accuracy. 89,90 The higher
acuterisk
the guides initial evaluation,selection of thesite ofcare(i.e.
high-sensitivity troponin levels at presentation, the greater
cor- the risk
of death.6,8,10,39 Multiple biomarkers have been associated
onary with
or intensive care unit, intermediate care unit, inpatient
mortality in NSTE-ACS, several of them conferring additive
moni-
prognostic value to cardiac troponin. 8,4850 Serum creatinine
tored unit
andor regular unit) and therapy, including antithrombotic
estimated glomerular ltration rate (eGFR) should alsotreatment
be deter- and timing of coronary angiography. Risk is highest at
mined in all patients with NSTE-ACS because they affect the prognosis
and are key elements of the Global Registry of Acute timeCoronary
of presentation and may remain elevated for several days, al-
Events (GRACE 2.0) risk calculation (see section 4.2).though
The exten-
rapidly declining over time, depending on clinical
sively validated natriuretic peptides (i.e. B-type natriuretic
presentation,
peptide,
N-terminal pro-B-type natriuretic peptide and midregional
comorbidities, coronary anatomy and revascularization. 98 The esti-
pro-A-type natriuretic peptide) provide prognostic information
mated risk onshould be communicated to the patient and their
topof cardiac troponin.91Tosome extent,the sameappliestohigh-
family.
sensitivity C-reactive protein and novel biomarkers such as midre-
gional pro-adrenomedullin, growth differentiation factor 15 and
copeptin. However, the assessment of these markers4.2.2 has so far notrhythm monitoring
Cardiac
been shown to improve patient management and their added value
Early revascularization as well as the use of antithrombotic agents
in risk assessment on top of the GRACE 2.0 risk calculation seems
and beta-blockers have markedly reduced the incidence of life-
marginal.Thereforetheroutineuseofthesebiomarkersforprognos-
threatening arrhythmias in the acute phase to ,3%, with most of
tic purposes cannot be recommended at the present the time.arrhythmic events occurring within 12 h of symptom on-
set.99,100 Patients with life-threatening arrhythmias more
4.2Ischaemic risk assessment frequently
hadpriorheart failure,LVejection fraction(LVEF) ,30%andtriple-
InNSTE-ACS,quantitativeassessmentofischaemic riskbymeansof
scores is superior to the clinical assessment alone. The vessel
GRACECAD. riskA patient with NSTE-ACS who presents early after
symptom
score provides the most accurate stratication of risk both on ad- onset, has no or mild to moderate cardiac biomarker ele-
vation, normal
mission and at discharge.92,93 The GRACE 2.0 risk calculator (http:// LV function and single-vessel CAD successfully trea-
tedwithPCImaybedischargedthenextday.Attheotherendofthe
www.gracescore.org/WebSite/default.aspx?ReturnUrl=%2f) pro-
vides a direct estimation, bypassing the calculation ofspectrum
a score, areof NSTE-ACS patients with multivessel CAD in whom
mortality while in hospital, at 6 months, at 1 year andcomplete
at 3 years. revascularization may not be achieved in one session
(or at all);
The combined risk of death or MI at 1 year is also provided. 94 these patients may have a complicated course (e.g.
heart
VariablesusedintheGRACE2.0riskcalculationincludeage,systolic
failure)
blood pressure, pulse rate, serum creatinine, Killip class at or prior cardiac disease, major comorbidities, advanced
presenta- age
or recent extensive myocardial necrosis.101,102 Cardiac troponin-
tion,cardiacarrestatadmission,elevatedcardiacbiomarkersandST
deviation. If the Killip class or serum creatinine valuesnegative
are not (i.e.
avail- unstable angina) patients without
recurrentorongoing
able, a modied score can be calculated by adding renal failure and
use of diuretics, respectively. The TIMI risk score usessymptoms
seven vari- and with normal ECG do not necessarily require rhythm
monitoring
ables in an additive scoring system: age e65 years, three or more or hospital admission.
NSTEMI
CAD risk factors, known CAD, aspirin use in the past 7 days, severe patients at low risk for cardiac arrhythmias require
angina(twoormoreepisodeswithin24 h),STchange e0.5rhythm mmand monitoring for d24 h or until coronary revascularization
(whichever comes rst) in an intermediate or coronary care unit,
positive cardiac marker (http://www.timi.org/index.php?page=
while individuals
calculators).82 It is simple to use,but its discriminativeaccuracy is in- at intermediate to high risk for cardiac
ferior to that of the GRACE risk score and the GRACE arrhythmia Table
2.0 risk cal- 7 Recommended unit and duration of cardiac
culation. While the value of risk scores as prognostic may require
rhythmrhythm
assessment monitoringmonitoring for .24
according h in an presentation
to clinical intensive or
coronary
tools is undisputed, the impact of risk score implementation oncare
after unit or in NSTE-ACS
established
pa- an intermediatediagnosiscare unit, depending on
tient outcomes has not been adequately investigated. the clinical presentation, degree of revascularization and early
95,96
post-revascularizationcourse(Table7).Itisrecommendedthatper-
Clinical Presentation Unit
sonnel adequately equipped and trainedRhythm
monitoring
to manage life-
threatening
Unstable angina Regular ward or discharge None
4.2.1 Acute risk assessment NSTEMI at low risk for cardiac
PatientswithsuspectedNSTE-ACSmustbeevaluatedrapidlyinorder arrhythmiasa Intermediate care unit
or coronary care unit d24 h
to identify individuals with ongoing myocardial ischaemia who are at intermediate to high
NSTEMI
at risk for cardiac arrhythmias b Intensive/coronary care units or
intermediate care unit >24 h
risk of life-threatening arrhythmias and need close surveillance as
well as immediate coronary angiography. Patients with suspected
NSTE-ACSshouldbeobservedininterdisciplinaryemergencydepart-
mentsorchestpainunitsuntilthediagnosisofMIisconrmedorruled NSTEMI Non-ST-elevation myocardial infarction.
aIf none of the following criteria: haemodynamically unstable, major
arrhythmias,
left ventricular ejection fraction ,40%, failed reperfusion, additional critical
coronary stenoses of major vessels or complications related to
percutaneous
revascularization.
bIf one or more of the above criteria are present.
 280 ESC Guidelines

arrhythmias and cardiac arrest accompany patients who are trans-

coronaryangiography,withCRUSADEfoundtobethemostdiscrim-
ferred between facilities during the time window in which they 107
inatory. re-However, in patients medically treated oron oral
quire continuous rhythm monitoring. anticoa-
gulants, the predictive value of these scores is not established.
4.2.3 Long-term risk Moreover, the impact on patient outcomes of integrating these
scores has not been investigated. Given these limitations, use of
In additiontoshort-termrisk factors,a numberofconditionsareas-
sociated with long-term risk, including acomplicatedclinicalthe course,
LV systolic dysfunction, atrial brillation, severity of CAD,CRUSADE
revascu- bleeding risk score may be considered in patients
under-
larizationstatus,evidenceofresidualischaemiaonnon-invasivetest-
ing and non-cardiac comorbidities. At 1 year, the rates of going coronary
death, MI angiography to quantify bleeding risk.
and recurrent ACS in contemporary NSTE-ACS registries are
.10%.Whileearlyeventsarerelatedtorupturedcoronaryplaques 4.4Recommendations for diagnosis,
and associated thrombosis, the majority of later events may be the
result of coronary and systemic atherosclerosis progression.risk98,103
stratication, imaging and rhythm
monitoring in patients with suspected
non-ST-elevation acute coronary
4.3Bleeding risk assessment syndromes
Major bleeding events are associated with increased mortality in
NSTE-ACS.104,105 Bleeding risk scores have been developed
from registry or trial cohorts in the setting of ACS and PCI.
TheCanRapidriskstratication ofUnstableangina patients SuppressRecommendations for diagnosis, risk stratication,
ADverse outcomes with Early implementation of the ACC/ imaging and rhythm monitoring in patients with
AHA guidelines (CRUSADE) bleeding risk score (http://www. suspected non-ST-elevation acute coronary
crusadebleedingscore.org) was developed from a cohort syndromesof 71277
NSTE-ACSpatients (derivation cohort) and further validated in a co-
hort of 17857 patients (validation cohort) from the same registry. 106
The CRUSADE bleeding risk score considered baseline patient char-
Recommendations Class28,
a Level b Ref.c
acteristics(i.e.femalegender,historyofdiabetes,historyofperipheral 109 I A
vasculardiseaseorstroke), admissionclinicalvariables (i.e. Diagnosis
heart rate, and risk stratication 112
systolic blood pressure, signs of heart failure) and admission labora-
It is recommended to base diagnosis
tory values (i.e. haematocrit, calculated creatinine clearance)and initial short-term ischaemic and
to esti-
mate the patients likelihood of an in-hospital major bleeding bleeding
event. risk stratication on a
It is recommended
combination to obtain a 12-lead
of clinical history,
However, model performance for the risk score was modest ECG within 10 min after rst medical
(C-statistic 0.68 inpatientstreated conservativelyand0.73symptoms,
inpatients
contact
vital signs, other physical
ndings, ECG and
and to have it immediately
laboratory results.
undergoing invasive approach). interpreted by an experienced I B 28
The Acute Catheterization and Urgent Intervention Triage strat- physician. It is recommended to obtain
egY (ACUITY) bleedingriskscorewasderived from a pooled cohort an additional 12-lead ECG in case of
of 17421 patients with ACS (both NSTE-ACS and STEMI) recruited recurrent symptoms or diagnostic
inthe ACUITYand Harmonizing OutcomeswithRevasculariZatiON uncertainty.
and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Additional ECG leads (V3R, V4R,
trials.104 Six independent baseline predictors (i.e. female gender, V7V9) are recommended if
ongoing I C
advanced age, elevated serum creatinine, white blood cell count,
anaemia and presentation as NSTEMI or STEMI) and one treat- ischaemia is suspected when
standard
ment-related variable [use of unfractionated heparin (UFH) and leads
a are inconclusive. 6,30
glycoprotein IIb/IIIa (GPIIb/IIIa)inhibitor rather thanbivalirudin Italone]
is recommendedto measure36, cardiac
troponins with sensitive or 39,
wereidentied.Thisriskscoreidentiedpatientsatincreasedriskfor I A
high-sensitivity assays and obtain the
5159,
non-CABG-related major bleeds at 30 days and subsequent 1results year within 60 min.
mortality. However, it has not been validated in an independent co- 108
hort,noriskcalculatorisavailableandmodelperformancefortherisk A rapid rule-out protocol at 0 h and
6,
3 h is recommended if high-sensitivity
score is modest (C-statistic 0.74). Changes in interventional practice,
cardiac troponin tests are 3036,available. I B
such as increasing use of radial access, reduction in the dose of UFH, 39,
use of bivalirudin, diminished use of GPIIb/IIIa inhibitors and adminis- 5159,
tration of more effective inhibitors of the platelet adenosine diphos- 108
phate (ADP) receptor P2Y12 (P2Y12 inhibitors), may all modify Arapidrule-outandrule-inprotocolat
the
predictive value of risk scores. Ischaemic and bleeding risks need 0 h and to 1 h is recommended if a
high-sensitivity cardiac troponin test
be weighed in the individual patient, although many of the predictors
with a validated 0 h/1 h algorithm
3034, is
of ischaemic events are also associated with bleeding complica- available. Additional testing after 36 h
tions.104,106 Overall,CRUSADEand ACUITY scoreshave reasonable 36,
is indicated if the rst two troponin I B
predictive value for major bleeding in ACS patients undergoing 39,
measurements are not conclusive and
5155
theclinicalconditionisstillsuggestiveof
ACS.

It is recommended to use established

risk scores for prognosis estimation. I B 84,94,
106
ESC Guidelines 281

TheuseoftheCRUSADEscorem
aybe
5.Treatment
IIb B 106,
considered in patients
107
undergoing 5.1Pharmacological treatment of
coronary angiography to
Imaging
quantify ischaemia
In patients
bleeding with no recurrence of
risk. 5.1.1 General supportive measures
chest pain, normal ECG ndings and The goal of pharmacological anti-ischaemic therapy is to decrease
normal levels of cardiac troponin myocardial oxygen demand (secondary to a decrease in heart rate,
(preferably high-sensitivity), but
64,74, blood pressure, preload or myocardial contractility) or to increase
suspected ACS, a non-invasive stress
I A 113, myocardial oxygen supply (by administration of oxygen or through
test (preferably with imaging) for
114 coronary vasodilation). If, following treatment, the patient does not
inducible ischaemia is recommended
before deciding on an invasive rapidly become free of ischaemic signs or symptoms, immediate
strategy. cor-
onary angiography is recommended independently of ECG ndings
Echocardiography is
andcardiactroponinlevels.WhiledatainNSTE-ACSarelacking,aran-
recommended to I domized comparison of oxygen vs. air administration in 441
C
evaluate regional and global LV normox-
function and to rule in or rule out aemic patients with STEMI showed no benet and possibly harm
differential diagnoses.d associated with oxygen administration. Oxygen should be adminis-
MDCT coronary angiography should tered when blood oxygen saturation is ,90% or if the patient is in
be considered as an alternative to re-
invasive angiography to exclude ACS spiratory distress.115 In patients whose ischaemic symptoms are not
IIa A 80
when there is a low to intermediate relieved by nitrates and beta-blockers, opiate administration is
likelihood of CAD and when cardiac
reason-
troponin and/or ECG are
inconclusive. ablewhilewaitingforimmediatecoronaryangiography,withthecaveat
Monitoring
thatmorphinemayslowintestinalabsorptionoforalplateletinhibitors.
Continuous rhythm monitoring
is
recommended untilI theC 101 5.1.2 Nitrates
diagnosis
Intravenous nitrates are more effective than sublingual nitrates
of NSTEMI is established or
ruled
with
out.
It is recommended to admit NSTEMI
regard to symptom relief and regression of ST depression. Under
patients to a monitored unit. I C 99,100 careful blood pressure monitoring, the dose should be titrated up-
wardsuntilsymptomsarerelieved,andinhypertensivepatientsuntil
Rhythm monitoringIIaup to
blood pressure is normalized, unless side effects (notably headache
C 24 h or PCI
(whichever comes rst) should be or hypotension) occur. Beyond symptom control, there is no indi-
considered in NSTEMI patients at low cation for nitrate treatment.116 In patients with recent intake of a
risk for cardiac arrhythmias.e phosphodiesterase type 5 inhibitor (i.e. within 24 h for sildenal
Rhythm monitoring for .24 h should or vardenal and 48 h for tadalal), nitrates should not be adminis-
IIa C patients at
be considered in NSTEMI tered due to the risk of severe hypotension.117
intermediate to high-risk for cardiac
arrhythmias.f
5.1.3 Beta-blockers
Intheabsenceofsignsorsymptomsof
Beta-blockers competitively inhibit the myocardial effects of circu-
ongoing ischaemia, rhythm monitoring
in unstable angina may be considered lating catecholamines and reduce myocardial oxygen consumption
IIbof C
in selected patients (e.g. suspicion by lowering heart rate, blood pressure and myocardial contractility.
coronary spasm or associated The evidence for the benecial effects of beta-blockers in
symptoms suggestive of arrhythmic NSTE-ACS is derived from a meta-analysis of 27 earlystudiesshow-
events). ing that beta-blocker treatment was associated with a signicant
13% relative risk reduction (RRR) of mortality in the rst week fol-
ACS acute coronary syndromes; CAD coronary artery disease; lowingMI.
ECG 118Inaddition,alatermeta-analysiscomprising73396pa-
electrocardiogram; LV left ventricular; MDCT multidetector tients with ACS showed an 8% RRR (P 0.04) for in-hospital
computed
tomography; NSTEMI non-ST-elevation myocardial infarction;mortality
PCI associated with beta-blockade, with no increase in cardio-
percutaneous coronary intervention. 0 h time of rst blood test; 1 h, 3 h
1
genic shock. 119 A registry study of 21 822 NSTEMI patients found
or 3 h after the rst blood test. that in patients at risk of developing cardiogenic shock (i.e. age
aClass of recommendation. .70 years, heart rate .110 beats/min, systolic blood pressure
bLevel of evidence.
,120 mmHg) the observed shock or death ratewas signicantly in-
cReferences supporting level of evidence.
creased in patients receiving beta-blockers within 24 h of hospital
dDoes not apply to patients discharged the same day in whom NSTEMI has
been admission.120 Therefore early administration of beta-blockers
ruled out. should be avoided in these patients if the ventricular function is un-
eIf none of the following criteria: haemodynamically unstable, major
known. Beta-blockers should not be administered in patients with
arrhythmias,
symptoms possibly related to coronary vasospasm or cocaine use,
left ventricular ejection fraction ,40%, failed reperfusion, additional critical
coronary stenoses of major vessels or complications related toas they might favour spasm by leaving alpha-mediated
percutaneous vasoconstric-
revascularization. tion unopposed by beta-mediated vasodilation.
f If one or more of the above criteria are present.
 282 ESC Guidelines

5.1.4 Other drug classes (see Web addenda) cytochromeP450(CYP)systemtogenerateanactivemetabolite(Ta-

5.1.5 Recommendations for anti-ischaemic drugs inblethe8). An estimated 85% of the prodrug is hydrolysed by esterases
acutephaseofnon-ST-elevationacutecoronarysyndromes into an inactive form, leaving only 15% of clopidogrel available for
transformation to the active metabolite, which selectively and irre-
versibly inactivates platelet P2Y12 receptors and thus inhibits
ADP-induced platelet aggregation.135,136 Dual antiplatelet therapy
Recommendations for anti-ischaemic drugs in the
(DAPT)comprisingaspirinandclopidogrelhasbeenshowntoreduce
acute phase of non-ST-elevation acute coronary
recurrent ischaemic events in the NSTE-ACS setting compared with
syndromes
aspirin alone.137,138 However, up to 10% of patients treated with the
combinationofaspirinandclopidogrelwillhavearecurrentischaemic
event in the rst yearafter anACS, with a rate ofstent thrombosis of
Recommendations Classa Levelb Ref.c up to 2%.139 This residual risk may be partly explained by suboptimal
platelet inhibition due to inadequate response to clopidogrel. Indeed,
I B 119
Early initiation of beta-blocker pharmacodynamic and pharmacokinetic studies have described sub-
treatment is recommended in patients stantial interindividual variability in the antiplatelet response to this
with ongoingischaemicsymptoms and drug and an increased risk of ischaemic and bleeding events in clopi-
without contraindications. dogrelhypo-andhyper-responders,respectively. 140143Thereisevi-
It is recommended to continue
I B 126
chronic beta-blocker therapy, unless dence that key gene polymorphisms are involved in both the
thepatientisinKillipclassIIIorhigher. variability of active metabolite generation and clinical efcacy of clo-
Sublingual or i.v. nitrates are pidogrel.144147
recommended to relieve angina;d i.v.
treatment is recommended
I C in patients
with recurrent angina, uncontrolled
hypertension or signs of heart failure. 5.2.2.2 Prasugrel
Prasugrel(60 mgloadingand10 mg/daymaintenancedose)isa pro-
drug that irreversibly blocks platelet P2Y12 receptors with a faster
In patients with suspected/conrmed
IIa B 127 onset and a more profound inhibitory effect than clopidogrel
vasospastic angina, calcium channel (Table 8). This compound has been tested against the 300 mg load-
blockers and nitrates should be
ing and 75 mg/day maintenance dose of clopidogrel in the TRial to
consideredandbeta-blockersavoided.
Assess Improvement in Therapeutic Outcomes by Optimizing
i.v. intravenous.
Platelet InhibitioN with PrasugrelThrombolysis In Myocardial
aClass of recommendation. Infarction (TRITON-TIMI 38), in which ACS patients (STEMI and
bLevel of evidence. NSTE-ACS) scheduled for PCI received the drugs during or after
cReferences supporting level of evidence.
theprocedure.148Inthe10074NSTE-ACSpatientsincluded,recur-
dShould not be administered in patients with recent intake of sildenal or
vardenal (,24 h) or tadalal (,48 h). rent CV events were reduced in prasugrel-treated patients at the
15-month follow-up [from 11.2% to 9.3%; relative risk (RR) 0.82
(95% CI 0.73, 0.93), P 0.002], driven by a signicant reduction
5.2Platelet inhibition in MI [from 9.2% to 7.1%; RRR 23.9% (95% CI 12.7, 33.7), P ,
5.2.1 Aspirin 0.001]. Severe bleeding complications were more common with
Aspirin(acetylsalicylicacid)irreversiblyinactivatesthecyclooxygen-
prasugrel[TIMI non-CABG major bleeds 2.4% vs. 1.8%; hazard ratio
ase (COX) activity of platelet prostaglandin endoperoxide (PGH)
(HR) 1.40(95%CI 1.05,1.88), P 0.02], dueto an increasein spon-
synthase 1 (COX-1), thereby suppressing thromboxane A2 pro-
taneous bleeds [1.6% vs. 1.1%; HR 1.51 (95% CI 1.09, 2.08), P
duction throughout the platelet lifespan. 128 Aspirin has 0.01] been
and fatal bleeds [0.4% vs. 0.1%; HR 4.19 (95% CI 1.58,
shown to be effective in patients with unstable angina; 11.11),thePincidence
0.002].149 Bleeding events were increased by more
of MI or death was consistently reduced in four RCTs in the
than four-fold in prasugrel-treated patients referred for early
pre-PCI era.129132 A meta-analysis of these trials suggests CABG. thatBasedon the markedreduction in denite orprobable stent
aspirin administration (up to 2 years) is associated thrombosis with a highly sig-
observedintheTRITON-TIMI 38overall[1.13%inthe
nicant 46% odds reduction in major vascular events. 133 The Clopi-
prasugrel arm vs. 2.35% in the clopidogrel arm; HR 0.48 (95% CI
dogrel and Aspirin Optimal Dose Usage to Reduce Recurrent 0.36, 0.64), P , 0.0001] and in patients with drug-eluting stents
EventsSeventhOrganizationtoAssessStrategiesinIschaemicSyn- (DESs) [0.84% vs. 2.31%, respectively; HR 0.36 (95% CI 0.22,
dromes (CURRENT-OASIS 7), which enrolled 25 0860.58), ACS (both
P , 0.0001], prasugrel should be considered in patients
NSTE-ACS and STEMI) patients undergoing invasivewho strategy,
present found
with stent thrombosis despite compliance with clo-
no difference between higher-dose (300325 mg/day) and lower-
pidogrel therapy.150,151 Prasugrel is contraindicated in patients
dose (75100 mg/day) aspirin.134 An oral loading dose with(150prior stroke/transient ischaemic attack (TIA) due to evidence
300 mg) of plain aspirin (non-enteric-coated formulation) is recom-
of net harm in this group in TRITON-TIMI 38. In addition, the
mended, while the recommended intravenous (i.v.)study dose is 150 mg.
showed no apparent benet in patients .75 years of age
No monitoring of its effects is required. The mechanisms or withoflow action
bodyweight (,60 kg).148 The Targeted Platelet Inhib-
of antiplatelet and anticoagulant agents are described itionintoFigure
Clarify4.the Optimal Strategy to Medically Manage Acute
Coronary Syndromes (TRILOGY ACS) trial is discussed in section
5.6.4.1.1.
5.2.2 P2Y12 inhibitors
5.2.2.1 Clopidogrel
Clopidogrel (300600 mg loading and 75 mg/day maintenance dose)
is an inactive prodrug that requires oxidation by the hepatic
 ESC Guidelines 283

ADP = adenosine diphosphate; AT = antithrombin; GP = glycoprotein; LMWH = low molecular weight heparin; Tx = thromboxane;
UFH = Unfractionated heparin. Vorapaxar is a protease-activated receptor 1 (PAR1) blocker.

Figure 4 Antithrombotic drugs for non-ST-elevation acute coronary syndromes. The gure depicts the targets of available antithrombotic
drugs that can be used to inhibit blood coagulation and platelet aggregation during and after thrombus formation.

5.2.2.3 Ticagrelor drugs metabolized through CYP3A, such as simvastatin, while mod-
Ticagrelorisanoral,reversiblybindingP2Y12inhibitorwithaplasma
erateCYP3Ainhibitors,suchasdiltiazem,increaseticagrelorplasma
half-life of 612 h. Ticagrelor also inhibits adenosine reuptake
levels and might delay the offset of effect. In the PLATelet inhibition
via and patient Outcomes (PLATO) trial, 18 624 patients with
equilabrative nucleosidetransporter 1 (ENT1) (Table8). moderate- to high-risk NSTE-ACS (planned for either conservative
Likeprasu- or invasive management) or STEMI were randomized to either clo-
grel, ticagrelorhas amorerapidandconsistent onset ofaction
pidogrel 75 mg/day, with a loading dose of 300600 mg, or
com-
pared with clopidogrel, as well as a faster offset of action with
more
rapid recovery of platelet function.152 Ticagrelor increases
levels of
 284 ESC Guidelines

Table 8 P2Y12 inhibitors

Clopidogrel Prasugrel Ticagrelor Cangrelor

Chemical class Thienopyridine Thienopyridine Cyclopentyl-triazolopyrimidine Stabilized ATP
Administration Oral analogue
Oral Oral Intravenous
60 mg orally then
Dose 300600 mg orally 10 mg a day 180
30 g/kg
mg orally
bolus and
then 75 mg a day then
4 g/kg/min infusion
Dosing in CKD 90 mg twice a
" Stage 3 day
(eGFR 3059 mL/min/1.73m2) No dose adjustment
No dose adjustment No dose adjustment No dose adjustment
" Stage 4
(eGFR 1529 mL/min/1.73m2) No dose adjustment
No dose adjustment No dose adjustment No dose adjustment

Use only for selected indications

" Stage 5
(e.g. stent thrombosis prevention) Not recommended Not recommended No dose adjustment
(eGFR <15 mL/min/1.73m 2)
Binding reversibility Irreversible
Irreversible Reversible Reversible
Active drug, with additional
Activation Prodrug, with variable Prodrug, with predictable
active metabolite Active drug
liver metabolism liver metabolism
Onset of loading dose effecta 26 hoursb
30 min b 30 minb 2 min
710 days 35 days 12 hours
Duration of effect 310 days
7 days c 5 daysc 1 hour
Withdrawal before surgery 5 daysc
3060 mine 612 hours 510 min
No Yes Yes (inactive metabolite only)
Plasma half-life of active P2Y12inhibitord 3060 min
Inhibition of adenosine reuptake No

ADP adenosine diphosphate; ATP adenosine triphosphate; CKD chronic kidney disease; eGFR estimated glomerular ltration rate.
a50% inhibition of ADP-induced platelet aggregation.
bOnset of effect may be delayed if intestinal absorption is delayed (e.g. by opiate).
cShortening may be considered if indicated by platelet function tests and low bleeding risk.
dAffecting the response to platelet transfusion.
eThe distribution phase half-life is reported since it most likely reects duration of clinically-relevant plasma levels, while the corresponding elimination phase
half-life is
approximately 7 hours.

ticagrelor 180 mg loading dose followed by 90 mg twice 5.2.2.4 Cangrelor

a day. 153
Patients undergoing PCI were allowed to receive an additional ani.v. adenosinetriphosphate(ATP) analogue that binds
Cangreloris
reversiblyandwithhighafnitytotheplateletP2Y
blinded 300 mg loading dose of clopidogrel (total loading dose 12receptorandhas

600 mg) or its placebo. Treatment was continued fora up short

to 12plasma half-life (,10 min) (Table 8). It produces a highly ef-
months, with a median duration of drug exposure offective9 months.inhibition
153 of ADP-induced platelet aggregation immediately
IntheNSTE-ACSsubgroup(n 11080),theprimarycompositeef-after i.v. bolus administration and allows for restoration of platelet
function
cacy endpoint (death from CV causes, MI or stroke) was signi- within 12 h of infusion discontinuation in NSTE-ACS pa-
tients.
cantly reduced with ticagrelor compared with clopidogrel [10.0% 157 Cangrelor (30 mg/kg bolus and 4 mg/kg/min infusion) in-
itiated
vs. 12.3%; HR 0.83 (95% CI 0.74, 0.93), P 0.0013] with similar at the commencement of PCI has been examined in three
re- clinical trials including a total of 24910 patients: one with clopidogrel
(600 mg)
ductions for CV death [3.7% vs. 4.9%; HR 0.77 (95% CI 0.64, 0.93), given at the beginning of PCI [Cangrelor versus Standard
Therapy
P 0.0070] and all-cause mortality [4.3% vs. 5.8%; HR 0.76 (95% to Achieve Optimal Management of Platelet Inhibition
CI (CHAMPION)-PCI], one with clopidogrel (600 mg) initiated at the
end ofrates
0.64, 0.90), P 0.0020].154 Differences in bleeding event PCI (CHAMPION-PLATFORM), and one with clopidogrel
were (300 or 600 mg) initiated either before or after PCI based on local
also similar in the NSTE-ACS subgroup compared with clinical practice (CHAMPION-PHOENIX) among patients without
the overall
prior P2Y12 or GPIIb/IIIa inhibition.158160 A meta-analysis of these
study, with increased risk of non-CABG-related PLATO-dened
major bleeds with ticagrelor compared with clopidogrel studies,
[4.8% in vs.
which 69% of patients were undergoing PCI for ACS, ob-
3.8%; HR 1.28 (95% CI 1.05, 1.56), P 0.0139] but no difference RRR in periprocedural death, MI, ischaemia-driven re-
served a 19%
vascularization
in life-threatening or fatal bleeds.154 The benets of ticagrelor com- and stent thrombosis [cangrelor 3.8% vs. clopidogrel
4.7%;
pared with clopidogrel in NSTE-ACS were independent of whether OR 0.81 (95% CI 0.71, 0.91), P 0.007], with a 39% RRR in
stent
ornotrevascularizationwasperformedintherst10daysafterran- thrombosis alone [cangrelor 0.5% vs. clopidogrel 0.8%; OR
0.61 (95%
domization.154 The reduction in denite stent thrombosis with tica- CI0.43,0.80),P 0.008].161 ThecombinationofTIMIma-
jor and
grelor in the NSTE-ACS subgroup [1.1% vs. 1.4%; HR 0.71 (95% CI minor bleeds was increased [cangrelor 0.9% vs. clopidogrel
0.43, 1.17] was consistent with that seen in the trial0.6%;
overall OR[1.4%
1.38 (95% CI 1.03, 1.86), P 0.007], but there was no in-
vs. crease in the rate of transfusions. The European Commission issued
1.9%; HR 0.67 (95% CI 0.50, 0.90), P 0.0091].155 In marketing
addition authorization
to for this compound in March 2015.
in-
creasedrates of minoror non-CABG-related major bleeding events
with ticagrelor, adverse effects included dyspnoea (without
bronchospasm), increased frequency of asymptomatic ventricular
pauses and increases in uric acid.153,156
ESC Guidelines 285

5.2.3 Timing of P2Y12 inhibitor administration In patients undergoing elective non-cardiac surgery, ticagrelor
Initiation of P2Y12 inhibitors soon after the diagnosisand
of NSTE-ACS
clopidogrelshould be discontinued 5 days beforesurgery, while
irrespectiveof management strategy has been recommended.
the interval162,163
should be increased to 7 days in patients on prasugrel,
This implies pretreatment, dened as P2Y12 inhibitor unless
administration
the patient is at high risk of stent thrombosis. 179 In the latter
before coronary angiography, in patients scheduledcase, for ana invasive
multidisciplinary decision is required to determine the best
approach.SubsequentlytheresultsoftheonlyRCTonP2Y strategy.
12inhibi- Longer discontinuation times (e.g. 7 days for ticagrelor
tor pretreatment in NSTE-ACS, the Comparison of Prasugrel
and 10 days at thefor clopidogrel or prasugrel) may be appropriate for
Time of Percutaneous Coronary Intervention or as Pretreatment
surgery at extremeat risk of bleeding (e.g. some types of neurosur-
the Time of Diagnosis in Patients with Non-ST Elevationgery).Myocardial
For NSTE-ACS patients, the risk of bleeds related to surgery
Infarction (ACCOAST) trial, were published. 164 The ACCOAST
must be balanced against the risk of recurrent ischaemic events
study compared pretreatment with prasugrel 30 mgrelated and a further
to discontinuation of therapy. The type of surgery, the is-
30 mg dose prior to PCI with a regimen of prasugrelchaemic
60 mg after risk and extent of CAD, the time since the acute episode
diagnostic angiography but prior to PCI among 4033and, patients
for patients
with who have undergone PCI, the time since the pro-
NSTEMI scheduled for early invasive strategy. The median
cedure duration
and the type of stent implanted are key elements of the dis-
ofpretreatmentwas4.3 h.Sixty-ninepercentofthepatientsunder-
cussion. Selected patients who require non-cardiac surgery after
went PCI, 6% required surgical revascularization and recently
the remainder
implanted stents may benet from bridging therapy with
were treated conservatively.164 At 7 days, patients randomized
small molecule to GPIIb/IIIa inhibitors (i.e. tiroban or eptibatide)
thepretreatmentarmexperiencednoreductionintheprimaryend-
after discontinuation of the P2Y12 inhibitor, while cangrelor has so
point (i.e. CV death, recurrent MI, stroke, urgent revascularization
far been tested as bridging therapy to CABG.181,182 In patients on
and bailout use of GPIIb/IIIa inhibitors) [HR 1.02 (95%DAPTCI 0.84,
following an episode of NSTE-ACS that was treated conser-
1.25), P 0.81], and no benets emerged at 30 days. vatively,
164 TIMI the
major
P2Y12 inhibitor may be discontinued. In surgical proce-
bleeds were signicantly increased in the pretreatment duresgroup
withatlow to moderate bleeding risk, surgeons should be
7 days [pretreatment 2.6% vs. no pretreatment 1.4%; encouraged
HR 1.90, to operate on patients on DAPT. Adherence to
(95% CI 1.19, 3.02), P 0.006]. Arguments for andDAPT againstshould be improved through education of patients, relatives
pretreat- and physicians in order to prevent avoidable CV events.
ment with P2Y12 inhibitors in NSTE-ACS patients have been dis-
cussed extensively and the topic remains controversial.165,166 As
the optimal timing of ticagrelor or clopidogrel administration
5.2.6 Durationin of dual antiplatelet therapy
NSTE-ACS patients scheduled for an invasive strategy In patients been
has not with NSTE-ACS, DAPT with aspirin and clopidogrel has
adequately investigated, no recommendation for orbeen againstrecommended for 1 yearoveraspirin alone, irrespectiveof re-
pretreat- vascularizationstrategyandstenttype,accordingtotheClopidogrel
ment with these agents can be formulated. Based on in the ACCOAST
Unstable Angina to Prevent Recurrent Events (CURE) study,
results, pretreatment with prasugrel is not recommended.
while the In TRITON-TIMI 38 and PLATO studies have demonstrated
NSTE-ACS patients planned for conservative management, P2Y12 in-
the superiority of a prasugrel- and ticagrelor-based regimen, re-
hibition (preferably with ticagrelor) is recommended, in the
spectively,overaclopidogrel-basedone.138,148,153A1-yearduration
absence of DAPT with clopidogrel was associated with a 26.9% RRR of
of contraindications, as soon as the diagnosis is conrmed.
death, MI or stroke (8.6% vs. 11.8%; 95% CI 3.9, 44.4; P 0.02)
vs. 1-month DAPT in the Clopidogrel for the Reduction of Events
5.2.4 Monitoring of P2Y12 inhibitors (see Web addenda) During Observation (CREDO) trial, which enrolled 2116 pa-
5.2.5 Premature discontinuation of oral antiplatelet tients.183 The study population comprised patients with stable
therapy CAD and low-risk NSTE-ACS undergoing PCI (each 50%), and no
Withdrawal of oral antiplatelet therapy may lead to interaction
an increased between ACS status and DAPT was observed.
risk Evidence to support the extension of DAPT after DES beyond
of recurrent events, particularly when the recommended 1 yearcourse of
in NSTE-ACS patients is limited (Table 9, see Web addenda).
therapy has not yet been completed.176178 Interruption of DAPT
Table 9 (see Web addenda) Main features of published
soon after stent implantation increases the risk of stent thrombosis,
randomized studies investigating various durations of
especially within the rst month after cessation.178 While
dual discontinu-
antiplatelet therapy following percutaneous coronary
ationof DAPT prior to cardiac surgery is discussed inintervention
sections (PCI)
5.6.6.1 The DAPT trial randomized patients who did not experience ad-
Webaddendaand5.6.6.2,inthecaseofanon-cardiacsurgicalproced-
verse events in the rst year after PCI to an additional 18 months of
ure that cannot be postponed, a minimum of 1 and thienopyridine
3 months DAPT(clopidogrel/prasugrel) or placebo. 184 Continued
for bare-metal stents (BMSs) and new-generation DESs, treatment with thienopyridine, as compared with placebo, reduced
respectively, the rates of stent thrombosis [0.4% vs. 1.4%; HR 0.29 (95% CI 0.17,
mightbeacceptable.179Inthissetting,surgeryshouldbeperformedin
0.48), P , 0.001] and majoradverse cardiovascularand cerebrovas-
hospitals having continuous catheterization laboratory availability,
cularevents [4.3% vs. 5.9%; HR 0.71 (95%CI 0.59, 0.85), P , 0.001].
so The rate of MI was lower with thienopyridine treatment than with
astotreatpatientsimmediatelyincaseofperioperativeMI. 179Ifinter-
placebo (2.1% vs. 4.1%; HR 0.47, P , 0.001). The rate of death from
ruption of DAPT becomes mandatory because of urgent high-risk
any cause was 2.0% in the group that continued thienopyridine
surgery(e.g.neurosurgery)orinthecaseofamajorbleedthatcannot
be controlled by local treatment, no alternative therapy can be pro-
posedasasubstitutetoDAPTtopreventstentthrombosis.Lowmo-
lecularweightheparin(LMWH)hasbeenadvocated,buttheproof of
efcacy for this indication is lacking.180 Whenever possible, aspirin
should be continued because early discontinuation of both
antiplate-
let drugs will further increase the risk of stent thrombosis.
 286 ESC Guidelines

therapyand1.5%in theplacebogroup[HR1.36(95%CI1.00,1.85), appeared consistent among patients receiving and not receiving
P 0.05]. The rate of moderate or severe bleeding was increased
GPIIb/IIIa inhibitors, the efcacy and safety of GPIIb/IIIa inhibitors
with continued thienopyridine treatment [2.5% vs. 1.6%; on HRtop1.61
of these P2Y12 inhibitors have not been prospectively ad-
(95% CI 1.21, 2.16), P 0.001].184 A meta-analysis including
dressed.153,197 In patients treated with prasugrel or ticagrelor,
32 287 patients enrolled in 10 RCTs compared differentGPIIb/IIIa
DAPT inhibitors should be limited to bailout situations or
durations.185 Nearly 50% of the patients had stable CAD. Studies complications during PCI. Dosing in patients with
thrombotic
werestratiedaccordingtotheDAPTdurationinthecontrolgroup impaired renal function is reported in Table 10. Additional
in order to avoid having 12-month DAPT duration included in both
informa-
study arms. As a consequence, it allowed comparison of tionoutcomes
on GPIIb/IIIa inhibitors may be found in sections 5.2.7.1
of either short-term or extended (i.e. beyond 12 months) DAPT while GPIIb/IIIa inhibitor-related thrombocytopenia is
5.2.7.3,
duration vs. 12-month therapy. Compared with 12-month DAPT, in section 5.8.7.1 (all in the Web addenda).
described
a shorter course of treatment was associated with a signicant re-
duction in major bleeds [OR 0.58 (95% CI 0.36, 0.92), P5.2.7.1
0.02], Upstream versus procedural initiation (see Web addenda)
while no statistically signicant differences in ischaemic 5.2.7.2
outcomes Combination with P2Y12 inhibitors (see Web addenda)
or stent thrombosis risks were observed, although a small to mod-
5.2.7.3 Adjunctive anticoagulant therapy (see Web addenda)
erate increase could not be excluded. Extended DAPT, 5.2.8comparedVorapaxar (see Web addenda)
with 12-month treatment, yielded a signicant reduction5.2.9 in MIRecommendations for platelet inhibition in
[OR 0.53 (95% CI 0.42, 0.66), P , 0.001] and stent thrombosis
non-ST-elevation acute coronary syndromes
[OR 0.33 (95% CI 0.21, 0.51), P , 0.001] while more major bleeds
occurred [OR 1.62 (95% CI 1.26, 2.09), P , 0.001]. In addition, all-
causedeathwassignicantlyincreasedintheextendedDAPTgroup
[OR 1.30 (95% CI 1.02, 1.66), P 0.03] while CV death did not dif-
fer among the groups.185 Recommendations for platelet inhibition in non-ST-
The Prevention of Cardiovascular Events in Patients withelevation
Prior acute coronary syndromes
Heart Attack Using Ticagrelor Compared to Placebo on a Back-
ground of Aspirin-Thrombolysis in Myocardial Infarction 54
(PEGASUS-TIMI 54) trial randomized 21162 patients who Recommendations
had had Classa Levelb Ref.c
an MI 13 years earlier to ticagrelor at a dose of 90 mg twice daily,
ticagrelor at a dose of 60 mg twice daily or placebo. 186 AtOral
a median
antiplatelet therapy
follow-up of 33 months, the study demonstrated a reduced rateisofrecommended for all
Aspirin
CV death, MI or stroke with ticagrelor [HR 0.85 (95% CI 0.75,patients without contraindications at
0.96), P 0.008 and HR 0.84 (95% CI 0.74, 0.95), P 0.004 for oral loading dosed of 150
an initial
90 mgand60 mgofticagrelorvs.placebo,respectively)andincreased300 mg (in aspirin-naiveI patients)
A 129 and
a
rates of major bleeding events (2.60% with 90 mg, 2.30% with 60 maintenance dose of 75100 132
mg/
mg daylong-termregardlessoftreatment
and 1.06% with placebo, P , 0.001).186 All-cause mortalitystrategy.
did not
differbetween thegroups.Ofimportance, mostpatientsbegantreat-
137,
ment with ticagrelor after an interruption in DAPT and all hadAprior P2Y12 inhibitor is recommended, in
148, I A
MI (context of secondary prevention in high-risk patients), while addition to aspirin, for 12 months
153
patients with a history of ischaemic stroke were excluded. In unlesstherearecontraindicationssuch
conclu-
sion, while a 1-year duration of DAPT in NSTE-ACS patients is as re-excessive risk of bleeds.
Ticagrelor (180mg loading dose,
commended, based on individual patient ischaemic and bleeding 90 mg twice daily) is recommended,
risk proles, DAPT duration may be shortened (i.e. 36 months) in the absence of contraindications, e
or extended (i.e. up to 30 months) in selected patients if required.for all patients at moderate-to-high
riskofischaemic events(e.g.elevated
5.2.7 Glycoprotein IIb/IIIa inhibitors cardiac troponins), regardless of I B 153
Intravenous GPIIb/IIIa inhibitors block platelet aggregation by initial treatment strategy and
inhibiting brinogen binding to a conformationally activated including those pretreated with
clopidogrel (which should be
form of the GPIIb/IIIa receptor on two adjacent platelets.128 A discontinued when ticagrelor is
meta-analysis of six RCTs involving 29 570 NSTE-ACS patients,started).
mainly medically managed, showed a 9% RRR in death or non-fatal
MI with GPIIb/IIIa inhibitors (10.7% vs. 11.5%, P 0.02) when Prasugrel (60 mg loading dose,
added to heparin.196 The greatest benet was observed in patients 10 mg daily dose)I is B 148,
undergoing PCI while on these agents [10.5% vs. 13.6%; OR 0.74 recommended 164
(95% CI 0.57, 0.96), P 0.02]. The use of GPIIb/IIIa inhibitors in patients who are proceeding
was associated with an increase in major bleeding complications to
Clopidogrel (300600 mg loading
PCI if no contraindication. e
without a signicant increase in intracranial haemorrhage. Many dose, 75 mg daily dose) is
of these trials predated the routine use of P2Y12 inhibitors. While
recommended for Ipatients
B 137 who
the relative efcacy of prasugrel and ticagrelor in the trials cannot receive ticagrelor or
prasugrel or who require oral
anticoagulation.

P2Y12 inhibitor administration for a 187

shorter duration of 36 months afterIIb A 189,
DESimplantationmay beconsideredin 192
patients deemed at high bleeding risk.
ESC Guidelines 287

It is not recommended to Table 10 Dosing of glycoprotein IIb/IIIa inhibitors in

administer III B 164 patients with normal and impaired renal function
prasugrel in patients in whom
coronary
Intravenous antiplatelet therapy Drug Recommendations
anatomy is not known.
GPIIb/IIIa inhibitors during PCI should Normal renal Stage 3 Stage 4 Stage 5
be considered for bailout situations or function or stage CKD CKD CKD
IIa C 12 CKD (eGFR (eGFR (eGFR
thrombotic complications. (eGFR 3059 mL/ 1529 mL/ <15 mL/
e60 mL/ min/1.73m min/1.73m min/1.73m
Cangrelor may be considered in P2Y12 min/1.73m2) 2) 2) 2)

inhibitornaivepatientsundergoingPCI. IIb A 158 No adjustment

161 Bolus of bolus,
180 g/kg reduce Not
It is not recommended to administer i.v., infusion rate recommended Not
GPIIb/IIIainhibitors III A 198,
in patientsinwhom infusion to recommended
coronary anatomy is not known.199 2 1 g/kg/min if
g/kg/min
Bolus 25 eGFR No
g/kg <50 No dose adjustment Not
Long-term P2Y12 inhibition adjustme 2of bolus,
or 10 g/kg mL/min/1.73m recomme
P2Y12 inhibitor administration i.v, nt reduce nded
infusion
Bolus infusion to
in addition to aspirin beyond 1 year 0.15 mg/kg 0.05
may be consideredIIb A careful
after 184, 0.25
org/kg/min
for dose adjustment in the g/kg/min
i.v., case of renal failure.
assessment of the ischaemic 186and Careful evaluation of haemorrhagic risk is needed.
infusion
bleeding risks of the patient. 0.125
g/kg/min
(max.10
General recommendations g/min)
CKD chronickidney disease; eGFR estimatedglomerular ltrationrate; i.v.
A proton pump inhibitor in
combination with DAPT is intravenous; kg kilograms bodyweight.
recommended in patients at higher Recommendations for the use of drugs listed in this table may vary
than average risk of gastrointestinal depending on
the exact labeling of each drug in the country where it is used.
bleeds (i.e. history of gastrointestinal
ulcer/haemorrhage, anticoagulant I B 208,
therapy, chronic NSAID/
corticosteroid use or two or more of
209 5.3Anticoagulation
the following: age e65 years, 5.3.1 Anticoagulation during the acute phase
dyspepsia, gastro-oesophageal reux Anticoagulantsareusedtoinhibitthrombingenerationand/oractiv-
disease, Helicobacter pylori infection, ity, thereby reducing thrombus-related events. There is evidence
chronic alcohol use). that anticoagulation is effective in reducing ischaemic events in
NSTE-ACS and that the combination with platelet inhibitors is
In patients on P2Y12 inhibitors who
need to undergo non-emergency more effective than either treatment alone.210 Several anticoagu-
major non-cardiac surgery,f lants, acting at different levels of the coagulation cascade, have
postponing surgery for at least 5 been approved or are under investigation for this indication
days IIa C (Figure 4). Anticoagulant doses in patients with impaired renal
after cessation of ticagrelor or func-
clopidogrel, and for 7 days for tion are reported in Table 11.
prasugrel, should be considered if
clinicallyfeasibleandunlessthepatie
nt
In case
is at of risk
high a non-cardiac surgical
of ischaemic events. 5.3.1.1 Unfractionated heparin
procedure that cannot be UFH has a pharmacokinetic prole with large interindividual
postponed variabil-
or of a bleeding complication, IIb C ityandanarrowtherapeuticwindow.Weight-adjustedi.v.administra-
discontinuation of the P2Y12
tionwithaninitialbolusof6070 IU/kguptoamaximumof5000 IU,
inhibitor
maybeconsideredafteraminimumof followed by an infusion of 1215 IU/kg/h up to a maximum of
1 1000 IU/h, is recommended. Anticoagulation level is usually moni-
and 3 months from PCI with BMS tored in the cardiac catheterization laboratory with activated
and bare-metal stent; CABG coronary artery bypass graft; clotting
BMS DAPT
dual
new-generation DES, respectively. time (ACT) and elsewhere with the activated partial
(oral) antiplatelet therapy; DES drug-eluting stent; GPIIb/IIIa
thromboplastin
glycoprotein IIb/
IIIa; NSAID non-steroidal anti-inammatory drug; NSTE-ACS time (aPTT; therapeutic window is 5075 s, corresponding to 1.5
non-ST-
elevation acute coronary syndromes; PCI percutaneous coronary 2.5 timestheupper limit ofnormal).UFH remains awidelyused anti-
intervention. coagulant in NSTE-ACS in the context of short delays to coronary
aClass of recommendation.
angiography and short hospital stays despite consistent evidence
bLevel of evidence.
cReferences supporting level of evidence.
for
dNon-enteric coated formulation; 75150 mg intravenously if oralgreater
ingestionbleeding risk compared with other strategies. 211 In the PCI
is not setting, UFH is given as an i.v. bolus either under ACT guidance (in
possible.
the rangeof250350 s,or200250 s if a GPIIb/IIIa inhibitoris given)
eContraindications for ticagrelor: previous intracranial haemorrhage or
ongoing or in a weight-adjusted manner (usually 70100 IU/kg, or 5070 IU/
kg in combination with a GPIIb/IIIa inhibitor). 212,213 UFH should be
bleeds.Contraindicationsforprasugrel:previousintracranialhaemorrhage,pre
vious stopped after PCI unless there is an established indication related
ischaemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel
is
to the procedure or to the patients condition. For heparin-induced
generally not recommended for patients e75 years of age or with thrombocytopenia
a (HIT) see section 5.8.7.2.
bodyweight
,60 kg.
fRecommendations for cardiac surgery are listed in section 5.6.6.2.
 288 ESC Guidelines

antithrombin with high afnity, thereby preventing thrombin gener-

Table 11 Dosing of anticoagulants in patients with ation(Figure4).Thecompoundhas100%bioavailabilityafters.c.injec-
normal and impaired renal function tion, with an elimination half-life of 17 h, allowing once-daily dosing.
No monitoring of anti-Xa activity and no dose adjustments are re-
Drug Recommendations quired and the compound does not induce HIT. In NSTE-ACS, the
Normal renal function Stage 4 CKD Stage 5 CKD
or stage 13 CKD recommendeddoseis2.5 mg/day.Duetoitsrenalelimination,fonda-
(eGFR (eGFR
(eGFR e30 mL/min/1.73m 2
1529) <15 parinux is contraindicated if eGFR is ,20 mL/min/1.73m2. In the fth
" Prior to coronary mL/min/1.73m
2 mL/min/1.73m Organization to Assess Strategies in Acute Ischaemic Syndromes
) )
angiography: 6070
2
(OASIS-5) study, which enrolled 20 078 patients with NSTE-ACS,
IU/kg
i.v. (max 5000 IU)
fondaparinux 2.5 mg s.c. once daily was non-inferior to enoxaparin
Unfractionateand No dose No dose with respect to ischaemic events [death, MI or refractory ischaemia
d infusion (1215 adjustme adjustme
heparin IU/kg/h) nt nt
at 9 days; HR 1.01 (95% CI 0.90, 1.13), P 0.007], but halved in-
(max 1000 IU/h), hospital major bleeds [HR 0.52 (95% CI 0.44, 0.61), P , 0.001] and
target signicantly reduced mortality at 30 days [2.9% vs. 3.5%; HR 0.83
aPTT 1.52.5x
control (95% CI 0.71, 0.97), P , 0.02] and 6 months [5.8% vs. 6.5%; HR
Enoxaparin " During 1 mg/kgPCIs.c. twice a day 1 mg/kg s.c. once a day Not0.89 (95% CI 0.80, 1.00), P , 0.05]. 218 In the subgroup of patients
recommended according to
Not recommended if who underwent PCI (n 6239), a signicantly lower rate of major
ACT or 70100 IU/kg
eGFR
i.v. in
<20 mL/min/1.73m
2 Not recommended
bleeding complications (including access site complications) was ob-
Fondaparinuxpatients 2.5 mg
nots.c. once a day
anticoagulated
served at 9 days in the fondaparinux group vs. enoxaparin [2.3% vs.
(5070 IU/kg if 5.1%; HR 0.45 (95% CI 0.34, 0.59), P , 0.001]. 203 The rate of major
concomitant bleeds was not inuenced by the timing of the intervention after in-
Bivalirudin Bolus
with 0.75 mg/kg i.v.,
GPIIb/IIIa
infusion 1.75 mg/kg/h* Not recommended Not recommended jection of the last dose of fondaparinux (1.6% vs. 1.3% for ,6 h vs.
inhibitors)
.6 h, respectively). Catheter thrombus was observed more fre-
quently with fondaparinux (0.9%) than with enoxaparin (0.4%), but
this complication was abolished by injection of an empirically deter-
mined bolus of UFH at the time of PCI. Subsequent studies have
ACT activated clotting time; aPTT activation partial thromboplastin time;
CKD chronic kidney disease; eGFR estimated glomerular ltration rate; IU
shown that a standard UFH bolus is recommended at the time of
PCIinpatientspretreatedwithfondaparinux. 219Ananalysisexploring
international units; i.v. intravenous; kg kilograms bodyweight; thes.c.
uptake
of fondaparinux compared with LMWH among 40616
subcutaneous;
5.3.1.2 *Infusion dose
Low molecular 1.4 mg/kg/h
weight heparin if eGFR e30 and d 60NSTEMI patients from a large-scale Scandinavian registry described
mL/min/1.73m2.
LMWH has a more
Recommendations forpredictable
the use of drugs doseeffect
listed in thisrelationship
a than
table may vary
reduction
UFH in in-hospital mortality [OR 0.75 (95% CI 0.63, 0.89)]
and causes
depending onHIT less frequently. The most widely used and in bleeding
agent in events [OR 0.54 (95% CI 0.42, 0.70)] associated
NSTE-ACS is enoxaparin,
the exact labeling of each drug 1 inmg/kg administered
the country with the use of fondaparinux, but the advantage disappeared at 30
subcutaneously
where it is used.
twice daily, while the dose is reduced to 1 mg/kg once days andif6 months, respectively.220 Overall, fondaparinux is consid-
a day
eGFR , 30 mL/min/1.73m2. LMWH should not be administered ered to be the parenteral anticoagulant with the most favourable ef-
in patients with eGFR , 15 mL/min/1.73m2. Monitoring cacysafety
of anti-Xaprole and is recommended regardless of the
activity is not necessary except in patients in whom management the eGFR is strategy, unless the patient is scheduled for
1530 mL/min/1.73m2 or bodyweight is .100 kg. In NSTE-ACS immediate
patients pretreated with enoxaparin, no additional enoxaparin coronary angiography.
is
re-
commendedduringPCIifthelastsubcutaneous(s.c.)enoxaparinin- 5.3.1.4 Bivalirudin
jection was administered ,8 h before PCI, whereas anBivalirudin additionalbinds directly to thrombin and thereby inhibits the
0.3 mg/kg i.v. bolus is recommended if the last s.c. enoxaparin thrombin-induced conversion of brinogen to brin. It inactivates
injec- brin-bound as well as uid-phase thrombin (Figure 4). As the
tion was administered e8 h before PCI.214,215 Crossing over
drug to an-
does not bind to plasma proteins, its anticoagulant effect is
other anticoagulant during PCI is strongly discouraged. more A
216 predictable than that of UFH. Bivalirudin is eliminated by
meta-analysis of all trials testing enoxaparin vs. UFHthekidneyandhasahalf-lifeof25in ACS minaftercessationoftheinfusion.
showed The anticoagulant activity of bivalirudin correlates well with aPTT
a marginallysignicant reduction in the combined endpoint and ACT of death
values. In NSTE-ACS patients, a bivalirudin dose of
or MI at 30 days in favour of enoxaparin [10.0% vs. 11.0%; 0.1 mg/kg OR i.v.
0.90
bolus followed by an infusion of 0.25 mg/kg/h was
(95% CI 0.81, 0.996), P 0.043] but no statistically tested signicant in the ACUITY trial in 13 819 moderate- to high-risk
differ- NSTE-ACS patients planned for an invasive strategy. 205 In patients
encesinmajorbleeds[6.3% withenoxaparinvs.5.4%withUFH;OR undergoing PCI, an additional i.v. bolus of 0.5 mg/kg bivalirudin
1.13 (95% CI 0.84, 1.54)] at 7 days. 217 A meta-analysis wasincluding
added before the procedure and the infusion dose was in-
23 trials and 30 966 patients documented the favourable creased safety
to 1.75 mg/kg/h before PCI and stopped at the end of the
and efcacy prole of enoxaparin compared with UFH during procedure.PCI, Patients were randomized to one of three unblinded
withsignicantreductionsindeath[RR0.66(95%CI0.57,0.76),P ,
treatments: UFH or LMWH plus GPIIb/IIIa inhibitor, bivalirudin
0.001], the composite of death or MI [RR 0.68 (95% plus CI 0.57, 0.81),inhibitor or bivalirudin with bailout use of GPIIb/IIIa
GPIIb/IIIa
P , 0.001], complications of MI [RR 0.75 (95% CI 0.6, 0.85), P ,
0.001]andmajorbleeds[RR0.80(95%CI0.68,0.95),P 0.009]. 211

5.3.1.3 Fondaparinux
TheparenteralselectivefactorXainhibitorfondaparinuxisasynthet-
ic pentasaccharide that binds reversibly and non-covalently to
ESC Guidelines 289

inhibitor. There was no signicant difference between UFH/LMWH

rivaroxaban 5 mg (4.0%). Non-CABG major bleeds occurred in
plus GPIIb/IIIa inhibitor vs. bivalirudin plus GPIIb/IIIa inhibitorfor
1.8% and2.4% the
with 2.5 and5 mg rivaroxaban,respectively,compared
composite ischaemiaendpointat 30days [death, MIorunplannedre-
with0.6%withplacebo[HR3.46forrivaroxaban2.5 mg(95%CI2.08,
vascularization for ischaemia 7.3% vs. 7.7%, respectively;
5.77), P ,RR 1.07 HR 4.47 for rivaroxaban 5 mg (95% CI 2.71, 7.36),
0.001;
(95% CI 0.92, 1.23), P 0.39] or for major bleeds P [5.7% vs. 5.3%;
, 0.001]. Intracranial haemorrhage rates were 0.4% with 2.5 mg
RR 0.93 (95% CI 0.78, 1.10), P 0.38]. Bivalirudinand with0.7%
bailout
withuse
5 mg rivaroxaban vs. 0.2% with placebo [HR 2.83
of GPIIb/IIIa inhibitor was non-inferior to UFH/LMWH combined
(95% CI 1.02, 7.86), P 0.04 for 2.5 mg; HR 3.74 (95% CI 1.39,
with a GPIIb/IIIa inhibitor with respect to the composite
10.07),ischaemia
P 0.005 for 5 mg].226 The use of rivaroxaban 2.5 mg twice
endpoint [7.8% vs. 7.3%; RR 1.08 (95% CI 0.93, 1.24), daily,P while
0.32],
not recommended in patients treated with ticagrelor or
but with a signicantly lower rate of major bleeds [3.0% vs. 5.7%;
prasugrel, might be considered in combination with aspirin and clopi-
RR 0.53 (95% CI 0.43, 0.65), P , 0.001]. In patientsdogrelifticagrelorandprasugrelarenotavailableforNSTEMIpatients
not pretreated
with clopidogrel prior to PCI, a signicant excess in ischaemic events
whohavehighischaemicandlowbleedingrisks.Itiscontraindicatedin
was observed in bivalirudin-treated patients vs. those receiving UFH/
patientswithapriorhistoryofischaemicstroke/TIAanditsuseiscau-
LMWH plus GPIIb/IIIa inhibitor [9.1% vs. 7.1%; RR 1.29 tioned(95% CI 1.03, .75 years of age or ,60 kg bodyweight.
in patients
1.63)].221,222Comparablendingswereobservedinatrialwithasimi-
lardesign,theIntracoronaryStentingandAnti-thromboticRegimen
Rapid Early Action for Coronary Treatment (ISAR-REACT) 4
study.223 The ISAR-REACT 3 study, the only head-to-head compari-
son between bivalirudin and UFH alone (140 IU/kg)5.3.3 Recommendations
published so far, for anticoagulation in
non-ST-elevation
was performed in 4570 stable CAD patients as well as biomarker- acute coronary syndromes
negative NSTE-ACS patients undergoing PCI; the study found com-
parable rates of death, MI and urgent revascularization Recommendations
at 30 days for anticoagulation in non-ST-
elevation
[5.9% in the bivalirudin arm vs. 5.0% in the UFH arm; OR 1.16 acute coronary syndromes
(95% CI 0.91, 1.49), P 0.23] but a reduction in bleeding events
[3.1% vs. 4.6%; OR 0.66 (95% CI 0.49, 0.90), P 0.008]. 224
Recommendations Classa Levelb Ref.c

5.3.2 Anticoagulation following the acute phase Parenteral anticoagulation is

recommended
Two phase III trials have compared non-vitamin K antagonist (VKA)at the timeof diagnosis
I B 227
oral anticoagulants (NOACs) (for mode of action, seeaccording
Figure 4)toto
both ischaemic and
bleeding
placebo in patients with recent ACS treated with aspirin and risks.
clopi-
dogrel who did not have atrial brillation or other indications for
Fondaparinux (2.5 mg s.c. daily) is
oral anticoagulation (OAC). The Apixaban for Prevention of Acute 218,
recommended as having the most
228, I B
IschaemicEvents(APPRAISE)2studyassessedtheeffectsoftheoral favourable efcacysafety prole
229
factor Xa inhibitor apixaban 5 mg twice daily compared with pla- regardless of the management
strategy.
cebo, in addition to standard-of-care antiplatelet therapy following
Bivalirudin (0.75 mg/kg i.v. bolus,
ACS; it was terminated early (median 8 months) due to a markedly followed by 1.75 mg/kg/hforup205, to 4 h
increased risk of severe bleeds, including intracranial haemorrhage,
after the procedure) is recommended
without any apparent benet in terms of ischaemic events. 225 The 222, I A
asanalternativetoUFHplusGPIIb/IIIa
223
study Anti-Xa Therapy to Lower Cardiovascular Events in Addition inhibitors during PCI.
to Aspirin with or without Thienopyridine Therapy in Subjects with
Acute Coronary SyndromeThrombolysis in Myocardial Infarction UFH70100 IU/kgi.v.(5070 IU/kgif
concomitant with GPIIb/IIIa inhibitors)
(ATLAS ACS 2-TIMI 51) has led to the European Medicines
is recommended inI patients
Agencys (EMAs) approval of rivaroxaban (2.5 mg twice daily) undergoing
for B 219,
PCI who did not receive
NSTEMIand STEMI patients afterthe acutephase.226 The trial com- 229
any anticoagulant.
pared rivaroxaban 2.5 mg or 5 mg twice daily (unlike the 20 mg
once-dailydoseforatrialbrillation)withplaceboin15 526patients
followingACS;50%hadNSTE-ACSand 93%receivedclopidogrelinIn patients on fondaparinux (2.5 mg
addition to aspirin at randomization. Patients with prior ischaemic
s.c. daily) undergoing PCI, a single i.v.
I B 219
stroke/TIA were excluded. At a mean follow-up of 13 months, bolus the of UFH (7085 IU/kg, or 50
primary efcacyendpoint of CV death, MI or strokewas 10.7% with 60 IU/kg in the case of concomitant
placebo,9.1%withrivaroxaban2.5 mg[HR0.84(95%CI0.72,0.97), use of GPIIb/IIIa inhibitors) is
P 0.02] and 8.8% with rivaroxaban 5 mg [HR 0.85 (95% CI recommended
0.73, during the procedure.
0.98), P 0.03], with no interaction by ACS subtype. Rates ofEnoxaparin
def- (1 mg/kg I s.c.
B twice
218, daily)
inite, probable or possible stent thrombosis were 2.2% and 2.3% or UFH are recommended when 230
fondaparinux is not available.
with 2.5 and 5 mg rivaroxaban, respectively, vs. 2.9% with placebo
(P 0.02 and P 0.04, respectively). Rates of CV death were signi-
Enoxaparinshouldbeconsideredasan
IIa B 211
cantly lower with rivaroxaban 2.5 mg compared with placeboanticoagulant
[2.7% for PCI in patients
vs. 4.1%; HR 0.66 (95% CI 0.51, 0.86), P 0.002] but not with pretreated with s.c. enoxaparin.

IIb i.v.
Additional ACT-guided B boluses
231 of
UFH during PCI may be considered
following initial UFH
Discontinuation treatment.
of anticoagulation
should be considered after PCI, unless
IIa C
otherwise indicated.
 290 ESC Guidelines

Crossover between UFH and LMWH Table 12 Suggested strategies to reduce bleeding risk
is not recommended. III B 216 related to PCI

In NSTEMI patients with no prior

" Anticoagulant doses adjusted to bodyweight and renal function,
stroke/TIA and at high ischaemic risk especially in women and elderly patients.
as well as low bleeding risk receiving " Radial approach preferred.
aspirin and clopidogrel, low-dose IIb B 226 " Proton pump inhibitors in patients on DAPT at higher than average risk
rivaroxaban (2.5 mg twice daily for of
approximately 1 year) may be gastrointestinal bleeds (i.e. history of gastrointestinal
considered after discontinuation of ulcer/haemorrhage,
parenteral anticoagulation. anticoagulant therapy, chronic NSAIDs/corticosteroid use, or two or
more among age e65 years, dyspepsia, gastrooesophageal reflux
disease,
ACT activated clotting time; GPIIb/IIIa glycoprotein IIb/IIIa; i.v. Helicobacter pylori infection, and chronic alcohol use).
intravenous; LMWH low molecular weight heparin; NSTEMI non- " In patients on OAC
ST- o PCI performed without interruption of VKAs or NOACs.
elevation myocardial infarction; PCI percutaneous coronary o In patients on VKAs, do not administer UFH if INR value >2.5.
intervention; o In patients on NOACs, regardless of the timing of the last
s.c. subcutaneous; TIA transient ischaemic attack; UFH administration of NOACs, add additional low-dose parenteral
unfractionated anticoagulation (e.g. enoxaparin 0.5 mg/kg i.v. or UFH 60 IU/kg).
heparin. o Aspirin indicated but avoid pretreatment with P2Y12 inhibitors.
aClass of recommendation. o GPIIb/IIIa inhibitors only for bailout of periprocedural complications.
bLevel of evidence.
cReferences supporting level of evidence.

DAPT dual (oral) antiplatelet therapy; GPIIb/IIIa glycoprotein IIb/IIIa;

5.4Managing oral antiplatelet agents in INR
international normalised ratio; NOACs non-vitamin K antagonist oral
patients requiring long-term oral anticoagulants; NSAIDs non-steroidal anti-inammatory drugs; OACs
oral
anticoagulants anticoagulants; PCI percutaneouscoronary intervention; UFH
5.4.1 Patients undergoing percutaneous coronary unfractionated
intervention abnormalheparin;
renal VKAs
and liver function
vitamin (1 point each), stroke, bleeding
K antagonists.
Approximately 68% of patients undergoing PCI have history or predisposition, labile INR, elderly (.65 years), drugs
an indica-
and alcohol
tion for long-term OAC with VKA or NOACs due to various con- (1 point each)] score} risks (Figure 5).234 Intheabsence
of safety
ditions such as atrial brillation, mechanical heart valves and efcacy data, the use of prasugrel or ticagrelor as
or venous
part ofbe
thromboembolism. In the periprocedural phase it should triple
con-therapy should be avoided. Gastric protection with a
sidered to perform coronary angiography on OAC, because inter-inhibitor is recommended. The dose intensity
proton pump
of OAC should
ruption of OAC and bridging with parenteral anticoagulants may be carefully monitored with a target INR of
lead to an increase in both thromboembolic episodes and patients treated with VKA (with the exception of
2.02.5 in
individuals with mechanical prosthetic valves in the mitral position).
bleeds.232234 The safety of PCI on NOACs without additional
In patients
parenteral anticoagulation is unknown, while no parenteral treated with NOACs, the lowest tested dose for stroke
antic-
oagulation is needed if the international normalized ratio (INR)should
prevention is be applied.
The
.2.5 in VKA-treated patients.235237 Strategies to minimise choice of stent type (newer-generation DES vs. BMS) in pa-
tients requiring
PCI-related complications in patients on oral anticoagulants are long-term anticoagulation is controversial in the
listed in Table 12. setting of NSTE-ACS. In the absence of conclusive data, the deci-
With respect to long-term antithrombotic treatment sion for PCI,
after the individual patient should also take into account the es-
a cohort study including 82 854 patients with atrialtimated
brillationprobability of subsequent target vessel revascularization
showed that long-term exposure of patients to triple (TVR) due to
therapy, de-restenosis. Although in stable CAD patients DAPT
is recommended
ned as the combination of aspirin, clopidogrel and OAC, was as- for at least 1 month after BMS and for 6 months
sociated with an increased riskof 1-year major [14.3% vs. 6.9%; HR of stent thrombosis (and other ischaemic compli-
after DES, the risk
2.08 (95% CI 1.64, 2.65)] and fatal bleeds [0.9% vs. cations)
0.3%; HR during
4.8 the period beyond 1 month and long-term appears
(95% CI 1.62, 14.02)] as compared with DAPT. 238 In the setting both stent types.240242 Data from the DAPT trial indi-
similar with
of NSTE-ACS, evidence to guide the management of cate a similar impact of prolonged DAPT administration irrespective
patients
of stent
undergoing PCI and requiring long-term OAC is limited. 234,239 type (BMS vs. DES).243 In addition, analyses on the risk of
adverse events
The indication for OAC should be reassessed and treatment con- among patients with DAPT cessation and patients
undergoing per-
tinued only if a compelling indication exists {e.g. paroxysmal, non-cardiac surgery indicate no differences between
sistent or permanent atrial brillation with a CHA2DSBMS and DES.177,244 Until data from RCTs become available, new-
2-VASc
[Cardiac failure, Hypertension, Age e 75 (2 points),generation
Diabetes, DESs are recommended over BMSs in patients requiring
OAC at low bleeding risk (HAS-BLED d2). For patients at high
Stroke (2 points)Vascular disease, Age 6574, Sex category]
score e2; mechanical heart valve; recent or a historybleeding risk (HAS-BLED e3) undergoing PCI who require OAC,
of recurrent
deep venousthrombosis orpulmonaryembolism}.Durationoftri-between a BMS and a new-generation DES needs to be
the choice
individualised.
ple therapy should be as limited as possible, depending on the
clin- In the Zotarolimus-eluting Endeavor Sprint Stent in Uncertain
ical setting as well asthe thromboembolic (CHA2DSDES 2-VAScCandidates
score) (ZEUS) trial, 1606 patients at either high bleeding
and bleeding {e.g. based on the HAS-BLED [hypertension,
 ESC Guidelines 291

NSTE-ACS patients with non-valvular

atrial fibrillation

Management PCI Medically

strategy managed / CABG

Low to High
Bleedin
intermediate (e.g. HAS-
3)
g risk
(e.g. HAS-BLED BLED
= 02)

Triple or
dual
O A C
0 therapya
Triple
O A C
therapy
Dual
therap
Dual
4 yb
therap
weeks Dual
yb
therap
yb
6
month O C or A O C or A O C or A
s12 months

O Monother
Lifelong
apyc

O A C
Aspirin 75100 mg daily Clopidogrel
Oral anticoagulation 75 mg daily
(VKA or NOACs)
ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CHA 2DS2-VASc = Cardiac failure, Hypertension, Age e75 [2 points],
Diabetes, Stroke [2 points]
Vascular disease, Age 6574, Sex category; DAPT = dual antiplatelet therapy; NOACs = non-vitamin K antagonist oral anticoagulants; NSTE-ACS =
non-ST-elevation acute
coronary syndrome; PCI = percutaneous coronary intervention; VKAs = vitamin K antagonists. Adapted from Lip et al. 234
aDual therapy with oral anticoagulation and clopidogrel may be considered in selected patients (low ischaemic risk).

bAspirin as an alternative to clopidogrel may be considered in patients on dual therapy (i.e., oral anticoagulation plus single antiplatelet); triple

therapy may be considered up to

12 months in very selected patients at high risk of ischaemic events (e.g. prior stent thrombosis on adequate antiplatelet therapy, stenting in the
left main or last remaining patent
coronary artery, multiple stenting in proximal coronary segments, two stents bifurcation treatment, or diffuse multivessel disease, especially in
diabetic patients).
cDual therapy with oral anticoagulation and an antiplatelet agent (aspirin or clopidogrel) beyond one year may be considered in patients at very

high risk of coronary events.

Figure 5 Antithrombotic strategies in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) and non-valvular atrial
In patients undergoing coronary stenting, dual antiplatelet therapy may be an alternative to triple or a combination of anticoagulants and single
brillation. antiplatelet therapy if the
CHA2DS2-VASc score is 1 (males) or 2 (females).

risk (52%), high thrombotic risk (17%) or low restenosis

and,
riskin(31%)
particular, in patients at high bleeding risk. While there
were randomized to implantation with either the zotarolimus-
were
eluting stent (n 802) or a BMS (n 804).245 Overall,no
4.6%
signicant
of differences in any bleeding events between
the population never received DAPT, 43.6% and 62.5%treatment
discontin-
ued it at 1 and 2 months, respectively, with 24.7% remaining
groups, on the limited size of the trial does not allow potential differ-
DAPT beyond 6 months. At 1 year, major adverse cardiovascular
ences in major bleeds to be reliably detected. As an additional
events (MACEs) were lower for those implanted with alimi-
zotarolimus-eluting stent compared with a BMS [17.5% tation,
vs. 22.1%;
the zotarolimus-eluting stent is no longer marketed in
HR 0.76 (95% CI 0.61, 0.95), P 0.011], driven by reductions
Europe. Thisin study suggests that a newer-generation DES may be
TVR [5.9% vs. 10.7%; HR 0.53 (95% CI 0.37, 0.75), P preferred
0.001], MI in patients who cannot tolerate long-term exposure to
[2.9% vs. 8.1%; HR 0.35 (95% CI 0.22, 0.56), P , 0.001]DAPT,
and den-
such as those needing chronic OAC.
ite/probable stent thrombosis [2.0% vs. 4.1%; HR 0.48 (95%
OmissionCI of aspirin while maintaining clopidogrel has been eval-
0.27, 0.88), P 0.019]. The benet of the zotarolimus-eluting
uatedintheWhatistheOptimalantiplatEletandanticoagulantther-
stent
over theBMS remainedconsistent acrossallprespeciedsubgroups
apy in patients with OAC and coronary StenTing (WOEST) trial,
which randomized 573 patients to dual therapy with OAC and clo-
pidogrel(75 mg/day)ortotripletherapywithOAC,clopidogreland
aspirin 80 mg/day.246 Treatment was continued for 1 month after
 292 ESC Guidelines

BMS placement (35% of patients) and for 1 year after recommended

DES place- in non-emergent cases. In emergency surgery, a
ment (65% of patients); follow-up was for 1 year.246 PCI was per-
com-
formed on VKA in half of the patients and one-third of binationofprothrombincomplexconcentrateoffourinactivatedfac-
them
presented with NSTE-ACS. The primary endpoint of any TIMI
tors (25 IU/kg) and oral vitamin K is required to obtain fast and
bleeds was signicantly reduced in the dual-therapy arm [19.5% restoration of haemostasis at the time of surgery. 180
sustained
vs. 44.9%; HR 0.36 (95% CI 0.26, 0.50), P , 0.001], while no signi-
While
cant differences in major bleeds were observed. The rates of MI, with urgent major surgery in patients treated with
experience
stroke, TVR or stent thrombosis did not differ signicantly, but all-
NOACsislimited,ithasbeensuggestedtouseprothrombincomplex
cause mortality was lower in the dual group (2.5% vs.concentrateofactivatedfactorstorestore
6.4%, P haemostasis.250 Inthe set-
0.027) at 1 year. Femoral access was used in the majority patients CABG, a 48 h interruption of NOACs is recom-
ting of planned
(74%). Whilethetrialwastoosmall to reliablyassessischaemicout-
mended. In ACS patients with an established indication for OAC,
comes and potential differences in major bleeds, dualthe therapy with agent (commonly aspirin) and then
antiplatelet
clopidogrel and OAC may be considered as an alternative to triple
anticoagulation
therapy in patients at high bleeding risk. In the Triple Therapy
should beinresumed
Pa- after CABG as soonasthe bleeding is controlled,
tients on Oral Anticoagulation After Drug Eluting Stentwhile
Implant-
triple therapy should be avoided. For antithrombotic therapy
ation (ISAR-TRIPLE) trial, 614 patients (one-third with ACS)
and CABG see sections 5.6.6.1 and 5.6.6.2.
undergoing stenting and requiring OAC were randomly assigned
toreceiveeither6-weekor6-monthclopidogreltherapyinaddition
to aspirin and VKA. The primary endpoint of death, MI, stent
5.4.3 Recommendations for combining antiplatelet
thrombosis, ischaemic stroke or TIMI major bleeding at 9 months
agents and anticoagulants in non-ST-elevation acute
did not differ between the 6-week and 6-month triple therapy
coronary syndrome patients requiring chronic oral
[9.8% vs. 8.8%; HR 1.14 (95% CI 0.68, 1.91), P 0.63]; the same
anticoagulation
was true for the combined incidence of death, MI, stent thrombosis
and ischaemic stroke [4.0% vs. 4.3%; HR 0.93 (95% CI 0.43, 2.05),
Recommendations for combining antiplatelet agents
P 0.87]. Furthermore, no difference in TIMI major bleeding
[5.3% vs. 4.0%; HR 1.35 (95% CI 0.64, 2.84), P 0.44]andanticoagulantsinnon-ST-elevationacutecoronary
was ob-
served.247 Finally, there are no data on the optimal timingsyndrome
of cessa-patients requiring chronic oral
anticoagulation
tion of any antiplatelet agent in stabilized NSTE-ACS patients who
underwent coronary stenting and require chronic OAC. Specical-
ly, it is not known whether there are differences according to the
type of OAC (NOACs versus VKA) or stent platform. In accord-
Recommendations Classa Levelb Ref.c
ance with a joint consensus document, discontinuation of any anti-
platelet agent at 1 year is encouraged in this patient population
In patients with a rm indication for I C
irrespective of stent type, while dual therapy with oral anticoagula-
OAC (e.g. atrial brillation with a
tion and one antiplatelet agent (aspirin or clopidogrel) may
CHA2be
DS2con-
-VASc score e2, recent
venous thromboembolism,
sidered in very selected patients at high risk of ischaemic events LV
(Figure 5).234 thrombus or mechanical valve
An early
prosthesis), OACinvasive coronary in
is recommended
angiography
addition (within
to antiplatelet 24 h) should
therapy.
be
considered in moderate- to high-
risk IIa C
5.4.2 Patients medically managed or requiring coronary patients,d irrespective of
artery bypass surgery OACexposure,toexpeditetreatment
With respect to NSTE-ACS patients who are medically managed, allocation (medical vs. PCI vs.
in an analysis of the nationwide Danish registry, 90-day bleeding
CABG)
risk was increased on triple therapy compared with OAC plus Initial
a todual
and antiplatelet
determine therapy
the optimal
single antiplatelet agent [HR 1.47 (95% CI 1.04, 2.08)], with awith
antithrombotic
non- regimen.
III C
signicant increase at 360 days [HR 1.36 (95% CI 0.95, 1.95)],aspirin
with- plus a P2Y12 inhibitor in
out differences in ischaemic events [HR 1.15 (95% CI 0.95, addition to OAC before coronary
angiography is not
1.40)].248 The same registry suggests that warfarin plus clopidogrel
recommended.
resulted in a non-signicant reduction in major bleeds [HR 0.78Patients undergoing coronary stenting
Anticoagulation
(95% CI 0.55, 1.12)] compared with triple therapy, with a non- During PCI, additional parenteral
signicant reduction in MI or coronary death [HR 0.69 (95% CI anticoagulation is recommended,
0.55, 1.12)].249 irrespective of the timing of the last
I C
Coronarysurgery in fullyanticoagulated patients is associateddoseofallNOACsandifINRis,2.5in
with
anincreasedbleedingrisk,thusinterruptionofVKApriortoCABGis VKA-treated patients.

Uninterrupted therapeutic IIa C

anticoagulation with VKA or NOACs
should be considered during the
periprocedural phase.
ESC Guidelines 293

Antiplatelet treatment 5.5Management of acute bleeding events

Following coronary stenting, DAPT
including new P2Y12 inhibitors
(see Web addenda)
should 5.5.1 General supportive measures (see Web
be considered as an alternative to addenda)
triple therapy for patients with IIa C 5.5.2 Bleeding events on antiplatelet agents (see Web
NSTE- addenda)
ACS and atrial brillation with a 5.5.3 Bleeding events on vitamin K antagonists (see Web
CHA2DS2-VASc score of 1 (in addenda)
males) 5.5.4 Bleeding events on non-vitamin K antagonist
Ifatlowbleedingrisk(HAS-BLED
or 2 (in females).
d2), oral anticoagulants (see Web addenda)
triple therapy with OAC, aspirin 5.5.5 Non-access-related bleeding events (see Web
(75100 mg/day) and clopidogrel IIa C addenda)
75 mg/day should be considered 5.5.6 Bleeding events related to percutaneous coronary
for 6
intervention (see Web addenda)
months, followed by OAC and
aspirin 5.5.7 Bleeding events related to coronary artery bypass
Ifathighbleedingrisk(HAS-BLED
75100 mg/day or clopidogrel e3), surgery (see Web addenda)
triple
(75mg/ therapy with OAC, aspirin (75 5.5.8 Transfusion therapy (see Web addenda)
100
day)mg/day)andclopidogrel75
continued up to 12 months. 5.5.9 Recommendations for bleeding management and
mg/day blood transfusion in non-ST-elevation acute coronary
should be considered for a duration IIa C syndromes
of
1 month, followed by OAC and
aspirin
75100 mg/day or clopidogrel Recommendations for bleeding management and
(75mg/ blood transfusion in non-ST-elevation acute coronary
Dual therapy with
day) continued up OAC
to 12 months syndromes
and clopidogrel
irrespective 75 stent
of the mg/day may
type (BMS
be
or considered as an alternative
to IIb Btherapy
triple antithrombotic 246, in
new-generation DES).
selected patients (HAS-BLED 248e3 Recommendations Classa Levelb Ref.c
and
low risk of stent thrombosis).
In patients with VKA-associated
life-threatening bleeding events, rapid
Theuseofticagrelororprasugrelaspart reversal of anticoagulation with
of triple therapy is not recommended. III C four-factor prothrombin complex
concentrate rather than with fresh
frozen plasma or recombinant
Vascular access and I stent
A type
251
activated factor VII should be
Radial over femoral access is
considered. In addition, repetitive
recommended for coronary DES over
The use of new-generation 10 mg i.v. doses of vitamin K IIa C
angiography and PCI.
BMS should be considered
IIa B 245,among should be administered by slow
patients requiring OAC. 252 injection.

Medically managed patients

OneantiplateletagentinadditiontoOAC
should be considered for up to 1 year. IIa C
In patients with NOAC-
associated
ongoing life-threatening bleeds,
ACS acute coronarysyndromes; BMS bare-metal stent; CHA 2DS2-VAScthe IIa C
administration of prothrombin
Cardiac failure, Hypertension, Age e75 (2 points), Diabetes, Stroke (2 complex concentrate or
points)
activated
Vascular disease, Age 6574, Sex category; DAPT dual (oral) antiplatelet
therapy; DES drug-eluting stent; INR international normalized ratio; prothrombin
In
complex
patients with anaemia and no
LV concentrates
evidence
should beof active bleed, blood
considered.
left ventricular; NOAC non-vitamin K antagonist oral anticoagulant;
NSTE-ACS non-ST-elevation acute coronary syndromes; OAC oral transfusion may be considered IIb C
anticoagulant/anticoagulation (it refers to both vitamin K and non-vitaminin the case of compromised
K haemodynamic status or
antagonist oral anticoagulants); PCI percutaneous coronary haematocrit ,25% or
intervention; haemoglobin level ,7 g/dL.
VKA vitamin K antagonist.
Triple therapy refers to aspirin, clopidogrel and OAC.
i.v. intravenous; NOAC non-vitamin K antagonist oral
HAS-
anticoagulant;
BLEDbleedingscoreincludeshypertension,abnormalrenalandliverfunction,
NSTE-ACS non-ST-elevation acute coronary syndromes; VKA
stroke, bleeding history or predisposition, labile INR (international
vitamin K
normalized
antagonist.
ratio), elderly (.65 years) and drugs increasing bleeding risk or alcohol
aClass of recommendation.
abuse.
bLevel of evidence.
When NOACs are combined with antiplatelet drugs, the lowest effective
cReferences supporting level of evidence.
dose for
stroke prevention should be used. When VKAs are combined with
antiplatelet
drugs, INR should not exceed 2.5.
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.
dRisk criteria are listed in Table 13.
 294 ESC Guidelines

5.6.1 Invasive coronary angiography

Table 13 Risk criteria mandating invasive strategy in Invasive coronary angiography maintains its central role in the
NSTE-ACS man-
agement of patients with NSTE-ACS. In the vast majority of cases
Very-high-risk criteria it
" Haemodynamic instability or cardiogenic shock allows clinicians to
" Recurrent or ongoing chest pain refractory to medical
treatment
conrm the diagnosis of ACS related to obstructive epicardial
" Life-threatening arrhythmias or cardiac arrest
" Mechanical complications of MI CAD(ortoruleoutacoronaryoriginofchestpain)and,asacon-
" Acute heart failure sequence, to guide antithrombotic treatment and avoid unneces-
" Recurrent dynamic ST-T wave changes, particularly sary exposure to antithrombotic agents;
with intermittent identify the culprit lesion(s);
ST-elevation establish the indication for coronary revascularization and assess
High-risk criteria the suitability of coronary anatomy for PCI and CABG and
" Rise or fall in cardiac troponin compatible with MI stratify the patients short- and long-term risk.
" Dynamic ST- or T-wave changes (symptomatic or
silent)
" GRACE score >140 5.6.1.1 Pattern of coronary artery disease
Intermediate-risk criteria Angiographic patterns of CAD in NSTE-ACS patients are diverse,
" Diabetes mellitus ranging from normal epicardial coronary arteries to a severely and
" diffusely diseased coronary artery tree. Up to 20% of patients with
NSTE-ACS have no lesions or non-obstructive lesions of epicardial
coronaryarteries, whileamong patients withobstructiveCAD,40
80% have multivessel disease.164,224,303,304 Bypass graft failures
" LVEF <40% or congestive heart failure and
" Early post-infarction angina left main coronary artery disease may be the underlying condition
" Prior PCI
in 5% and up to 10% of patients presenting with NSTE-ACS, re-
" Prior CABG
" GRACE risk score >109 and <140 spectively. The left anterior descending coronary artery is the
Low-risk criteria most frequent culprit vessel in both STEMI and NSTEMI-ACS
" Any characteristics not mentioned above (in up to 40% of patients).164,224,303306 Regarding the distribution
within the infarct-related artery, culprit lesions in NSTE-ACS are
more often located within the proximal and mid segments, with
approximately the same frequency in the two segments. 305,306
CABG coronary artery bypass graft; eGFR estimated glomerular
ltration
rate; GRACE Global Registryof Acute Coronary Events;LVEF left 5.6.1.2 Identication of the culprit lesion
ventricular
ejection fraction; PCI percutaneous coronary intervention; MI
In order to characterize a coronarylesion as culprit on
myocardial angiography,
infarction. at least two of the following morphological features suggestive
of
acute plaque rupture should be present:306308 intraluminal lling
defects consistent with thrombus (i.e. acute occlusion
abruptlyend-
ing with a squared-off or convex upstream termination or an intra-
5.6Invasive coronary angiography and luminal lling defect in a patent vessel within or adjacent to a
stenotic region with surrounding homogeneous contrast opacica-
revascularization tion), plaque ulceration (i.e. presence of contrast and hazy contour
Invasive coronary angiography, followed if indicated by beyond the vessel lumen), plaque irregularity (i.e. irregular
coronary margins
revascularization, is performed in the majority of patients
oroverhangingedges),dissection orimpairedow.Pathological and
hospita- intracoronary imaging studies have documented the simultaneous
lised with NSTE-ACS in regions with well-developed healthcare
occurrence of multiple vulnerable plaques, mostly as thin-cap -
systems. The decision for an invasive strategy should broatheroma.
carefully 309311 Angiographic studies have conrmed these
weigh the risks of invasive diagnostics and the benetsndings,
in termsshowing that in up to 40% of NSTEMI-ACS patients with
of diagnostic accuracy, risk stratication and assessment of the
obstructive CAD, multiple complex plaques fullling the criteria
risks related to revascularization. The decision for ofaculpritlesionmaybeobserved.306,308,312,313Nearlyone-quarter
revasculariza- of NSTEMIpatients present with anacuteoccludedcoronaryartery
tion takes into account the risk in terms of morbidity and
and two-thirds of the occlusions are already collateralised at the
mortality timeofangiographicexamination.223,310Asaconsequence,differen-
associated with the proposed modality (PCI or CABG) and thebetween an acute/subacute and chronic occlusion may
tiation
benets in terms of short- and long-term prognosis, symptom re- be challenging and identication of the culprit lesion
sometimes
lief,qualityoflifeanddurationofhospitalstay.Theindicationforan
based solely on angiography may not be possible.
invasive approach, the timing for myocardial revascularization
Diffuse precordial ST depression more pronounced in leads V 4
and V6 may indicate a culprit lesion located in the mid left anterior des-
the selection of the revascularization modality dependcendingcoronaryartery,whilechangesmoreevidentinleadsV
on 2V3
numer- may be moresuggestiveof aculprit lesion locatedin the left circum-
ous factors, including clinical presentation, comorbidities, risk 314 Diffuse ST depression including both precordial and
ex artery.
stratication (as outlined in section 4), presence of high-risk fea-
tures specic for a revascularization modality, frailty, cognitive
sta-
tus, estimated life expectancy and functional and anatomic
severity
as well as pattern of CAD.
ESC Guidelines 295

extremity leads associated with ST-elevation e1 mm patients

in lead deteriorated
aVR while on medical therapy (crossover), the trials
may indicate either left main coronary artery as thedid culprit
not include
lesion consecutive patients and excluded those with
or proximal occlusion of the left anterior descending very-high-risk
coronary ar- features and advances in percutaneous treatment
tery in the presence of severe three-vessel CAD.315,316
such The
as correl-
single-stent strategy for bifurcation lesions, radial approach,
ation of ECG changes with the culprit lesion is weakened
new-generation
in the DES as well as more effective P2Y12 inhibitors
presence of left coronary artery dominance, multivessel
werenotavailableorbroadlyimplementedinthetrials.Despitethese
disease
and distal location of the culprit lesion.317 Echocardiography
limitations, orthe results of RCTs and their meta-analyses support the
left ventriculography may also help to identify the culprit
broad implementation
lesion cor- of a routine invasive strategy and highlight
responding to a regional wall motion abnormality. Finally,
the roleapproxi-
of risk stratication in the decision process. Specic sub-
mately 25% of NSTEMI patients have angiographically groupsnormalof high-risk patients that, while beneting from an early inva-
epicardial coronary arteries or non-obstructive CAD. sive management,
164,303,304 A pose additional challenges in terms of treatment
provocativetest,suchaswithacetylcholineorergonovine,andnewer
(e.g. diabetic patients, the elderly, frail patients or those with renal
intracoronary imaging methods (i.e. optical coherence in- tomography)
may sometimes help to identify the culprit lesion orsufciency)
the underlying
are discussed in their respective sections.
pathology, such as medial thickness due to abnormal media
contrac- 5.6.3 Timing of invasive strategy
tion in coronary spasm or supercial erosions of non-obstructive
5.6.3.1 Immediate invasive strategy (,2 h)
thin-cap broatheroma.318320 Very-high-riskNSTE-ACSpatients(i.e.withatleastonevery-high-risk
criterion according to Table 13) have been generally excluded from
RCTs.Owingtoapoorshort-andlong-termprognosisifleftuntreat-
5.6.1.3 Fractional ow reserve ed, an immediate (i.e. ,2 h from hospital admission, analogous to
STEMImanagement)invasivestrategywithintenttoperformrevascu-
The achievement of maximal hyperaemia may be unpredictable in
NSTEMI because of the dynamic nature of coronarylarization
lesions and is recommended, irrespective of ECG or biomarker nd-
ings. Centres without STEMI programmes should transfer the
theassociatedacutemicrovasculardysfunction.Asaresult,fraction-
al ow reserve (FFR) may be overestimated and the patient immediately (Figure 6). The management of patients with
haemodynamic
relevanceofacoronarystenosisunderestimated.320Sofar,thevalue cardiac arrest and no ST elevation on ECG needs to
out-of-hospital
be individualized
of FFR-guided PCI in this setting has not been properly addressed. and requires multidisciplinary consultation in the
emergency department. While conscious survivors should undergo
5.6.2 Routine invasive vs. selective invasive approachimmediate coronary angiography, comatose survivors should rst
be investigated
While PCI associated with antithrombotic therapy results in culprit for non-coronary conditions, if appropriate, and cor-
onary
lesion stabilization, thereby reducing the risk of target lesionangiography should be performed directly after in the absence
associated(re)infarction,CABGprovidesprotectionagainstcompli- non-coronary cause of the cardiac arrest. 325
of an obvious
cations (i.e. occlusion/subocclusion, but possibly not distal embol-
ization) originating from culprit lesions as well as from disease
progression in the vessel segments proximal to the5.6.3.2
anastomotic
Early invasive strategy (,24 h)
sites.321 Compared with a selective invasive strategy, Earlyinvasivestrategyisdenedascoronaryangiographyperformed
a routine inva-
sive strategy in NSTE-ACS has been shown to improve within24
clinicalhofhospitaladmission.Theoptimaltimingofinvasivecor-
outcomesandreducerecurrentACSepisodes,subsequentrehospi-
onary angiography and revascularization in NSTE-ACS patients
talization and revascularization. A meta-analysis ofhas sevenbeenRCTs
investigated
in in multiple RCTs and meta-analyses. A
8375 NSTE-ACS patients with frequent use of thienopyridines,
meta-analysis of four RCTs with 4013 NSTE-ACS patients com-
GPIIb/IIIa inhibitors and stents showed that a routine pared
invasive
an early
strat-
(i.e. time to angiography 1.1614 h) with a delayed
egywasassociatedwithalowerriskofdeath[4.9%vs.6.5%;RR0.75
(i.e. time to angiography 20.886 h) invasive strategy. While there
(95% CI 0.63, 0.90), P 0.001], MI [7.6% vs. 9.1%;were RR 0.83
no signicant
(95% CI differences in terms of death or MI, the early in-
0.72, 0.96), P 0.012] and rehospitalization for recurrent
vasive strategy
ACS was associated with a statistically signicant lower
[19.9% vs. 28.7%; RR 0.69 (95% CI 0.65, 0.74), P , risk0.0001]
of recurrent
at a ischaemia [RR 0.59 (95% CI 0.38, 0.92), P
mean follow-up of 2 years.322 A meta-analysis of eight 0.02]RCTs
andinshorter duration of hospital stay [by 28% (95% CI 22,
10 150 NSTE-ACS patients showed that the benet in35), favour
P , 0.001]
of a and a trend towards fewer major bleeds [RR 0.78
routine invasive strategy for the composite endpoint (95%
of death
CI 0.57,or 1.07), P 0.13] and major adverse cardiac events
MI was conned to biomarker-positive patients [OR 0.68 [RR 0.91
(95%(95% CI 0.82, 1.01), P 0.09].326 An updated
CI 0.56, 0.82) vs. OR 1.01 (95% CI 0.79, 1.28) in biomarker-negative
meta-analysis of seven RCTs in 5370 NSTE-ACS patients and of
patients, interaction P 0.03].323 An individual patient
four data
observational studies in 77 499 patients compared an early
meta-analysisofthreeRCTswithlong-termfollow-updatathrough-
(,24 h) with a delayed invasive strategy.327 The results of the
out 5 years in 5467 NSTE-ACS patients reported a lower pooled risk
analysis
of CV of RCTs showed no signicant benet for death
death or MI [14.7% vs. 17.9%; HR 0.81 (95% CI 0.71, [3.9%
0.93),
vs.P4.7%;
OR 0.83 (95% CI 0.64, 1.09), P 0.18], MI [7.5%
0.002] in favour of a routine over a selective invasivevs. strategy;
7.8%; ORthe 1.15 (95% CI 0.65, 2.01), P 0.63] or major bleeds
most pronounced difference was observed in high-risk [2.8%patients
vs. 3.7%; OR 0.76 (95% CI 0.56, 1.04), P 0.09], and similar
(accordingtoariskscoredevelopedbytheauthorsbasedonclinical
outcomes were reported in the observational studies. Yet an early
characteristics), with an absolute risk reduction of 2.0%,
invasive 3.8%
strategy
and was associated with a lower risk of refractory
11.1% among low-, intermediate- and high-risk patients,ischaemiarespective-
[3.8% vs. 7.3%; OR 0.55 (95% CI 0.35, 0.86), P 0.008].
ly.324 Of note, the benet of revascularization in the RCTThree
wasoflikely
the trials included in the mentioned meta-analyses com-
underestimated because revascularization was allowed paredwhena strategy of immediate (e.g. primary PCI-like approach) vs.
 296 ESC Guidelines

Symptoms
Onset

First medical contact NSTE-

ACS diagnosis

PCI EMS or NonPCI

center center

Immediate transfer to PCI

Very Very
center
high high

High High
Same-day transfer

Intermedi Intermed
ate iate
Transfer
Low Low

Transfer
optional

Immedi Early Non-

Invasiv
ate invasi invasive
e
ve testing if
(<72
Invasive (<24 appropria
hr)
(<2 hr) hr) te
EMS = emergency medical services; PCI = percutaneous
coronary intervention.

Figure 6 Selection of non-ST-elevation acute coronary syndrome (NSTE-ACS) treatment strategy and timing according to initial risk
stratication.

early and/or delayed intervention in NSTE-ACS patients. analysisofhigh-riskpatients(i.e.one-thirdofpatientswithaGRACE

304,328,329
There were no differences with respect to the primary endpoints
risk score .140), an early invasive strategy lowered the risk of
based on biomarker elevation after intervention or withdeath,
respect MI or stroke [13.9% vs. 21.0%; HR 0.65 (95% CI 0.48,
to secondary clinical outcomes (except for a higher rate 0.89),
of MI in
theimmediateinvasiveapproachinoneofthestudies).328However,P 0.006], whereas the difference was not signicant for patients
the design and interpretation of these studies is challenging
with a from
GRACE risk score d140 [7.6% vs. 6.7%; HR 1.12 (95% CI
a 0.81, 1.56), P 0.48; P 0.01 for heterogeneity]. 303 Importantly,
methodologicalpointofview,becauseincasesofearlyintervention,
an early invasive strategy did not trigger any safety issue in this
biomarkers had not returned to normal values or were trial.
still in the
ascending phase of the curve.Thereforeit may be difcult, In aif post
not im-
hoc analysis of the ACUITY trial, a delay to PCI .24 h was
possible, to differentiate between the evolution of the index
anindependentpredictorof30-dayand1-yearmortality.
MI 330Theex-
and cessofischaemiceventsassociatedwiththePCI .24 hstrategywas
an ischaemic complication of the revascularization procedure.
most apparent among moderate- and high-risk patients
There is evidence to suggest a benet of an early invasivestrategy
(according
in patients with a high-risk prole. The largest individualtoRCT
theto TIMI risk score). Overall, an early invasive strategy is
date, Timing of Intervention in Acute Coronary Syndromes recom- (TI-
MACS), randomly assigned 3031 NSTE-ACS patients to mended an early in patients with at least one high-risk criterion (Table 13).
(,24 h, median time 14 h) or delayed (median time 50 This h) interven-
implies timely transfer for patients admitted to hospitals
tion. At 6 months, the primary composite endpoint of death,
with- MI or
stroke was not different between the early and delayedout invasive
onsite catheterization facilities (Figure 6).
strategy [9.6% vs. 11.3%; HR 0.85 (95% CI 0.68, 1.06), P 0.15].
Thesecondaryendpointofdeath,MI,strokeorrefractoryischaemia5.6.3.3 Invasive strategy (,72 h)
was reduced by 28% in favour of the early invasivestrategyThis is[9.5%
the recommended maximal delay for angiography in
vs. patients
12.9%; HR 0.72 (95% CI 0.58, 0.89), P 0.003]. In thewith pre- atleastoneintermediaterisk criterion, recurrent symptoms or
specied known ischaemia on non-invasive testing.324,327 Even if hospital
transfer is required, the 72 h window for coronary angiography
should be complied with.
ESC Guidelines 297

5.6.3.4 Selective invasive strategy NSTEMI.333 In 36% of the patients, clopidogrel was prescribed within
Patients with no recurrence of symptoms and none7of days
the ofcriteria
discharge. In 8562 propensity scorematched patients, pa-
listed in Table 13 are to be considered at low risk of tients
ischaemic
who were prescribed clopidogrel had lower rates of all-cause
events. In these patients, a non-invasive stress test mortality
(preferably [8.3% vs. 13.0%; adjusted HR 0.63 (95% CI 0.54, 0.72), P,
withimaging)forinducibleischaemiaisrecommendedbeforedecid-
0.01] and the composite of death or MI [13.5% vs. 17.4%; HR 0.74
ing on an invasive strategy.331 (95% CI 0.66, 0.84), P , 0.01], but not MI alone [6.7% vs. 7.2%; HR
0.93 (95% CI 0.78, 1.11), P 0.30], compared with non-users of
clopi-
In summary, available data indicate that an earlydogrel.as opposedThe association
to a between clopidogrel use and the composite
of
delayed invasive strategy is safe and associated with a lower risk of
refractory ischaemia and a shorter duration of hospital deathorMIwassignicantamongpatientspresentingwithNSTEMI[HR
stay. The se-
0.67(95%CI0.59,0.76)]comparedwiththosepresentingwithunstable
lection of the optimal timing of invasive coronary angiography and
revascularization should be guided by individual risk angina [HR 1.25 (95% CI 0.94, 1.67), P for interaction ,0.01].
stratication.
It is recommended that patients at very high risk (i.e. The withTRILOGY
at least ACS trial randomized 7243 patients with NSTE-
ACS
onevery-high-riskcriterion)undergoanimmediateinvasivestrategy ,75yearsofageselectedformedicalmanagementtoclopido-
(,2 h). In patients at high risk (i.e. with at least onegrel or prasugrel
high-risk criter- for a median duration of 17 months. 334 Allocation
to prasugrel
ion), an early invasive strategy (,24 h) is recommended. In patients was not associated with a statistically signicant reduc-
tion in the
with at least one intermediate-risk criterion, the invasive strategy primary endpoint of death from CV causes, MI or stroke
[13.9%
may be delayed but a maximum 72 h window from admission to in the prasugrel group and 16.0% in the clopidogrel group;
HR
coronary angiography is recommended. In low-risk patients, a 0.91 (95% CI 0.79, 1.05), P 0.21]. While non-CABG TIMI ma-
jor bleeding
non-invasive stress test (preferably with imaging) for inducible is- rates did not differ among the groups, TIMI major and
minor
chaemia is recommended before deciding on an invasive strategy. bleeding events were more frequent in the prasugrel group
[1.9%vs.1.3%;HR1.54(95%CI1.06,2.23),P 0.02].InthePLATO
study, 5216 patients (28% of the total PLATO population) admitted
5.6.4 Conservative treatment to hospital for ACS were specied as planned for non-invasive man-
5.6.4.1 In patients with coronary artery disease agement, although by the end of follow-up, 3143 (60.3%) patients
5.6.4.1.1 Non-obstructive CAD. A pooled data analysis had beenfrom eight
managed non-invasively. In the population intended for
NSTE-ACS RCTs showed that 9.6% of the patients had non-
non-invasive management, the incidence of the primary endpoint,
obstructive CAD. Compared with patients with obstructivea composite CAD,of CV death, MI and stroke, was lower with ticagrelor
those individuals were younger and more often female, while fewer
than with clopidogrel [12.0% vs. 14.3%; HR 0.85 (95% CI 0.73, 1.00,
had diabetes mellitus, previous MI or prior PCI. Thirty-day death
P 0.04]. Overall or mortality was also lower [6.1% vs. 8.2%; HR 0.75
MI was less frequent among patients with non-obstructive(95% CI CAD 0.61, 0.93), P 0.01]. The incidence of non-CABG TIMI
(2.2%) vs. obstructive CAD (13.3%) [adjusted OR 0.15 major (95%bleedsCI was numerically higher in the ticagrelor-treated pa-
0.11, 0.20)]. Thirty-day death or MI and 6-month mortality were
tients [2.8% vs. 2.2%; HR 1.33 (95% CI 0.91, 1.94), P 0.142]. 335
also lower among patients with non-obstructive CAD [adjusted
OR 0.19 (95% CI 0.14, 0.25) and adjusted OR 0.37 (95% CI 0.28,
0.49), respectively].332 While invasive evaluation and, 5.6.4.1.2 CAD not amenable to revascularization. Data regarding pa-
if appropriate
tients
and feasible, revascularization are indicated in patients at high with ACS is- who are not amenable to revascularization due
chaemic risk, in a proportion of them this strategy is not offered be-CAD are sparse. The available observational stud-
to severe/diffuse
cause of the perception that patients might not benet ies included
in terms mainly
of patients with stable CAD and refractory an-
gina.
event reductiondue to the estimated increased risk related to 336,337 Although the prognosis differs according to patient

coronary angiography and/or revascularizationor quality characteristics

of life. (e.g. age, prior CABG or PCI, LV dysfunction, con-
Patients in whom an invasive strategy may be withheld byheart
gestive the failure), overall, patients not amenable to revasculari-
treat- zation have higher mortality compared with patients who are
ing physicians may include very elderly or frail patients (section 336 The main objective of pharmacological treatment
revascularized.
5.8.1); patients with comorbidities such as dementia, is relief
severe from refractory angina, as detailed in the 2013 ESC guide-
chronic lines on the management of stable CAD.63
renal insufciency (section 5.8.3) or cancer and patients at high risk
of bleeding complications (section 4.3). Usually these 5.6.4.2 In patients
patient cat- with normal coronary angiogram (see Web
egories have been excluded from RCTs. addenda)
TakoTsubo
With respect to oral antiplatelet therapy in the context cardiomyopathy, non-CAD-associated coronary
of medic-
thromboembolism,
ally managed NSTE-ACS, the CURE study randomized 12 562 pa- vasospasm and microvascular disease may all
causeNSTE-ACS.Whiletheseconditionshavebeenextensivelycov-
tients to clopidogrel or placebo in addition to aspirin for 312
months (mean duration of treatment 9 months). The ered in the 2013
majority of pa-ESC guidelines on the management of stable CAD,
the
tientsweretreatedconservatively, while ,40% underwent coronarymost relevant features are summarised in the Web addenda. 63
revascularization during the study period. The primary outcome, a
composite of death from CV causes, non-fatal MI or stroke at 1
year, occurred in 9.3% of the patients in the clopidogrel group and
5.6.5 Percutaneous coronary intervention
11.4% of the patients in the placebo group [RR 0.80 (95% CI 0.72, aspects and challenges
5.6.5.1 Technical
0.90), P , 0.001]. There were signicantly more patients Although with suspected
major or conrmed NSTE-ACS represents the most
bleeds in the clopidogrel group than in the placebofrequent
group [3.7% vs. for coronary angiography and PCI worldwide,
indication
2.7%; RR 1.38 (95% CI 1.13, 1.67), P 0.001].137 A registry looked
fewstudiesfocusonthetechnicalaspectsofPCIinthissetting.Hence
at the comparative effectiveness of clopidogrel vs.informationonPCItechniquesandoutcomeshastobederivedlarge-
no clopidogrel in
16 365 medically managed patients with unstable lyfromPCIstudiesorfromtrialsandregistriesencompassingACSpa-
angina and
tients. As for all other manifestations of CAD, stent implantation in
 298 ESC Guidelines

the setting of NSTE-ACS helps to reduce abrupt vessel ACS closure

patientsandimplement a transition from transfemoral to transradial
restenosis associated with balloon angioplasty and itaccess.
shouldHowever,
be con- prociency in the femoral approach should be
sidered the standard treatment strategy. Based on at maintained,
least compar- as this access is indispensable in a variety of
able safety and superior efcacy (i.e. prevention of restenosis
procedures,
and need for repeat revascularization), new-generation including
DESs are
intra-aortic balloon counterpulsation implantation, struc-
recommended over BMSs in NSTE-ACS.345347 DAPT isturalheartdiseaseinterventionsandperipheralrevascularizationpro-
recom-
mended for 12 months irrespective of stent type, while cedures.
in patients
A consensus document has proposed a stepwise approach
at high ischaemic risk not experiencing bleeding events,
to favour
DAPTthe maytransition from a femoral to a radial approach. 351
be extended (see section 5.2.6). The impact of thrombectomy has
not been established by adequately sized RCTs in NSTE-ACS. This
treatment modality cannot be recommended considering 5.6.5.3 the lack
Revascularization strategies and outcomes
of benet observed in STEMI.348 While FFR is considered the inva-
There is a lack of prospective randomized investigations addressing
sive gold standard for the functional assessment of lesion
the type severity
(i.e. complete vs. incomplete) and timing (i.e. simultaneous
instableCAD,itsroleinNSTE-ACSstillneedstobedened.Strat-vs. staged) ofrevascularizationin NSTE-ACS. A completerevascular-
egies to reduce bleeding risk related to PCI are listedization
in Table 12.
strategy of signicant lesions should be pursued in multivessel
disease patients with NSTE-ACS based on two considerations. First,
5.6.5.2 Vascular access several studies showing the benet of early intervention when com-
TheRadIalVsfemorALaccessforcoronaryintervention(RIVAL)trial
pared with the conservative approach in patients with NSTE-ACS
randomized 7021 ACS patients (both STEMI and NSTE-ACS) mandated to ra-
a complete revascularization strategy, irrespective of the
dial or femoral artery access.349 The primary outcome, a composite
possibility to identify and/or treat the culprit lesion.352354 Second,
of death, MI, stroke or non-CABG-related major bleeds at 30 days,
multiplePCIandNSTE-ACStrialshaveshownadetrimentalprognos-
occurred in 3.7% of patients in the radial access group compared
tic effect of incomplete revascularization. Accordingly, a residual
with 4.0% of patients in the femoral access group [HR SYNergy(95%
0.92 CI percutaneous coronary intervention with TAXus
between
0.72, 1.17), P 0.50]. The Study of Access Site for Enhancement of
and cardiac surgery (SYNTAX) score .8 has been shown to be in-
PCI for Women (SAFE-PCI) trial randomized women undergoing
dependently associated with a poor 30-day and 1-year prognosis, in-
coronaryangiography,andifrequiredPCI,toradialorfemoralaccess.
cluding higher mortality after PCI in patients with moderate- and
Thestudywasstoppedearlyduetoalowerthanexpectedeventrate.
high-risk ACS.355,356 However, the presence of important unmeas-
Among the 1787 patients enrolled (.50% presented with uredconfoundingfactorsinretrospectivestudiesshowingworseout-
NSTE-ACS), 691 underwent PCI. There was no signicant comesdifference
in patients who did not receive complete revascularization
intheprimaryefcacyendpointofbleeding orvascularcomplications
cannotbeexcluded.Sincepursuingcompletenessofrevascularization
between radial and femoral access among women undergoing PCI
for some patients with complex coronary anatomy may mean in-
[radial 1.2% vs. 2.9% femoral; OR 0.39 (95% CI 0.12, 1.27), Pthe
creasing riskof PCI (e.g. in the presence of complex chronic total
0.12], while in the overall cohort of women undergoing coronaryor requiring CABG, it is reasonable, in the absence of
occlusions)
angiography a benet was detected [0.6% in the radial group vs.
compellingclinicaldata,totailortheneedforcompleterevasculariza-
1.7% in the femoral group; OR 0.32 (95% CI 0.12, 0.90), P
tiontoage,generalpatientconditionandcomorbidities.Thedecision
0.03].350 In the Minimizing Adverse Haemorrhagic Events by all
to treat TRans-
the signicant lesions in the same setting or to stage the
radial Access Site and Systemic Implementation of angioX (MATRIX)
procedures should be based on clinical presentation, comorbidities,
trial, 8404ACSpatients wererandomlyallocated toradialorfemoral
complexity of coronary anatomy, ventricular function, revasculariza-
access. The rst co-primary outcome of 30-day MACE,tion dened as
modality and patient preference.
death, MI or stroke, occurred in 8.8% of patients with Withrespecttooutcomes,periproceduralcomplicationsofPCIas
radial access
and 10.3% of patients with femoral access [RR 0.85 wellasthelong-termischaemicrisk
(95% CI 0.74, remainhigherin NSTE-ACSthan
0.99), two-sided P 0.031; formally non-signicant at inthe pre-patients, despite contemporary management. Accordingly,
stable
specied a of 0.025).251 The second co-primary outcome of of CV death, MI or stroke in NSTE-ACS patients in recent
the risk
30-day net adverse clinical events [MACE or non-CABG Bleeding
trials was approximately 10% and 15% at 1 and 2 years follow-up,
AcademicResearchConsortium(BARC)majorbleeding]wasexperi-
re-
encedin9.8%and11.7%ofpatients{RR0.83(95%CI0.73,0.96),P spectively.154,206ForACSpatientswhounderwentPCI,revasculariza-
0.009]. Radial access was associated with a lower risk of all-cause
tionproceduresrepresentthemostfrequent,mostcostlyandearliest
mortality [1.6% vs. 2.2%; RR 0.72 (95% CI 0.53, 0.99), P for
cause 0.045],
rehospitalization.357,358 This reects both planned (i.e.
while the rates of cardiac mortality, MI and stroke were
staged) signi-
not as well as unplanned revascularization procedures due to
cantly different. The two groups had similar rates of symptoms
urgent TVRor CV event recurrence.357,358
and stent thrombosis. Major BARC 3 or 5 bleeding was signicantly
reduced in the radial group [1.6% vs. 2.3%; RR 0.67 (95% CI 0.49,
0.92),P 0.013].Radialaccesswasassociatedwithsignicantlylower
5.6.6 Coronary
rates of surgical access site repair or transfusion of blood products. artery bypass surgery
Approximately10%ofNSTE-ACSpatientsmayrequireCABGduring
An updated meta-analysis including MATRIX found a signicant re-
ductionin majorbleeds;death,MI orstroke andin all-causetheir mortality
index hospitalization.359 A Danish nationwide cohort study
showed
associated with radial as compared with femoral access.251 Radial that theac-proportion of patients undergoing CABG
for
cess,performedbyexperiencedoperators,isrecommendedoverthe NSTE-ACS decreased from 2001 to 2009, while the proportion
of patients
transfemoral access in ACS. It is recommended that centres treating undergoing coronary angiography and PCI markedly
increased.360 NSTE-ACS patients requiring CABG represent a
challenging group of patients, mainly because of the difculties in
bal-
ancingischaemicandbleedingrisksinrelationtothetimingofsurgery
andperioperativeantithrombotictherapy.Inaddition,NSTE-ACSpa-
tients present with a higher proportion of surgical high-risk
ESC Guidelines 299

characteristics, including older age, female gender,5.6.6.3

left mainTechnical aspects and outcomes (see Web addenda)
coronary 5.6.7 Percutaneous coronary intervention vs. coronary
artery bypass surgery
diseaseandLVdysfunctioncomparedwithpatientsundergoingelect-
ive CABG.361 In the absence of randomized data, optimal While timing
the main advantages of PCI in the setting of NSTE-ACS are
for faster revascularization of the culprit lesion, a lower risk of stroke
non-emergent CABG in NSTE-ACS patients should be and the absence of deleterious effects of cardiopulmonary bypass
determined
on the ischaemic myocardium, CABG may more frequently offer
individually, as detailed in section 5.6.6.1, Web addenda.
completerevascularizationinadvanced multivesselCAD.However,
no contemporary RCT comparing PCI with CABG in patients with
NSTE-ACS and multivessel CAD is available. Accordingly, in nearly
5.6.6.1 Timing of surgery and antithrombotic drug
all trials comparing an early with a delayed invasive strategy, or a
discontinuation
routine invasive with a selective invasive strategy, the decision to
(see Web addenda)
perform PCI or CABG was left to the discretion of the investigator.
5.6.6.2 Recommendations for perioperative management of
A post hoc analysis of 5627 NSTE-ACS patients with multivessel
antiplatelet
CAD included in the ACUITY trial showed that 78% underwent
therapy in non-ST-elevation acute coronary syndrome patients
PCI while the remaining patients were treated surgically. 374 After
requiring
propensity-score matching, there were no differences among
coronary artery bypass surgery
1056 patients in mortality at 1 month (CABG 2.5% vs. PCI 2.1%;
P 0.69) and 1 year (CABG 4.4% vs. PCI 5.7%; P 0.58). PCI-
Recommendations for perioperative management treated of patients experienced lower rates of stroke (0% vs. 1.1%;
antiplatelet therapy in non-ST-elevation acute P 0.03), MI (8.8%% vs. 13.3%; P 0.03), major bleeds (9.1% vs.
coronarysyndrome patients requiring coronaryartery 45.5%; P , 0.001) and renal injury (14.2% vs. 31.7%; P , 0.001),
bypass surgery but had signicantly higher rates of unplanned revascularization
than CABG (3.1% vs. 0.2%; P , 0.001) during the periprocedural
137, period. At 1 year, the risk of stroke remained lower among PCI-
Recommendations 148,
Class I
a Levelb Ref.c
A treated patients (0% vs. 1.1%; P 0.03), whereas unplanned revas-
153
cularization (12% vs. 0.2%; P , 0.001) and MACE tended to be
Irrespective of the revascularization more common (25.0% vs. 19.2%; P 0.053). A subgroup analysis
strategy, a P2Y12 inhibitor is of an individual patient data meta-analysis of 10 RCTs comparing
It is recommended
recommended that the
in addition Heart
to aspirin CABG and PCI reported similar mortality after a median follow-up
Team
and estimate the 12monthsunless
maintainedover individual bleeding of 5.9 years among 2653 stabilised NSTE-ACS patients with multi-
and are
there ischaemic risksI and
contraindicationsC guide
such the
as vessel CAD [9.6% in the CABG group vs. 11.1% in the PCI group;
timing ofrisk
excessive CABG as well asevents.
of bleeding HR 0.95 (95% CI 0.80, 1.12)].377
management of DAPT.
As both the SYNergy Yield of the New Strategy of Enoxaparin,
Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY)
It is recommended to perform CABG and Future Revascularization Evaluation in Patients with Diabetes
without delay in patients
I C with Mellitus: Optimal Management of Multivessel Disease (FREEDOM)
haemodynamic instability, ongoing trials compared PCI and CABG in patients with multivessel CAD
myocardial ischaemiaor very-high-risk and included up to one-third of patients with unstable angina or
coronary anatomy, regardless of
NSTE-ACS, it is reasonable to use the criteria applied in patients
antiplatelet treatment.
with stable CAD to guide the choice of revascularization modality
Aspirin is recommendedI A 624 h
365, among stabilised patients with NSTE-ACS.378380 While the major-
post-CABG in the absence 366 of ongoing
bleeding events. ity of patients with single-vessel CAD should undergo ad hoc PCI of
the culprit lesion, the revascularization strategy in an individual
It is recommended to continue NSTE-ACS patient with multivessel CAD should be discussed in
low-dose aspirin until CABG. I B 367 the context of a Heart Team and be based on the clinical status
369
285,CABG as well as the severity and distribution of the CAD and the lesion
In stabilised patients requiring
370,
who are on DAPT, discontinuation of IIa B characteristics. The SYNTAX score was found to be useful in the
ticagrelor and clopidogrel 5371 days prediction of death, MI and revascularization among NSTE-ACS pa-
before and prasugrel 7 days prior to tientsundergoingPCIandmayhelpguidethechoicebetweenrevas-
surgery should be considered.
After CABG,resuming P2Y12 inhibitor cularizationstrategies.381PCIoftheculpritlesiondoesnotrequirea
therapy should be IIa considered as soon case-by-case review by the Heart Team when an ad hoc interven-
C
as deemed safe. tion is indicated based on clinical or angiographic grounds, such as
ongoing ischaemia, haemodynamic instability, pulmonary oedema,
Platelet function testing may be recurrent ventricular arrhythmias or total occlusion of the culprit
considered in shortening the time
IIb B 372
window to CABG following P2Y12
coronary artery requiring urgent revascularization. Following PCI
inhibitor discontinuation. of the culprit lesion, stabilised NSTE-ACS patients with multivessel

ACS acute coronary syndromes; CABG coronary artery bypass

graft;
DAPT dual (oral) antiplatelet therapy.
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.
 300 ESC Guidelines

CAD may be discussed within the Heart Team if delayed CABG of

An invasive strategy (<72 h) is
the non-culprit vessels is an option. recommended in patients with at
least
5.6.8 Management of patients with cardiogenic shock one of the following intermediate-
Cardiogenic shock may develop in up to 3% of NSTE-ACS patients risk
during hospitalization and has become the most frequent cause criteria:
of diabetes mellitus
in-hospital mortality in this setting.382384 One or more partial orrenal insufciency (eGFR I A 322,
,60 mL/min/1.73 m2)
complete vessel occlusions may result in severe heart failure, LVEF ,40% or congestive heart 324
espe- failure
cially in casesofpre-existingLVdysfunction, reduced cardiacoutput early post-infarction angina
and ineffective peripheral organ perfusion. More than two-thirds recent PCI
of prior CABG
patients have three-vessel CAD. Cardiogenic shock may also beGRACE risk score .109 and
re- ,140,
lated to mechanical complications of NSTEMI, including mitralorre- recurrent symptoms or known
ischaemia
gurgitation related to papillary muscle dysfunction or ruptureInand patients on non-invasive
with none of thetesting.
ventricular septal or free wall rupture. In patients with above
cardiogenic mentioned risk criteria and no
recurrent symptoms, I non-
A 113,
shock, immediate coronary angiography is indicated and PCI is
invasive 114
the testing for ischaemia (preferably
most frequently used revascularization modality. If the coronary with imaging) is recommended
anatomy is not suitable for PCI, patients should undergo before deciding on an invasive
emergent evaluation.
CABG. The value of intra-aortic balloon counterpulsation in MIIn centres experienced I Awith radial
251
complicated by cardiogenic shock has been challenged.385 Extra- access, a radial approach is
corporeal membrane oxygenation and/or implantable LV assist recommended for coronary
devices may be considered in selected patients. angiography and PCI. 242,
In patients undergoing PCI,
new-generation DESs are 252,
5.6.9 Recommendations for invasive coronary 386
recommended. I A
angiography and revascularization in non-ST-elevation 390
In patients with multivessel CAD,
acute coronary syndromes
it is recommended to base the
revascularization strategy (e.g. ad
Recommendations for invasive coronary angiography hoc culprit-lesion PCI, multivessel
and revascularization in non-ST-elevation acute PCI, CABG) on the clinical status
coronary syndromes and comorbidities as well as the
disease severity (including I C
distribution, angiographic lesion
characteristics, SYNTAX score),
Recommendations Classa Levelb Ref.c according to the local Heart Team
protocol.
An immediate invasive strategy
(<2 h)isrecommendedinpatientswith
In patients in whom a short DAPT
at least one of the following I C duration (30 days) is planned
very-high-risk criteria:
because IIb B 245
haemodynamic instability or
of an increased bleeding risk, a
cardiogenic shock
new-
recurrent or ongoing chest
generation DES may be
pain refractory to medical
considered
treatment BMS a bare-metal stent; CABG coronary artery bypass grafting;
over BMS.
life-threatening arrhythmias or CAD coronary artery disease; DAPT dual (oral) antiplatelet
cardiac arrest therapy;
mechanical complications of MI DES drug-eluting stent; eGFR estimated glomerular ltration rate;
acuteheartfailurewithrefractory
An early invasive strategy (<24 h) GRACE Global Registry of Acute Coronary Events; LVEF left
isangina or ST deviation
recommended in patients with at ventricular
recurrentdynamicST-orT-wave
least one of the following high-risk ejection fraction; MI myocardial infarction; NSTE-ACS non-ST-
elevation
changes, particularly with
criteria: 303, acute coronary syndromes; PCI percutaneous coronary intervention;
intermittent
rise or fall inST-elevation.
cardiac troponin I A 326, SYNTAX SYNergy between percutaneous coronary intervention with
compatible with MI 327 TAXus and cardiac surgery.
dynamic ST- or T-wave changes Timing to coronary angiography is calculated from hospital admission.
(symptomatic or silent) aClass of recommendation.

GRACE score .140. bLevel of evidence.

cReferences supporting level of evidence.
ESC Guidelines 301

5.7Genderspecicities(seeWebaddenda) Recommendations for the management of diabetic

5.8Special populations and conditions patients with non-ST-elevation acute coronary
(see Web addenda) syndromes

5.8.1 The elderly and frail patients (see Web addenda)

5.8.1.1 Recommendations for the management of elderly Recommendations Classa Levelb Ref.c
patients with
non-ST-elevation acute coronary syndromes Blood glucose control
It is recommended to screen all
patients with NSTE-ACS for diabetes
I C
and to monitor blood glucose levels
Recommendations for the management of elderly frequently in patients with known
patients with non-ST-elevation acute coronary diabetes or admission hyperglycaemia.
syndromes
Glucose-lowering therapy should
be considered in ACS patients with
blood glucose .10 mmol/L IIa C
Recommendations I C Classa Levelb Ref.c
(.180 mg/dL), with the target
adapted to comorbidities, while
It Elderly
is recommended to tailor
patients should be considered episodes of hypoglycaemia should be
antithrombotic
for an invasivetreatment according
strategy and, if avoided.
toappropriate,
bodyweight revascularization
and renal function. Less stringent glucose control
408,after should be considered both in
careful evaluation of potential
414 risks
IIa A the
and benets, estimated life 418 expectancy,
acute phase and at follow-up in IIa C
comorbidities, quality of life, frailty and
patients with more advanced
patient values and preferences.
cardiovascular disease, older
age,
longer diabetes duration and
Adjusted dosing regimens of Antithrombotic
more treatment and invasive strategy
IIa C
beta-blockers, ACE inhibitors, ARBs It is recommended to administer
comorbidities.
and statins should be considered to the same antithrombotic treatment
prevent side effects. in diabetic and non-diabetic
I C
patients.
ACE angiotensin-converting enzyme; ARB angiotensin receptor blocker;
NSTE-ACS non-ST-elevation acute coronary syndromes.
aClass of recommendation. 352,
bLevel of evidence.
An invasive strategy is recommended
441,
cReferences supporting level of evidence. over non-invasive management.
442 I A
It is recommended to monitor renal
function for 23 days after coronary
angiography or PCI in patients with
I C or on
baseline renal impairment
5.8.2 Diabetes mellitus (see Web addenda) metformin.
5.8.2.1 Recommendations for the management of diabetic
patients with 240,
non-ST-elevation acute coronary syndromes
In patients undergoing PCI,241, I A
new-generation DESs are 443
In patients withover
recommended stabilised
BMSs.multivessel
CAD and an acceptable surgical
379,
risk, CABG is recommended over
436, I A
PCI. 444

In patients with stabilised multivessel

CAD and a SYNTAX score d22, PCI
IIa as
should be considered B an435,
alternative
to CABG. 445

ACS acute coronary syndromes; BMS bare-metal stent; CABG

coronary
artery bypass grafting; CAD coronary artery disease; DES drug-
eluting
stent; NSTE-ACS non-ST-elevation acute coronary syndromes;
PCI percutaneous coronary intervention; SYNTAX SYNergy
between percutaneous coronary intervention with TAXus and
cardiac surgery.
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.
 302 ESC Guidelines

5.8.3 Chronic kidney disease (see Web addenda) 5.8.4 Left ventricular dysfunction and heart failure
5.8.3.1 Dose adjustment of antithrombotic agents (see Web
(see Web addenda)
addenda) 5.8.4.1 Recommendations for the management of
5.8.3.2 Recommendations for the management of patientspatients
with with
chronic acute heart failure in the setting of non-ST-elevation
kidney disease and non-ST-elevation acute coronary syndromes
acute
coronary syndromes

Recommendations for the management of patients Recommendations for the management of patients
with chronic kidney disease and non-ST-elevation with acute heart failure in the setting of non-ST-
acute coronary syndromes elevation acute coronary syndromes

Recommendations Classa Levelb Ref.c Recommendations Classa Levelb Ref.c

I C
It is recommended to assess kidney It is recommended to perform
function by eGFR in all
I patients.
B 453, I C emergency echocardiography to
454 assess LV and valvular function
and exclude mechanical
It is recommended to administer the 1,
Immediate coronary angiography is
complications.
same rst-line antithrombotic recommended in patients with475, I B
treatment
Depending as on
in patients with
the degree ofnormal
renal 476
acute heart failure with refractory
kidneyfunction,withappropriatedose
dysfunction, it is recommended to angina, ST deviation or cardiogenic
adjustment if indicated.
switch parenteral anticoagulation to shock.
Immediate PCI is recommended for
I B 453,
UFH or to adjust the doses 454
of patients with cardiogenic
I B shock
475 if
fondaparinux, enoxaparin and coronary anatomy is suitable.
bivalirudin, as well asthe dose of small
molecule GPIIb/IIIa inhibitors. Emergency CABG is recommended
for patients with cardiogenic shock if
I B 475
thecoronaryanatomyisnotamenable
It is recommended to switch s.c. or i.v.
I Cinfusion adjusted to PCI.
anticoagulation to UFH
totheaPTTwheneGFRis,30mL/min/
1.73m2(forfondaparinux,wheneGFRis It is recommended that patients with
,20mL/min/1.73 m2). mechanical complications
I C of NSTE-
ACS are immediately discussed by the
In patients undergoing an invasive Heart Team.
strategy, hydrationI with
A isotonic
455 saline
460
and low- or iso-osmolar contrast IABPinsertionshouldbeconsideredin
media (at lowest possible volume) are patients with haemodynamic
IIa C
recommended. instability/cardiogenic shock due to
Coronary angiography and, if needed, mechanical complications.
revascularization are
I recommended
B 448 Short-term mechanical circulatory
after careful assessment of the risk IIb C
support in patients with cardiogenic
benetratio, in particularwith respect shock may be considered.
to the severity of renal dysfunction.

I BPCI,461, Routine use of IABP

III in patients
B 385, with
In patients undergoing cardiogenic shock is not 477
new-generation DESs are 462 recommended.
recommended over BMSs.
CABG should be considered over PCI
IIa B 463,
in patients with multivessel CAD CABG coronary artery bypass grafting; IABP intra-aortic balloon
464
whosesurgicalriskproleisacceptable pump;
and life expectancy is .1 year. LV leftventricular;NSTE-ACS=non-ST-
elevationacutecoronarysyndromes;
PCI should be considered over PCI percutaneous coronary intervention.
CABG in patients IIa
with multivessel Withrespecttodetailedmedicalmanagementofacuteheartfailure,weref
B 465,
CAD whose surgical risk prole erthe
466
is high or life expectancy is ,1 year. reader to dedicated guidelines.469
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.

aPTT activated partial thromboplastin time; BMS bare metal stent;

CABG
coronary artery bypass graft; CAD coronary artery disease; CKD
chronic
kidney disease; DES drug-eluting stent; eGFR estimated glomerular
ltration
rate; GP glycoprotein; i.v. intravenous; PCI percutaneous coronary
intervention; s.c. subcutaneous; UFH unfractionated heparin.
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.
ESC Guidelines 303

5.8.4.2 Recommendations for the management of patients 5.8.5 Atrial brillation (see Web addenda)
with 5.8.5.1 Recommendations for the management of atrial
heart failure following non-ST-elevation acute coronary brillation in
syndromes patients with non-ST-elevation acute coronary syndromes

Recommendations for the management of patients Recommendations for the management of atrial
with heart failure following non-ST-elevation acute brillation in patients with non-ST-elevation acute
coronary syndromes coronary syndromes

Recommendations Class
469,a Levelb Ref.c
478
An ACE inhibitor(orARB,if an481 ACE
inhibitor is not tolerated) is
recommended in patients with LVEF
d40% after stabilization, to reduce
A beta-blocker is recommended
the risk of death, recurrent 469,
MI and
in patients with an LVEF d40%
hospitalization for heart failure.
482the
after stabilization, to reduce
risk of death, recurrent MI486
and
hospitalization for heart failure.
Mineralocorticoid receptor
antagonists are recommended to
reduce the risk of heart failure
hospitalization and death in all
patients with persistent symptoms
(NYHA class IIIV) and LVEF d35%
despite treatment with an ACE
inhibitor (or an ARB, if an ACE
inhibitor is not tolerated) and a
beta-blocker.
Mineralocorticoid receptor
antagonists, preferably
eplerenone, I B 469,
arerecommendedtoreducetheris525
k range for at least 3 weeks.
of cardiovascular hospitalization
and
Device
death intherapy (CRT-D
patients or ICD,
with LVEF
depending
d40%. on QRS duration) is
recommended in symptomatic
patients with severe LV dysfunction
(LVEF d35%) despite optimal
medical therapy .40 days after the
acute event and without options of
revascularization. Patients should be
expected to survive .1 year with
good functional status.
In patients with CAD and LVEF
d35%, testing for residual
ischaemia
and subsequent
revascularization
should be considered prior to IIa B 491,
primary prophylactic ICD/CRT-D
implantation. After
revascularization,
assessmentofreverseLVremodell
ing
upto6monthsshouldbeconsidere
d angiotensin-converting enzyme; ARB angiotensin receptor
ACE
prior to primary prophylactic
blocker;
CAD coronary artery disease; CRT-D cardiac resynchronization
ICD/
therapy
CRT-D implantation.
debrillator; ICD implantable cardioverter debrillator; LV left
ventricular; LVEF left ventricular ejection fraction; MI myocardial
infarction; NYHA New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.
Recommendations Classa Levelb Ref.c
I A I A 497
In the absence of contraindications, it
is recommended to administer
anticoagulant drugs to all patients at
Investigationstodetectischaemiashould
presentation.
be considered in patients
IIa C with atrial
brillationandelevatedcardiactroponin
I A
levels.
Patients with rapid ventricular rate
Electrical cardioversion is
recommended in haemodynamically
I C
unstable patients.
Electrical or pharmacological
cardioversion with amiodarone is
I A 487, recommended in patients when a
488 decision is made to restore sinus
rhythm non-urgently (rhythm control
strategy). This strategy should only be
employed in patients with the rst
I C
episode of atrial brillation of ,48 h
duration (or in patients with no
evidence of left atrial appendage
thrombus on TOE) or if the patient
was anticoagulated in the therapeutic
Intravenous beta-blockers are
recommended to slow the rapid
ventricular response
I toCatrial
brillation in haemodynamically
I A 489, stable
490 patients.
Intravenous administration of cardiac
glycosides may beIIb C
considered for
ventricular rate control if the
response to beta-blockers is not
sufcient.
Intravenous administration of
non-dihydropyridine calcium
antagonists (verapamil, diltiazem)IIbmayC
be considered to slow a rapid
492
ventricular response to atrial brillation
in patients not on beta-blockers and
with no signs of heart failure.
Administration of class I
antiarrhythmic agents
III (e.g.
B 498
encainide,
ecainide) is not recommended.
Vernakalant is not recommended. III C 493
TOE transoesophageal echocardiography.
aClass of recommendation.
bLevel of evidence.
cReferences supporting level of evidence.
 304 ESC Guidelines

5.8.6 Anaemia (see Web addenda)
5.8.7 Thrombocytopenia
5.8.7.1
ThrombocytopeniarelatedtoGPIIb/IIIainhibitors(Webaddenda)
5.8.7.2 Heparin-induced thrombocytopenia (Web addenda)
5.8.7.3 Recommendations for the management of (IMPROVE-IT) randomized a total of 18 144 patients with recent
thrombocytopenia in
non-ST-elevation acute coronary syndromes
Recommendations for the management of
thrombocytopenia in non-ST-elevation acute
coronary syndromes
Recommendations Classa Levelb Ref.c
Immediate interruption of GPIIb/IIIa
inhibitor and/or heparin (UFH,
I C
LMWH, other heparin products) is
recommended in case of
thrombocytopenia ,100 000/mL (or
.50% relative drop from baseline
platelet count) occurring during
In patients treated with GP IIb/IIIa
treatment.
inhibitors, platelet transfusion is
recommended in case of major
I C
active
bleeding events or in the presence
of
severe (,10000/mL) asymptomatic
thrombocytopenia.
Treatment with a non-heparin
I C
anticoagulant is recommended in case
of documented or suspected HIT.
Use of anticoagulants with low or no
risk of HIT or brief administration of
UFH or LMWH, when these are
I C
chosen, are recommended to prevent
the occurrence of HIT.
should be increased in those receiving a low- or moderate-intensity
statin treatment at presentation, unless they have a history of in-
tolerance to high-intensity statin therapy or other characteristics
that may inuence safety.522,527,528 In this regard, the IMProved Re-
duction of Outcomes: Vytorin Efcacy International Trial
ACS (NSTEMI 47%, STEMI 29% and unstable angina 24%) and
LDL cholesterol ,125 mg/dL (,2.5 mmol/L) to either ezetimibe
10 mg/simvastatin 40 mg or simvastatin 40 mg (simvastatin was
up-titrated to 80 mg if LDL cholesterol was .79 mg/dL or
2.04 mmol/L). Over a period of 7 years, the composite primary end-
pointofCVdeath,MI,hospitaladmissionforunstableangina,coronary
revascularization or stroke was signicantly lower in the combined
treatment arm compared with the statin-only arm [32.7% vs.
34.7%;
HR 0.94 (95% CI0.89, 0.99), P 0.016].529 IMPROVE-ITwas the rst
study powered for clinical outcomes to show a modest benet with a
non-statinagentaddedtoastatin.Asalimitation,notallpatientsinthe
control arm were on a high-intensity statin regimen. Based on the
re-
sults of the trial, further LDL cholesterol lowering with a non-statin
agent should be considered in patients with LDL cholesterol
e70 mg/dL (e1.8 mmol/L) after NSTE-ACS despite a maximally
tolerated dose of statin. At the time of nalizing the guidelines, this
recommendation applies only to ezetimibe.
5.9.1.2 Antithrombotic therapy
Duration of antiplatelet treatment and anticoagulation during the
chronic phase are discussed in sections 5.2.6 and 5.3.2,
respectively.
5.9.1.3 ACE inhibition
ACE inhibitors are recommended in patients with systolic LV dys-
functionorheartfailure,hypertensionordiabetes(agentsanddoses
of proven efcacy should be employed). ARBs are indicated in pa-
tients who are intolerant of ACE inhibitors. 478480,530,531

5.9.1.4
GP glycoprotein; HIT heparin-induced thrombocytopenia; LMWH Beta-blockers
low
molecular weight heparin; UFH unfractionated heparin. Beta-blockersarerecommended,intheabsenceofcontraindications,
aClass of recommendation.
in patients with reduced systolic LV function (LVEF d40%). Agents
bLevel of evidence.
cReferences supporting level of evidence.
and doses of proven efcacy should be administered. 482486 Beta-
blocker therapy has not been investigated in contemporary RCTs
in patients after NSTE-ACS and no reduced LV function or heart fail-
ure. In a large-scale observational propensity-matched study in pa-
5.8.8 Patients requiring chronic analgesic or tients with known prior MI, beta-blocker use was not associated
anti-inammatory treatment (see Web addenda) with a lower risk of CV events or mortality. 532
5.8.9 Non-cardiac surgery (see Web addenda)
5.9Long-term management
5.9.1 Medical therapy for secondary prevention 5.9.1.5 Mineralocorticoid receptor antagonist therapy
SecondarypreventionofCVevents,includingoptimalmedicaltherapy,
AldosteroneantagonisttherapyisrecommendedinpatientswithLV
otherstrategiesforriskfactormodicationandlifestylechangessuchas
dysfunction (LVEF d40%) and heart failure or diabetes after
diet, exercise and smoking cessation, is of paramount importance
NSTE-ACS.Eplerenonetherapyhasbeenshownto reducemorbid-
be- ity and mortality in these patients after ACS.487,488,525
cause after an ACS episode, patients remain at high risk for
recurrent
ischaemic events.521 Secondary prevention has been shown to
have a 5.9.1.6 Antihypertensive therapy
Antihypertensive therapy (blood pressure goal ,140/90 mmHg)
majorimpactonlong-termoutcomeinthesepatients. 478,479,482,521526
is recommended according to the European Society of
Hypertension/ESC guidelines on the management of arterial
hypertension.533
5.9.1.1 Lipid-lowering treatment
It is recommended to initiate high-intensity statin therapy [i.e.
statin
5.9.1.7 Glucose-lowering
regimens that reduce low-density lipoprotein (LDL) cholesterol by therapy in diabetic patients
Thistopicisbeyondthescopeofthepresentdocumentandwasdis-
50%] as earlyas possible afteradmission in all NSTE-ACS patients
(in the absence of contraindications). The intensity ofcussed
statin in recent guidelines.433 As a general rule, the more
therapy advanced
ESC Guidelines 305

the CV disease, the older the patient, the longer the diabetes dur-
Participationinawell-
ationandthemorecomorbiditiesthatarepresent,thelessstringent structuredcardiac
535,
the glucose control should be. 541 IIa A
rehabilitation programme to
Core components and goals of cardiac rehabilitation, including 546
modify
physical activity counselling, diet/nutrition counselling, smoking
lifestyle habits and increase
ces- In patients with LDL cholesterol
adherence
e70
sation, weight control and goals for lipid and blood pressure man- mg/dL (e1.8
to treatment mmol/L)
should be despite a
maximally IIa B statin
considered.tolerated 529 dose, further
agement should be stated in the discharge letter. 534
reduction in LDL cholesterol with a
non-statin agente should be considered.
5.9.2 Lifestyle changes and cardiac rehabilitation
Enrolment in a well-structured cardiac rehabilitation/secondary pre-
vention programme after NSTE-ACS should be considered,A as systolic
it canblood pressure goal
enhance patient compliance with the medical regimen and of promote
,140mmHgshouldbeconsidered. IIa B 547
lifestyle changes, including regular physical exercise and smoking 549
ces-
sation,andallowsfordietarycounselling.521,535Aerobicexercisetrain-
ing within a cardiac rehabilitation programme should be ACEoffered to
angiotensin-converting enzyme; ARB angiotensin receptor blocker;
patients after NSTE-ACS, with the need for an evaluationLDL low-density lipoprotein; LVEF left ventricular ejection fraction;
of both
NSTE-ACS non-ST-elevation acute coronary syndromes.
ex- aClass of recommendation.
ercisecapacityandexercise-associatedrisk.Iffeasible,regularexercise
bLevel of evidence.

training three or more times a week and 30 min per sessionis

cReferences supporting level of evidence.
dSerum creatinine ,221 mmol/L (2.5 mg/dL) for men and ,177 mmol/L
recom-
(2.0 mg/dL) for women; serum potassium concentration ,5.0 mmol/L.
mended. Sedentary patients should be strongly encouraged to start
eAtthetimeofnalizingtheguidelines,thisrecommendationappliesonlytoezetimibe.
light-intensity exercise programmes after adequate exercise-
related
riskstratication.Smokingcessationisahighlyeffectivemeasuretore-
duce morbidity and mortality in patients after ACS. 521,536
6.Performance measures
5.9.3 Recommendations for long-term management after
non-ST-elevation acute coronary syndromes
Variationsintheapplicationofevidence-
basedstrategiesareassociated
Recommendations for long-term management after with signicant differences in outcome. Several large registries
non-ST-elevation acuteClassa coronary
Levelb Ref.csyndromes have
showndecienciesinthetreatmentofNSTE-ACSpatientswhencom-
pared with recommendations from contemporary guidelines.
Recommendations (for the Under-
recommendations on antithrombotic utilization of evidence-based treatments is common. Adherence
It is recommended Ito advise
A 536, all
treatment,seesections5.2.9and5.3.3) to
patients on lifestyle changes (including
537
smoking cessation, regular physical guidelineshasbeencorrelatedwithimprovementsinpatientoutcom
activity and a healthy diet). es Table 14 Performance measures in NSTE-ACS
It is recommended to start522, patients
inACS,includingreducedmortality. 550,551Thuspriorityneedstobegi-
high-intensitystatin therapy as early as I
527, A ven to improving the utilization of evidence-based guidelines.
possible, unless contraindicated,
528 and
maintain it long term.
Continu-" Use of aspirin
ous monitoring of performance indicators is strongly
" Use of ticagrelor/prasugrel/clopidogrel
An ACE inhibitor is recommended in encouraged
" Use to
of fondaparinux/bivalirudin/UFH/enoxaparin
478
patients with LVEF d40% or heart enhancethequalityoftreatmentandminimizeunwarrantedvariatio
" Use of beta-blocker at discharge in patients with LV
481,
failure, hypertension or diabetes, ns dysfunction
530, I A
unless contraindicated. An ARB " Use of statins
531, in evidence-based care. Consistent application of therapies
provides an alternative, particularly if " Use of ACE-inhibitor or ARB in patients with systolic
538
ACE inhibitors are not tolerated. based on
LV dysfunction
Beta-blockertherapyisrecommended
or heart failure, hypertension or diabetes
in patients with LVEF
I d40%,
A 482unless " Use of early invasive procedures in intermediate- to
contraindicated. 486 high-risk patients
" Smoking cessation advice/counselling
Mineralocorticoid receptor " Enrolment in a secondary prevention/ cardiac
antagonists,preferablyeplerenone,are
487, rehabilitation
recommended in patients with
488, LVEF I A programme
d35% and either heart failure
525or " Development of regional and/or national
diabetes after NSTE-ACS but no performancetoindicators
programmes measure systematically and
signicant renal dysfunction or provide feedback
individual hospitalsto
hyperkalaemia.d

Adiastolicbloodpressuregoalof ,90 I A 539,

ACE angiotensin-converting enzyme; ARB angiotensin receptor
mmHg is recommended (,85 mmHg 540
blocker;
in diabetic patients). LV left ventricular; NSTEMI non-ST-elevation myocardial
infarction;
UFH unfractionated heparin.
robust evidence may have larger effects on real-life CV health
than
those
306 seen in selected trial populations, especiallywith ESC Guidelines
thecombined
implementation of several effective treatment modalities. Such
pro- pain,hypertensionorheartfailure.Oxygentherapyshouldbeapplied
grammeshavebeenimplementedsuccessfullyinseveralcountries,in-
in the presence of a blood oxygen saturation ,90% or respiratory
cluding Sweden [the Swedish Web-system for Enhancement and
distress. Morphine (i.v. or s.c.) or alternative opiates are reserved
Development of Evidence-based care in Heart diseasefor Evaluated
patientswithpersisting severechestpain.Inpatientswithongoing
Ac- chest pain and inconclusive ECG, consider immediate echocardiog-
cording to Recommended Therapies (SWEDEHEART)],raphy the UKto exclude alternative diagnoses (if appropriate in
[Myocardial Infarction National Audit Project (MINAP) registry],
conjunction
Germany, Italy and Israel on a regional basis, or in intermittent
with CT angiography) such as pulmonary embolism, pericarditis or
pro- aortic dissection and at the same time to reinforce the suspicion of
grammes in many other countries. These performance measure (i.e. by identifying a focal wall motion abnormality). In
NSTE-ACS
programmes are also proposed and developed by thethe ESCsetting
through
of ongoing myocardial ischaemia or haemodynamic
the continuous ACS Registry within the Euro Heart Surveycom-
Program. promise (the clinical suspicion should be corroborated by the echo-
The most useful performance indicators for monitoring and
cardiographicndingofregionalwallmotionabnormality) thepatient
improv- shouldundergoimmediatecoronaryangiographyirrespectiveofECG
ing the standards of care in NSTEMI are listed in Tableor14.
biomarker ndings to prevent life-threatening ventricular arrhyth-
mias and limit myocardial necrosis. Blood work on admission
7.Summary of management should
include at least (preferably high-sensitivity) cardiac troponin T or I,
strategy serum creatinine, haemoglobin, haematocrit, platelet count, blood
glucoseandINRinpatientsonVKA.Theresultsofthetroponinmea-
This section summarises the diagnostic and therapeutic surements
steps dis- should be available within 60 min and troponin
measure-
cussedintheprevioussections.Thegoalistooutlinethemostimport-
ant steps in the management of patients with NSTE-ACS. ment Inshould
each be repeated at 13 h if high-sensitivity troponin assays
individual patient, decision making should take into account theVital signs should be assessed on a regular basis. In case
are used.
pa- of
hospital
tients history (e.g. age, comorbidities), clinical presentation admission, guidance in the choice of the unit is described
(e.g.
on- in
going myocardial ischaemia, haemodynamic or electrical Table 7. Patients with suspected NSTE-ACS should be observed in
instability), interdisciplinary emergency departments or chest pain units until
the diagnosis of MI is conrmed or ruled out. If the diagnosis of
ndingsobtainedduringtheinitialassessment(i.e.ECG,cardiactropo-
nin), timing and expected riskbenet ratio of available NSTE-ACS
therapies is conrmed, the lipid prole should be assessed in the
(i.e. early phase of admission. In case of ongoing ischaemia, debrillator
pharmacological, invasive assessment, revascularization).patches should be placed until urgent revascularization is
performed.
Step 1: Initial evaluation and pathway Itis recommendedthatmedicalandparamedicalpersonnelcaring for
Chest pain or other atypical symptoms prompt the patient to seek
suspected NSTE-ACSpatients haveaccessto debrillatorequipment
medical attention. All patients with suspected NSTE-ACS andmust be
are trained in advanced cardiac life support.
admitted to an emergency department and evaluated rapidly by a
Step 2: Diagnosis validation, risk
qualied physician. The delay between rst medical contact and
ECG should be d10 min. The cardiac rhythm of the patient assessment
should and rhythm monitoring
be monitored (Table 7). Once the initial clinical assessment, complemented by the 12-lead
The working diagnosis of NSTE-ACS and the initial management
ECG and the rst cardiac troponin measurement, has substan-
should be based on the following parameters: tiated the diagnosis of NSTE-ACS, antithrombotic treatment (as
described in step 3) as well as anti-anginal treatment (i.e. beta-
Chest pain characteristics, duration and persistence blockers
as well as anda nitrates) should be started. Further management of
the
symptom-oriented physical examination (e.g. systolic blood patient is based on responsiveness to anti-anginal treatment
pressure, and risk assessment, as quantied by the GRACE 2.0 risk score
(http://www.gracescore.org/WebSite/default.aspx?ReturnUrl=%
heart rate, cardiopulmonary auscultation, Killip classication)
Assessment of the probability of CAD based on chest2f), painaschar-
well as on results of the subsequent troponin measurement
acteristics, age, gender, CV risk factors, known CAD (atand13 h, if high-sensitivity assays are used). Echocardiography is
non-
cardiac manifestations of atherosclerosis useful to identify abnormalities suggestive of myocardial ischaemia
or necrosis
12-lead ECG (to detect ST deviation or other abnormalities sug- (i.e. segmental hypokinesia or akinesia) and should be
gestive of myocardial ischaemia or necrosis) performed immediately in patients with haemodynamic instability
On the basis of these ndings, the patient can be assigned to one CVorigin.Ifaortic dissectionor pulmonaryembolism
of suspected
of is suspected, echocardiography, D-dimer assessment and CT
four working diagnoses: angiography should be implemented according to the respective
ESC guidelines.42,43 Rhythm monitoring up to 24 hours or
STEMI PCI (whichever comes rst) should be considered in NSTEMI pa-
NSTE-ACS with ongoing ischaemia or haemodynamictients at low risk for cardiac arrhythmias (i.e. with none of the fol-
instability
NSTE-ACS without ongoing ischaemia or haemodynamic lowing criteria: haemodynamically unstable, major arrhythmias,
instability LVEF ,40%, failed reperfusion, additional critical coronary sten-
NSTE-ACS unlikely oses or complications related to PCI). Rhythm monitoring for
.24 hours
The treatment of patients with STEMI is covered in the respective should be considered in NSTEMI patients at intermedi-
ate to
ESC guidelines.1 The assignment to the category unlikely must be high-risk for cardiac arrhythmias (i.e. if one or more of the
above
done with caution, especially in patients with a specic condition, criteria are present).
such as the elderly and those with diabetes mellitus, and only
when another explanation is obvious. The initial treatment
measure
should include nitrates (sublingual or i.v.) if there is persisting
ESC Guidelines 307
Step 3: Antithrombotic treatment
The choice of the antithrombotic regimen in NSTE-ACS should be
based on the selected management strategy (i.e. conservative vs.
andshouldnotbechangedduringPCI.Inpatientspretreatedwithfon-
in- daparinux, UFH must be added before PCI. In anticoagulant-naive
vasive) as well as the chosen revascularization modality
pa- (PCI vs.
CABG).Dosingofantithromboticagents(Tables8,10and11)should
tients, consider bivalirudin. If CABG is planned and the patient is on
take into account patient age and renal function. Aspirin
a and
paren- P2Y12inhibitor,thisshouldbestoppedandsurgerydeferrediftheclin-
teral anticoagulation are recommended. In patients intended for a
ical conditionandtheangiographicndingspermit.Ifcoronaryangiog-
conservative treatment and not at high bleeding risk, ticagrelor
raphy shows no options for revascularization, owing to the extent
(pre- of
ferred over clopidogrel) is recommended once the NSTEMI diagno-
the lesions and/or poor distal run-off, freedom from angina should
sis is established. In patients intended for an invasive
be strategy,
the aimed for by intensifying medical therapy.
optimaltimingoftheadministrationofticagrelor(preferredoverclo-
pidogrel) has not been adequately investigated, while Step 6: Hospital
prasugrel is discharge and
re- post-discharge management
commended only after coronary angiography prior toAlthough
PCI. in NSTE-ACS most adverse events occur in the early
phase, the risk for MI or death remains elevated over several
Step 4: Invasive strategy months. Intense risk factor modication and lifestyle changes are
warranted in all patients following NSTE-ACS, and enrolment in a
Radialaccessforcoronaryangiographyand,ifneeded,revasculariza-
tion is recommended. Strategies to reduce bleeding cardiac rehabilitation programme after discharge can enhance pa-
complications
tient adherence
related to PCI are summarised in Table 12. The timing of angiog- to the medical regimen, may be supportive of risk
factor modication and is associated with improved outcomes.
raphy (calculated from rst medical contact) can be classied into
four categories based on the risk prole of the individual patient ac-
cording to Table 13 and Figure 6. 8.Gaps in evidence
Immediate invasive strategy (<2 h). Paralleling the STEMI
The role of genetic testing to individualize treatment and ultim-
pathway, this strategy should be undertaken for patients with on-
ately improve patient outcomes remains to be established.
going ischaemia, characterized by at least one very-high-risk cri-
While both sensitive and high-sensitivity cardiac troponin assays
terion. Centres without ongoing STEMI programmes should
show superior diagnostic accuracy compared with conventional
transfer the patient immediately.
assays, it is unknown whether high-sensitivity assays provide a
Earlyinvasivestrategy(<24 h).Mostpatientsinthiscategory
clinically meaningful advantage over sensitive assays and
respond to the initial pharmacological treatment but are at in-
whether
creased risk and need early angiography followed by revascular-
there are clinically relevant differences among various high-
ization.Patientsqualifyiftheyhaveatleastonehigh-riskcriterion.
sensitivity assays. The incremental value of copeptin over high-
This implies timely transfer for patients admitted to hospitals
sensitivity cardiac troponin assays remains to be fully elucidated.
without onsite catheterization facilities.
The performance of the 1 h algorithm to rule in and rule out
Invasive strategy (<72 h). This is the recommended maximal
acute MI in patients presenting with chest pain to the emergency
delay for coronaryangiography in patients without recurrence of
department has not been tested within an RCT. The best man-
symptoms but with at least one intermediate-risk criterion. Ur-
agement of patients assigned to the observational zone accord-
gent transfer to a hospital with onsite catheterization facilities
ing to the 1 h algorithm remains to be dened.
is not necessary, but the 72 h window for coronary angiography
The role of CT angiography as a rule-out tool for acute MI in the
should be complied with.
emergency department needs to be reassessed in the context of
Selectiveinvasivestrategy.Patientswithnorecurrenceofchest
high-sensitivity cardiac troponin assays.
pain, no signs of heart failure, no abnormalities in the initial or
The development of a single clinical risk score that assesses both
subse-
ischaemic and bleeding risks would be desirable.
quent ECG and no increase in (preferably high-sensitivity) cardiac
The role of beta-blockers duringand afteran NSTE-ACS episode
troponinlevel areatlowriskof subsequentCVevents.Inthissetting,
in patients with normal or mildly depressed LV function needs to
a non-invasive stress test (preferably with imaging) for inducible
be investigated.
is-
The optimal timing of ticagrelor administration in patients in-
chaemia is recommended before deciding on an invasive
tended for an invasive strategy needs to be dened.
strategy.
Additional data are necessary to establish the optimal duration of
dual antiplatelet therapy following stent implantation.
Step 5: Revascularization modalities The development of antidotes to normalise haemostasis in pa-
In the absence of dedicated trials, recommendations for tients
PCIwith
and ongoing major bleeding events while on P2Y12 inhibi-
tors orCAD.
CABG in stabilised NSTE-ACS are similar to those for stable NOACs should be accelerated.
The safety,
In patients with single-vessel disease, PCI with stenting of the effectiveness and optimal duration of combined
culprit oral anticoagulant and antiplatelet therapy in patients requiring
chronic
lesion is the rst choice. In patients with multivessel disease, theoral anticoagulation deserves further investigation.
deci- While several RCTs have compared CABG and PCI in popula-
sion for PCI or CABG should be individualized through tionscomprising
consultation mainlystable CADpatientswith multivessel dis-
with the Heart Team. A sequential approach, consisting ease,contemporarycomparativeinvestigationsin
of treating theNSTE-ACS
setting
the culprit lesion with PCI followed by elective CABG with areoflacking.
proof
ischaemia and/or FFR of the non-culprit lesions, may be The value of FFR-guided PCI in NSTE-ACS requires adequate
advantageous investigation.
in selected patients. In patients on a single antiplatelet agent
(aspirin)
undergoingPCI,theadditionofaP2Y12inhibitor(prasugrelorticagre-
lor preferred over clopidogrel) is recommended. The anticoagulant
should be selected based on both the ischaemic and bleeding
risks
 308
The burden of late CV events despite optimal pharmacological
treatment, including effective P2Y12 inhibitors and statins, Invasive strategy
calls
forreappraisalofthepathophysiologyoftheseadverseoutcomes of the following very-high-risk criteria:
and innovative preventive strategies.
Clinical trials areunder wayto examinewhethera profound LDL shock; recurrent or ongoing chest pain
cholesterollowering or immune-modulating therapy (e.g.
PCSK-9 inhibition, intense CETP inhibition, methotrexate or
monoclonalanti-IL-1b antibodies) in addition to maximally
toler-
ated statin treatment may improve long-term prognosis.
Theoptimalhaemoglobin/haematocritthresholdthatshouldtrig-
ger blood transfusion in anaemic patients with NSTE-ACS
needs
to be determined.
9.To do and not to do messages
from the guidelines
Recommendations Classa Levelb
Diagnosis
1 Similarlytothe0hand3hprotocol,arapid
rule-out and rule-in protocol at 0 h and 1 h
is recommended if a high-sensitivity cardiac
troponin test with a validated 0 h/1 h I B
algorithmisavailable.Additionaltestingafter
36 h is indicated if the rst two troponin
measurements are not conclusive and the
clinical condition is still suggestive of ACS.
2 Echocardiography is recommended
to I C
evaluateregionalandglobalLVfunctionan
d coronary angiography and PCI.
Antiplatelet treatment
to rule
3 A P2Y in or rule out differential
12 inhibitor is recommended, in
diagnoses.
addition to aspirin, for 12 months unless
there are contraindications
I Asuch as
excessive risk of bleeds.
Ticagrelor (180mg loading dose, 90mg
twice daily) is recommended, in the
absence of contraindications,c for all
patients at moderate to high risk of
I B
ischaemic events (e.g. elevated cardiac
troponins),regardlessofinitialtreatment
strategy and including those pretreated
with clopidogrel (which should be
discontinued when ticagrelor is started).
Prasugrel (60 mg loading dose, 10
mg I B
daily dose) is recommended in
patients
who are proceeding to PCI if there
Clopidogrel
are (300600 mg loading dose,
75
nomg daily dose) is recommended
contraindications. c for
I receive
B aClass of recommendation.
patients who cannot ticagrelor
or prasugrel or who require oral
anticoagulation.
4 It is not recommended to administer III B ious
prasugrel in patients in whom the
coronary anatomy is not known.
ESC Guidelines
5 An immediate invasive strategy (,2 h) is
recommendedinpatientswithatleastone
haemodynamic instability or cardiogenic
refractory to medical treatment;
life-threatening arrhythmias or cardiac I C
arrest; mechanical complications of MI;
acute heart failure with refractory
angina
or ST deviation; recurrent dynamic ST-
or
T-wave changes, particularly with
intermittent ST elevation.
6 An early invasive strategy (,24 h) is
recommendedinpatientswithatleastone
of the following high-risk criteria: rise or
fallincardiactroponincompatiblewithMI;
dynamic ST- or T-wave changes
I A
(symptomatic or silent); GRACE score
.140.
7 An invasive strategy (,72 h) is
recommendedinpatientswithatleasto
ne
of the following intermediate-risk
criteria:
W diabetes mellitus
W renal insufciency (eGFR ,60 mL/
min/1.73 m2) I A
W LVEF ,40% or congestive heart
failure
W early post-infarction angina
W recent PCI
W prior CABG
W GRACEriskscore .109and ,140,
or recurrent symptoms or known
ischaemia on non-invasive testing.
Coronary revascularization
8 In centres experienced with radial
access,
a radial approach is Irecommended
A
for
9 In patients with multivessel CAD, it is
recommended to base the
revascularization strategy (e.g. ad hoc
culprit-lesionPCI,multivesselPCI,CABG)
on the clinical status and comorbidities as I C
well as the disease severity (including
distribution, angiographic lesion
characteristics,SYNTAXscore) according
to the local Heart Team protocol.
Secondary cardiovascular prevention
10 It is recommended to start high-
intensity
I as
statin therapy as early A possible,
unless
contraindicated, and maintainit
longterm.
ACS acute coronary syndromes; CABG coronary artery bypass graft;
CAD coronary artery disease; eGFR estimated glomerular ltration rate;
GRACE Global Registry of Acute Coronary Events; LV left ventricular;
LVEF left ventricular ejection fraction; MI myocardial infarction; PCI
percutaneous coronary intervention; SYNTAX SYNergy between
percutaneous coronary intervention with TAXus and cardiac surgery.
bLevel of evidence.
cContraindications for ticagrelor: previous intracranial haemorrhage or
ongoing
bleeds.Contraindicationsforprasugrel:previousintracranialhaemorrhage,prev
ischaemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel
is
generally not recommended for patients e75 years of age or with a
bodyweight
,60 kg.
 ESC Guidelines 309

Cardiology, Lia Bang; Egypt: Egyptian Society of Cardiology, Adel El

10.Web addenda and companion
Etriby; Estonia: Estonian Society of Cardiology, Toomas Marandi; Fin-
land: Finnish Cardiac Society, Mikko Pietila ; Former Yugoslav Re-
documents public of Macedonia: Macedonian Society of Cardiology, Sasko
Kedev; France: French Society of Cardiology, Rene Koning; Georgia:
Georgian Society of Cardiology, Alexander Aladashvili; Germany:
All Web gures and Web tables are available in the onlineCardiacSociety,
German addenda Franz-Josef Neumann; Greece: Hellenic Car-
at: http://www.escardio.org/Guidelines-&-Education/Clinical-
diologicalSociety,KostantinosTsious;Hungary:HungarianSocietyof
Practice-Guidelines/Acute-Coronary-Syndromes-ACS-in-patients-
Cardiology, Da vid Becker; Iceland: Icelandic Society of Cardiology,
presenting-without-persistent-ST-segm Thorarinn Gunason; Israel: Israel Heart Society, Shlomi Matetzky;
Questions and answers companion manuscriptsItaly: Italianguide-
of these Federation of Cardiology, Leonardo Bolognese; Kazakh-
lines are available via this same link. stan: Association of Cardiologists of Kazakhstan, Aisulu Mussagaliyeva;
Kyrgyzstan: Kyrgyz Society of Cardiology, Medet Beishenkulov; Lat-
via: Latvian Society of Cardiology, Gustavs Latkovskis; Lithuania:
11.Acknowledgements Lithuanian Society of Cardiology, Pranas Serpytis; Luxembourg: Lux-
embourg Society of Cardiology, Bruno Pereira; Malta: Maltese Cardiac
Society, Caroline Jane Magri; Moldova: Moldavian Society of Cardi-
We are indebted to Veronica Dean, Nathalie Cameron, Catherine
ology, Aurel Grosu; Morocco: Moroccan Society of Cardiology, Saadia
DespresandtheentireESCPracticeGuidelinesStafffortheirinvalu-
Abir-Khalil;Norway:NorwegianSocietyofCardiology,AlfIngeLarsen;
able support throughout the project. Poland: Polish Cardiac Society, Andrzej Budaj; Portugal: Portuguese
Society of Cardiology, Jorge M. Vieira Mimoso; Romania: Romanian
Society of Cardiology, Carmen Ginghina; Russia: Russian Society of
12.Appendix Cardiology, Oleg Averkov; Serbia: Cardiology Society of Serbia, Milan
A. Nedeljkovic; Slovakia: Slovak Society of Cardiology, Martin Studen-
c an; Spain: Spanish Society of Cardiology, Jose A. Barrabe s; Sweden:
ESC Committee for Practice Guidelines (CPG): Jose Luis Zamorano
SwedishSocietyofCardiology,ClaesHeld;Switzerland:SwissSociety
(Chairperson) (Spain), Victor Aboyans (France), Stephan Achenbach Hans Rickli; The Netherlands: Netherlands Society of
of Cardiology,
(Germany), Stefan Agewall (Norway), Lina Badimon (Spain), Gonzalo
Cardiology, Ron J.G. Peters; Tunisia: Tunisian Society of Cardiology
Baro n-Esquivias (Spain), Helmut Baumgartner (Germany), Jeroen J. Bax
andCardio-VascularSurgery,MohamedSami Mourali;Turkey:Turkish
(TheNetherlands),He ctorBueno(Spain),ScipioneCarerj (Italy),Veron-
SocietyofCardiology,EnverAtalar; UK:British Cardiovascular Society,
ica Dean (France), etin Erol (Turkey), Donna FitzsimonsNeil(UK), OliverUkraine: Ukrainian Association of Cardiology, Alexan-
Swanson;
Gaemperli (Switzerland), Paulus Kirchhof (UK/Germany), Philippe Kolh
der Parkhomenko.
(Belgium), Patrizio Lancellotti (Belgium), Gregory Y.H. Lip (UK), Petros
Section Coordinators afliations: Jean-Philippe Collet, ACTION
Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotrstudy
Ponikowski
Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitie -
(Poland), Marco Rof (Switzerland), Adam Torbicki (Poland),
SalpeAntonio
trie `re Hospital (AP-HP), Sorbonne Universite s UPMC (Paris 6),
Vaz Carneiro (Portugal), Stephan Windecker (Switzerland).
F-75013 Paris, France, Tel: +33 1 42 16 30 13, Fax: +33 1 42 16 29
ESC National Cardiac Societies actively involved in the31,review
Email: jean-philippe.collet@psl.aphp.fr
process of the 2015 ESC Guidelines for the Management of Acute
Christian Cor- Department of Cardiology, University Hospital
Mueller,
onarySyndromesinPatientsPresentingWithoutPersistentST-Segment
Basel, Petersgraben 4, CH-4031 Basel, Switzerland, Tel: +41 61 265
Elevation: 25 25, Fax: +41 61 265 53 53, Email: christian.mueller@usb.ch
Armenia: Armenian Cardiologists Association, Aram Chilingaryan;
Marco Valgimigli: Thoraxcenter, Erasmus MC, s Gravendijkwal 230,
Austria: Austrian Society of Cardiology, Franz Weidinger;
3015 Azerbai-
CE Rotterdam, The Netherlands, Tel: +31 10 7033938,
jan: Azerbaijan Society of Cardiology, Ruslan Najafov;Fax:
Belgium:
+31 10 7035258, Email: m.valgimigli@erasmusmc.nl
BelgianSocietyofCardiology,PeterR.Sinnaeve;Bosnia&Herzegov-
ina: Association of Cardiologists of Bosnia & Herzegovina, Ibrahim
Terzic ;Bulgaria:Bulgarian SocietyofCardiology,Arman Postadzhiyan;
Croatia: Croatian Cardiac Society, Davor Milic ic ; Cyprus: Cyprus So-
ciety of Cardiology, Christos Eftychiou; Czech Republic: Czech Soci-
ety of Cardiology, Petr Widimsky; Denmark: Danish Society of

The CME text 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation is accredited
by the European
Board for Accreditation in Cardiology (EBAC). EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical
Education (EACCME),
which is an institution of the European Union of Medical Specialists (UEMS). In compliance with EBAC/EACCME Guidelines, all authors participating in this
programme have disclosed
any potential conicts of interest that might cause a bias in the article. The Organizing Committee is responsible for ensuring that all potential conicts of interest
relevant to the
programme are declared to the participants prior to the CME activities.
CME questions for this article are available at: European Heart Journal http://www.oxforde-learning.com/eurheartj and European Society of Cardiology
http://www.escardio.org/
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