Anda di halaman 1dari 59

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

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

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 ESC Guidelines

The burden of late CV events despite optimal pharmacological


treatment, including effective P2Y12 inhibitors and statins, Invasive strategy
5 An immediate invasive strategy (,2 h) is
calls recommendedinpatientswithatleastone
forreappraisalofthepathophysiologyoftheseadverseoutcomes of the following very-high-risk criteria:
and innovative preventive strategies. haemodynamic instability or cardiogenic
Clinical trials areunder wayto examinewhethera profound LDL shock; recurrent or ongoing chest pain
cholesterollowering or immune-modulating therapy (e.g. refractory to medical treatment;
PCSK-9 inhibition, intense CETP inhibition, methotrexate or life-threatening arrhythmias or cardiac I C
monoclonalanti-IL-1b antibodies) in addition to maximally arrest; mechanical complications of MI;
toler- acute heart failure with refractory
ated statin treatment may improve long-term prognosis. angina
or ST deviation; recurrent dynamic ST-
Theoptimalhaemoglobin/haematocritthresholdthatshouldtrig- or
ger blood transfusion in anaemic patients with NSTE-ACS T-wave changes, particularly with
needs intermittent ST elevation.
to be determined. 6 An early invasive strategy (,24 h) is
recommendedinpatientswithatleastone
of the following high-risk criteria: rise or
fallincardiactroponincompatiblewithMI;
9.To do and not to do messages dynamic ST- or T-wave changes
I A

from the guidelines (symptomatic or silent); GRACE score


.140.

7 An invasive strategy (,72 h) is


recommendedinpatientswithatleasto
ne
of the following intermediate-risk
criteria:
Recommendations Classa Levelb
W diabetes mellitus
W renal insufciency (eGFR ,60 mL/
Diagnosis min/1.73 m2) I A
1 Similarlytothe0hand3hprotocol,arapid W LVEF ,40% or congestive heart
rule-out and rule-in protocol at 0 h and 1 h failure
is recommended if a high-sensitivity cardiac W early post-infarction angina
troponin test with a validated 0 h/1 h I B W recent PCI
algorithmisavailable.Additionaltestingafter W prior CABG
36 h is indicated if the rst two troponin W GRACEriskscore .109and ,140,
measurements are not conclusive and the or recurrent symptoms or known
clinical condition is still suggestive of ACS. ischaemia on non-invasive testing.
Coronary revascularization
2 Echocardiography is recommended 8 In centres experienced with radial
to I C access,
a radial approach is Irecommended
A
evaluateregionalandglobalLVfunctionan for
d coronary angiography and PCI.
Antiplatelet treatment 9 In patients with multivessel CAD, it is
to rule
3 A P2Y in or rule out differential
12 inhibitor is recommended, in
diagnoses. recommended to base the
addition to aspirin, for 12 months unless revascularization strategy (e.g. ad hoc
there are contraindications
I Asuch as culprit-lesionPCI,multivesselPCI,CABG)
excessive risk of bleeds. on the clinical status and comorbidities as I C
well as the disease severity (including
distribution, angiographic lesion
Ticagrelor (180mg loading dose, 90mg characteristics,SYNTAXscore) according
twice daily) is recommended, in the to the local Heart Team protocol.
absence of contraindications,c for all
patients at moderate to high risk of Secondary cardiovascular prevention
I B
ischaemic events (e.g. elevated cardiac 10 It is recommended to start high-
troponins),regardlessofinitialtreatment intensity
strategy and including those pretreated I as
statin therapy as early A possible,
with clopidogrel (which should be unless
discontinued when ticagrelor is started). contraindicated, and maintainit
Prasugrel (60 mg loading dose, 10 longterm.
mg I B ACS acute coronary syndromes; CABG coronary artery bypass graft;
daily dose) is recommended in CAD coronary artery disease; eGFR estimated glomerular ltration rate;
patients GRACE Global Registry of Acute Coronary Events; LV left ventricular;
who are proceeding to PCI if there LVEF left ventricular ejection fraction; MI myocardial infarction; PCI
Clopidogrel
are (300600 mg loading dose, percutaneous coronary intervention; SYNTAX SYNergy between
75
nomg daily dose) is recommended
contraindications. c for percutaneous coronary intervention with TAXus and cardiac surgery.
I receive
B aClass of recommendation.
patients who cannot ticagrelor
bLevel of evidence.
or prasugrel or who require oral
cContraindications for ticagrelor: previous intracranial haemorrhage or
anticoagulation.
ongoing
bleeds.Contraindicationsforprasugrel:previousintracranialhaemorrhage,prev
4 It is not recommended to administer III B ious
ischaemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel
prasugrel in patients in whom the is
coronary anatomy is not known. 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/
guidelines. Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W,
13.References Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC,
Armstrong PW, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G,
1. Steg PG, James SK, Atar D, Badano LP, Blomstrom-LundqvistLuepkerC, BorgerRV,MA, Di
Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D,
Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, GershlickLopez-Sendon
AH, JL, Robertson RM, Weaver D, Tendera M, Bove AA,
Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Parkhomenko
Lenzen MJ, AN, Vasilieva EJ, Mendis S. Third universal denition of myocardial
Mahaffey KW, Valgimigli M, van t Hof A, Widimsky P, Zahger D. ESC guidelines
infarction. Eur Heart J 2012;33:25512567.
for the management of acute myocardial infarction in patients presenting
3. Roe with
MT, Harrington RA, Prosper DM, Pieper KS, Bhatt DL, Lincoff AM,
ST-segment elevation. Eur Heart J 2012;33:25692619. Simoons ML, Akkerhuis M, Ohman EM, Kitt MM, Vahanian A, Ruzyllo W,
2. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, WhiteKarschHD,K, Katus HA, Topol EJ. Clinical and therapeutic prole of patients present-
Califf RM,
Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM, ing Johanson
with acuteP,coronary syndromes who do not have signicant coronary artery
Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA,
310 ESC Guidelines

disease. The Platelet Glycoprotein IIb/IIIa in Unstable Angina:


specicReceptor
chestpainSuppres-
characteristics inthe early diagnosis of acute myocardialinfarc-
sion Using Integrilin Therapy (PURSUIT) trial investigators. tion.
Circulation
JAMA Intern2000;102:
Med 2014;174:241249.
11011106. 25. Persson A, Hartford M, Herlitz J, Karlsson T, Omland T, Caidahl K. Long-term
4. Reynolds HR, Srichai MB, Iqbal SN, Slater JN, Mancini GB, prognostic
Feit F, Pena-Sing value I, of mitral regurgitation in acute coronary syndromes. Heart
Axel L, Attubato MJ, Yatskar L, Kalhorn RT, Wood DA, Lobach2010;96:18031808.
IV,
Hochman JS. Mechanisms of myocardial infarction in women 26. Grani
without C, angio-
Senn O, Bischof M, Cippa PE, Hauffe T, Zimmerli L, Battegay E,
graphically obstructive coronary artery disease. CirculationFranzen
2011;124: D. Diagnostic performance of reproducible chest wall tenderness to
14141425. rule out acute coronary syndrome in acute chest pain: a prospective diagnostic
5. LarsenAI,GalbraithPD,GhaliWA,NorrisCM,GrahamMM,KnudtsonML.Char-
study. BMJ Open 2015;5:e007442
acteristics and outcomes of patients with acute myocardial 27.infarction
Devon HA, andRosenfeld
angio- A, Steffen AD, Daya M. Sensitivity, specicity, and sex dif-
graphically normal coronary arteries. Am J Cardiol 2005;95:261263.
ferences in symptoms reported on the 13-item acute coronary syndrome check-
6. Thygesen K, Mair J, Giannitsis E, Mueller C, Lindahl B, Blankenberg
list. J Am Heart
S, Huber AssocK, 2014;3:e000586
Plebani M, Biasucci LM, Tubaro M, Collinson P, Venge P, Hasin28. DiercksDB,PeacockWF,HiestandBC,ChenAY,
Y, Galvani M, PollackCVJr,KirkJD, SmithSC
Koenig W, Hamm C, Alpert JS, Katus H, Jaffe AS. How to useJr,high-sensitivity
Gibler WB, Ohman car- EM, Blomkalns AL, Newby LK, Hochman JS, Peterson ED,
diac troponins in acute cardiac care. Eur Heart J 2012;33:22522257.
Roe MT. Frequency and consequences of recording an electrocardiogram .10
7. Braunwald E, Morrow DA. Unstable angina: is it time for a minutes
requiem? after
Circulation
arrival in an emergency room in non-ST-segment elevation acute
2013;127:24522457. coronary syndromes (from the CRUSADE initiative). Am J Cardiol 2006;97:
8. Mueller C. Biomarkers and acute coronary syndromes: an 437442.update. Eur Heart J
2014;35:552556. 29. Okamatsu K, Takano M, Sakai S, Ishibashi F, Uemura R, Takano T, Mizuno K. Ele-
9. Reichlin T, Twerenbold R, Maushart C, Reiter M, Moehring vated
B, Schaubtroponin
N, T levels and lesion characteristics in non-ST-elevation acute cor-
Balmelli C, Rubini Gimenez M, Hoeller R, Sakarikos K, Drexler onary B, Haaf
syndromes.
P, Circulation 2004;109:465470.
Osswald S, Mueller C. Risk stratication in patients with unstable
30. Reichlin
angina T, Hochholzer
using ab- W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S,
solute serial changes of 3 high-sensitive troponin assays. Am SchaubHeartN,J 2013;165:
Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R,
371378, e373. Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with
10. Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, Balmelli
sensitive C,cardiac
Winklertroponin
K, assays. N Engl J Med 2009;361:858867.
Kurz S, Stelzig C, Freese M, Drexler B, Haaf P, Zellweger C, 31.Osswald
Keller T,S,Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, Bickel C, Baldus S,
Mueller C. Introduction of high-sensitivity troponin assays: Warnholtz
impact on A, myocardial
Frohlich M, Sinning CR, Eleftheriadis MS, Wild PS, Schnabel RB,
infarction incidence and prognosis. Am J Med 2012;125:12051213,
Lubos E,e1201.Jachmann N, Genth-Zotz S, Post F, Nicaud V, Tiret L, Lackner KJ,
11. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Munzel
Robertson
TF, Blankenberg
DH, S. Sensitive troponin I assay in early diagnosis of acute
Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub myocardial
WS, infarction. N Engl J Med 2009;361:868877.
Braunwald E. Ability of minor elevations of troponins I and 32.
T toKeller
predict
T, Zeller
benetT, Ojeda F, Tzikas S, Lillpopp L, Sinning C, Wild P, Genth-Zotz S,
from an early invasive strategy in patients with unstable angina
Warnholtzand non-ST
A, Giannitsis
eleva-E, Mockel M, Bickel C, Peetz D, Lackner K, Baldus S,
tion myocardial infarction: results from a randomized trial. Munzel
JAMA 2001;286:
T, Blankenberg S. Serial changes in highly sensitive troponin I assay and
24052412. early diagnosis of myocardial infarction. JAMA 2011;306:26842693.
12. Bugiardini R, Manfrini O, De Ferrari GM. Unanswered questions
33. GiannitsisE,
for management
BeckerM, Kurz K,Hess G,Zdunek D, KatusHA. High-sensitivitycar-
of acute coronarysyndrome:risk stratication of patients with diacminimal
troponin disease
T for or
early prediction of evolving non-ST-segment elevation myo-
normal ndings on coronary angiography. Arch Intern Med 2006;166:13911395.
cardial infarction in patients with suspected acute coronary syndrome and
13. Wallentin L, Lindholm D, Siegbahn A, Wernroth L, Becker negative
RC, Cannon troponin
CP, results on admission. Clin Chem 2010;56:642650.
Cornel JH, Himmelmann A, Giannitsis E, Harrington RA, Held 34. C,
Haaf
Husted
P, Drexler
S, B, Reichlin T, Twerenbold R, Reiter M, Meissner J, Schaub N,
Katus HA, Mahaffey KW, Steg PG, Storey RF, James SK. Biomarkers
Stelzig C,inFreese
relation M, Heinzelmann A, Meune C, Balmelli C, Freidank H,
to the effects of ticagrelor in comparison with clopidogrel inWinkler
non-ST-elevation
K, Denhaerynck K, Hochholzer W, Osswald S, Mueller C. High-
acute coronary syndrome patients managed with or without sensitivity
in-hospital cardiac
revascu- troponin in the distinction of acute myocardial infarction
larization:asubstudyfromtheProspectiveRandomizedPlateletInhibitionandPa-
from acute cardiac noncoronary artery disease. Circulation 2012;126:3140.
tient Outcomes (PLATO) trial. Circulation 2014;129:293303. 35. Apple FS. A new season for cardiac troponin assays: its time to keep a scorecard.
14. LibbyP.Mechanismsofacutecoronarysyndromesandtheirimplicationsforther-
Clin Chem 2009;55:13031306.
apy. N Engl J Med 2013;368:20042013. 36. Rubini Gimenez M, Hoeller R, Reichlin T, Zellweger C, Twerenbold R, Reiter M,
15. BadimonL, Padro T, Vilahur G. Atherosclerosis,plateletsand Moehring
thrombosisinacute
B, Wildi K, Mosimann T, Mueller M, Meller B, Hochgruber T, Ziller R,
ischaemic heart disease. Eur Heart J Acute Cardiovasc CareSou 2012;1:6074.
SM, Murray K, Sakarikos K, Ernst S, Gea J, Campodarve I, Vilaplana C, Haaf P,
16. Davi G, Patrono C. Platelet activation and atherothrombosis.Steuer N Engl
S, Minners
J Med 2007;J, Osswald S, Mueller C. Rapid rule out of acute myocardial in-
357:24822494. farction using undetectable levels of high-sensitivity cardiac troponin. Int J Cardiol
17. McManus DD, Gore J, Yarzebski J, Spencer F, Lessard D, Goldberg
2013;168:38963901.
RJ. Recent
trends in the incidence, treatment, and outcomes of patients 37. Agewall
with STEMI S, Giannitsis
and E, Jernberg T, Katus H. Troponin elevation in coronary vs.
NSTEMI. Am J Med 2011;124:4047. non-coronary disease. Eur Heart J 2011;32:404411.
18. Savonitto S, Ardissino D, Granger CB, Morando G, Prando 38.MD,
Goodacre
MafriciSW, A, Bradburn M, Cross E, Collinson P, Gray A, Hall AS. The Rando-
Cavallini C, Melandri G, Thompson TD, Vahanian A, Ohman misedAssessmentofTreatmentUsingPanelAssayofCardiacMarkers(RATPAC)
EM, Califf RM,
Van de Werf F, Topol EJ. Prognostic value of the admission electrocardiogram
trial: a randomised controlled trial of point-of-care cardiac markers in the emer-
in acute coronary syndromes. JAMA 1999;281:707713. gency department. Heart 2011;97:190196.
19. Mandelzweig L, Battler A, Boyko V, Bueno H, Danchin N, 39.
Filippatos
Reichlin G, T, Gitt
Schindler
A, C, Drexler B, Twerenbold R, Reiter M, Zellweger C,
Hasdai D, Hasin Y, Marrugat J, Van de Werf F, Wallentin L, Behar
Moehring S. The B, Second
Ziller R, Hoeller R, Rubini Gimenez M, Haaf P, Potocki M, Wildi K,
Euro Heart Survey on Acute Coronary Syndromes: characteristics,
BalmelliC,FreeseM,StelzigC,FreidankH,OsswaldS,MuellerC.One-hour
treatment, rule-
and outcome of patients with ACS in Europe and the Mediterranean
out and rule-inbasin of in acute myocardial infarction using high-sensitivity cardiac tropo-
2004. Eur Heart J 2006;27:22852293. nin T. Arch Intern Med 2012;172:12111218.
20. Terkelsen CJ, Lassen JF, Norgaard BL, Gerdes JC, Jensen40. T, Gotzsche
Reichlin T, LB,Irfan A, Twerenbold R, Reiter M, Hochholzer W, Burkhalter H,
Nielsen TT, Andersen HR. Mortality rates in patients with ST-elevation
Bassetti S, Steuervs. S, Winkler K, Peter F, Meissner J, Haaf P, Potocki M,
non-ST-elevation acute myocardial infarction: observationsDrexlerB,OsswaldS,MuellerC.Utilityofabsoluteandrelativechangesincardiac
from an unselected
cohort. Eur Heart J 2005;26:1826. troponin concentrations in the early diagnosis of acute myocardial infarction. Cir-
21. Campeau L. Letter: grading of angina pectoris. Circulation culation
1976;54:522523.
2011;124:136145.
22. Canto JG, Fincher C, Kiefe CI, Allison JJ, Li Q, Funkhouser41.
E, Irfan
Centor A, RM,
Twerenbold R, Reiter M, Reichlin T, Stelzig C, Freese M, Haaf P,
Selker HP, Weissman NW. Atypical presentations among Medicare Hochholzer beneciaries
W, Steuer S, Bassetti S, Zellweger C, Freidank H, Peter F,
with unstable angina pectoris. Am J Cardiol 2002;90:248253. Campodarve I, Meune C, Mueller C. Determinants of high-sensitivity troponin
23. MackayMH,RatnerPA,JohnsonJL,HumphriesKH,BullerCE.Genderdifferences
T among patients with a noncardiac cause of chest pain. Am J Med 2012;125:
in symptoms of myocardial ischaemia. Eur Heart J 2011;32:31073114.
491498, e491.
24. Rubini Gimenez M, Reiter M, Twerenbold R, Reichlin T, Wildi42. Konstantinides
K, Haaf P, Wicki SV, K,Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N,
Zellweger C, Hoeller R, Moehring B, Sou SM, Mueller M, Denhaerynck
Gibbs JS, HuismanK, MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J,
Meller B, Stallone F, Henseler S, Bassetti S, Geigy N, OsswaldMaack S, Mueller
C, Mayer C. Sex-
E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH,
ESC Guidelines 311

Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Krivoshei


Zompatori L,M.
Hillinger
2014 P, Herrmann T, Campodarve I, Rentsch K, Bassetti S,
ESC guidelines on the diagnosis and management of acute Osswald
pulmonary
S, Mueller
embolism.
C. One-hour rule-in and rule-out of acute myocardial infarc-
Eur Heart J 2014;35:30333069, 3069a3069k. tion using high-sensitivity cardiac troponin I. Am J Med 2015;128:861870.e4.
43. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo 56.
RD,ThanEggebrecht
M, CullenH, L, Reid CM, Lim SH, Aldous S, Ardagh MW, Peacock WF,
Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwoger Parsonage
M, Haverich WA,A, Ho HF, Ko HF, Kasliwal RR, Bansal M, Soerianata S, Hu D,
Iung B, Manolis AJ, Meijboom F, Nienaber CA, Rof M, Rousseau Ding R, H,Hua Q, Seok-Min K, Sritara P, Sae-Lee R, Chiu TF, Tsai KC, Chu FY,
Sechtem U, Sirnes PA,Allmen RS, Vrints CJ.2014 ESC guidelinesChen WK, onthe
Changdiagnosis
WH, Flaws DF, George PM, Richards AM. A 2-h diagnostic
andtreatmentofaorticdiseases:documentcoveringacuteandchronicaorticdis-
protocol to assess patients with chest pain symptoms in the Asia-Pacic region
eases of the thoracic and abdominal aorta of the adult. The (ASPECT):
Task Forcea prospective
for the observational validation study. Lancet 2011;377:
Diagnosis and Treatment of Aortic Diseases of the European 10771084.
Society of Cardi-
ology (ESC). Eur Heart J 2014;35:28732926. 57. Than M, Cullen L, Aldous S, Parsonage WA, Reid CM, Greenslade J, Flaws D,
44. Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Hammett
MorgenthalerCJ, BeamNG, DM, Ardagh MW, Troughton R, Brown AF, George P,
Bergmann A, Potocki M, Noveanu M, Breidthardt T, ChristFlorkowski
A, Boldanova CM, T,Kline JA, Peacock WF, Maisel AS, Lim SH, Lamanna A,
Merki R, Schaub N, Bingisser R, Christ M, Mueller C. Incremental
RichardsAM.2-houraccelerateddiagnosticprotocoltoassesspatientswithchest
value of copep-
tin for rapid rule out of acute myocardial infarction. J Ampainsymptomsusingcontemporarytroponinsastheonlybiomarker:theADAPT
Coll Cardiol 2009;54:
6068. trial. J Am Coll Cardiol 2012;59:20912098.
45. Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM,
58. Roth
Cullen A,L,Bickel
MuellerC, C, Parsonage WA, Wildi K, Greenslade JH, Twerenbold R,
Baldus S, Sinning CR, Wild PS, Lubos E, Peetz D, Kunde J,Aldous
Hartmann S, Meller
O, B,Tate JR, Reichlin T, Hammett CJ, Zellweger C,UngererJP, Ru-
Bergmann A, Post F, Lackner KJ, Genth-Zotz S, Nicaud V,bini TiretGimenez
L, Munzel M,TF,
Troughton R, Murray K, Brown AF, Mueller M, George P,
Blankenberg S. Copeptin improves early diagnosis of acute Mosimann
myocardial T, Flaws
infarction.
DF, Reiter M, Lamanna A, Haaf P, Pemberton CJ,
J Am Coll Cardiol 2010;55:20962106. Richards AM, Chu K, Reid CM, Peacock WF, Jaffe AS, Florkowski C, Deely JM,
46. Raskovalova T, Twerenbold R, Collinson PO, Keller T, Bouvaist
Than M.H,Validation
Folli C, of high-sensitivity troponin I in a 2-hour diagnostic strategy
Giavarina D, Lotze U, Eggers KM, Dupuy AM, Chenevier-Gobeaux toassess30-dayoutcomesinemergencydepartmentpatientswithpossibleacute
C,
Meune C, Maisel A, Mueller C, Labarere J. Diagnostic accuracycoronary of combined
syndrome. car-
J Am Coll Cardiol 2013;62:12421249.
diactroponinandcopeptinassessmentforearlyrule-outofmyocardialinfarction:
59. Twerenbold R, Wildi K, Jaeger C, Gimenez MR, Reiter M, Reichlin T,
a systematic review and meta-analysis. Eur Heart J AcuteWalukiewicz
Cardiovasc A, Care
Gugala
2014;3:
M, Krivoshei L, Marti N, Moreno Weidmann Z,
1827. Hillinger P, Puelacher C, Rentsch K, Honegger U, Schumacher C, Zurbriggen F,
47. Lipinski MJ, Escarcega RO, DAscenzo F, Magalhaes MA,FreeseM,Stelzig
Baker NC, Torguson C,CampodarveI,Bassetti
R, S, OsswaldS, Mueller C.Optimal cut-
Chen F, Epstein SE, Miro O, Llorens P, Giannitsis E, Lotze offU, levelsof
Lefebvremoresensitive
S, cardiac troponinassays for the early diagnosis of myo-
Sebbane M, Cristol JP, Chenevier-Gobeaux C, Meune C, Eggers cardialKM, infarction in patients with renal dysfunction. Circulation 2015;131:
Charpentier S, Twerenbold R, Mueller C, Biondi-Zoccai G,20412050.
Waksman R. A sys-
tematic review and collaborative meta-analysis to determine60. Tong the
KL,incremental
Kaul S, Wang va-XQ, Rinkevich D, Kalvaitis S, Belcik T, Lepper W,
lueofcopeptinforrapidrule-outofacutemyocardialinfarction.AmJCardiol2014;
Foster WA, Wei K. Myocardial contrast echocardiography versus thrombolysis
113:15811591. in myocardial infarction score in patients presenting to the emergency depart-
48. Mockel M, Searle J, Hamm C, Slagman A, Blankenberg S, mentHuberwithK,chest
Katuspain
H, and a nondiagnostic electrocardiogram. J Am Coll Cardiol
Liebetrau C, Muller C, Muller R, Peitsmeyer P, von Recum2005;46:920927.
J, Tajsic M,
VollertJO,GiannitsisE.Earlydischargeusingsinglecardiactroponinandcopeptin
61. Grenne B, Eek C, Sjoli B, Dahlslett T, Uchto M, Hol PK, Skulstad H, Smiseth OA,
testinginpatientswithsuspected acutecoronarysyndrome(ACS):arandomized,
Edvardsen T, Brunvand H. Acute coronary occlusion in non-ST-elevation acute
controlled clinical process study. Eur Heart J 2015;36:369376.
coronarysyndrome:outcome andearly identicationbystrain echocardiography.
49. Maisel A, Mueller C, Neath SX, Christenson RH, MorgenthalerHeart 2010;96:15501556.
NG, McCord J,
Nowak RM, Vilke G, Daniels LB, Hollander JE, Apple FS, 62. Cannon
Lancellotti
C, P, Price S, Edvardsen T, Cosyns B, Neskovic AN, Dulgheru R,
Nagurney JT, Schreiber D, deFilippi C, Hogan C, Diercks DB, Flachskampf
Stein JC, FA, Hassager C, Pasquet A, Gargani L, Galderisi M, Cardim N,
Headden G, Limkakeng AT Jr, Anand I, Wu AH, Papassotiriou HaugaaJ, Hartmann
KH, Ancion O, A, Zamorano JL, Donal E, Bueno H, Habib G. The use of
Ebmeyer S, Clopton P, Jaffe AS, Peacock WF. Copeptin helps echocardiography
in the early detec- in acute cardiovascular care: recommendations of the Euro-
tion of patients with acute myocardial infarction: primarypean resultsAssociation
of the CHOPIN
of Cardiovascular Imaging and the Acute Cardiovascular Care
trial (CopeptinHelps inthe early detection OfPatients withAssociation.
acute myocardialIN-
Eur Heart J Acute Cardiovasc Care 2015;4:35.
farction). J Am Coll Cardiol 2013;62:150160. 63. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A,
50. Balmelli C, Meune C, Twerenbold R, Reichlin T, Rieder S, Bugiardini
Drexler B, R,Rubini
Crea F, MG,Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK,
Mosimann T, Reiter M, Haaf P, Mueller M, Ernst S, Ballarino HulotP, Alafy
JS, Marx
AA, N, Opie LH, Psterer M, Prescott E, Ruschitzka F, Sabate M,
Zellweger C, Wildi K, Moehring B, Vilaplana C, Bernhard D, Senior
MerkR,S,Taggart DP, van der Wall EE, Vrints CJ, Zamorano JL,
Ebmeyer S, Freidank H, Osswald S, Mueller C. Comparison Baumgartner
of the performances
H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R,
of cardiac troponins, including sensitive assays, and copeptin
FerrariinR, theHasdai
diagnostic
D, Hoesof AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P,
acute myocardial infarction and long-term prognosis between Linhart women
A, Nihoyannopoulos
and men. P, Piepoli MF, Ponikowski P, Sirnes PA,
Am Heart J 2013;166:3037. Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Valgimigli M,
51. Body R, Carley S, McDowell G, Jaffe AS, France M, Cruickshank
Claeys MJ, K, Donner-Banzhoff
Wibberley C, N, Frank H, Funck-Brentano C, Gaemperli O,
Nuttall M,Mackway-Jones K. Rapid exclusionof acutemyocardial Gonzalez-Juanatey
infarctioninpa- JR, Hamilos M, Husted S, James SK, Kervinen K,
tients with undetectable troponin using a high-sensitivityKristensen
assay. J Am SD,Coll
Maggioni
Cardiol AP, Pries AR, Romeo F, Ryden L, Simoons ML,
2011;58:13321339. Steg PG, Timmis A, Yildirir A. 2013 ESC guidelines on the management of stable
52. Bandstein N, Ljung R, Johansson M, Holzmann MJ. Undetectable
coronary artery
high-sensitivity
disease: the Task Force on the Management of Stable Coronary
cardiac troponin T level in the emergency department and Artery
risk Disease
of myocardial
of thein-European Society of Cardiology. Eur Heart J 2013;34:
farction. J Am Coll Cardiol 2014;63:25692578. 29493003.
53. Zhelev Z, Hyde C, Youngman E, Rogers M, Fleming S,64. Slade
Shah T, BN,
Coelho
Balaji
H, G, Alhajiri A, Ramzy IS, Ahmadvazir S, Senior R. Incremental diag-
Jones-Hughes T, Nikolaou V. Diagnostic accuracy of single nostic
baseline
and measurement
prognostic value of contemporary stress echocardiography in a chest
of ElecsystroponinT high-sensitiveassay for diagnosis of acute
pain unit:
myocardial
mortality infarc-
and morbidity outcomes from a real-world setting. Circ Cardi-
tion in emergency department: systematic review and meta-analysis.
ovasc ImagingBMJ 2013;6:202209.
2015;
350:h15. 65. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P,
54. Reichlin T, Twerenbold R, Wildi K, Gimenez MR, Bergsma PoldermansD,VoigtJU,ZamoranoJL.Stressechocardiographyexpertconsensus
N, Haaf P, Druey S,
Puelacher C, Moehring B, Freese M, Stelzig C, Krivoshei L,statementexecutive
Hillinger P, Jager C,summary: European Association of Echocardiography
Herrmann T, Kreutzinger P, Radosavac M, Weidmann ZM,(EAE) Pershyna
(a registered
K, branch of the ESC). Eur Heart J 2009;30:278289.
Honegger U, Wagener M, Vuillomenet T, Campodarve I,66. Bingisser
Gaibazzi R,N,
Miro
Reverberi
O, C, Badano L. Usefulness of contrast stress-echocar-
Rentsch K, Bassetti S, Osswald S, Mueller C. Prospective diography
validation of or a
exercise-electrocardiography
1-hour to predict long-term acute coronary
algorithm to rule-out and rule-in acute myocardial infarctionsyndromes
using ain high-
patients presenting with chest pain without electrocardiographic
sensitivity cardiac troponin T assay. CMAJ 2015;187:E243E252.abnormalities or 12-hour troponin elevation. Am J Cardiol 2011;107:161167.
55. Rubini Gimenez M, Twerenbold R, Jaeger C, Schindler67. C, Puelacher
Gaibazzi N, C,Squeri
Wildi K,A, Reverberi C, Molinaro S, LorenzoniV, Sartorio D, Senior R.
Reichlin T, Haaf P, Merk S, Honegger U, Wagener M, Druey Contrast
S, Schumacher
stress-echocardiography
C, predicts cardiac events in patients with
312 ESC Guidelines

suspected acute coronary syndrome but nondiagnostic electrocardiogram


Platelet IIB/IIIA and antagonism for the reduction of acute global organization network.
normal 12-hour troponin. J Am Soc Echocardiogr 2011;24:13331341. J Am Coll Cardiol 2001;38:6471.
68. Ingkanisorn WP, Kwong RY, Bohme NS, Geller NL, Rhoads 86.KL,Mueller
Dyke CK, C,Neumann FJ, Perach W, Perruchoud AP, Buettner HJ.Prognosticvalue
Paterson DI, Syed MA, Aletras AH, Arai AE. Prognosis of negative of theadenosine
admission electrocardiogram in patients with unstable angina/
stress magnetic resonance in patients presenting to an emergency non-ST-segment
department elevation myocardial infarction treated with very early revascu-
with chest pain. J Am Coll Cardiol 2006;47:14271432. larization. Am J Med 2004;117:145150.
69. Kwong RY, Schussheim AE, Rekhraj S, Aletras AH, Geller 87. N, Davis
HolmvangJ, Christian
L, Clemmensen
TF, P, Lindahl B, Lagerqvist B, Venge P, Wagner G,
Balaban RS, Arai AE. Detecting acute coronary syndrome in Wallentin
the emergency L, Grandede- P. Quantitative analysis of the admission electrocardiogram
partment with cardiac magnetic resonance imaging. Circulation identies
2003;107:
patients with unstable coronary artery disease who benet the most
531537. from early invasive treatment. J Am Coll Cardiol 2003;41:905915.
70. Cury RC, Shash K, Nagurney JT, Rosito G, Shapiro MD, Nomura 88. TanNS,GoodmanSG,YanRT,ElbarouniB,Budaj
CH, Abbara S, A,FoxKA,GoreJM,BriegerD,
Bamberg F, Ferencik M, Schmidt EJ, Brown DF, Hoffmann U, Lopez-Sendon
Brady TJ. Cardiac J, Langer A, van de Werf F, Steg PG, Yan AT. Comparative prog-
magnetic resonance with T2-weighted imaging improves detection nostic value
of patients
of T-wave inversion and ST-segment depression on the admission
with acute coronary syndrome in the emergency department. electrocardiogram
Circulation 2008;in non-ST-segment elevation acute coronary syndromes.
118:837844. Am Heart J 2013;166:290297.
71. Lockie T, Nagel E, Redwood S, Plein S. Use of cardiovascular89. Rubini
magnetic Gimenezresonance
M, Twerenbold R, Reichlin T, Wildi K, Haaf P, Schaefer M,
imaging in acute coronary syndromes. Circulation 2009;119:16711681.
Zellweger C, Moehring B, Stallone F, Sou SM, Mueller M, Denhaerynck K,
72. Udelson JE, Beshansky JR, Ballin DS, Feldman JA, Grifth JL, Mosimann
Handler J, Heller T, Reiter
GV,M, Meller B, Freese M, Stelzig C, Klimmeck I, Voegele J,
Hendel RC, PopeJH, Ruthazer R, Spiegler EJ, Woolard RH, SelkerHP.Hartmann Myocardial
B, Rentsch K, Osswald S, Mueller C. Direct comparison of
perfusion imaging for evaluation and triage of patients with high-sensitivity-cardiac
suspected acute car- troponin I vs. T for the early diagnosis of acute myocardial in-
diac ischemia: a randomized controlled trial. JAMA 2002;288:26932700.
farction. Eur Heart J 2014;35:23032311.
73. Lim SH, Anantharaman V, Sundram F, Chan ES, Ang ES, 90. Yo SL,
HaafJacob
P, Reichlin
E, Goh A, T, Twerenbold R, Hoeller R, Rubini Gimenez M, Zellweger C,
Tan SB, Chua T. Stress myocardial perfusion imaging for the Moehring
evaluationB,and Fischer
triageC, Meller B, Wildi K, Freese M, Stelzig C, Mosimann T,
of chest pain in the emergency department: a randomized controlled
Reiter M, Mueller
trial. J Nucl
M, Hochgruber T, Sou SM, Murray K, Minners J, Freidank H,
Cardiol 2013;20:10021012. Osswald S, Mueller C. Risk stratication in patients with acute chest pain using
74. NabiF,ChangSM,XuJ,GigliottiE,MahmarianJJ.Assessingriskinacutechestpain:
three high-sensitivity cardiac troponin assays. Eur Heart J 2014;35:365375.
the value of stress myocardial perfusion imaging in patients 91.admitted
Thygesen through
K, MairtheJ, Mueller C, Huber K, Weber M, Plebani M, Hasin Y,
emergency department. J Nucl Cardiol 2012;19:233243. Biasucci LM, Giannitsis E, Lindahl B, Koenig W, Tubaro M, Collinson P, Katus H,
75. Samad Z, Hakeem A, Mahmood SS, Pieper K, Patel MR, Simel GalvaniM,VengeP,AlpertJS,HammC,JaffeAS.
DL, Douglas PS. A Recommendationsfortheuseof
meta-analysis and systematic review of computed tomography natriuretic
angiography peptidesas ain acute cardiac care: a position statement from the study
diagnostictriagetoolforpatientswithchestpainpresentingtotheemergencyde-
group on biomarkers in cardiology of the ESC working group on acute cardiac
partment. J Nucl Cardiol 2012;19:364376. care. Eur Heart J 2012;33:20012006.
76. Goldstein JA, Gallagher MJ, ONeill WW, Ross MA, ONeil BJ, 92.Raff
Aragam
GL. A rando-
KG, Tamhane UU, Kline-Rogers E, Li J, Fox KA, Goodman SG, Eagle KA,
mized controlled trial of multi-slice coronary computed tomography
Gurm HS. forDoesevalu-simplicity compromise accuracy in ACS risk prediction? A retro-
ation of acute chest pain. J Am Coll Cardiol 2007;49:863871.spective analysis of the TIMI and GRACE risk scores. PLoS One 2009;4:e7947.
77. Goldstein JA, Chinnaiyan KM, Abidov A, Achenbach S, Berman 93. deAraujoGoncalvesP,FerreiraJ,AguiarC,Seabra-GomesR.TIMI,PURSUIT,and
DS, Hayes SW,
Hoffmann U, Lesser JR, Mikati IA, ONeil BJ, Shaw LJ, Shen MY,GRACEriskscores:sustainedprognosticvalueandinteractionwithrevasculariza-
Valeti US,
Raff GL. The CT-STAT (coronary computed tomographic angiography tion in NSTE-ACS.
for sys- Eur Heart J 2005;26:865872.
tematic triage of acute chest pain patients to treatment) trial.
94. FoxJ Am KA,
Coll Fitzgerald
Cardiol G, Puymirat E, Huang W, Carruthers K, Simon T, Coste P,
2011;58:14141422. Monsegu J, Gabriel Steg P, Danchin N, Anderson F. Should patients with acute
78. Hoffmann U, Truong QA, Schoenfeld DA, Chou ET, Woodardcoronarydiseasebestratiedformanagementaccordingtotheirrisk?Derivation,
PK, Nagurney JT,
Pope JH, Hauser TH, White CS, Weiner SG, Kalanjian S, Mullins externalvalidation
ME, Mikati I, and outcomes using the updated GRACE risk score. BMJ Open
Peacock WF, Zakroysky P, Hayden D, Goehler A, Lee H, Gazelle 2014;4:e004425.
GS,
Wiviott SD, Fleg JL, Udelson JE. Coronary CT angiography versus
95. Foxstandard
KA, Anderson evalu-FA Jr, Dabbous OH, Steg PG, Lopez-Sendon J, Van de Werf F,
ation in acute chest pain. N Engl J Med 2012;367:299308. Budaj A, Gurnkel EP, Goodman SG, Brieger D. Intervention in acute coronary
79. Litt HI, Gatsonis C, Snyder B, Singh H, Miller CD, Entrikin DW,syndromes:
Leamingdo JM,patients undergo intervention on the basis of their risk character-
Gavin LJ, Pacella CB, Hollander JE. CT angiography for safe discharge
istics? The ofGlobal Registry of Acute Coronary Events (GRACE). Heart 2007;93:
patients with possible acute coronary syndromes. N Engl J Med 177182.
2012;366:
13931403. 96. Bawamia B, Mehran R, Qiu W, Kunadian V. Risk scores in acute coronary syn-
80. Hulten E, Pickett C, Bittencourt MS, Villines TC, Petrillo S, Di
drome
Carli and
MF, percutaneous coronary intervention: a review. Am Heart J 2013;
Blankstein R. Outcomes after coronary computed tomography 165:441450.
angiography in
theemergencydepartment:asystematicreviewandmeta-analysisofrandomized,
97. Scirica BM. Acute coronary syndrome: emerging tools for diagnosis and risk as-
controlled trials. J Am Coll Cardiol 2013;61:880892. sessment. J Am Coll Cardiol 2010;55:14031415.
81. Ayaram D, Bellolio MF, Murad MH, Laack TA, Sadosty AT,98. Erwin
ChangPJ, Hollander
WC, Boersma JE, E, Granger CB, Harrington RA, Califf RM, Simoons ML,
Montori VM, Stiell IG, Hess EP. Triple rule-out computed tomographic
Kleiman NS, angiog-Armstrong PW. Dynamic prognostication in non-ST-elevation acute
raphyfor chestpain: a diagnostic systematicreviewand meta-analysis.
coronary syndromes:
Acad Emerginsights from GUSTO-IIB and PURSUIT. Am Heart J 2004;
Med 2013;20:861871. 148:6271.
82. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, 99.Papuchis
Rahimi K, G, Watzlawek S, Thiele H, Secknus MA, Hayerizadeh BF, Niebauer J,
Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI riskSchuler score for G. unstable
Incidence, time course, and predictors of early malignant ventricular
angina/non-ST elevation MI: a method for prognostication and arrhythmias
therapeutic after
deci-non-ST-segment elevation myocardial infarction in patients
sion making. JAMA 2000;284:835842. with early invasive treatment. Eur Heart J 2006;27:17061711.
83. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, 100. Cannon
Piccini CP,JP, White
Van deJA, Mehta RH, Lokhnygina Y, Al-Khatib SM, Tricoci P, Pollack CV
Werf F, Avezum A, Goodman SG, Flather MD, Fox KA. Predictors Jr, Montalescot
of hospital G, Van de Werf F, Gibson CM, Giugliano RP, Califf RM,
mortality in the global registry of acute coronary events. Arch Harrington
Intern Med RA,2003;
Newby LK. Sustained ventricular tachycardia and ventricular
163:23452353. brillation complicating non-ST-segment-elevation acute coronary syndromes.
84. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van Circulation
de Werf F,2012;126:4149.
Avezum A, Goodman SG, Flather MD, Anderson FA Jr, Granger 101. CB.
Drew Prediction
BJ, Califf RM, Funk M, Kaufman ES, Krucoff MW, Laks MM, Macfarlane PW,
ofriskofdeathandmyocardialinfarctioninthesixmonthsafterpresentationwith
Sommargren C, Swiryn S, Van Hare GF. Practice standards for electrocardio-
acute coronary syndrome: prospective multinational observational graphicstudymonitoring in hospital settings: an American Heart Association scientic
(GRACE). BMJ 2006;333:1091. statement from the councils on cardiovascular nursing, clinical cardiology, and
85. Kaul P, FuY, Chang WC, Harrington RA, Wagner GS,GoodmanSG,Granger
cardiovascular CB, disease in the young: endorsed by the International Society of
Moliterno DJ, Van de Werf F, Califf RM, Topol EJ, Armstrong PW. Computerized
Prognostic va- Electrocardiology and the American Association of Critical-Care
lue of ST segment depression in acute coronary syndromes:Nurses. insightsCirculation
from 2004;110:27212746.
PARAGON-A applied to GUSTO-IIB. PARAGON-A and GUSTO IIB Investigators.
ESC Guidelines 313

102. DresslerR,DryerMM,ColettiC,MahoneyD,DooreyAJ.Alteringoveruseofcar-
therapy: results from the American College of Cardiologys NCDRw. Am Heart J
diac telemetry in non-intensive care unit settings by hardwiring 2011;161:864870.
the use of Ameri-
can Heart Association guidelines. JAMA Intern Med 2014;174:18521854.
121. Theroux P, Taeymans Y, Morissette D, Bosch X, Pelletier GB, Waters DD. A ran-
103. FoxKA,AndersonFAJr, Goodman SG,StegPG,PieperK,QuillA,GoreJM.Time
domized study comparing propranolol and diltiazem in the treatment of unstable
course of events in acute coronary syndromes: implications for angina.
clinical J Ampractice
Coll Cardiol 1985;5:717722.
from the grace registry. Nat Clin Pract Cardiovasc Med 2008;5:580589.
122. Parodi O, Simonetti I, Michelassi C, Carpeggiani C, Biagini A, LAbbate A,
104. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane Maseri AJ,A.Parise
Comparison
H, of verapamil and propranolol therapy for angina pectoris
Fahy M, Manoukian SV, Feit F, Ohman ME, Witzenbichler B, Guagliumiat rest: a G, randomized, multiple-crossover, controlled trial in the coronary care
Lansky AJ, Stone GW. A risk score to predict bleeding in patients unit.withAmacuteJ Cardiolcor-1986;57:899906.
onary syndromes. J Am Coll Cardiol 2010;55:25562566. 123. LubsenJ,TijssenJG.Efcacyofnifedipineandmetoprololintheearlytreatmentof
105. Steg PG, Huber K, Andreotti F, Arnesen H, Atar D, BadimonunstableL, Bassand angina
JP, De in the coronary care unit: ndings from the Holland Interuniver-
Caterina R, Eikelboom JA, Gulba D, Hamon M, Helft G, Fox KA,sity Kristensen
Nifedipine/Metoprolol
SD, Trial (HINT). Am J Cardiol 1987;60:18A25A.
Rao SV, Verheugt FW, WidimskyP, Zeymer U, Collet JP. Bleeding 124. Hansen
in acuteJF. coron-
Treatment with verapamil afteran acute myocardial infarction. Review
ary syndromes and percutaneous coronary interventions: position oftheDanishStudiesonVerapamilinMyocardialInfarction(DAVITIandII).Drugs
paper by the
working group on thrombosis of the European Society of Cardiology.1991;42(Suppl Eur Heart 2):4353.
J 2011;32:18541864. 125. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A,
106. Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, VarshavskyS,
Wang TY, WolffAA,SkeneA,McCabe CH,BraunwaldE. Effectsofranolazine
GiblerWB,OhmanEM,RoeMT,PollackCVJr,PetersonED,AlexanderKP.Base- on recurrent cardiovascular events in patients with non-ST-elevation acute cor-
lineriskofmajorbleedinginnon-ST-segment-elevationmyocardialinfarction:the
onary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297:
CRUSADE (Can Rapid risk stratication of Unstable angina patients 17751783.Suppress
ADverse outcomes with Early implementation of the ACC/AHA 126.guidelines)
Miller CD, Roe MT, Mulgund J, Hoekstra JW, Santos R, Pollack CV Jr, Ohman EM,
bleeding score. Circulation 2009;119:18731882. Gibler WB, Peterson ED. Impact of acute beta-blocker therapy for patients with
107. Abu-Assi E, Raposeiras-Roubin S, Lear P, Cabanas-Grandio non-ST-segment
P, Girondo M, elevation myocardial infarction. Am J Med 2007;120:685692.
Rodriguez-Cordero M, Pereira-Lopez E, Romani SG, Gonzalez-Cambeiro
127. Yasue H,C,Takizawa A, Nagao M, Nishida S, Horie M, Kubota J, Omote S,
Alvarez-Alvarez B, Garcia-Acuna JM, Gonzalez-Juanatey JR. Comparing
Takaoka K, the
Okumura
pre- K. Long-term prognosis for patients with variant angina
dictive validity of three contemporary bleeding risk scores in and acute inuential
coronary factors.
syn- Circulation 1988;78:19.
drome. Eur Heart J Acute Cardiovasc Care 2012;1:222231. 128. Patrono C, Andreotti F, Arnesen H, Badimon L, Baigent C, Collet JP, De
108. Weber M, Bazzino O, Navarro Estrada JL, de Miguel R, Salzberg Caterina S, Fuselli
R, Gulba
JJ, D, Huber K, Husted S, Kristensen SD, Morais J, Neumann FJ,
Liebetrau C, Woelken M, Moellmann H, Nef H, Hamm C. Improved Rasmussendiagnostic LH, Siegbahn A, Steg PG, Storey RF, Van de Werf F, Verheugt F. Anti-
and prognostic performance of a new high-sensitive troponinplateletT assay agents in patientsfor the treatment and prevention of atherothrombosis. Eur Heart J
with acute coronary syndrome. Am Heart J 2011;162:8188. 2011;32:29222932.
109. Akkerhuis KM, Klootwijk PA, Lindeboom W, Umans VA, Meij 129.S,Risk
Kint of PP,myocardial infarction and death during treatment with low dose aspirin
Simoons ML. Recurrentischaemia during continuous multileadand ST-segment
intravenous mon- heparin in men with unstable coronary artery disease. The
itoring identies patients with acute coronary syndromes at high RISC risk
group.
of adverse
Lancet 1990;336:827830.
cardiac events; meta-analysis of three studies involving 995 130.
patients.
Lewis HD EurJr,
Heart
DavisJ JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE
2001;22:19972006. 3rd, SchnaperHW, LeWinterMM,LinaresE,PougetJM,SabharwalSC,CheslerE,
110. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger DeMots
J, Meinertz
H. Protective
T. effects of aspirin against acute myocardial infarction and
Emergencyroomtriageofpatientswithacutechestpainbymeansofrapidtesting
death in men with unstable angina. Results of a Veterans Administration cooperative
for cardiac troponin T or troponin I. N Engl J Med 1997;337:16481653.
study. N Engl J Med 1983;309:396403.
111. AntmanEM,TanasijevicMJ,ThompsonB,SchactmanM,McCabeCH,CannonCP,
131. Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M,
Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Stasiak Cardiac-specicJ, deGuise P, PelletierGB, Rinzler D, WatersDD. Aspirin, heparin, orboth
troponin I levels to predict the risk of mortality in patients with
to acute
treat acute
coronary unstable angina. N Engl J Med 1988;319:11051111.
syndromes. N Engl J Med 1996;335:13421349. 132. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G,
112. Scirica BM, Morrow DA, Budaj A, Dalby AJ, Mohanavelu S, Qin KostukJ, Aroesty
WJ, Melendez
J, LJ, Myers MG, Sackett DL, Sealey BJ, Tanser PH. Aspirin,
Hedgepeth CM, Stone PH, Braunwald E. Ischemia detected onsulnpyrazone,
continuous elec- or both in unstable angina. Results of a Canadian multicenter trial.
trocardiographyafteracute coronarysyndrome:observations fromthe N Engl JMERLIN-Med 1985;313:13691375.
TIMI 36 (metabolic efciency with ranolazine for less ischemia 133.in Antithrombotic Trialists Collaboration. Collaborative meta-analysis of rando-
non-ST-elevation acute coronary syndrome-thrombolysis in myocardial
mised trials infarc-
of antiplatelet therapy for prevention of death, myocardial infarction,
tion 36) trial. J Am Coll Cardiol 2009;53:14111421. and stroke in high risk patients. BMJ 2002;324:7186.
113. Nyman I, Wallentin L, Areskog M, Areskog NH, Swahn E. 134. Risk stratication
Mehta SR,BassandJP,Chrolavicius
by S,DiazR,EikelboomJW,FoxKA,GrangerCB,
early exercise testing after an episode of unstable coronary artery
Jolly S,disease.
Joyner CD, TheRupprecht HJ, Widimsky P, Afzal R, Pogue J, Yusuf S. Dose
RISC study group. Int J Cardiol 1993;39:131142. comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J
114. Amsterdam EA, Kirk JD, Diercks DB, Lewis WR, Turnipseed SD. MedImmediate
2010;363:930942. ex-
ercise testing to evaluate low-risk patients presenting to the 135.
emergency
Savi P, Labouret
depart- C, Delesque N, Guette F, Lupker J, Herbert JM. P2Y 12, a new
ment with chest pain. J Am Coll Cardiol 2002;40:251256. platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Commun
115. Stub D, Smith K, Bernard S, Nehme Z, Stephenson M, Bray2001;283:379383.
JE, Cameron P,
Barger B, Ellims AH, Taylor AJ, Meredith IT, Kaye DM. Air versus
136. oxygen
Savi P, Herbert
in JM. Clopidogrel and ticlopidine: P2Y12 adenosine
ST-segment-elevation myocardial infarction. Circulation 2015;131:21432150.
diphosphate-receptorantagonists for the prevention of atherothrombosis. Semin
116. Borzak S, Cannon CP, Kraft PL, Douthat L, Becker RC, Palmeri ThrombST, HenryHemost T, 2005;31:174183.
HochmanJS,FuchsJ,Antman EM,McCabe C,BraunwaldE. Effectsofprioraspirin
137. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopido-
and anti-ischemic therapy on outcome of patients with unstable grelangina.
in addition TIMIto 7 aspirin in patients with acute coronary syndromes without
Investigators. Thrombin inhibition in myocardial ischemia. AmST-segment
J Cardiol 1998;81:elevation. N Engl J Med 2001;345:494502.
678681. 138. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K,
117. Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5
Rupprecht inhibitors
H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment
used for the treatment of erectile dysfunction or pulmonary hypertension.
withclopidogrelandaspirinfollowedbylong-termtherapyinpatientsundergoing
Circulation 2010;122:8895. percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:
118. Yusuf S, Wittes J, Friedman L. Overview of results of randomized
527533. clinical trials in
heart disease. I. Treatments following myocardial infarction. 139.
JAMA Parodi
1988;260:
G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, Buonamici P,
20882093. Gensini GF, Abbate R, Antoniucci D. High residual platelet reactivity after clopi-
119. Chatterjee S, Chaudhuri D, Vedanthan R, Fuster V, Ibanez B, dogrel
Bangalore
loading S,and long-term cardiovascular events among patients with acute
Mukherjee D. Early intravenous beta-blockers in patients withcoronaryacute coronarysyndromes undergoing PCI. JAMA 2011;306:12151223.
syndromea meta-analysis of randomized trials. Int J Cardiol140. 2013;168:915921.
Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I,
120. Kontos MC, Diercks DB, Ho PM, Wang TY, Chen AY, Roe MT.NovikovI,PresH,SavionN,VaronD,HodH.Clopidogrelresistanceisassociated
Treatment and
outcomes in patients with myocardial infarction treated with with acuteincreased
beta-blocker risk of recurrent atherothrombotic events in patients with acute
myocardial infarction. Circulation 2004;109:31713175.
314 ESC Guidelines

141. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM,Skerjanec Ferenc M,S,Gick BhattM,DL. Platelet inhibition with cangrelor in patients undergoing
Caputo A, Buttner HJ, Neumann FJ. Impact of the degree of peri-interventional
PCI. N Engl J Med 2009;361:23182329.
plateletinhibitionafterloadingwithclopidogrelonearlyclinicaloutcomeofelect-
159. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G,
ive coronary stent placement. J Am Coll Cardiol 2006;48:17421750. Kleiman NS, Goodman SG, White HD, Mahaffey KW, Pollack CV Jr,
142. Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schomig A,Manoukian
Kastrati A, SV, von Widimsky P, Chew DP, Cura F, Manukov I, Tousek F, Jafar MZ,
Beckerath N. Platelet reactivity after clopidogrel treatment assessed
Arneja J,with Skerjanec S, Harrington RA. Intravenous platelet blockade with cangre-
point-of-care analysis and early drug-eluting stent thrombosis. lorJ Am
duringCollPCI.
Cardiol
N Engl J Med 2009;361:23302341.
2009;53:849856. 160. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ,
143. Aradi D, Storey RF, Komocsi A, Trenk D, Gulba D, Kiss RG, Husted Leonardi S, S,
Bonello
GallupL,D, Bramucci E, Radke PW, Widimsky P, Tousek F, Tauth J,
Sibbing D, Collet JP, Huber K. Expert position paper on the role Spriggs
of platelet
D, McLaurin
func- BT, Angiolillo DJ, Genereux P, Liu T, Prats J, Todd M,
tion testinginpatients undergoing percutaneous coronaryintervention.SkerjanecS,WhiteHD,Harrington
Eur Heart RA.Effectofplateletinhibitionwithcangrelor
J 2014;35:209215. during PCI on ischemic events. N Engl J Med 2013;368:13031313.
144. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet161. E, Meneveau
StegPG,BhattDL,HammCW,StoneGW,GibsonCM,MahaffeyKW,LeonardiS,
N,
Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants Liu T, Skerjanec
of re- S, Day JR, Iwaoka RS, Stuckey TD, Gogia HS, Gruberg L,
sponse to clopidogrel and cardiovascular events. N Engl J MedFrenchWJ,WhiteHD,
2009;360: Harrington RA.Effect of cangreloronperiproceduralout-
363375. comes in percutaneous coronary interventions: a pooled analysis of patient-level
145. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot
data. L, Brugier
Lancet 2013;382:19811992.
D,
Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot 162. Hamm
G. Cytochrome
CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D,
P450 2C19 polymorphism in young patients treated with clopidogrel Gielen S, after
Hubermyo-K,Ohman M,PetrieMC, Sonntag F, Uva MS,StoreyRF, Wijns W,
cardial infarction: a cohort study. Lancet 2009;373:309317. Zahger D. ESC guidelines for the management of acute coronary syndromes in
146. Gurbel PA, Tantry US, Shuldiner AR, Kereiakes DJ. Genotyping: patients
one piece
presenting
of the without persistent ST-segment elevation: the Task Force
puzzle to personalize antiplatelet therapy. J Am Coll Cardiol 2010;56:112116.
for the management of acute coronary syndromes (ACS) in patients presenting
147. CaylaG,HulotJS,OConnorSA,PathakA,ScottSA,GruelY,SilvainJ,VignalouJB,
without persistent ST-segment elevation of the European Society of Cardiology
Huerre Y, de la Briolle A, Allanic F, Beygui F, Barthelemy O, Montalescot
(ESC). Eur Heart G, J 2011;32:29993054.
ColletJP.Clinical,angiographic,andgeneticfactorsassociatedwithearlycoronary
163. Bellemain-Appaix A,Brieger D, BeyguiF, Silvain J, PenaA, CaylaG, Barthelemy O,
stent thrombosis. JAMA 2011;306:17651774. Collet JP, Montalescot G. New P2Y12 inhibitors versus clopidogrel in percutan-
148. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo eouscoronaryintervention:ameta-analysis.JAmCollCardiol2010;56:15421551.
W, Gottlieb S,
Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer 164.
J, Weerakkody
MontalescotG, G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, ten
Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients Berg with
JM, acute
Miller cor-
DL, Costigan TM, Goedicke J, Silvain J, Angioli P, Legutko J,
onary syndromes. N Engl J Med 2007;357:20012015. Niethammer M, Motovska Z, Jakubowski JA, Cayla G, Visconti LO, Vicaut E,
149. De Servi S, Goedicke J, Schirmer A, Widimsky P. Clinical outcomesWidimsky forP.Pretreatmentwithprasugrelinnon-ST-segmentelevationacutecor-
prasugrel
versus clopidogrel in patients with unstable angina or non-ST-elevation
onary syndromes.myocar- N Engl J Med 2013;369:9991010.
dial infarction: an analysis from the TRITON-TIMI 38 trial. Eur 165.
HeartCollet
J Acute
JP, Silvain
Cardi-J, Bellemain-Appaix A, Montalescot G. Pretreatment with P2Y 12
ovasc Care 2014;3:363372. inhibitors in non-ST-segment-elevation acute coronary syndrome: an outdated
150. Pena A, Collet JP, Hulot JS, Silvain J, Barthelemy O, Beygui F, and Funck-Brentano
harmful strategy. C, Circulation 2014;130:19041914.
Montalescot G. Can we override clopidogrel resistance? Circulation
166. Valgimigli
2009;119: M. Pretreatment with P2Y12 inhibitors in non-ST-segment-elevation
28542857. acute coronary syndrome is clinically justied. Circulation 2014;130:18911903.
151. Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, 167.
Herrman
Stone JP,GW, VanWitzenbichler
de B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC,
Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM. Intensive Henryoral TD, antipla-
Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H,
telet therapy for reduction of ischaemic events including stent Kirtane
thrombosis
AJ, Brodie
in pa-BR, Mehran R, Stuckey TD. Platelet reactivity and clinical out-
tients with acute coronary syndromes treated with percutaneous comes coronary
after coronary artery implantation of drug-eluting stents (ADAPT-DES): a
intervention and stenting in the TRITON-TIMI 38 trial: a subanalysisprospectiveof a rando-
multicentre registry study. Lancet 2013;382:614623.
mised trial. Lancet 2008;371:13531363. 168. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S,
152. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C,RobbinsTeng R, M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari DE,
Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy StinisD, CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ. Standard-
Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment vs high-dose of the clopidogrel
on- based on platelet function testing after percutaneous
set andoffset of theantiplatelet effects of ticagrelorversusclopidogrelinpatients
coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:
with stable coronaryartery disease: the Onset/Offset study.Circulation2009;120:
10971105.
25772585. 169. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Muller U, Richardt G,
153. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson Jakubowski
H, Held C, Horrow JA, Neumann
J, FJ. A randomized trial of prasugrel versus clopidogrel
HustedS,JamesS,KatusH,MahaffeyKW,SciricaBM,SkeneA,StegPG,StoreyRF, in patients with high platelet reactivity on clopidogrel after elective percutaneous
Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel coronary
in patients
intervention
with with implantation of drug-eluting stents: results of the
acute coronary syndromes. N Engl J Med 2009;361:10451057.TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent
154. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann PlacementA,on Maya
Clopidogrel
J, to Guide Alternative Therapy With Prasugrel) study.
Husted S, Steg PG, Cornel JH, Storey RF, Stevens SR, Wallentin J AmL, James
Coll Cardiol
SK. Tica-2012;59:21592164.
grelorvs. clopidogrel inpatients with non-ST-elevation acutecoronarysyndrome
170. Collet JP, Cuisset T, Range G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P,
with or without revascularization: results from the PLATO trial.Carrie Eur Heart
D, Boueri
J 2014;Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monsegu J,
35:20832093. Sabouret P, OConnor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthelemy O,
155. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey BeyguiF,SilvainJ,VicautE,MontalescotG.Bedsidemonitoringtoadjustantiplate-
KW, Meier B,
StoreyRF,WojdylaDM,LewisBS,MaurerG,Wallentin L,JamesSK.Stentthrom- let therapy for coronary stenting. N Engl J Med 2012;367:21002109.
bosis with ticagrelor versus clopidogrel in patients with acute 171. coronary
Mega JL,syn- Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM,
dromes: an analysis from the prospective, randomized PLATOBraunwald trial. Circulation
E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardio-
2013;128:10551065. vascular outcomes after treatment with clopidogrel and prasugrel in the
156. Storey RF, Becker RC, Harrington RA, Husted S, James SK, Cools TRITON-TIMI
F, Steg 38 PG,trial: a pharmacogenetic analysis. Lancet 2010;376:13121319.
Khurmi NS, Emanuelsson H, Cooper A, Cairns R, Cannon CP, 172.
Wallentin
Trenk D, L. Hochholzer
Char- W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C,
acterization of dyspnoea in PLATO study patients treated withSchmiebusch
ticagrelor or P, clo-
Bestehorn HP, Buttner HJ, Neumann FJ. Cytochrome P450
pidogrel and its association with clinical outcomes. Eur Heart 2C19 J 2011;32:
681G.A polymorphism and high on-clopidogrel platelet reactivity asso-
29452953. ciated with adverse 1-year clinical outcome of elective percutaneous coronary
157. StoreyRF,OldroydKG,WilcoxRG.OpenmulticentrestudyoftheP2 intervention
Treceptor with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008;51:
antagonistAR-C69931MXassessingsafety,tolerabilityandactivityinpatientswith
19251934.
acute coronary syndromes. Thromb Haemost 2001;85:401407. 173. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR,
158. Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM,Antman Gibson EM, CM,Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic
Pollack CV Jr, Montalescot G, Mahaffey KW, Kleiman NS, Goodman polymorphisms
SG, and the response to prasugrel: relationship to pharmacokinetic,
Amine M, Angiolillo DJ, Becker RC, Chew DP, French WJ, Leischpharmacodynamic,
F, Parikh KH, and clinical outcomes. Circulation 2009;119:25532560.
ESC Guidelines 315

174. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl
ofdualantiplatelettherapyafterzotarolimus-elutingstents:theOPTIMIZErando-
M, Dick A,
Marquis JF, OBrien E, Goncalves S, Druce I, Stewart A, GollobmizedMH,trial.
So DY JAMA
. 2013;310:25102522.
Point-of-care genetic testing for personalisation of antiplatelet
189. Gwontreatment
HC, Hahn (RAPIDJY, Park KW, Song YB, Chae IH, Lim DS, Han KR, Choi JH,
GENE): a prospective, randomised, proof-of-concept trial. Lancet
Choi SH, 2012;379:
Kang HJ, Koo BK, Ahn T, Yoon JH, Jeong MH, Hong TJ, Chung WY,
17051711. Choi YJ, Hur SH, Kwon HM, Jeon DW, Kim BO, Park SH, Lee NH, Jeon HK,
175. Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt
Jang Y,FW, KimHuber
HS. Six-month
K, versus 12-month dual antiplatelet therapy after im-
Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atarplantation
D, Pathak of A, drug-eluting stents: the efcacy of xience/promus versus cypher
KjeldsenK,StoreyRF.Expertpositionpaperontheuseofprotonpumpinhibitors
to reduce late loss after stenting (EXCELLENT) randomized, multicenter study.
in patients with cardiovascular disease and antithromboticCirculation
therapy. Eur 2012;125:505513.
Heart J
2013;34:17081713, 1713a1713b. 190. Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, Castriota F,
176. Ho PM, Spertus JA, Masoudi FA, Reid KJ, Peterson ED, MagidColombo
DJ, Krumholz
F, Tebaldi HM,M, Fuca G, Kubbajeh M, Cangiano E, Minarelli M, Scalone A,
Rumsfeld JS. Impact of medication therapy discontinuationCavazza
on mortality C, Frangione
after A, Borghesi M, Marchesini J, Parrinello G, Ferrari R. Short-
myocardial infarction. Arch Intern Med 2006;166:18421847. versus long-term duration of dual-antiplatelet therapy after coronary stenting: a
177. Mehran R, Baber U, Steg PG, Ariti C, Weisz G, Witzenbichler
randomized
B, Henrymulticenter
TD, trial. Circulation 2012;125:20152026.
Kini AS, Stuckey T, Cohen DJ, Berger PB, Iakovou I, Dangas 191.G,ColomboA,ChieffoA,FrasheriA,GarboR,Masotti-CentolM,SalvatellaN,Oteo
Waksman R,
Antoniucci D, Sartori S, Krucoff MW, Hermiller JB, Shawl F, Dominguez
Gibson CM, JF, Steffanon L, Tarantini G, Presbitero P, Menozzi A, Pucci E, Mauri J,
Chieffo A, Alu M, Moliterno DJ, Colombo A, Pocock S. Cessation
CesanaBM,GiustinoG,SardellaG.Second-generationdrug-elutingstentimplant-
of dual antipla-
telet treatment and cardiac events after percutaneous coronary
ation followed
intervention by 6- versus 12-month dual antiplatelet therapy: the SECURITY
(PARIS): 2 year results from a prospective observational study.
randomized
Lancet 2013;clinical trial. J Am Coll Cardiol 2014;64:20862097.
382:17141722. 192. Schulz-Schupke S, Byrne RA, ten Berg JM, Neumann FJ, Han Y, Adriaenssens T,
178. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, LockhartTolg PB, Moliterno
R, Seyfarth DJ,M, Maeng M, Zrenner B, Jacobshagen C, Mudra H, von
OGara P, Whitlow P. Prevention of premature discontinuation Hodenberg
of dual antiplate-
E, Wohrle J, Angiolillo DJ, von Merzljak B, Rifatov N, Kufner S,
let therapy in patients with coronary artery stents: a science
Morath
advisoryT, Feuchtenberger
from the A, Ibrahim T, Janssen PW, Valina C, Li Y, Desmet W,
American Heart Association, American College of Cardiology, Abdel-Wahab
Society forM, Car-
Tiroch K, Hengstenberg C, Bernlochner I, Fischer M,
diovascular Angiography and Interventions, American College Schunkert
of Surgeons,
H, Laugwitzand KL, Schomig A, Mehilli J, Kastrati A. ISAR-SAFE: a rando-
American Dental Association, with representation from themized,
American double-blind,
College placebo-controlled trial of 6 vs. 12 months of clopidogrel ther-
of Physicians. Circulation 2007;115:813818. apy after drug-eluting stenting. Eur Heart J 2015;36:12521263.
179. Kristensen SD, Knuuti J, Saraste A, Anker S, Botker HE, 193.
Hert Gilard
SD, FordM, Barragan
I, P, Noryani AA, Noor HA, Majwal T, Hovasse T, Castellant P,
Gonzalez-Juanatey JR, Gorenek B, Heyndrickx GR, Hoeft A,Schneeberger
Huber K, Iung M, B, Maillard L, Bressolette E, Wojcik J, Delarche N, Blanchard D,
Kjeldsen KP, Longrois D, Luscher TF, Pierard L, Pocock S, Price
Jouve S, B,RofOrmezzano
M, O, Paganelli F, Levy G, Sainsous J, Carrie D, Furber A,
Sirnes PA, Sousa-Uva M, Voudris V, Funck-Brentano C. 2014 Berland
ESC/ESA J, Darremont
guidelines O, Le Breton H, Lyuycx-Bore A, Gommeaux A,
on non-cardiac surgery: cardiovascular assessment and management.
Cassat C, KermarrecEur Heart A,J Cazaux P, Druelles P, Dauphin R, Armengaud J,
2014;35:23832431. Dupouy P, Champagnac D, Ohlmann P, Endresen K, Benamer H, Kiss RG,
180. Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt
Ungi I, U, Boschat
NashefJ,SA. Morice MC. 6- versus 24-month dual antiplatelet therapy after
Guideline on antiplatelet and anticoagulation managementimplantation
in cardiac surgery.
of drug-eluting stents in patients nonresistant to aspirin: the rando-
Eur J Cardiothorac Surg 2008;34:7392. mized, multicenter ITALIC trial. J Am Coll Cardiol 2015;65:777786.
181. Savonitto S, DUrbano M, Caracciolo M, Barlocco F, Mariani
194. Lee
G, Nichelatti
CW, Ahn JM, M, Park DW, Kang SJ, Lee SW, Kim YH, Park SW, Han S, Lee SG,
Klugmann S, De Servi S. Urgent surgery in patients with a Seong
recently IW,implanted
Rha SW, cor- Jeong MH, Lim DS, Yoon JH, Hur SH, Choi YS, Yang JY,
onary drug-eluting stent: a phase II studyof bridging antiplatelet
Lee NH, therapy
Kim HS, with
Leetir-
BK, Kim KS, Lee SU, Chae JK, Cheong SS, Suh IW,
oban during temporary withdrawal of clopidogrel. Br J AnaesthPark 2010;104:
HS, Nah DY, Jeon DS, Seung KB, Lee K, Jang JS, Park SJ. Optimal duration
285291. of dual antiplatelet therapy after drug-eluting stent implantation: a randomized,
182. Angiolillo DJ, Firstenberg MS, Price MJ, Tummala PE, Hutyra
controlled
M, Welsby trial.IJ,Circulation 2014;129:304312.
Voeltz MD, Chandna H, Ramaiah C, Brtko M, Cannon L, Dyke 195. C,
Collet
Liu T,JP, Silvain J, Barthelemy O, Range G, Cayla G, Van Belle E, Cuisset T,
Montalescot G, Manoukian SV, Prats J, Topol EJ. Bridging antiplatelet
Elhadad S,therapySchiele F, Lhoest N, Ohlmann P, Carrie D, Rousseau H, Aubry P,
with cangrelor in patients undergoing cardiac surgery: a randomized
Monsegu J,controlled
Sabouret P, OConnor SA, Abtan J, Kerneis M, Saint-Etienne C,
trial. JAMA 2012;307:265274. BeyguiF,VicautE,MontalescotG.Dual-antiplatelettreatmentbeyond1yearafter
183. SteinhublSR,BergerPB,MannJT3rd,FryET,DeLagoA,WilmerC,TopolEJ.Early
drug-eluting stent implantation (ARCTIC-INTERRUPTION): a randomised trial.
and sustained dual oral antiplatelet therapy following percutaneous
Lancet 2014;384:15771585.
coronary
intervention: a randomized controlled trial. JAMA 2002;288:24112420.
196. Rof M, Chew DP, Mukherjee D, Bhatt DL, White JA, Moliterno DJ, Heeschen C,
184. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, CutlipHamm
DE, Steg CW, PG,
Robbins MA, Kleiman NS, Theroux P, White HD, Topol EJ. Platelet
Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR glycoprotein
Jr, IIb/IIIa inhibition in acute coronary syndromes. Gradient of benet re-
Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzarilated DE, Garratt
to the revascularization
KN, strategy. Eur Heart J 2002;23:14411448.
Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM. Twelve 197.
or 30
ODonoghue
months ofM, Antman EM, Braunwald E, Murphy SA, Steg PG, Finkelstein A,
dual antiplatelet therapy after drug-eluting stents. N Engl JPenny
Med 2014;371:
WF, Fridrich V, McCabe CH, Sabatine MS, Wiviott SD. The efcacy and
21552166. safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients
185. Navarese EP, Andreotti F, Schulze V, Kolodziejczak M, Buffon
with acute
A, Brouwer
coronary M, syndromes undergoing percutaneous intervention: a
Costa F, Kowalewski M, Parati G, Lip GY, Kelm M, ValgimigliTRITON-TIMI
M. Optimal duration
38 (Trial to Assess Improvement in Therapeutic Outcomes by
of dual antiplatelet therapy after percutaneous coronary intervention
Optimizing Platelet
with drug Inhibition with PrasugrelThrombolysis in Myocardial Infarc-
eluting stents: meta-analysis of randomised controlled trials.
tionBMJ38)2015;350:
analysis. J Am Coll Cardiol 2009;54:678685.
h1618. 198. Stone GW,BertrandME,MosesJW, Ohman EM,LincoffAM, WareJH,PocockSJ,
186. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen McLaurin
EC, Magnani
BT, CoxG, DA, Jafar MZ, Chandna H, Hartmann F, Leisch F, Strasser RH,
Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj Desaga
A, Theroux
M, Stuckey P, TD, Zelman RB, Lieber IH, Cohen DJ, Mehran R, White HD.
Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, MurphyRoutine SA,upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhi-
Wiviott SD, Held P, Braunwald E, Sabatine MS. Long-term use bitors
of ticagrelor
in acute coronary
in pa- syndromes: the ACUITY timing trial. JAMA 2007;297:
tients with prior myocardial infarction. N Engl J Med 2015;372:17911800.
591602.
187. Kim BK, Hong MK, Shin DH, Nam CM, Kim JS, Ko YG, Choi 199.D,Giugliano
Kang TS,RP, ParkWhite
BE, JA, Bode C, Armstrong PW, Montalescot G, Lewis BS, van t
Kang WC, Lee SH, Yoon JH, Hong BK, Kwon HM, Jang Y. A new Hofstrategy
A, Berdan forLG, dis-Lee KL, Strony JT, Hildemann S, Veltri E, Van de Werf F,
continuation of dual antiplatelet therapy: the RESET trial (real
Braunwald
safety and E, Harrington
efcacy RA, Califf RM, Newby LK. Early versus delayed, provi-
of3-monthdualantiplatelettherapyfollowingendeavorzotarolimus-elutingstent
sional eptibatide in acute coronary syndromes. N Engl J Med 2009;360:
implantation). J Am Coll Cardiol 2012;60:13401348. 21762190.
188. Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA, 200.
Botelho
Wang RV,TY,King
WhiteSB 3rd,
JA, Tricoci P, Giugliano RP, Zeymer U, Harrington RA,
Negoita M, Liu M, de Paula JE, Mangione JA, Meireles GX, Castello
Montalescot HJ Jr, G, James SK, Van de Werf F, Armstrong PW, Braunwald E,
Nicolela EL Jr, Perin MA, Devito FS, Labrunie A, Salvadori DCaliff
Jr, Gusmao
RM, Newby M, LK. Upstream clopidogrel use and the efcacy and safety of
Staico R, Costa JR Jr, de Castro JP, Abizaid AS, Bhatt DL. Three
earlyeptibatide
vs twelve months treatment in patientswith acute coronarysyndrome:an analysis
315a ESC Guidelines

fromtheearlyglycoproteinIIb/IIIainhibitioninpatientswithnon-ST-segmentele-
patients with non-ST-segment elevation acute coronary syndromes managed
vation acute coronary syndrome (early ACS) trial. Circulation 2011;123:722730.
with an intended early invasive strategy: primary results of the SYNERGY rando-
201. Judge HM, Buckland RJ, HolgateCE, Storey RF. Glycoprotein IIb/IIIa
mizedand trial.
P2Y JAMA
12re-2004;292:4554.
ceptor antagonists yield additive inhibition of platelet aggregation,
217. Murphy
granule SA,secre-
Gibson CM, Morrow DA, Van de Werf F, Menown IB, Goodman SG,
tion, soluble CD40 l release and procoagulant responses. Platelets Mahaffey
2005;16: KW, Cohen M, McCabe CH, Antman EM, Braunwald E. Efcacy and
398407. safety of the low-molecular weight heparin enoxaparin compared with unfractio-
202. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein
natedheparinacrosstheacutecoronarysyndromespectrum:a
H, Graf I, meta-analysis. Eur
Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger Heart
PB, J 2007;28:20772086.
Schomig A. Abciximab in patients with acute coronary syndromes 218. YusufS,MehtaSR,ChrolaviciusS,AfzalR,PogueJ,GrangerCB,BudajA,PetersRJ,
undergoing
percutaneous coronary intervention after clopidogrel pretreatment: Bassand the ISAR-
JP, Wallentin L, Joyner C, Fox KA. Comparison of fondaparinux and en-
REACT 2 randomized trial. JAMA 2006;295:15311538. oxaparin in acute coronary syndromes. N Engl J Med 2006;354:14641476.
203. Jolly SS, Faxon DP, Fox KA, Afzal R, Boden WE, Widimsky P,219.StegStegPG, Valentin
PG, Jolly V, SS, Mehta SR, Afzal R, Xavier D, Rupprecht HJ, Lopez-Sendon JL,
Budaj A, Granger CB, Joyner CD, Chrolavicius S, Yusuf S, Mehta Budaj
SR. EfcacyA, DiazandR, Avezum A, Widimsky P, Rao SV, Chrolavicius S, Meeks B,
safety of fondaparinux versus enoxaparin in patients with acuteJoynercoronary C, Pogue
syn- J, Yusuf S. Low-dose vs standard-dose unfractionated heparin
dromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines:
for percutaneous
results coronary intervention in acute coronary syndromes treated
fromtheOASIS5(FifthOrganizationtoAssessStrategiesinIschemicSyndromes)
with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA 2010;304:
trial. J Am Coll Cardiol 2009;54:468476. 13391349.
204. White HD, Chew DP, Hoekstra JW, Miller CD, Pollack CV Jr, Feit
220.F,Szummer
Lincoff AM, K, Oldgren J, Lindhagen L, Carrero JJ, Evans M, Spaak J, Edfors R,
Bertrand M, Pocock S, Ware J, Ohman EM, Mehran R, Stone GW. JacobsonSafety and SH,ef-Andell P, Wallentin L, Jernberg T. Association between the use of
cacyofswitchingfromeitherunfractionatedheparinorenoxaparintobivalirudin
fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients
in patients with non-ST-segment elevation acute coronary syndromes with non-ST-segment
managed elevation myocardial infarction. JAMA 2015;313:707716.
with an invasive strategy: results from the ACUITY (Acute Catheterization
221. Stone GW, andWhite HD, Ohman EM, Bertrand ME, Lincoff AM, McLaurin BT,
Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2008;51:17341741.
Cox DA, Pocock SJ, Ware JH, Feit F, Colombo A, Manoukian SV, Lansky AJ,
205. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses Mehran JW, R, Moses JW. Bivalirudin in patients with acute coronary syndromes
White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier
undergoingAR, percutaneous coronary intervention: a subgroup analysis from the
Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht Acute Catheterization
HJ, and Urgent Intervention Triage strategY (ACUITY) trial.
Hoekstra J, Mehran R, Ohman EM. Bivalirudin for patients with acuteLancet coronary
2007;369:907919.
syndromes. N Engl J Med 2006;355:22032216. 222. Stone GW, Ware JH, Bertrand ME, Lincoff AM, Moses JW, Ohman EM,
206. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de White
WerfHD, F, Feit F, Colombo A, McLaurin BT, Cox DA, Manoukian SV, Fahy M,
White HD, Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Clayton
LeonardiTC, S, Mehran R, Pocock SJ. Antithrombotic strategies in patients with
Rorick TL, Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier acute
A, coronary syndromes undergoing early invasive management: one-year re-
Cornel JH, Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukemasults JW, from the ACUITY trial. JAMA 2007;298:24972506.
Lewis BS, Lincoff AM, Montalescot G, Nicolau JC, Ogawa H, Psterer
223. Kastrati
M, A, Neumann FJ, Schulz S, Massberg S, Byrne RA, Ferenc M, Laugwitz KL,
Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, WhellanPache DJ,J, Ott I, Hausleiter J, Seyfarth M, Gick M, Antoniucci D, Schomig A,
WidimskyP,StronyJ,HarringtonRA,MahaffeyKW.Thrombin-receptorantagon-Berger PB, Mehilli J. Abciximab and heparin versus bivalirudin for
ist vorapaxar in acute coronary syndromes. N Engl J Med 2012;366:2033.
non-ST-elevation myocardial infarction. N Engl J Med 2011;365:19801989.
207. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, 224.
FishKastrati
MP, FoxA,KA, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Buttner HJ, Khattab AA,
Lipka LJ, Liu X, Nicolau JC, Ophuis AJ, Paolasso E, Scirica BM, Spinar
Schulz J, S, Blankenship JC, Pache J, Minners J, Seyfarth M, Graf I, Skelding KA,
TherouxP, WiviottSD, StronyJ,Murphy SA. Vorapaxar inthe secondary DirschingerJ,RichardtG,BergerPB,SchomigA.Bivalirudinversusunfractionated
preven-
tion of atherothrombotic events. N Engl J Med 2012;366:14041413. heparin during percutaneous coronary intervention. N Engl J Med 2008;359:
208. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer 688696.
TJ, Shook TL,
Lapuerta P, Goldsmith MA, Laine L,Scirica BM, Murphy SA, Cannon 225. AlexanderJH,Lopes
CP. Clopido- RD,JamesS, KilaruR,He Y, MohanP,BhattDL, Goodman S,
grel with or without omeprazole in coronary artery disease. N Engl Verheugt
J Med FW,2010; Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De
363:19091917. Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D,
209. Moukarbel GV, Bhatt DL. Antiplatelet therapy and proton pump Leiva-Pons
inhibition: JL,clin-
Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R,
ician update. Circulation 2012;125:375380. White H,Ruda M,GeraldesM,LawrenceJ,HarringtonRA, WallentinL. Apixaban
210. Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusufwith antiplatelet
S. Unfractio-therapy after acute coronary syndrome. N Engl J Med 2011;365:
nated heparin and low-molecular-weight heparin in acute coronary 699708.syndrome
without ST elevation: a meta-analysis. Lancet 2000;355:19361942.226. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P,
211. Silvain J, Beygui F, Barthelemy O, Pollack C Jr, Cohen M, ZeymerCohen U, Huber
M, Cook-Bruns
K, N, Fox KA, Goto S, Murphy SA, Plotnikov AN,
Goldstein P, Cayla G, Collet JP, Vicaut E, Montalescot G. EfcacyandSchneider
safetyofD,en- Sun X, Verheugt FW, Gibson CM. Rivaroxaban in patients with a
oxaparin versus unfractionated heparin during percutaneous coronaryrecent acuteinterven-coronary syndrome. N Engl J Med 2012;366:919.
tion: systematic review and meta-analysis. BMJ 2012;344:e553. 227. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the in-
212. Lee MS, Wali AU, Menon V, Berkowitz SD, Thompson TD, Califf cidence
RM, Topol of myocardial
EJ, infarction and death in patients with unstable angina. A
Granger CB, Hochman JS. The determinants of activated partialmeta-analysis.
thromboplastinJAMA 1996;276:811815.
time, relation of activated partial thromboplastin time to clinical
228.outcomes,
Simoons ML, andBobbink IW, Boland J, Gardien M, Klootwijk P, Lensing AW,
optimal dosing regimens for heparin treated patients with acuteRuzyllo
coronary W, syn-
Umans VA, Vahanian A, Van De Werf F, Zeymer U. A dose-nding
dromes: a review of GUSTO-IIb. J Thromb Thrombolysis 2002;14:91101.study of fondaparinux in patients with non-ST-segment elevation acute coronary
213. Hassan WM, Flaker GC, Feutz C, Petroski GF, Smith D. Improved syndromes:
anticoagulation
the pentasaccharide in unstable angina (PENTUA) study. J Am Coll
with a weight-adjusted heparin nomogram in patients with acute Cardiol
coronary2004;43:21832190.
syn-
dromes: a randomized trial. J Thromb Thrombolysis 1995;2:245249.229. Mehta SR, Steg PG, Granger CB, Bassand JP, Faxon DP, Weitz JI, Afzal R, Rush B,
214. Collet JP, Montalescot G, Lison L, Choussat R, Ankri A, Drobinski
PetersG, Sotirov
RJ, Natarajan
I, MK, Velianou JL, Goodhart DM, Labinaz M, Tanguay JF,
Thomas D. Percutaneous coronary intervention after subcutaneous Fox KA,enoxaparin
Yusuf S. Randomized, blinded trial comparing fondaparinux with unfrac-
pretreatment in patients with unstable angina pectoris. Circulationtionated
2001;103:
heparin in patients undergoing contemporary percutaneous coronary
658663. intervention:ArixtraStudy inPercutaneouscoronaryIntervention:aRandomized
215. Martin JL, Fry ET, Sanderink GJ, Atherley TH, Guimart CM, Chevalier
Evaluation PJ, (ASPIRE) pilot trial. Circulation 2005;111:13901397.
Ozoux ML, Pensyl CE, Bigonzi F. Reliable anticoagulation with230.enoxaparin
Petersen in JL,
pa-Mahaffey KW, Hasselblad V, Antman EM, Cohen M, Goodman SG,
tients undergoing percutaneous coronary intervention: the pharmacokinetics
Langer A, Blazing of MA, Le-Moigne-Amrani A, de Lemos JA, Nessel CC,
enoxaparin in PCI (PEPCI) study. Catheter Cardiovasc Interv 2004;61:163170.
Harrington RA, Ferguson JJ, Braunwald E, Califf RM. Efcacy and bleeding compli-
216. Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman cations S, among patients randomized to enoxaparin or unfractionated heparin for
Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, Armstrong PW,antithrombin
Avezum A, therapy in non-ST-segment elevation acute coronary syndromes: a
Aylward P, Becker RC, Biasucci L, Borzak S, Col J, Frey MJ, Fry E, systematic
Gulba DC, overview. JAMA 2004;292:8996.
Guneri S, Gurnkel E, Harrington R, Hochman JS, Kleiman NS, Leon 231. Brener
MB, SJ, Moliterno DJ, Lincoff AM, Steinhubl SR, Wolski KE, Topol EJ. Relation-
Lopez-Sendon JL, Pepine CJ, Ruzyllo W, Steinhubl SR, Teirstein PS, ship between activated clotting time and ischemic or hemorrhagic complications:
Toro-Figueroa L, White H. Enoxaparin vs unfractionated heparin in high-risk
ESC Guidelines 315b

analysis of 4 recent randomized clinical trials of percutaneous


246. Dewilde
coronary WJ,interven-
Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP,
tion. Circulation 2004;110:994998. Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van t Hof AW,
232. Gilard M, Blanchard D, Helft G, Carrier D, Eltchaninoff H,tenBerg
Belle L, JM.Use
Finet G,ofclopidogrelwith
Le orwithoutaspirininpatientstakingoralanti-
BretonH, BoschatJ. Antiplatelet therapyin patients with anticoagulants
coagulant therapyand
undergo- undergoing percutaneous coronary intervention: an open-
ing percutaneous coronary stenting (from STENTing and oral label,
antiCOagulants
randomised, controlled trial. Lancet 2013;381:11071115.
[STENTICO]). Am J Cardiol 2009;104:338342. 247. Fiedler KA, Maeng M, Mehilli J, Schulz-Schu pke S, Byrne RA, Sibbing D,
233. Ruiz-Nodar JM, Marin F, Hurtado JA, Valencia J, Pinar E, Pineda
Hoppmann J, Gimeno
P, Schneider
JR, S, Fusaro M, Ott I, Kristensen SD, Ibrahim T,
Sogorb F, Valdes M, Lip GY. Anticoagulant and antiplatelet therapy
Massberg use S, in
Schunkert
426 pa- H, Laugwitz K-L, Kastrati A, Sarafoff N. Duration of triple
tients with atrial brillation undergoing percutaneous coronary therapy
intervention
in patients andrequiring oral anticoagulation after drug-eluting stent implant-
stent implantation implications for bleeding risk and prognosis.ation:J theAm ISAR-TRIPLE
Coll Cardiol trial. J Am Coll Cardiol 2015;65:16191629.
2008;51:818825. 248. Lamberts M, Olesen JB, Ruwald MH, Hansen CM, Karasoy D, Kristensen SL,
234. Lip GY, Windecker S, Huber K, Kirchhof P, Marin F, ten Berg KoberJM,L, Haeusler
Torp-Pedersen
KG, C, Gislason GH, Hansen ML. Bleeding after initiation
Boriani G, Capodanno D, Gilard M, Zeymer U, Lane D, Storey of multiple
RF, Bueno antithrombotic
H, drugs, including triple therapy, in atrial brillation pa-
Collet JP, Fauchier L, Halvorsen S, Lettino M, Morais J, Muellertientsfollowingmyocardialinfarctionandcoronaryintervention:anationwideco-
C, Potpara TS,
Rasmussen LH, Rubboli A, Tamargo J, Valgimigli M, Zamorano hortJL.study.
Management
Circulation 2012;126:11851193.
of antithrombotic therapy in atrial brillation patients presenting
249. Lamberts
with acute M, Gislason
cor- GH, Olesen JB, Kristensen SL, Schjerning Olsen AM,
onary syndrome and/or undergoing percutaneous coronaryMikkelsen or valve interven-
A, Christensen CB, Lip GY, Kober L, Torp-Pedersen C, Hansen ML.
tions: a joint consensus document of the European SocietyOralanticoagulationandantiplateletsinatrialbrillationpatientsaftermyocardial
of Cardiology
working group on thrombosis, European Heart Rhythm Association infarction(EHRA),and coronary intervention. J Am Coll Cardiol 2013;62:981989.
European Association of Percutaneous Cardiovascular Interventions
250. Sie P, Samama (EAPCI) CM, Godier A, Rosencher N, Steib A, Llau JV, Van der Linden P,
andEuropeanAssociationofAcuteCardiacCare(ACCA)endorsedbytheHeartPernod G, Lecompte T, Gouin-Thibault I, Albaladejo P. Surgery and invasive pro-
RhythmSociety(HRS)andAsia-PacicHeartRhythmSociety(APHRS).EurHeart
cedures in patients on long-term treatment with direct oral anticoagulants:
J 2014;35:31553179. thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Peri-
235. Beyer-Westendorf J, Gelbricht V, Forster K, Ebertz F, Kohler operative
C, Werth Haemostasis
S, and the French Study Group on Thrombosis and Haemostasis.
Kuhlisch E, Stange T, Thieme C, Daschkow K, Weiss N. Peri-interventional
Arch Cardiovascman- Dis 2011;104:669676.
agement of novel oral anticoagulants in daily care: results 251.from
Valgimigli
the prospective
M, Gagnor A, Calabro P, Frigoli E, Leonardi S, Zaro T, Rubartelli P,
Dresden NOAC registry. Eur Heart J 2014;35:18881896. Briguori C, Ando G, Repetto A, Limbruno U, Cortese B, Sganzerla P, Lupi A,
236. Dewilde WJ, Janssen PW, Kelder JC, Verheugt FW, De Smet Galli
BJ,M,Adriaenssens
Colangelo S,T,Ierna S, Ausiello A, Presbitero P, Sardella G, Varbella F,
Vrolix M, Brueren GB, Vandendriessche T, Van Mieghem C, Esposito Cornelis G, K, Vos
Santarelli
J, A, Tresoldi S, Nazzaro M, Zingarelli A, de Cesare N,
Breet NJ, ten Berg JM. Uninterrupted oral anticoagulation versusRigattieribridging
S, Tosi inP,pa-
Palmieri C, Brugaletta S, Rao SV, Heg D, Rothenbuhler M,
tients with long-term oral anticoagulation during percutaneous VranckxP,JuniP.Radialversusfemoralaccessinpatientswithacutecoronarysyn-
coronary inter-
vention: subgroup analysis from the WOEST trial. EuroIntervention
dromes undergoing
2015 Mar 5;invasive management: a randomised multicentre trial. Lancet
10(11). pii: 20140202-08. doi:10.4244/EIJY14M06_07. [Epub 2015;385:24652476.
ahead of print]
237. Kiviniemi T, Karjalainen P, Pietila M, Ylitalo A, Niemela252.
M, Vikman
Bangalore S, Puurunen
S, Toklu B, M,Amoroso N, Fusaro M, Kumar S, Hannan EL, Faxon DP,
Biancari F, Airaksinen KE. Comparison of additional versus Feit no additional
F. Bare metal heparin
stents, durable polymer drug eluting stents, and biodegradable
during therapeutic oral anticoagulation in patients undergoing polymerpercutaneous
drug eluting cor-stents for coronary artery disease: mixed treatment com-
onary intervention. Am J Cardiol 2012;110:3035. parison meta-analysis. BMJ 2013;347:f6625.
238. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, 253.
Raunso
Dutton J, Gadsboll
RP. Haemostatic
N, resuscitation. Br J Anaesth 2012;109(Suppl 1):i39i46.
Gislason GH, Folke F, Andersen SS, Schramm TK, Abildstrom 254. SZ,
Di Minno
Poulsen G, HE,
Silver MJ, Murphy S. Monitoring the entry of new platelets into the
Kober L, Torp-Pedersen C. Risk of bleeding with single, dual, circulation
or triple therapy
after ingestion of aspirin. Blood 1983;61:10811085.
with warfarin, aspirin, and clopidogrel in patients with atrial
255.brillation.
Vilahur G,Arch ChoiIntern
BG, Zafar MU, Viles-Gonzalez JF, Vorchheimer DA, Fuster V,
Med 2010;170:14331441. Badimon JJ. Normalization of platelet reactivity in clopidogrel-treated subjects.
239. Faxon DP, Eikelboom JW, Berger PB, Holmes DR Jr, BhattJ DL, Thromb
MoliternoHaemostDJ, 2007;5:8290.
BeckerRC,AngiolilloDJ.Antithrombotictherapyinpatientswithatrialbrillation
256. HanssonEC,ShamsHakimiC,Astrom-OlssonK,HesseC,WallenH,DellborgM,
undergoing coronary stenting: a North American perspective: Albertsson
executive P, Jeppsson
sum- A. Effects of ex vivo platelet supplementation on platelet
mary. Circ Cardiovasc Interv 2011;4:522534. aggregability in blood samples from patients treated with acetylsalicylic acid, clo-
240. StettlerC,AllemannS,WandelS,KastratiA,MoriceMC,SchomigA,PstererME,
pidogrel, or ticagrelor. Br J Anaesth 2014;112:570575.
Stone GW, Leon MB, de Lezo JS, Goy JJ, ParkSJ, Sabate M,257. Suttorp
ZafarMJ, MU,Kelbaek
Santos-Gallego
H, C, Vorchheimer DA, Viles-Gonzalez JF, Elmariah S,
Spaulding C, Menichelli M, Vermeersch P, Dirksen MT, Cervinka Giannarelli
P, De Carlo
C, Sartori
M, S, Small DS, Jakubowski JA, Fuster V, Badimon JJ. Platelet
Erglis A, Chechi T, Ortolani P, Schalij MJ, Diem P, Meier B, Windecker
function normalization
S, Juni P. after a prasugrel loading-dose: time-dependent effect of
Drugelutingandbaremetalstentsinpeoplewithandwithoutdiabetes:collabora-
platelet supplementation. J Thromb Haemost 2013;11:100106.
tive network meta-analysis. BMJ 2008;337:a1331. 258. Patel RJ, Witt DM, Saseen JJ, Tillman DJ, Wilkinson DS. Randomized, placebo-
241. BangaloreS,KumarS,FusaroM,AmorosoN,KirtaneAJ,Byrne controlled RA,WilliamsDO, trial of oral phytonadione for excessive anticoagulation. Pharmacother-
SlaterJ,CutlipDE,FeitF.Outcomeswithvariousdrugelutingorbaremetalstents
apy 2000;20:11591166.
in patients with diabetes mellitus: mixed treatment comparison
259. Fondevila
analysisCG, of 22,844
GrossoSH, Santarelli MT, Pinto MD. Reversalof excessive oralan-
patient years of follow-up from randomised trials. BMJ 2012;345:e5170.
ticoagulation with a low oral dose of vitamin K1 compared with acenocoumarine
242. Bangalore S, Kumar S, Fusaro M, Amoroso N, Attubato MJ, discontinuation.Aprospective,randomized,openstudy.BloodCoagulFibrinolysis2001;
Feit F, Bhatt DL,
Slater J. Short- and long-term outcomes with drug-eluting and 12:916.
bare-metal coron-
ary stents: a mixed-treatment comparison analysis of 117 260.762Ageno
patient-years
W, Crowther of M, Steidl L, Ultori C, Mera V, Dentali F, Squizzato A,
follow-up from randomized trials. Circulation 2012;125:28732891.Marchesi C, Venco A. Low dose oral vitamin K to reverse acenocoumarol-
243. Kereiakes DJ, Yeh RW, Massaro JM, Driscoll-Shempp P, Cutlip inducedDE, coagulopathy:
Steg PG, a randomized controlled trial. Thromb Haemost 2002;88:
Gershlick AH, Darius H, Meredith IT, Ormiston J, Tanguay JF,4851. Windecker S,
Garratt KN, Kandzari DE, Lee DP, Simon DI, Iancu AC, Trebacz 261. Ageno
J, Mauri W,L.Garcia
Anti- D, Silingardi M, Galli M, Crowther M. A randomized trial com-
platelet therapy duration following bare metal or drug-eluting paringcoronary
1 mg of stents:
oral vitamin K with no treatment in the management of
the dual antiplatelet therapy randomized clinical trial. JAMAwarfarin-associated
2015;313: coagulopathy in patients with mechanical heart valves. J Am
11131121. Coll Cardiol 2005;46:732733.
244. Hawn MT, Graham LA, Richman JS, Itani KM, Henderson 262.WG,Crowther
MaddoxMA, TM.Ageno
Risk W, Garcia D, Wang L, Witt DM, Clark NP, Blostein MD,
ofmajoradversecardiaceventsfollowingnoncardiacsurgeryinpatientswithcor-
Kahn SR, Vesely SK, Schulman S, Kovacs MJ, Rodger MA, Wells P, Anderson D,
onary stents. JAMA 2013;310:14621472. Ginsberg J, Selby R, Siragusa S, Silingardi M, Dowd MB, Kearon C. Oral vitamin
245. Valgimigli M, Patialiakas A, Thury A, McFadden E, Colangelo K versus
S, Campo placebo G, to correct excessive anticoagulation in patients receiving war-
Tebaldi M, Ungi I, Tondi S, Rof M, Menozzi A, de Cesare N, Garbofarin: R,a randomized trial. Ann Intern Med 2009;150:293300.
Meliga E, Testa L, Gabriel HM, Airoldi F, Ferlini M, Liistro F,
263.
Dellavalle
Crowther A, MA, Julian J, McCarty D, Douketis J, Kovacs M, Biagoni L, Schnurr T,
Vranckx P, BriguoriC; ZEUS Investigators. Zotarolimus-eluting McGinnis
versusJ,bare-metal
Gent M, Hirsh J, Ginsberg J. Treatment of warfarin-associated coagu-
stents in uncertain drug-eluting stent candidates. J Am Colllopathy
Cardiolwith 2015;65:
oral vitamin K: a randomised controlled trial. Lancet 2000;356:
805815. 15511553.
315c ESC Guidelines

264. Ageno W, Garcia D, Aguilar MI, Douketis J, Finazzi G, Imberti


281. Ndrepepa
D, Iorio A, G, KeyNeumann
NS, FJ, Richardt G, Schulz S, Tolg R, Stoyanov KM, Gick M,
Lim W, Marietta M, Prisco D, Sarode R, Testa S, Tosetto A, Crowther
IbrahimM. T, Preven-
Fiedler KA, Berger PB, Laugwitz KL, Kastrati A. Prognostic value of ac-
tion and treatment of bleeding complications in patients receiving
cess and vitamin
non-access
K an- sites bleeding after percutaneous coronary intervention. Circ
tagonists, part 2: treatment. Am J Hematol 2009;84:584588.Cardiovasc Interv 2013;6:354361.
265. AgenoW,GallusAS,WittkowskyA,CrowtherM,HylekEM,PalaretiG.Oralanti-
282. Marso SP, Amin AP, House JA, Kennedy KF, Spertus JA, Rao SV, Cohen DJ,
coagulant therapy: antithrombotic therapy and prevention ofMessenger
thrombosis, JC,9th
Rumsfeld
ed: JS. Association between use of bleeding avoidance strat-
American College of Chest Physicians evidence-based clinical egies
practice
and risk guidelines.
of periprocedural bleeding among patients undergoing percutan-
Chest 2012;141:e44S88S. eous coronary intervention. JAMA 2010;303:21562164.
266. Liesenfeld KH, Staab A, Hartter S, Formella S, Clemens 283.
A, LehrSchulz-Schupke
T. Pharmaco- S, Helde S, Gewalt S, Ibrahim T, Linhardt M, Haas K, Hoppe K,
metric characterization of dabigatran hemodialysis. Clin Pharmacokinet
Bottiger C, Groha 2013;52: P, Bradaric C, Schmidt R, Bott-Flugel L, Ott I, Goedel J,
453462. Byrne RA, Schneider S, Burgdorf C, Morath T, Kufner S, Joner M, Cassese S,
267. EerenbergES,KamphuisenPW,SijpkensMK,MeijersJC,BullerHR,LeviM.Rever-
Hoppmann P, Hengstenberg C, Pache J, Fusaro M, Massberg S, Mehilli J,
sal of rivaroxaban and dabigatran by prothrombin complex concentrate:
Schunkert H,aLaugwitz rando- KL, Kastrati A. Comparison of vascular closure devices
mized, placebo-controlled, crossover study in healthy subjects.vs manual
Circulation compression
2011; after femoral artery puncture: the ISAR-CLOSURE ran-
124:15731579. domized clinical trial. JAMA 2014;312:19811987.
268. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, 284.Lee G, Shi Luan
J, Ji H,
P, Ren F, Wang G, Xu M, Xue Y, Chen M, Qi J, Li L. Protective effects of
Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U. tranexamicacidonclopidogrelbeforecoronaryarterybypassgrafting:amulticen-
A specic antidote
for reversal of anticoagulation by direct and indirect inhibitors
terof randomized
coagulationtrial. fac-JAMA Surg 2013;148:538547.
tor Xa. Nat Med 2013;19:446451. 285. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, Claeys MJ,
269. Verheugt FW, Steinhubl SR, Hamon M, DariusH, Steg PG,Valgimigli
Harrington M,RA,MarsoHorrowSP, J, Husted S, James SK, Mahaffey KW, Nicolau JC,
Rao SV, Gershlick AH, Lincoff AM, Mehran R, Stone GW. Incidence,
Sciricaprognostic
BM, Storey RF, Vintila M, Ycas J, Wallentin L. Ticagrelor versus clopidogrel
impact, and inuence of antithrombotic therapy on access and in nonaccess
patients with siteacute coronary syndromes undergoing coronary artery bypass
bleeding in percutaneous coronary intervention. JACC Cardiovascsurgery: Interv
results
2011;4:
from the PLATO (PLATelet inhibition and patient Outcomes)
191197 trial. J Am Coll Cardiol 2011;57:672684.
270. Ndrepepa G, Schulz S, Neumann FJ, Byrne RA, Hoppmann 286.P, Mehta
Cassese RH, S,Sheng
Ott I, S, OBrien SM, Grover FL, Gammie JS, Ferguson TB,
Fusaro M, Ibrahim T, Tada T, Richardt G, Laugwitz KL, SchunkertPetersonH, Kastrati
ED. Reoperation
A. for bleeding in patients undergoing coronary artery
Bleeding after percutaneous coronary intervention in womenbypass and men surgery:
matched incidence, risk factors, time trends, and outcomes. Circ Cardiovasc
for age, body mass index, and type of antithrombotic therapy. QualAmOutcomes
Heart J 2013; 2009;2:583590.
166:534540. 287. PaoneG,LikoskyDS,BrewerR,TheurerPF,BellGF,CoganCM,PragerRL.Trans-
271. Vranckx P, Campo G, Anselmi M, Bolognese L, Colangelo S, fusionof1and2unitsofredbloodcellsisassociatedwithincreasedmorbidityand
Biondi-Zoccai G,
Moreno R, Piva T, Favero L, Prati F, Nazzaro M, Diaz Fernandez mortality.
JF, Ferrari Ann R,Thorac Surg 2014;97:8793; discussion 9384.
Valgimigli M. Does the site of bleeding matter? A stratied 288.
analysis
Ferraris
on location
VA, Saha SP, Oestreich JH, Song HK, Rosengart T, Reece TB, Mazer CD,
of TIMI-graded bleedings and their impact on 12-month outcome Bridges in patients
CR, Despotis GJ, Jointer K, Clough ER. 2012 update to the Society of
with ST-segment elevation myocardial infarction. EuroIntervention
Thoracic 2012;8:7178.
Surgeons guideline on use of antiplatelet drugs in patients having cardiac
272. Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Corneland noncardiac
JH, French operations.
J, Ann Thorac Surg 2012;94:17611781.
Held C, Horrow J, Husted S, Lopez-Sendon J, Lassila R, Mahaffey
289. Vivacqua
KW, A, Koch CG, Yousuf AM, Nowicki ER, Houghtaling PL, Blackstone EH,
StoreyRF, Harrington RA,Wallentin L.Bleedingcomplicationswith Sabik theP2Y
JF 3rd. 12re-
Morbidity of bleeding after cardiac surgery: is it blood transfusion,
ceptor antagonists clopidogrel and ticagrelor in the PLATeletreoperation
inhibition and forpa-
bleeding, or both? Ann Thorac Surg 2011;91:17801790.
tient Outcomes (PLATO) trial. Eur Heart J 2011;32:29332944. 290. Hardy JF, Belisle S, Van der Linden P. Efcacy and safety of activated recombinant
273. Lopes RD, Subherwal S, Holmes DN, Thomas L, Wang TY, factor Rao SV, VIIMagnus
in cardiac surgical patients. Curr Opin Anaesthesiol 2009;22:9599.
OhmanE,RoeMT,PetersonED,AlexanderKP.Theassociationofin-hospitalma-
291. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, Straka Z,
jor bleeding with short-, intermediate-, and long-term mortality
Piegasamong LS, Akar
olderAR, pa-Jain AR, Noiseux N, Padmanabhan C, Bahamondes JC,
tients with non-ST-segment elevation myocardial infarction. Novick
Eur Heart RJ, JVaijyanath
2012;33: P, Reddy S, Tao L, Olavegogeascoechea PA, Airan B,
20442053. Sulling TA, Whitlock RP, Ou Y, Ng J, Chrolavicius S, Yusuf S. Off-pump or on-
274. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom pumpJ,coronary-artery
Kaul S, bypass grafting at 30 days. N Engl J Med 2012;366:
Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M,14891497.
Vranckx P,
Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg 292.PG,Rao White
SV, Jollis
H. Stan-JG, Harrington RA, Granger CB, Newby LK, Armstrong PW,
dardized bleeding denitions for cardiovascular clinical trials:Moliterno
a consensus DJ, Lindblad
report L, Pieper K, Topol EJ, Stamler JS, Califf RM. Relationship
from the bleeding academic research consortium. Circulation of2011;123:
blood transfusion and clinical outcomes in patients with acute coronary syn-
27362747. dromes. JAMA 2004;292:15551562.
275. Ndrepepa G, Schuster T, Hadamitzky M, Byrne RA, Mehilli 293.J, Neumann
Sherwood FJ, MW, Wang Y, Curtis JP, Peterson ED, Rao SV. Patterns and outcomes
Richardt G, Schulz S, Laugwitz KL, Massberg S, Schomig A, Kastrati
of redblood A. Validation
cell transfusion in patients undergoing percutaneous coronary inter-
of the bleeding academic research consortium denition of bleeding
vention.inJAMA patients
2014;311:836843.
with coronary artery disease undergoing percutaneous coronary
294. Nikolsky
intervention.
E, Mehran R, Sadeghi HM, Grines CL, Cox DA, Garcia E, Tcheng JE,
Circulation 2012;125:14241431. Grifn JJ, Guagliumi G, Stuckey T, Turco M, Fahy M, Lansky AJ, Stone GW. Prog-
276. Ndrepepa G, Guerra E, Schulz S, Fusaro M, Cassese S, Kastrati
nosticA.impact
Weightofofblood the transfusion after primary angioplasty for acute myocardial
bleedingimpactonearlyandlatemortalityafterpercutaneouscoronaryinterven-
infarction:analysisfromtheCADILLAC(ControlledAbciximabandDeviceInves-
tion. J Thromb Thrombolysis 2015;39:3542. tigation to Lower Late Angioplasty Complications) trial. JACC Cardiovasc Interv
277. BaberU,KovacicJ,Kini AS,SharmaSK,DangasG,MehranR.Howseriousaprob-
2009;2:624632.
lem is bleeding in patients with acute coronary syndromes? 295.
CurrSilvain
Cardiol J, Abtan
Rep 2011;J, Kerneis M, Martin R, Finzi J, Vignalou JB, Barthelemy O,
13:312319. OConnor SA, Luyt CE, Brechot N, Mercadier A, Brugier D, Galier S, Collet JP,
278. Ndrepepa G, Berger PB, Mehilli J, Seyfarth M, Neumann FJ,Chastre
Schomig J, Montalescot
A, Kastrati A.G. Impact of red blood cell transfusion on platelet aggre-
Periprocedural bleeding and 1-year outcome after percutaneous gation coronary
and inammatory
inter- response in anemic coronary and noncoronary patients:
ventions: appropriateness of including bleeding as a component the TRANSFUSION-2
of a quadruple study (impact of transfusion of red blood cell on platelet
end point. J Am Coll Cardiol 2008;51:690697. activation and aggregation studiedwith owcytometry use and light transmission
279. Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J,aggregometry).
Montalescot G, J Am Coll Cardiol 2014;63:12891296
WhiteK,GoldbergRJ.Predictorsofmajorbleedinginacutecoronarysyndromes:
296. CarsonJL,CarlessPA,HebertPC.Transfusionthresholdsandotherstrategiesfor
the Global Registry of Acute Coronary Events (GRACE). Eur Heartguiding J 2003;24:
allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2012;4:
18151823. CD002042.
280. Leibundgut G, Pache J, Schulz S, Berger PB, Ferenc M, Gick
297.M, Kansagara
Mehilli J, Kastrati
D, Dyer A, E, Englander H, Fu R, Freeman M, Kagen D. Treatment of an-
Neumann FJ. Collagen plug vascular closure devices and reduced emia in riskpatients
of bleedingwith heart disease: a systematic review. Ann Intern Med 2013;159:
with bivalirudin versus heparin plus abciximab in patients undergoing
746757. percutan-
eous coronary intervention for non ST-segment elevation 298.myocardial
Chatterjee infarction.
S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of
J Interv Cardiol 2013;26:623629. blood transfusion with increased mortality in myocardial infarction: a
ESC Guidelines 315d

meta-analysis and diversity-adjusted study sequential analysis.


coronary JAMA lesion
Internmorphologies
Med as assessed by intravascular ultrasound and optical
2013;173:132139. coherence tomography. Int J Cardiol 2013;165:506511.
299. Cooper HA, Rao SV, Greenberg MD, Rumsey MP, McKenzie 320. PijlsM, Alcorn
NH, Tanaka KW, N, Fearon WF. Functional assessment of coronary stenoses: can
Panza JA. Conservative versus liberal red cell transfusion in weacute
live without
myocardial it? Eur in- Heart J 2013;34:13351344.
farction (the CRIT randomized pilot study). Am J Cardiol321.
2011;108:11081111.
Gersh BJ, Frye RL. Methods of coronary revascularizationthings may not be as
300. AlexanderKP,ChenAY,WangTY,RaoSV,NewbyLK,LaPointeNM,OhmanEM,they seem. N Engl J Med 2005;352:22352237.
Roe MT, Boden WE, Harrington RA, Peterson ED. Transfusion 322. Bavry
practice AA,and Kumbhani
out- DJ, Rassi AN, Bhatt DL, Askari AT. Benet of early invasive
comes in non-ST-segment elevation acute coronary syndromes. therapy Am in Heart
acute Jcoronary
2008; syndromes: a meta-analysis of contemporary rando-
155:10471053. mized clinical trials. J Am Coll Cardiol 2006;48:13191325.
301. Holst LB, Petersen MW, Haase N, Perner A, Wetterslev 323.
J. Restrictive
ODonoghueM, versus BodenWE,BraunwaldE,Cannon
lib- CP,Clayton TC,deWinterRJ,
eral transfusion strategy for red blood cell transfusion: systematic
Fox KA, Lagerqvist
review of ran- B, McCullough PA, Murphy SA, Spacek R, Swahn E,
domised trials with meta-analysis and trial sequential analysis.
Wallentin BMJ L, 2015;350:
Windhausen F, Sabatine MS. Early invasive vs conservative treatment
h1354. strategies inwomen and men with unstable angina and non-ST-segment elevation
302. Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA,myocardial
Angelini GD, infarction: a meta-analysis. JAMA 2008;300:7180.
Reeves BC. Liberal or restrictive transfusion after cardiac
324.surgery.
FoxKA,ClaytonTC,DammanP,PocockSJ,deWinterRJ,TijssenJG,LagerqvistB,
N Engl J Med
2015;372:9971008. Wallentin L. Long-term outcome of a routine versus selective invasive strategy in
303. Mehta SR, Granger CB, Boden WE, Steg PG, Bassand JP,patients Faxon DP, with Afzal
non-ST-segment
R, elevation acute coronary syndrome a
Chrolavicius S, Jolly SS, Widimsky P, Avezum A, Rupprechtmeta-analysis
HJ, Zhu J, Col J,of individual patient data. J Am Coll Cardiol 2010;55:24352445.
Natarajan MK, Horsman C, Fox KA, Yusuf S. Early versus325. delayed
Noc M, invasive
Fajadet inter-
J, Lassen JF, Kala P, MacCarthy P, Olivecrona GK, Windecker S,
vention in acute coronary syndromes. N Engl J Med 2009;360:21652175.
Spaulding C.Invasivecoronarytreatmentstrategiesforout-of-hospitalcardiacar-
304. Thiele H, Rach J, Klein N, Pfeiffer D, Hartmann A, Hambrecht
rest: aR,consensus
Sick P, Eitel statement
I, from the European Association for Percutaneous
Desch S, Schuler G. Optimal timing of invasive angiography CardiovascularInterventions(EAPCI)/StentForLife(SFL)groups.EuroIntervention
in stable
non-ST-elevation myocardial infarction: the Leipzig immediate 2014;10:3137.
versus early and
late PercutaneouS coronary intervention triAl in NSTEMI326. (LIPSIA-NSTEMI
Katritsis DG,trial). Siontis GC, Kastrati A, vant Hof AW, Neumann FJ, Siontis KC,
Eur Heart J 2012;33:20352043. Ioannidis JP. Optimal timing of coronary angiography and potential intervention
305. Ndrepepa G, Mehilli J, Schulz S, Iijima R, Keta D, Byrne RA,
in non-ST-elevation
Pache J, Seyfarthacute M, coronary syndromes. Eur Heart J 2011;32:3240.
Schomig A, Kastrati A. Patterns of presentation and outcomes
327. Navarese
of patients EP, with
Gurbel PA, Andreotti F, Tantry U, Jeong YH, Kozinski M,
acute coronary syndromes. Cardiology 2009;113:198206.Engstrom T, Di Pasquale G, Kochman W, Ardissino D, Kedhi E, Stone GW,
306. KerenskyRA, Wade M, DeedwaniaP, Boden WE, PepineCJ. Kubica
Revisiting
J. Optimalthe culprit
timing of coronary invasive strategy in non-ST-segment eleva-
lesion in non-Q-wave myocardial infarction. Results from the tionVANQWISH
acute coronary trial syndromes: a systematic review and meta-analysis. Ann Intern
angiographic core laboratory. J Am Coll Cardiol 2002;39:14561463
Med 2013;158:261270.
307. Ambrose JA, Winters SL, Stern A, Eng A, Teichholz LE,328.GorlinRiezebos
R, FusterV. RK, Ronner
Angio- E, Ter Bals E, Slagboom T, Smits PC, ten Berg JM,
graphic morphology and the pathogenesis of unstable angina Kiemeneij
pectoris. F, Amoroso
J Am CollG, Patterson MS, Suttorp MJ, Tijssen JG, Laarman GJ. Im-
Cardiol 1985;5:609616. mediateversusdeferredcoronaryangioplastyinnon-ST-segment elevationacute
308. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfehcoronary
M, ONeillsyndromes.
WW. Mul- Heart 2009;95:807812.
tiple complex coronary plaques in patients with acute myocardial
329. Montalescot infarction. G, Cayla
N G, Collet JP, Elhadad S, Beygui F, Le Breton H, Choussat R,
Engl J Med 2000;343:915922. Leclercq F, Silvain J, Duclos F, Aout M, Dubois-Rande JL, Barthelemy O,
309. Libby P. Inammation in atherosclerosis. Arterioscler ThrombDucrocq VascG, Biol
Bellemain-Appaix
2012;32: A, Payot L, Steg PG, Henry P, Spaulding C,
20452051. Vicaut E. Immediate vs delayed intervention for acute coronarysyndromes: a ran-
310. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the domized
vulnerable
clinical plaque.
trial. JAMA 2009;302:947954.
J Am Coll Cardiol 2006;47:C13C18. 330. Sorajja P, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P, Costantini C,
311. Vergallo R, Ren X, Yonetsu T, Kato K, Uemura S, Yu B, JiaStuckeyT,TchengJE,MehranR,LanskyAJ,GrinesCL,StoneGW.Impactofdelay
H, Abtahian F,
Aguirre AD, Tian J, Hu S, Soeda T, Lee H, McNulty I, Park SJ, toJang
angioplasty
Y, Prasad inA,patients with acute coronary syndromes undergoing invasive
Lee S, Zhang S, Porto I, Biasucci LM, Crea F, Jang IK. Pancoronary
management: plaqueanalysisvulner- from the ACUITY (Acute Catheterization and Urgent
ability in patients with acute coronary syndrome and ruptured Intervention
culprit plaque:
Triage strategY)
a trial. J Am Coll Cardiol 2010;55:14161424.
3-vessel optical coherence tomography study. Am Heart331. J 2014;167:5967.
Amsterdam EA, Kirk JD, Bluemke DA, Diercks D, Farkouh ME, Garvey JL,
312. Cheruvu PK, Finn AV, Gardner C, Caplan J, Goldstein J, Stone
Kontos GW,MC,Virmani
McCordR,J, Miller TD, Morise A, Newby LK, Ruberg FL,
Muller JE. Frequencyanddistributionof thin-cap broatheromaandrupturedpla-
Scordo KA, Thompson PD. Testing of low-risk patients presenting to the emer-
ques in human coronary arteries: a pathologic study. J Amgency Coll Cardiol
department 2007;50: with chest pain: a scientic statement from the American
940949. Heart Association. Circulation 2010;122:17561776.
313. Shishehbor MH, Lauer MS, Singh IM, Chew DP, Karha 332. J, Brener
De Ferrari
SJ, Moliterno
GM, FoxDJ, KA, White JA, Giugliano RP, Tricoci P, Reynolds HR,
EllisSG,TopolEJ,BhattDL.Inunstableanginaornon-ST-segmentacutecoronary
Hochman JS, Gibson CM, Theroux P, Harrington RA, Van de Werf F,
syndrome, should patients with multivessel coronaryartery White
diseaseHD,undergo
Califf RM, mul-Newby LK. Outcomes among non-ST-segment elevation
tivessel or culprit-only stenting? J Am Coll Cardiol 2007;49:849854.
acute coronary syndromes patients with no angiographically obstructive coron-
314. Sgarbossa EB, Birnbaum Y, Parrillo JE. Electrocardiographicary artery
diagnosis disease:
of acute observations from 37,101 patients. Eur Heart J Acute Cardiovasc
myocardial infarction: current concepts for the clinician. Am CareHeart2014;3:3745.
J 2001;141:
507517. 333. Solomon MD, Go AS, Shilane D, Boothroyd DB, Leong TK, Kazi DS, Chang TI,
315. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakamura
Hlatky MA.S,Comparative
Yoshida M, effectiveness of clopidogrel in medically managed pa-
Mitsuba N, Hata T. Electrocardiographic features in patients tients
withwithacute unstable
myocar- angina and non-ST-segment elevation myocardial infarction.
dial infarction associated with left main coronaryarteryocclusion.
J Am Coll Heart
Cardiol2004;90:
2014;63:22492257.
10591060. 334. RoeMT,ArmstrongPW,FoxKA,WhiteHD,PrabhakaranD,GoodmanSG,Cor-
316. de Winter RJ, Verouden NJ, Wellens HJ, Wilde AA. A new nel ECGJH, sign
BhattDL,
of proximalClemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE,
LAD occlusion. N Engl J Med 2008;359:20712073. Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A,
317. TahvanainenM,NikusKC,HolmvangL,ClemmensenP,SclarovskyS,BirnbaumY,
Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD,
Kelbaek H, Huhtala H, Tilsted HH, Eskola MJ. Factors associated
Merkely with
B, failure
Gasparovicto V, Corbalan R, Cinteza M, McLendon RC, Winters KJ,
identify the culprit artery by the electrocardiogram in inferior
Brown ST-elevation
EB, Lokhnygina myo- Y, Aylward PE, Huber K, Hochman JS, Ohman EM; TRIL-
cardial infarction. J Electrocardiol 2011;44:495501. OGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syn-
318. Tanaka A, Shimada K, Tearney GJ, Kitabata H, Taguchi H,dromesFukudawithout S, Kashiwagi
revascularization.
M, N Engl J Med 2012;367:12971309.
Kubo T, Takarada S, Hirata K, Mizukoshi M, Yoshikawa J, 335.
Bouma JamesBE, SK,Akasaka
Roe MT, T. Cannon CP, Cornel JH, HorrowJ, Husted S, Katus H, Morais J,
Conformational change in coronary artery structure assessed Stegby PG,
optical
Storey coher-
RF, Stevens S, Wallentin L, Harrington RA. Ticagrelor versus clo-
ence tomography in patients with vasospastic angina. J Am pidogrel
Coll Cardiol
in patients
2011;58: with acute coronary syndromes intended for non-invasive
16081613. management: substudy from prospectiverandomised PLATelet inhibition and pa-
319. Kato M, Dote K, Sasaki S, Kagawa E, Nakano Y, Watanabe tientY, Outcomes
Higashi A, (PLATO)Itakura K, trial. BMJ 2011;342:d3527.
Ochiumi Y, Takiguchi Y. Presentations of acute coronary 336.
syndrome
Williams related
B, Menonto M, Satran D, Hayward D, Hodges JS, Burke MN, Johnson RK,
Poulose AK, Traverse JH, Henry TD. Patients with coronary artery disease not
315e ESC Guidelines

amenable to traditional revascularization: prevalence and 3-year 352.mortality.


Cannon CP, CathetWeintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N,
Cardiovasc Interv 2010;75:886891. Neumann FJ, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM,
337. Henry TD, Satran D, Hodges JS, Johnson RK, Poulose AK, Campbell Braunwald
AR, E. Comparison of early invasive and conservative strategies in patients
Garberich RF, Bart BA, Olson RE, Boisjolie CR, Harvey KL, Arndt TL, with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor
Traverse JH. Long-term survival in patients with refractory angina. tiroban.
Eur Heart N EnglJ J Med 2001;344:18791887.
2013;34:26832688. 353. Fox KA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlain DA,
338. Dorfman TA, Iskandrian AE. Takotsubo cardiomyopathy: state-of-the-art
ShawTR, WheatleyDJ,
review. PocockSJ,RandomizedInterventionTrialof unstableAn-
J Nucl Cardiol 2009;16:122134. gina I. Interventional versus conservative treatment for patients with unstable an-
339. BellandiB, Salvadori C,Parodi G,Ebert AG, Petix N, Del PaceS, Boni
ginaA, orPestelliF,
non-ST-elevation myocardial infarction: the British Heart Foundation
Fineschi M, Giomi A, Cresti A, Giuliani G, Venditti F, Querceto L, Gensini
RITA 3 randomised
GF, trial. Randomized intervention trial of unstable angina. Lancet
Bolognese L, Bovenzi F. [Epidemiology of Tako-Tsubo cardiomyopathy: 2002;360:743751.
the Tus-
cany registry for Tako-Tsubo cardiomyopathy ]. G Ital Cardiol (Rome)
354. Wallentin
2012;13:L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1
5966. year after an invasive compared with a non-invasive strategy in unstable
340. Sy F, Basraon J, Zheng H, Singh M, Richina J, Ambrose JA. Frequency
coronary-artery
of takotsubo disease: the FRISC II invasive randomised trial. Lancet 2000;
cardiomyopathy in postmenopausal women presenting with an acute 356:916.coronary
syndrome. Am J Cardiol 2013;112:479482. 355. Farooq V, Serruys PW, Bourantas CV, Zhang Y, Muramatsu T, Feldman T,
341. Jaguszewski M, Osipova J, Ghadri JR, Napp LC, Widera C, Franke Holmes
J, Fijalkowski
DR, Mack M, M, Morice MC, Stahle E, Colombo A, de Vries T, Morel MA,
NowakR,FijalkowskaM,VolkmannI,KatusHA,WollertKC,BauersachsJ,ErneP, Dawkins KD, Kappetein AP, Mohr FW. Quantication of incomplete revascular-
Luscher TF, Thum T, Templin C. A signature of circulating microRNAs izationdifferenti-
and its association with ve-year mortality in the SYNergy between per-
ates takotsubo cardiomyopathy from acute myocardial infarction. cutaneous
Eur Heartcoronary
J intervention with TAXus and cardiac surgery (SYNTAX)
2014;35:9991006. trial validation of the residual SYNTAX score. Circulation 2013;128:141151
342. Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the356. diagnosis
Genereux of P, Palmerini T, Caixeta A, Rosner G, Green P, Dressler O, Xu K,
Tako-Tsubo cardiomyopathy and long-term prognosis. Herz 2010;35:240243.
Parise H, Mehran R, Serruys PW, Stone GW. Quantication and impact of un-
343. Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem
treatedcoronaryarterydiseaseafterpercutaneouscoronaryintervention:there-
U. Coronary
arteryspasmasafrequentcauseofacutecoronarysyndrome:theCASPAR(Cor- sidual SYNTAX (SYNergy between PCI with TAXus and cardiac surgery) score.
onary Artery Spasm in Patients with Acute coRonary syndrome) study. J Am Coll J Am Cardiol
Coll 2012;59:21652174.
Cardiol 2008;52:523527. 357. Curtis JP, Schreiner G, Wang Y, Chen J, Spertus JA, Rumsfeld JS, Brindis RG,
344. Mohri M, Koyanagi M, Egashira K, Tagawa H, Ichiki T, Shimokawa KrumholzHM.All-causereadmissionandrepeatrevascularizationafterpercutan-
H, Takeshita A.
Angina pectoris caused by coronary microvascular spasm. Lancet eous
1998;351:
coronary intervention in a cohort of Medicare patients. J Am Coll Cardiol
11651169. 2009;54:903907.
345. Raber L, Kelbaek H, Ostojic M, Baumbach A, Heg D, Tuller D,358. von Meadows
Birgelen C, ES, Bae JP, Zagar A, Sugihara T, Ramaswamy K, McCracken R,
Rof M, Moschovitis A, Khattab AA, Wenaweser P, Bonvini R, PedrazziniHeiselmanG, D. Rehospitalization following percutaneous coronary intervention
Kornowski R, Weber K, Trelle S, Luscher TF, Taniwaki M, Matter CM, forMeier
commercially
B, insured patientswith acute coronarysyndrome:a retrospective
Juni P, Windecker S. Effect of biolimus-eluting stents with biodegradable
analysis.polymerBMC Res Notes 2012;5:342.
vs bare-metal stents on cardiovascularevents among patients 359. with Ranasinghe
acute myocar- I, Alprandi-Costa B, Chow V, Elliott JM, Waites J, Counsell JT,
dial infarction: the COMFORTABLE AMI randomized trial. JAMA 2012;308:
Lopez-Sendon J, Avezum A, Goodman SG, Granger CB, Brieger D. Risk strati-
777787 cation in the setting of non-ST elevation acute coronary syndromes 19992007.
346. Sabate M, Cequier A, Iniguez A, Serra A, Hernandez-Antolin R, Am Mainar
J Cardiol
V, 2011;108:617624.
Valgimigli M, Tespili M, den Heijer P, Bethencourt A, Vazquez N, 360. Martensson S, Gyrd-Hansen D, Prescott E, Andersen PK, Zwisler AD, Osler M.
Gomez-Hospital JA, Baz JA, Martin-Yuste V, van Geuns RJ, AlfonsoTrends
F, Bordes in time
P, to invasive examination and treatment from 2001 to 2009 in pa-
Tebaldi M, Masotti M, Silvestro A, Backx B, Brugaletta S, van Es GA,tients admitted rst time with non-ST elevation myocardial infarction or unstable
Serruys PW. Everolimus-eluting stent versus bare-metal stent in ST-segment
angina in Denmark. ele- BMJ Open 2014;4:e004052.
vation myocardial infarction (examination): 1 year results of a361.
randomised
FukuiT, TabataM,
con- Morita S, TakanashiS. Earlyandlong-term outcomes of coron-
trolled trial. Lancet 2012;380:14821490. ary artery bypass grafting in patients with acute coronary syndrome versus stable
347. Valgimigli M, Tebaldi M, Borghesi M, Vranckx P, Campo G, Tumscitzangina C, pectoris. J Thorac Cardiovasc Surg 2013;145:15771583, e1571.
Cangiano E, Minarelli M, Scalone A, Cavazza C, Marchesini J, Parrinello
362. Weiss G. Two-
ES, Chang DD, Joyce DL, Nwakanma LU, Yuh DD. Optimal timing of cor-
year outcomes after rst- or second-generation drug-eluting or bare-metal
onary artery stentbypass after acute myocardial infarction: a review of California dis-
implantation in all-comer patients undergoing percutaneous coronary charge interven-
data. J Thorac Cardiovasc Surg 2008;135:503511, e501503.
tion:apre-speciedanalysisfromthePRODIGYstudy(prolongingdualantiplate-
363. Deyell MW, Ghali WA, Ross DB, Zhang J, Hemmelgarn BR. Timing of nonemer-
let treatment after grading stent-induced intimal hyperplasia study).
gent JACC
coronary artery bypass grafting and mortality after non-ST elevation acute
Cardiovasc Interv 2014;7:2028. coronary syndrome. Am Heart J 2010;159:490496.
348. Lagerqvist B, Frobert O, Olivecrona GK, Gudnason T, Maeng364. M, Alstrom
Parikh SV, P, de Lemos JA, Jessen ME, Brilakis ES, Ohman EM, Chen AY, Wang TY,
Andersson J, Calais F, Carlsson J, Collste O, Gotberg M, Hardhammar Peterson
P, ED, Roe MT, Holper EM. Timing of in-hospital coronary artery bypass
Ioanes D, Kallryd A, Linder R, Lundin A, Odenstedt J, Omerovic E,graft
Puskar surgery
V, for non-ST-segment elevation myocardial infarction patients results
Todt T, Zelleroth E, Ostlund O, James SK. Outcomes 1 year after thrombus
from the National
as- Cardiovascular Data Registry ACTION Registry-GWTG
piration for myocardial infarction. N Engl J Med 2014;371:11111120. (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get
349. Jolly SS, Yusuf S, Cairns J, Niemela K, Xavier D, Widimsky P, Budaj
WithA,The Niemela
Guidelines).
M, JACC Cardiovasc Interv 2010;3:419427.
Valentin V, Lewis BS, Avezum A, Steg PG, Rao SV, Gao P, Afzal365. R, Joyner
Lim E,CD, Ali Z, Ali A, Routledge T, Edmonds L, Altman DG, Large S. Indirect com-
Chrolavicius S, Mehta SR. Radial versus femoral access for coronary parison
angiography
meta-analysis of aspirin therapy after coronary surgery. BMJ 2003;327:
and intervention in patients with acute coronary syndromes (RIVAL): 1309. a rando-
mised, parallel group, multicentre trial. Lancet 2011;377:14091420.
366. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves
350. Rao SV, Hess CN, Barham B, Aberle LH, Anstrom KJ, Patel TB, Jorgensen
vein graft JP, patency early and late after coronary artery bypass graft surgery. A
Mazzaferri EL Jr., Jolly SS, Jacobs A, Newby LK, Gibson CM, Kong DF,placebo-controlled, randomized study. Circulation 1991;83:15261533.
Mehran R, Waksman R, Gilchrist IC, McCourt BJ, Messenger JC,367. Peterson
Biondi-Zoccai
ED, GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F,
Harrington RA, Krucoff MW. A registry-based randomized trial comparing
Testa L, Sheiban
radial I, Sangiorgi G. A systematic review and meta-analysis on the ha-
and femoral approaches in women undergoing percutaneous coronary zards of interven-
discontinuing or not adhering to aspirin among 50,279 patients atrisk for
tion: the SAFE-PCI for Women (Study of Access Site for Enhancement coronaryof PCI artery
for disease. Eur Heart J 2006;27:26672674.
Women) trial. JACC Cardiovasc Interv 2014;7:857867. 368. Sun JC, Whitlock R, Cheng J, Eikelboom JW, Thabane L, Crowther MA, Teoh KH.
351. Hamon M, Pristipino C, Di Mario C, Nolan J, Ludwig J, Tubaro M,The Sabate
effect M,of pre-operative aspirin on bleeding, transfusion, myocardial infarction,
Mauri-Ferre J, Huber K, Niemela K, Haude M, Wijns W, Dudek D, Fajadet
and mortality
J, in coronary artery bypass surgery: a systematic review of rando-
Kiemeneij F. Consensus document on the radial approach in percutaneous
mized andcar- observational studies. Eur Heart J 2008;29:10571071.
diovascular interventions: position paper by the European Association
369. DejaofMA, Percu-
Kargul T, Domaradzki W, Stacel T, Mazur W, Wojakowski W, Gocol R,
taneousCardiovascularInterventionsandworkinggroupsonAcuteCardiacCareGaszewska-Zurek E, Zurek P, Pytel A, Wos S. Effects of preoperative aspirin in
and Thrombosis of the European Society of Cardiology. EuroIntervention
coronary2013;8: artery bypass grafting: a double-blind, placebo-controlled, randomized
12421251. trial. J Thorac Cardiovasc Surg 2012;144:204209.
ESC Guidelines 315f

370. Biancari F, Airaksinen KE, Lip GY. Benets and risks of using
andefcacyofdrug-elutingstentsinwomen:apatient-levelpooledanalysisofran-
clopidogrel before
coronary artery bypass surgery: systematic review and meta-analysis
domised trials. of Lancet
rando- 2013;382:18791888.
mized trials and observational studies. J Thorac Cardiovasc
387. Kaiser
Surg 2012;143:
C, Galatius S, Erne P, Eberli F, Alber H, Rickli H, Pedrazzini G, Hornig B,
665675, e664. Bertel O, Bonetti P, De Servi S, Brunner-La Rocca HP, Ricard I, Psterer M.
371. Nijjer SS, WatsonG,Athanasiou T, Malik IS.Safetyof clopidogrelbeingcontinued
Drug-eluting versus bare-metal stents in large coronary arteries. N Engl J Med
until the time of coronary artery bypass grafting in patients
2010;363:23102319.
with acute coronary
syndrome: a meta-analysis of 34 studies. Eur Heart J 2011;32:29702988.
388. GreenhalghJ,HockenhullJ,RaoN,DundarY,DicksonRC,BagustA.Drug-eluting
372. MahlaE,SuarezTA,BlidenKP,RehakP,MetzlerH,SequeiraAJ,Cho stents P, versus
SellJ,FanJ,
bare metal stents for angina oracute coronary syndromes. Cochrane
Antonino MJ, Tantry US, Gurbel PA. Platelet function measurement-based
Database Syst Rev strat-2010;5:CD004587
egy to reduce bleeding and waiting time in clopidogrel-treated
389. Kirtane patients
AJ, Gupta
undergo- A, Iyengar S, Moses JW, Leon MB, Applegate R, Brodie B,
ing coronary artery bypass graft surgery: the timing based Hannan
on platelet
E, Harjaifunction
K, Jensen LO, Park SJ, Perry R, Racz M, Saia F, Tu JV,
strategy to reduce clopidogrel-associated bleeding related Waksman
to CABGR, (TARGET-
Lansky AJ, Mehran R, Stone GW. Safety and efcacy of drug-eluting
CABG) study. Circulation Cardiovasc Interv 2012;5:261269. and bare metal stents: comprehensive meta-analysis of randomized trials and ob-
373. Rastan AJ, Eckenstein JI, Hentschel B, Funkat AK, Gummertservational
JF, Dollstudies.
N, Walther Circulation
T, 2009;119:31983206.
Falk V, Mohr FW. Emergency coronary artery bypass graft 390.surgery
Moses for JW, acute
Mehran cor-R, Nikolsky E, Lasala JM, Corey W, Albin G, Hirsch C,
onary syndrome: beating heart versus conventional cardioplegic
Leon MB,cardiac Russellarrest
ME, Ellis SG, Stone GW. Outcomes with the paclitaxel-eluting
strategies. Circulation 2006;114:I477485. stent in patients with acute coronary syndromes: analysis from the TAXUS-IV
374. Ben-Gal Y, Moses JW, Mehran R, Lansky AJ, Weisz G, Nikolsky
trial. J AmE, Argenziano
Coll CardiolM, 2005;45:11651171.
Williams MR, Colombo A, Aylward PE, Stone GW. Surgical 391.versus
YanAT, percutaneous
Yan RT, Tan M, FungA, CohenEA, Fitchett DH, Langer A, Goodman SG,
revascularization for multivessel disease in patients with CanadianAcuteCoronarySyndromes1and2RegistryInvestigators.Management
acute coronary syn-
dromes: analysis from the ACUITY (Acute Catheterizationpatterns
and Urgent in relation
Interven- to risk stratication among patients with non-ST elevation
tion Triage strategY) trial. JACC Cardiovasc Interv 2010;3:10591067.
acute coronary syndromes. Arch Intern Med 2007;167:10091016.
375. Harling L, Moscarelli M, Kidher E, Fattouch K, Ashraan392.
H, Athanasiou
Poon S, Goodman T. The ef- SG, Yan RT, Bugiardini R, Bierman AS, Eagle KA, Johnston N,
fect of off-pump coronary artery bypass on mortality after Huynh
acuteT, coronary
Grondinsyn- FR, Schenck-Gustafsson K, Yan AT. Bridging the gender gap:
drome: a meta-analysis. Int J Cardiol 2013;169:339348. insights from a contemporary analysis of sex-related differences in the treatment
376. Stamou SC, Hill PC, Haile E, Prince S, Mack MJ, Corso PJ.andClinical
outcomes outcomesof patients
of with acute coronary syndromes. Am Heart J 2012;163:
nonelective coronary revascularization with and without cardiopulmonary
6673. by-
pass. J Thorac Cardiovasc Surg 2006;131:2833. 393. Canto JG, Rogers WJ, Goldberg RJ, Peterson ED, Wenger NK, Vaccarino V,
377. Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth Kiefe J, Brooks
CI, Frederick
MM, PD, Sopko G, Zheng ZJ, Investigators N. Association of age
Carrie D, Clayton TC, Danchin N, Flather M, Hamm CW, Hueb and sex WA,withKahler myocardial
J, infarction symptom presentation and in-hospital mortal-
Kelsey SF, King SB, Kosinski AS, Lopes N, McDonald KM, Rodriguez
ity. JAMA 2012;307:813822.
A,
Serruys P, Sigwart U, Stables RH, Owens DK, Pocock SJ.394.Coronary
Mehilliartery
J, Kastrati
bypass A, Dirschinger J, Pache J, Seyfarth M, Blasini R, Hall D,
surgery compared with percutaneous coronary interventions Neumannfor multivessel
FJ, Schomig dis-A. Sex-based analysis of outcome in patients with acute
ease: acollaborative analysis of individual patient datafrommyocardial
ten randomisedinfarction trials.
treated predominantly with percutaneous coronary inter-
Lancet 2009;373:11901197. vention. JAMA 2002;287:210215.
378. MohrFW,MoriceMC,KappeteinAP,FeldmanTE,StahleE,ColomboA,MackMJ,
395. Alfredsson J, Lindback J, Wallentin L, Swahn E. Similar outcome with an invasive
Holmes DR Jr, Morel MA, Van Dyck N, Houle VM, Dawkins strategy
KD, Serruys in menPW. and women with non-ST-elevation acute coronary syndromes:
Coronary artery bypass graft surgery versus percutaneous from
coronary
the Swedish
intervention
Web-system for Enhancement and Development of Evidence-
inpatientswiththree-vesseldiseaseandleftmaincoronarydisease:5-yearfollow-
based care in Heart disease Evaluated According to Recommended Therapies
up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629638.
(SWEDEHEART). Eur Heart J 2011;32:31283136.
379. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas 396.G, ChewMack DP, M,Juergens
Yang M, C, French J, Parsonage W, Horsfall M, Brieger D, Quinn S. An
Cohen DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, examination
Magnuson EA, of clinical intuition in risk assessment among acute coronary syn-
Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousadromes JE, Rankin patients:
J, observations from a prospective multi-center international ob-
Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal servational
S, King S registry.
3rd, Int J Cardiol 2014;171:209216.
Bertrand M, Fuster V. Strategies for multivessel revascularization
397. Gore MO, in patients
Seliger SL, Delippi CR, Nambi V, Christenson RH, Hashim IA,
with diabetes. N Engl J Med 2012;367:23752384. Hoogeveen RC, Ayers CR, Sun W, McGuire DK, Ballantyne CM, de Lemos JA.
380. WindeckerS,KolhP, AlfonsoF, ColletJP,CremerJ,FalkV, FilippatosG,HammC,
Age- and sex-dependent upper reference limits for the high-sensitivity cardiac
Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser
troponin U, Laufer
T assay. G,J Am Coll Cardiol 2014;63:14411448.
Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini
398. Dey GG, S,Taggart
Flather DP, MD, Devlin G, Brieger D, Gurnkel EP, Steg PG, Fitzgerald G,
Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS
Jacksonguidelines
EA, Eagle KA, Global Registry of Acute Coronary Events Investigators.
on myocardial revascularization. Eur Heart J 2014;35:25412619.
Sex-related differences in the presentation, treatment and outcomes among pa-
381. Palmerini T, Genereux P, Caixeta A, Cristea E, Lansky A, tients
Mehran withR, acute
Dangas coronary
G, syndromes: the Global Registry of Acute Coronary
Lazar D, Sanchez R, Fahy M, Xu K, Stone GW. Prognostic valueEvents. of Heart
the SYNTAX2009;95:2026.
score in patients with acute coronary syndromes undergoing
399. Hochman
percutaneous JS, Tamis cor-JE, Thompson TD, Weaver WD, White HD, Van de Werf F,
onaryintervention:analysisfromtheACUITY(AcuteCatheterizationandUrgent
Aylward P, TopolEJ, Califf RM. Sex, clinical presentation, and outcome in patients
Intervention Triage strategY) trial. J Am Coll Cardiol 2011;57:23892397.
withacutecoronarysyndromes.GlobalUseofStrategiestoOpenOccludedCor-
382. HasdaiD,HarringtonRA,HochmanJS,CaliffRM,BattlerA,BoxJW, onaryArteriesinAcuteCoronarySyndromesIIbInvestigators.NEnglJMed1999;
SimoonsML,
Deckers J, TopolEJ, Holmes DR Jr. Platelet glycoprotein IIb/IIIa
341:226232.
blockade and out-
come of cardiogenic shock complicating acute coronary 400.
syndromes
Wiviott SD, without
Cannon per-CP, Morrow DA, Murphy SA, Gibson CM, McCabe CH,
sistent ST-segment elevation. J Am Coll Cardiol 2000;36:685692.
Sabatine MS, Rifai N, Giugliano RP, DiBattiste PM, Demopoulos LA,
383. Holmes DR Jr., Berger PB, Hochman JS, Granger CB, Thompson
Antman EM, TD, Braunwald
Califf RM, E. Differential expression of cardiac biomarkers by gen-
VahanianA,BatesER, TopolEJ. Cardiogenicshock in patientswithder in acuteischemic
patients with unstable angina/non-ST-elevation myocardial infarction: a
syndromes with and without ST-segment elevation. CirculationTACTICS-TIMI
1999;100: 18 (Treat Angina with Aggrastat and determine Cost of Therapy
20672073. with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction
384. Hollenberg SM, Kavinsky CJ, Parrillo JE. Cardiogenic shock.
18) substudy.
Ann InternCirculation
Med 1999;2004;109:580586.
131:4759. 401. Terkelsen CJ, Sorensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, Vach W,
385. ThieleH,ZeymerU,NeumannFJ,FerencM,OlbrichHG,HausleiterJ,RichardtG,
Johnsen SP, Thuesen L, Lassen JF. System delayand mortality among patients with
Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht
STEMI treated R, Fuhrmann
with primary
J, percutaneous coronary intervention. JAMA 2010;
Bohm M, Ebelt H, Schneider S, Schuler G, Werdan K. Intraaortic
304:763771.balloon support
for myocardial infarction with cardiogenic shock. N Engl 402.
J MedAlexander
2012;367: KP, Chen AY, Newby LK, Schwartz JB, Redberg RF, Hochman JS,
12871296. Roe MT, Gibler WB, Ohman EM, Peterson ED. Sex differences in major bleeding
386. Stefanini GG, Baber U, Windecker S, Morice MC, Sartoriwith S, Leon
glycoprotein
MB, Stone IIb/IIIa
GW, inhibitors: results from the CRUSADE (Can Rapid risk
Serruys PW, Wijns W, Weisz G, Camenzind E, Steg PG, Smits stratication
PC, Kandzari of Unstable
D, angina patients Suppress ADverse outcomes with Early
Von Birgelen C, Galatius S, Jeger RV, Kimura T, Mikhail GW, implementation
Itchhaporia D,of the ACC/AHA guidelines) initiative. Circulation 2006;114:
Mehta L, Ortega R, Kim HS, Valgimigli M, Kastrati A, Chieffo13801387.
A, Mehran R. Safety
315g ESC Guidelines

403. Jneid H, Fonarow GC, Cannon CP, Hernandez AF, Palacios 421.
IF, Maree
Ekerstad AO,N, Swahn E, Janzon M, Alfredsson J, Lofmark R, Lindenberger M,
Wells Q, Bozkurt B, Labresh KA, Liang L, Hong Y, Newby LK, Fletcher
CarlssonG, P. Frailty is independentlyassociated with short-term outcomes for eld-
Peterson E, Wexler L. Sex differences in medical care and early erlydeath
patients
afterwithacutenon-ST-segment elevation myocardial infarction. Circulation
myocardial infarction. Circulation 2008;118:28032810. 2011;124:23972404.
404. VaccarinoV,ParsonsL,PetersonED,RogersWJ,KiefeCI,CantoJ.Sexdifferences
422. Giraldez RR, Clare RM, Lopes RD, Dalby AJ, Prabhakaran D, Brogan GX Jr,
in mortality afteracute myocardial infarction: changes from 1994 Giugliano
to 2006.
RP, Arch
JamesIn-SK, Tanguay JF, Pollack CV Jr, Harrington RA, Braunwald E,
tern Med 2009;169:17671774. Newby LK. Prevalence and clinical outcomes of undiagnosed diabetes mellitus
405. Mehilli J, Kastrati A, Bollwein H, Dibra A, Schuhlen H, Dirschinger
and prediabetes
J, Schomigamong A. patients with high-risk non-ST-segment elevation acute
Gender and restenosis after coronary artery stenting. Eur Heart coronary
J 2003;24:
syndrome. Am Heart J 2013;165:918925, e912.
15231530. 423. Conaway DG, OKeefe JH, Reid KJ, Spertus J. Frequency of undiagnosed
406. Blomkalns AL, Chen AY, Hochman JS, Peterson ED, Trynosky diabetes
K, Diercksmellitus
DB, in patients with acute coronary syndrome. Am J Cardiol 2005;
Brogan GX Jr, Boden WE, Roe MT, Ohman EM, Gibler WB, Newby 96:363365.
LK. Gender
disparities in thediagnosis andtreatmentof non-ST-segment 424.
elevationacute
NorhammarA,TenerzA,NilssonG,HamstenA,EfendicS,Ryden
cor- L,Malmberg K.
onary syndromes: large-scale observations from the CRUSADE Glucose
(Can Rapid
metabolism
risk in patients with acute myocardial infarction and no
stratication of Unstable angina patients Suppress ADverse outcomes
previous withdiagnosis
Early of diabetes mellitus: a prospective study. Lancet 2002;359:
implementation of the American College of Cardiology/American 21402144.
Heart Associ-
ation guidelines) national quality improvementinitiative. J Am425.CollCardiol
Bartnik M,2005;45:
Ryden L, Malmberg K, Ohrvik J, Pyorala K, Standl E, Ferrari R,
832837. Simoons M, Soler-Soler J. Oral glucose tolerance test is needed for appropriate
407. Gale CP, Cattle BA, Woolston A, Baxter PD, West TH, Simms classication
AD, Blaxillof J, glucose regulation in patients with coronary artery disease: a re-
GreenwoodDC, FoxKA, WestRM. Resolvinginequalitiesincare?Reducedmor-
port from the Euro Heart Survey on Diabetes and the Heart. Heart 2007;93:
tality in the elderly after acute coronary syndromes. The myocardial
7277. ischaemia na-
tional audit project 2003-2010. Eur Heart J 2012;33:630639. 426. DotevallA,HasdaiD,WallentinL,BattlerA,RosengrenA.Diabetesmellitus:clin-
408. Bauer T, Koeth O, Junger C, Heer T, Wienbergen H, Gitt A, icalZahn presentation
R, Senges J,and outcome in men and women with acute coronary syn-
ZeymerU.Effectofaninvasivestrategyonin-hospitaloutcomeinelderlypatients
dromes. Data from the Euro Heart Survey ACS. Diabet Med 2005;22:15421550.
with non-ST-elevation myocardial infarction. Eur Heart J 2007;28:28732878.
427. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP,
409. AlexanderKP,NewbyLK,CannonCP,ArmstrongPW,GiblerWB,RichMW,Van Antman EM. Diabetes and mortality following acute coronary syndromes. JAMA
de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz 2007;298:765775.
HM,
Ohman EM. Acute coronary care in the elderly, part I: non-ST-segment-elevation
428. Angiolillo DJ. Antiplatelet therapy in diabetes: efcacy and limitations of current
acute coronary syndromes: a scientic statement for healthcare treatment
professionals
strategies and future directions. Diabetes Care 2009;32:531540.
fromtheAmericanHeartAssociationCouncilonClinicalCardiology: 429. FerreiroJL,
incollabor- Angiolillo DJ. Diabetes and antiplatelet therapy inacute coronarysyn-
ation with the Society of Geriatric Cardiology. Circulation 2007;115:25492569.
drome. Circulation 2011;123:798813.
410. RosengrenA, Wallentin L, Simoons M, GittAK, Behar S, BattlerA,
430. BartnikHasdaiM, D.Malmberg
Age, K, Norhammar A, Tenerz A, Ohrvik J, Ryden L. Newly de-
clinical presentation, and outcome of acute coronarysyndromes tectedabnormalglucosetolerance:animportantpredictoroflong-termoutcome
inthe Euroheart
acute coronary syndrome survey. Eur Heart J 2006;27:789795. after myocardial infarction. Eur Heart J 2004;25:19901997.
411. Brieger D, Eagle KA, Goodman SG, Steg PG, Budaj A, White 431.K, De Montalescot
Caterina R,G. Madonna R, Sourij H, Wascher T. Glycaemic control in acute cor-
Acute coronary syndromes without chest pain, an underdiagnosed onary syndromes:
and under- prognostic value and therapeutic options. Eur Heart J 2010;31:
treated high-risk group: insights fromthe global registry of acute
15571564.
coronaryevents.
Chest 2004;126:461469. 432. Svensson AM, McGuire DK, Abrahamsson P, Dellborg M. Association between
412. Reiter M, Twerenbold R, Reichlin T, Haaf P, Peter F, Meissner hyper-
J, Hochholzer
and hypoglycaemia
W, and 2 year all-cause mortality risk in diabetic patients
Stelzig C, Freese M, Heinisch C, Breidthardt T, Freidank H, Winkler
with acute
K, coronary events. Eur Heart J 2005;26:12551261.
CampodarveI,GeaJ,Mueller C. Earlydiagnosis ofacute myocardialinfarctioninthe
433. Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C,
elderlyusingmoresensitivecardiactroponinassays.EurHeartJ2011;32:13791389.
Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J,
413. Fox KA, Eagle KA, Gore JM, Steg PG, Anderson FA. The global Patrono
registry
C, Seferovic
of acute P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J,
coronary events, 1999 to 2009GRACE. Heart 2010;96:10951101. Valensi P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H,
414. Skolnick AH, Alexander KP, Chen AY, Roe MT, Pollack CV Jr,Dean Ohman V, Erol
EM, C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J,
Rumsfeld JS, Gibler WB, Peterson ED, Cohen DJ. Characteristics, Kolhmanagement,
P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P,
and outcomes of 5,557 patients age e90 years with acute coronary Sirnes PA, syndromes:
Tamargo JL, Torbicki A, Wijns W, Windecker S, De Backer G,
results from the CRUSADE initiative. J Am Coll Cardiol 2007;49:17901797.
Ezquerra EA, Avogaro A, Badimon L, Baranova E, Betteridge J, Ceriello A,
415. Devlin G, Gore JM, Elliott J, Wijesinghe N, Eagle KA, Avezum Funck-Brentano
A, Huang W, C, Gulba DC, Kjekshus JK, Lev E, Mueller C, Neyses L,
Brieger D. Management and 6-month outcomes in elderly and Nilsson
very elderly
PM, Perk pa-J, Reiner Z, Sattar N, Schachinger V, Scheen A, Schirmer H,
tients with high-risk non-ST-elevation acute coronary syndromes: Stromberg
the Global
A, Sudzhaeva S, Viigimaa M, Vlachopoulos C, Xuereb RG. ESC guide-
Registry of Acute Coronary Events. Eur Heart J 2008;29:12751282. lines on diabetes, pre-diabetes, and cardiovascular diseases developed in collab-
416. Malkin CJ, Prakash R, Chew DP. The impact of increased age oration
on outcome
with the from
EASD. a Eur Heart J 2013;34:30353087.
strategy of early invasive management and revascularisation 434.inVerges
patientsB, Avignon
with acute A, Bonnet F, Catargi B, Cattan S, Cosson E, Ducrocq G,
coronarysyndromes: retrospective analysis study fromthe ACACIA Elbaz registry.
M, FredenrichBMJ A, Gourdy P, Henry P, Lairez O, Leguerrier AM,
Open 2012;2:e000540. Monpere C, Moulin P, Verges-Patois B, Roussel R, Steg G, Valensi P. Consensus
417. Bach RG, Cannon CP, Weintraub WS, DiBattiste PM, Demopoulos statement LA, on the care of the hyperglycaemic/diabetic patient during and in the
Anderson HV, DeLucca PT, Mahoney EM, Murphy SA, Braunwald immediate
E. The effect
follow-up of acute coronary syndrome. Diabetes Metab 2012;38:
of routine, early invasive management on outcome for elderly 113127.
patients with
non-ST-segment elevation acute coronary syndromes. Ann435. InternKappetein
Med 2004; AP, Head SJ, Morice MC, Banning AP, Serruys PW, Mohr FW,
141:186195. Dawkins KD, Mack MJ. Treatment of complex coronary artery disease in patients
418. Savonitto S, Cavallini C, Petronio AS, Murena E, Antonicelliwith
R, Sacco
diabetes:
A, 5-year results comparing outcomes of bypass surgery and percu-
Steffenino G, Bonechi F, Mossuti E, Manari A, Tolaro S, Toso A,taneous
Daniotticoronary
A, intervention in the SYNTAX trial. Eur J Cardiothorac Surg 2013;
Piscione F, Morici N, Cesana BM, Jori MC, De Servi S. Early aggressive
43:10061013. versus ini-
tially conservative treatment in elderly patients with non-ST-segment
436. Kapur A, elevation
Hall RJ, Malik IS, Qureshi AC, Butts J, de Belder M, Baumbach A,
acute coronary syndrome: a randomized controlled trial. JACC Angelini
Cardiovasc G, deInterv
Belder A, Oldroyd KG, Flather M, Roughton M,
2012;5:906916. Nihoyannopoulos P, Bagger JP, Morgan K, Beatt KJ. Randomized comparison of
419. Andreotti F, Rocca B, Husted S, Ajjan RA, Ten Berg J, Cattaneopercutaneous
M, Collet JP, coronary
De intervention with coronary artery bypass grafting in dia-
Caterina R, Fox KA, Halvorsen S, Huber K, Hylek EM, Lip GY, Montalescot
betic patients. G, 1-year results of the CARDIA (Coronary Artery Revascularization
MoraisJ,PatronoC,VerheugtFW,WallentinL,WeissTW,StoreyRF.Antithrom-
in DIAbetes) trial. J Am Coll Cardiol 2010;55:432440.
botictherapyintheelderly:expertpositionpaperoftheEuropeanSocietyofCar-
437. RofM,AngiolilloDJ,KappeteinAP.Currentconceptsoncoronaryrevasculariza-
diology Working Group on Thrombosis. Eur Heart J 2015 Jul 9;tion doi:in10.1093/
diabetic patients. Eur Heart J 2011;32:27482757.
eurheartj/ehv304 [Epub ahead of print]. 438. Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW,
420. Alalo J, Alexander KP, Mack MJ, Maurer MS, Green P, Allen LA, Goodman
PopmaSG, JJ, Corbalan R, Purdy DA, Murphy SA, McCabe CH, Antman EM.
Ferrucci L, Forman DE. Frailty assessment in the cardiovascular Greater
care ofclinical
olderbenet of more intensive oral antiplatelet therapy with prasugrel
adults. J Am Coll Cardiol. 2014;63:74762. inpatientswith diabetes mellitus inthetrialto assessimprovementintherapeutic
ESC Guidelines 315h

outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis


of contrast In medium-induced
Myo- nephropathy in patients undergoing coronary angi-
cardial Infarction 38. Circulation 2008;118:16261636. ography: a randomized trial. JAMA 2008;300:10381046.
439. James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny
456. Merten
F, MayaGJ, J, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ,
Nicolau JC,Spinar J,Storey RF, StevensSR, Wallentin L.Ticagrelor Bersinvs.clopidogrel
RM, Van Moore A, Simonton CA 3rd, Rittase RA, Norton HJ,
in patients with acute coronary syndromes and diabetes: a substudy
Kennedy from TP. Prevention
the of contrast-induced nephropathywith sodium bicarbon-
PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heartate: aJ 2010;31:
randomized controlled trial. JAMA 2004;291:23282334.
30063016. 457. Jo SH, Youn TJ, Koo BK, Park JS, Kang HJ, Cho YS, Chung WY, Joo GW, Chae IH,
440. Rof M, Chew DP, Mukherjee D, Bhatt DL, White JA, Heeschen Choi C,DJ,Hamm Oh BH,CW,Lee MM, Park YB, Kim HS. Renal toxicity evaluation and com-
Moliterno DJ, Califf RM, White HD, Kleiman NS, Theroux P, Topol parisonEJ. Platelet
between Visipaque (iodixanol) and Hexabrix (ioxaglate) in patients with
glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients
renal insufciency
with undergoing coronary angiography: the RECOVER study: a ran-
non-ST-segment-elevation acute coronary syndromes. Circulation domized 2001;104:
controlled trial. J Am Coll Cardiol 2006;48:924930.
27672771. 458. Maioli M, Toso A, Leoncini M, Micheletti C, Bellandi F. Effects of hydration in
441. ODonoghue ML, Vaidya A, Afsal R, Alfredsson J, Boden WE,contrast-induced
Braunwald E, acute kidney injury after primary angioplasty: a randomized,
Cannon CP, Clayton TC, de Winter RJ, Fox KA, Lagerqvist B, McCullough
controlled trial. PA, Circ Cardiovasc Interv 2011;4:456462.
Murphy SA, Spacek R, Swahn E, Windhausen F, Sabatine MS. 459.An Aspelin
invasive P, Aubry
or con-P, FranssonSG,StrasserR, Willenbrock R,Berg KJ. Nephrotoxic
servative strategy in patients with diabetes mellitus and non-ST-segment
effects in high-risk eleva-patients undergoing angiography. N Engl J Med 2003;348:
tion acute coronary syndromes: a collaborative meta-analysis 491499.
of randomized
trials. J Am Coll Cardiol 2012;60:106111. 460. Solomon RJ, Natarajan MK, Doucet S, Sharma SK, Staniloae CS, Katholi RE,
442. Rof M, Topol EJ. Percutaneous coronary intervention in diabetic
Gelormini patients
JL, Labinaz
with M, Moreyra AE. Cardiac Angiography in Renally Impaired
non-ST-segment elevation acute coronary syndromes. Eur Heart PatientsJ 2004;25:
(CARE) study: a randomized double-blind trial of contrast-induced ne-
190198. phropathy in patients with chronic kidney disease. Circulation 2007;115:
443. Daemen J, Garcia-Garcia HM, Kukreja N, Imani F, de Jaegere 31893196.
PP, Sianos G, van
Domburg RT, Serruys PW. The long-term value of sirolimus- 461.
andTsai TT, Messenger JC, Brennan JM, Patel UD, Dai D, Piana RN, Anstrom KJ,
paclitaxel-eluting stents over bare metal stents in patients withEisenstein
diabetes EL,mellitus.
Dokholyan RS, Peterson ED, Douglas PS. Safety and efcacy of
Eur Heart J 2007;28:2632. drug-eluting stents in older patients with chronic kidney disease: a report from
444. Verma S, Farkouh ME, Yanagawa B, Fitchett DH, Ahsan MR,the Ruel linked
M, Sud CathPCI
S, Registry-CMS claims database. J Am Coll Cardiol 2011;58:
Gupta M, Singh S, Gupta N, Cheema AN, Leiter LA, Fedak PW,18591869. Teoh H,
Latter DA, Fuster V, Friedrich JO. Comparison of coronary artery
462. ShenoyC,BouraJ,OrshawP,HarjaiKJ.Drug-elutingstentsinpatientswithchron-
bypass surgery
andpercutaneouscoronaryinterventioninpatientswithdiabetes:ameta-analysis
ic kidney disease: a prospective registry study. PLoS One 2010;5:e15070.
of randomised controlled trials. Lancet Diabetes Endocrinol 463.
2013;1:317328.
Chang TI, Shilane D, Kazi DS, Montez-Rath ME, Hlatky MA, Winkelmayer WC.
445. HakeemA, Garg N, BhattiS, Rajpurohit N, Ahmed Z, UretskyBF. Multivessel
Effectiveness
coronary of artery bypass grafting versus percutaneous coronary inter-
percutaneous coronary intervention with drug-eluting stents vention
compared in ESRD.
with by- J Am Soc Nephrol 2012;23:20422049.
pass surgery in diabetics with multivessel coronary disease: 464.
comprehensive
ZhengH,XueS,LianF,HuangRT,HuZL,
sys- WangYY.Meta-analysisofclinicalstud-
tematic review and meta-analysis of randomized clinical data. iesJ comparing
Am Heart Assoc coronary artery bypass grafting with percutaneous coronary inter-
2013;2:e000354. vention in patients with end-stage renal disease. Eur J Cardiothorac Surg 2013;43:
446. Ezekowitz J, McAlister FA, Humphries KH, Norris CM, Tonelli459467.
M, Ghali WA,
Knudtson ML. The association among renal insufciency, pharmacotherapy,
465. Fox CS, Muntner and P, Chen AY, Alexander KP, Roe MT, Cannon CP, Saucedo JF,
outcomes in 6,427 patients with heart failure and coronary arteryKontosdisease.
MC, Wiviott J Am SD. Use of evidence-based therapies in short-term out-
Coll Cardiol 2004;44:15871592. comes of ST-segment elevation myocardial infarction and non-ST-segment eleva-
447. Szummer K, Lundman P, Jacobson SH, Schon S, Lindback J,tion Stenestrand
myocardial U,infarction in patients with chronic kidney disease: a report from
Wallentin L, Jernberg T. Relation between renal function, presentation,
the National useCardiovascular
of Data Acute Coronary Treatment and Intervention
therapies and in-hospital complications in acute coronary syndrome:
Outcomes data
Network
from registry. Circulation 2010;121:357365.
the SWEDEHEART register. J Intern Med 2010;268:4049. 466. YanLQ,GuoLJ,ZhangFC,GaoW.Therelationshipbetweenkidneyfunctionand
448. Szummer K, Lundman P, Jacobson SH, Schon S, Lindback J,angiographically-derived
Stenestrand U, SYNTAX score. Can J Cardiol 2011;27:768772.
Wallentin L, Jernberg T. Inuence of renal function on the effects
467. StegPG,
of early DabbousOH,
revas- FeldmanLJ, Cohen-Solal A,Aumont MC, Lopez-Sendon J,
cularization in non-ST-elevation myocardial infarction: data fromBudaj theA,Swedish
Goldberg RJ, Klein W, Anderson FAJr. Determinants and prognostic im-
Web-system for Enhancement and Development of Evidence-based pact of heartcare infailure complicating acute coronary syndromes: observations from
Heart disease Evaluated According to Recommended Therapies the (SWEDE-
Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:
HEART). Circulation 2009;120:851858. 494499.
449. James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel 468.
JH,Roger
Harrington VL. Epidemiology
RA, of heart failure. Circ Res 2013;113:646659.
Horrow J, Katus H, Keltai M, Lewis BS, Parikh K, Storey RF, 469.
Szummer McMurrayK, JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K,
Wojdyla D, Wallentin L. Ticagrelor versus clopidogrel in acuteFalk coronary
V, Filippatos
syn- G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L,
dromes in relation to renal function: results from the PLATeletLip inhibition
GY, Maggioniand pa- AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK,
tient Outcomes (PLATO) trial. Circulation 2010;122:10561067. Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA,
450. GrandMaison A, Charest AF, Geerts WH. Anticoagulant useZannad in patients F, Zeiher
with A. ESC guidelines for the diagnosis and treatment of acute
chronic renal impairment. Am J Cardiovasc Drugs 2005;5:291305. and chronic heart failure 2012. Eur Heart J 2012;33:17871847.
451. Capodanno D, Angiolillo DJ. Antithrombotic therapyinpatients
470. Thiele
with chronickid-
H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, de
ney disease. Circulation 2012;125:26492661. Waha A, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I,
452. KubitzaD,BeckaM,MueckW,HalabiA,MaatoukH,KlauseN,LufftV,WandDD,Hambrecht R, Lauer B, Bohm M, Ebelt H, Schneider S, Werdan K, Schuler G.
Philipp T, Bruck H. Effects of renal impairment on the pharmacokinetics,
Intra-aortic balloonpharma-counterpulsation in acute myocardial infarction complicated
codynamics and safety of rivaroxaban, an oral, direct factor Xa by cardiogenic
inhibitor. Br shock J Clin (IABP-SHOCK II): nal 12 month results of a randomised,
Pharmacol 2010;70:703712. open-label trial. Lancet 2013;382:16381645.
453. ColletJP, Montalescot G, AgnelliG, Vande Werf F, GurnkelEP,471. Lopez-SendonJ,
Kirklin JK, Naftel DC, Kormos RL, Stevenson LW, Pagani FD, Miller MA,
Laufenberg CV, Klutman M, Gowda N, Gulba D. Non-ST-segment Baldwin elevation
JT, Young JB. The Fourth INTERMACS Annual Report: 4,000 implants
acute coronary syndrome in patients with renal dysfunction: and benet counting.
of J Heart Lung Transplant 2012;31:117126.
low-molecular-weight heparin alone or with glycoprotein IIb/IIIa
472. Kirklin
inhibitorsJK. Long-term
on mechanical circulatory support: could it really have a public
outcomes. The Global Registry of Acute Coronary Events. Eurhealth Heartimpact?
J 2005;26: Eur J Cardiothorac Surg 2013;44:198200.
22852293. 473. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson L, Miller M, Young JB.
454. Fox KA, Bassand JP, Mehta SR, Wallentin L, Theroux P, Piegas Long-term
LS, Valentin
mechanical
V, circulatory support (destination therapy): on track to
Moccetti T, Chrolavicius S, Afzal R, Yusuf S. Inuence of renal function
competeon with
theheart
ef- transplantation? J Thorac Cardiovasc Surg 2012;144:
cacyand safetyof fondaparinux relative to enoxaparin in non 584603;
ST-segment discussion
eleva- 597588.
tion acute coronary syndromes. Ann Intern Med 2007;147:304310.474. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL,
455. Brar SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ,Shi Desai
VC, Solomon
N, Ree M,SD, Swedberg K, Zile MR. Angiotensin-neprilysin inhibition ver-
Shah AI, Burchette RJ. Sodium bicarbonatevs sodium chloridesus forenalapril
the prevention
in heart failure. N Engl J Med 2014;371:9931004.
315i ESC Guidelines

475. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley brillationdeveloped
JD, Buller CE, with the special contribution of the European Heart
Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early revascularization
Rhythm Association. in Eur Heart J 2012;33:27192747.
acute myocardial infarction complicated by cardiogenic shock. 494.SHOCK
Camm investiga-
AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC,
tors. Should we emergently revascularize occluded coronariesAl-Attar
for cardiogenic
N, Hindricks G, Prendergast B, Heidbuchel H, Aleri O, Angelini A,
shock. N Engl J Med 1999;341:625634. Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M,
476. Hochman JS, Sleeper LA, Webb JG, Dzavik V, Buller CE, Aylward Hohloser
P, ColSH, J, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the
White HD. Early revascularization and long-term survival in cardiogenic
management shockof atrial brillation: the task force for the management of atrial bril-
complicating acute myocardial infarction. JAMA 2006;295:25112515.lationoftheEuropeanSocietyofCardiology(ESC).EurHeartJ2010;31:23692429.
477. Buerke M, Prondzinsky R, Lemm H, Dietz S, Buerke U, Ebelt 495. H,Lippi
Bushnaq
G, Picanza
H, A, Formentini A, Bonfanti L, Cervellin G. The concentration of
Silber RE, Werdan K. Intra-aortic balloon counterpulsation in thetroponin
treatmentI is increased
of in patients with acute-onset atrial brillation. Int J Cardiol
infarction-relatedcardiogenicshockreviewofthecurrentevidence.ArtifOrgans
2014;173:579580.
2012;36:505511. 496. Hijazi Z, Siegbahn A, Andersson U, Granger CB, Alexander JH, Atar D, Gersh BJ,
478. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy Mohan TE, P,Davis
HarjolaBR, VP, Horowitz J, Husted S, Hylek EM, Lopes RD, McMurray JJ,
Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer Wallentin
M, Rouleau L. High-sensitivity
J, troponin I for risk assessment in patients with atrial
Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM. Effect ofbrillation:
captoprilinsights
on from the Apixaban for Reduction in Stroke and Other
mortalityand morbidity in patients with left ventricular dysfunction
Thromboembolic
after myocar- Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation
dial infarction. Results of the survival and ventricular enlargement
2014;129:625634.
trial. The SAVE
investigators. N Engl J Med 1992;327:669677. 497. HartRG,BenaventeO,McBrideR,PearceLA.Antithrombotictherapytoprevent
479. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni
stroke in patients
AP, with atrial brillation: a meta-analysis. Ann Intern Med 1999;131:
Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger492501. JD, Henis M,
Edwards S, Zelenkofske S, Sellers MA, Califf RM. Valsartan, 498.
captopril,
Echt DS,or bothLiebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH,
in myocardial infarction complicated by heart failure, left ventricular
Arensberg dysfunction,
D, Baker A, Friedman L, Greene HL, Huther ML, Richardson DW,
or both. N Engl J Med 2003;349:18931906. and the CAST Investigators. Mortality and morbidity in patients receiving encai-
480. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson
nide, ecainide,
B, Ostergren or placebo.
J, The Cardiac Arrhythmia Suppression Trial. N Engl J
Pfeffer MA, Swedberg K. Effects of candesartan in patients with Med chronic
1991;324:781788.
heart fail-
ure and reduced left-ventricular systolic function intolerant499.
to angiotensin-
Younge JO, Nauta ST, Akkerhuis KM, Deckers JW, van Domburg RT. Effect of an-
converting-enzyme inhibitors: the CHARM-Alternative trial. Lancetemiaonshort-andlong-termoutcomeinpatientshospitalizedforacutecoronary
2003;362:
772776. syndromes. Am J Cardiol 2012;109:506510.
481. Effectofenalaprilonsurvivalinpatientswithreducedleftventricularejectionfrac-
500. Bassand JP, Afzal R, Eikelboom J, Wallentin L, Peters R, Budaj A, Fox KA,
tions and congestive heart failure. The SOLVD investigators. NJoyner
Engl JCD, MedChrolavicius
1991; S, Granger CB, Mehta S, Yusuf S. Relationship between
325:293302. baseline haemoglobin and major bleeding complications in acute coronary syn-
482. Dargie HJ. Effect of carvedilol on outcome after myocardial dromes.
infarction Eur in Heart
patients J 2010;31:5058.
with left-ventricular dysfunction: the CAPRICORNrandomised 501.
trial.
ChaseAJ,FretzEB,WarburtonWP,KlinkeWP,CarereRG,PiD,BerryB,HiltonJD.
Lancet 2001;
357:13851390. Association of the arterial access site at angioplasty with transfusion and mortality:
483. CIBIS-II Investigators. The cardiac insufciency bisoprolol study
the IIM.O.R.T.A.L
(CIBIS-II): astudy ran- (Mortality benet Of Reduced Transfusion after percutan-
domised trial. Lancet 1999;353:913. eous coronary intervention via the Arm or Leg). Heart 2008;94:10191025.
484. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi 502.
P, Agostoni
Rouleau JL, P, Biondi-Zoccai GG, de Benedictis ML, Rigattieri S, Turri M, Anselmi M,
TenderaM,CastaigneA,RoeckerEB,Schultz MK,DeMetsDL.Effectofcarvedilol
Vassanelli C, Zardini P, Louvard Y, Hamon M. Radial versus femoral approach for
on survival in severe chronic heart failure. N Engl J Med 2001;344:16511658.
percutaneous coronary diagnostic and interventional procedures; systematic over-
485. MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic viewheart
andfailure:
meta-analysis of randomized trials. J Am Coll Cardiol 2004;44:349356.
metoprolol CR/XL randomised intervention trial in congestive 503.heart
McClure
failure MW, Berkowitz SD, Sparapani R, Tuttle R, Kleiman NS, Berdan LG,
(MERIT-HF). Lancet 1999;353:20012007. Lincoff AM, Deckers J, Diaz R, Karsch KR, Gretler D, Kitt M, Simoons M,
486. FlatherMD,ShibataMC, Coats AJ,VanVeldhuisenDJ, ParkhomenkoA,BorbolaJ,
Topol EJ, Califf RM, Harrington RA. Clinical signicance of thrombocytopenia
Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J,during
Tavazzi a non-ST-elevation
L, acute coronary syndrome. The Platelet Glycoprotein
SpinarovaL, TomanJ,Bohm M,AnkerSD, ThompsonSG, Poole-WilsonPA.Ran-
IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PUR-
domizedtrialtodetermine theeffect ofnebivololonmortalityandcardiovascular
SUIT) trial experience. Circulation 1999;99:28922900.
hospital admission in elderly patients with heart failure (SENIORS).
504. MerliniEur PA,HeartRossiJ M, Menozzi A, Buratti S, Brennan DM, Moliterno DJ, Topol EJ,
2005;26:215225. Ardissino D. Thrombocytopenia caused by abciximab or tiroban and its associ-
487. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg ationK, with
Shi H, clinical
Vincent outcome
J, in patients undergoing coronary stenting. Circulation
Pocock SJ, Pitt B. Eplerenone in patients with systolic heart failure
2004;109:22032206.
and mild symp-
toms. N Engl J Med 2011;364:1121. 505. Gore JM, Spencer FA, Gurnkel EP, Lopez-Sendon J, Steg PG, Granger CB,
488. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A,FitzGerald
Palensky J,G, Wittes
Agnelli J. G. Thrombocytopenia in patients with an acute coronary
The effect of spironolactone on morbidity and mortality in patients
syndrome with (from
severethe Global Registry of Acute Coronary Events [GRACE]). Am
heart failure. Randomized aldactone evaluation study investigators.
J Cardiol N 2009;103:175180.
Engl J Med
1999;341:709717. 506. Vora AN, Chenier M, Schulte PJ, Goodman S, Peterson ED, Pieper K,
489. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS,Jolicoeur
Daubert ME,Mahaffey
JP, KW,White H, WangTY. Long-term outcomesassociated
Higgins SL, Brown MW, Andrews ML. Prophylactic implantationwith of ahospital
debrillator acquired thrombocytopenia among patients with non-ST-segment
in patients with myocardial infarction and reduced ejection fraction.
elevation N Engl
acute J Med
coronary syndrome. Am Heart J 2014;168:189196, e181.
2002;346:877883. 507. Greinacher A, Selleng K. Thrombocytopenia in the intensive care unit patient.
490. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R,Hematology
Domanski M, Am Soc Hematol Educ Program 2010;2010:135143.
Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing 508. Warkentin
N, TE. Drug-induced immune-mediated thrombocytopeniafrom pur-
Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone
pura to thrombosis.
or an N Engl J Med 2007;356:891893.
implantable cardioverter-debrillator for congestive heart failure.
509. Dasgupta
N Engl J Med H, Blankenship JC, Wood GC, Frey CM, Demko SL, Menapace FJ.
2005;352:225237. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/
491. Al-Khatib SM, Hellkamp AS, Lee KL, Anderson J, Poole JE, Mark IIIa DB,
receptor
Bardyinhibitors:
GH. a pooled analysis. Am Heart J 2000;140:206211.
Implantable cardioverter debrillator therapy in patients with 510.
priorValgimigli
coronaryM, re-Biondi-Zoccai G, Tebaldi M, vant Hof AW, Campo G, Hamm C, ten
vascularization in the Sudden Cardiac Death in HEart Failure Trial
Berg(SCD-HEFT).
J,BologneseL,Saia F, Danzi GB, BriguoriC,Okmen E,KingSB, Moliterno DJ,
J Cardiovasc Electrophysiol 2008;19:10591065. Topol EJ. Tiroban as adjunctive therapy for acute coronary syndromes and per-
492. Barsheshet A, Goldenberg I, Moss AJ, Huang DT, Zareba W,cutaneous
McNitt S, Klein coronaryHU, intervention: a meta-analysis of randomized trials. Eur Heart J
Guetta V. Effect of elapsed time from coronary revascularization 2010;31:3549.
to implantation
of a cardioverter debrillator on long-term survival in the MADIT-II
511. Tempelhof
trial. MW, Benzuly KH, Fintel D, Krichavsky MZ. Eptibatide-induced
J Cardiovasc Electrophysiol 2011;22:12371242. thrombocytopenia: with thrombosis and disseminated intravascular coagulation
493. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloserimmediately
SH, Hindricks after left
G, main coronary artery percutaneous coronary angioplasty.
Kirchhof P. 2012 focused update of the ESC guidelines for the Tex management
Heart Inst Jof2012;39:8691.
at-
rial brillation: an update of the 2010 ESC guidelines for the management of atrial
ESC Guidelines 315j

512. Arnold DM, Nazi I, Warkentin TE, Smith JW, Toltl LJ, GeorgeKirchhof
JN, Kelton P, JG.
Kjeldsen
Ap- SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM,
proach to the diagnosis and management of drug-induced immune Schmieder thrombocyto-
RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F. 2013
penia. Transfus Med Rev 2013;27:137145. ESH/ESC guidelines for the management of arterial hypertension. Eur Heart J
513. McCulloughJ.Overviewofplatelettransfusion.SeminHematol2010;47:235242.
2013;34:21592219.
514. Kelton JG, Arnold DM, Bates SM. Nonheparin anticoagulants534. for Piepoli
heparin-induced
MF, Corra U, Abreu A, Cupples M, Davos C, Doherty P, Hofer S,
thrombocytopenia. N Engl J Med 2013;368:737744. Garcia-PorreroE,RauchB,Vigorito C,VollerH, Schmid JP.Challengesinsecond-
515. Warkentin TE, Kelton JG. Temporal aspects of heparin-inducedary prevention
thrombocyto- of cardiovascular diseases: a review of the current practice. Int J
penia. N Engl J Med 2001;344:12861292. Cardiol 2015;180:114119.
516. PatrignaniP,PatronoC.Cyclooxygenaseinhibitors:frompharmacologytoclinical
535. Clark AM, Hartling L, Vandermeer B, McAlister FA. Meta-analysis: secondary pre-
read-outs. Biochim Biophys Acta 2015;1851:422432. vention programs for patients with coronary artery disease. Ann Intern Med 2005;
517. Patrono C, Baigent C. Nonsteroidal anti-inammatory drugs143:659672.
and the heart. Circu-
lation 2014;129:907916. 536. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessa-
518. Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Barontion JA, inBombardier
patients with C, coronary heart disease: a systematic review. JAMA 2003;290:
Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk8697. E, Hawkey C,
Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine537. L, LanasIestra A,JA,Lance
Kromhout
P, D, van der Schouw YT, Grobbee DE, Boshuizen HC, van
Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell
StaverenP, Wilson WA. K,Effect size estimates of lifestyle and dietary changes on all-cause
Wittes J, Baigent C. Vascular and upper gastrointestinal effects
mortality
of non-steroidal
in coronary artery disease patients: a systematic review. Circulation
anti-inammatory drugs: meta-analyses of individual participant 2005;112:924934.
data from rando-
mised trials. Lancet 2013;382:769779. 538. FoxKM; EURopean trialOn reductionof cardiac eventswith Perindopril instable
519. Devereaux PJ, Xavier D, Pogue J, Guyatt G, Sigamani A, Garutti
coronary I, Leslie
Artery K, disease Investigators. Efcacy of perindopril in reduction of car-
Rao-Melacini P, Chrolavicius S, Yang H, Macdonald C, Avezum diovascular
A, Lanthierevents L, among patients with stable coronary artery disease: rando-
Hu W, Yusuf S. Characteristics and short-term prognosis of perioperative
mised, double-blind, myo- placebo-controlled, multicentre trial (the EUROPA study).
cardial infarction in patients undergoing noncardiac surgery:Lancet
a cohort 2003;362:782788.
study. Ann
Intern Med 2011;154:523528. 539. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J,
520. Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger RahnO, KH,Villar
WedelJC, H, Westerling S. Effects of intensive blood-pressure lowering
Wang CY, Garutti RI, Jacka MJ, Sigamani A, Srinathan S, BiccardandBM, low-dose
Chow aspirin
CK, in patients with hypertension: principal results of the Hyper-
Abraham V, Tiboni M, Pettit S, Szczeklik W, Lurati Buse G, Botto
tension F, Guyatt
Optimal G, Treatment (HOT) randomised trial. Lancet 1998;351:17551762.
Heels-Ansdell D, Sessler DI, Thorlund K, Garg AX, Mrkobrada 540. M,UK Thomas
Prospective
S, Diabetes Study Group. Tight blood pressure control and risk of
Rodseth RN, Pearse RM, Thabane L, McQueen MJ, VanHelder macrovascular
T, Bhandari M, and microvascular complications in type 2 diabetes: UKPDS 38.
Bosch J, Kurz A, Polanczyk C, Malaga G, Nagele P, Le ManachBMJ Y, Leuwer
1998;317:703713.
M,
Yusuf S. Association between postoperative troponin levels 541.
andTaylorRS,BrownA,EbrahimS,JolliffeJ,NooraniH,ReesK,SkidmoreB,StoneJA,
30-day mortality
among patients undergoing noncardiac surgery. JAMA 2012;307:22952304.
Thompson DR, Oldridge N. Exercise-based rehabilitation for patients with cor-
521. Chow CK, Jolly S, Rao-Melacini P, Fox KA, Anand SS, Yusuf onary
S. Association
heart disease:
of diet,systematic review and meta-analysis of randomized con-
exercise, and smoking modication with risk of early cardiovascular
trolled eventstrials. Am after
J Med 2004;116:682692.
acute coronary syndromes. Circulation 2010;121:750758.542. TaylorRS, UnalB,Critchley JA,Capewell S. Mortalityreductions inpatients receiv-
522. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, ingBelder
exercise-based
R, Joyal SV, cardiacrehabilitation: how muchcanbeattributedtocardiovas-
Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid cularlowering
risk factor
with improvements?
sta- Eur J Cardiovasc Prev Rehabil 2006;13:369374.
tins after acute coronary syndromes. N Engl J Med 2004;350:14951504.
543. Hammill BG, Curtis LH, Schulman KA, Whellan DJ. Relationship between cardiac
523. A randomized trial of propranolol in patients with acute myocardial
rehabilitation infarction.
and long-term risks of death and myocardial infarction among eld-
I. Mortality results. JAMA 1982;247:17071714. erly Medicare beneciaries. Circulation 2010;121:6370.
524. Vantrimpont P, Rouleau JL, Wun CC, Ciampi A, Klein M, Sussex
544. Perk B, Arnold
J, De Backer
JM, G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C,
Moye L, Pfeffer M. Additive benecial effects of beta-blockers Benlian
to angiotensin-P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G,
converting enzyme inhibitors in the Survival and Ventricular Hobbs
Enlargement R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M,
(SAVE) study. J Am Coll Cardiol 1997;29:229236. Syvanne M, Scholte op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F.
525. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker Europeanguidelinesoncardiovasculardisease
B, Bittman R, Hurley S, prevention inclinicalpractice(ver-
Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker,
sion 2012).
in patients The with
Fifth left
Joint Task Force of the European Society of Cardiology and
ventricular dysfunction after myocardial infarction. N Engl J Med
other2003;348:13091321.
societies on cardiovascular disease prevention in clinical practice (consti-
526. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockadetuted
on mortality
by representatives
among of nine societies and by invited experts). Eur Heart J
high-risk and low-risk patients after myocardial infarction. N 2012;33:16351701.
Engl J Med 1998;339:
489497. 545. Heran BS, Chen JM, Ebrahim S, Moxham T, Oldridge N, Rees K, Thompson DR,
527. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala
Taylor N,RS.Peto Exercise-based
R, cardiac rehabilitation for coronary heart disease. Co-
Barnes EH, Keech A, Simes J, Collins R. Efcacy and safety of more
chrane intensive
Database low-
Syst Rev 2011;1:CD001800.
ering of LDL cholesterol: a meta-analysis of data from 170,000
546. Janssen
participants V, DeinGucht
26 V, Dusseldorp E, Maes S. Lifestyle modication programmes
randomised trials. Lancet 2010;376:16701681. for patients with coronary heart disease: a systematic review and meta-analysis of
528. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, FruchartrandomizedJC, Gotto controlled
AM, trials. Eur J Prev Cardiol 2013;20:620640.
GretenH,KasteleinJJ,ShepherdJ,WengerNK.Intensivelipidloweringwithatorvas-
547. Zhang Y, Zhang X, Liu L, Zanchetti A. Is a systolic blood pressure target ,140
tatin in patients with stable coronary disease. N Engl J Med 2005;352:14251435.
mmHg indicated in all hypertensives? Subgroup analyses of ndings from the ran-
529. CannonCP,Blazing MA,GiuglianoRP,McCaggA,WhiteJA,TherouxP,DariusH,
domized fever trial. Eur Heart 2011;32:15001508.
Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, 548.
De Poole-Wilson
Lucca P, Im K,PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N,
Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA,Just Braunwald
H, Fox KA, E, Pocock SJ, Clayton TC, Motro M, Parker JD, Bourassa MG,
Califf RM. Ezetimibe added to statin therapy after acute coronary
Dart AM, syndromes.
Hildebrandt N P, Hjalmarson A, Kragten JA, Molhoek GP, Otterstad JE,
Engl J Med 2015;372:238797. Seabra-Gomes R, Soler-Soler J, Weber S. Effect of long-acting nifedipine on mor-
530. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.tality
Effects and of cardiovascular
an morbidity in patients with stable angina requiring treat-
angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
ment (ACTION eventstrial):
in randomised controlled trial. Lancet 2004;364:849857.
high-risk patients. The Heart Outcomes Prevention Evaluation549. Study
Zanchetti Investiga-
A, Grassi G, Mancia G. When should antihypertensive drug treatment
tors. N Engl J Med 2000;342:145153. be initiated and to what levels should systolic blood pressure be lowered? A crit-
531. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H,icalDagenais
reappraisal. G, Sleight
J Hypertens
P, 2009;27:923934.
Anderson C. Telmisartan, ramipril, or both in patients at high
550.risk NallamothuB,FoxKA,KennellyBM,VandeWerfF,GoreJM,StegPG,GrangerCB,
for vascular
events. N Engl J Med 2008;358:15471559. DabbousOH, Kline-RogersE, Eagle KA.Relationship of treatmentdelays and mor-
532. Bangalore S, Steg G, Deedwania P, Crowley K, Eagle KA, Goto talityS,inOhman patients EM,
undergoing brinolysis and primary percutaneous coronary inter-
Cannon CP, Smith SC, Zeymer U, Hoffman EB, Messerli FH, Bhatt vention.TheGlobalRegistryofAcuteCoronaryEvents.Heart2007;93:15521555.
DL; Reach
Registry Investigators. Beta-blocker use and clinical outcomes
551. Mukherjee
in stable outpati- D, Fang J, Chetcuti S, Moscucci M, Kline-Rogers E, Eagle KA. Impact of
ents with and without coronary artery disease. JAMA 2012;308:13401349.
combination evidence-based medical therapy on mortality in patients with acute
533. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bo coronary
hm M, syndromes.
Christiaens T, Circulation 2004;109:745749.
Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T,