2014 AHA NSTEMI Management

AHA/ACC Guideline
2014 AHA/ACC Guideline for the Management

of Patients With Non–ST-Elevation Acute
Coronary Syndromes: Executive Summary
A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines
Developed in Collaboration With the Society for Cardiovascular Angiography
and Interventions and the Society of Thoracic Surgeons
Endorsed by the American Association for Clinical Chemistry
WRITING COMMITTEE MEMBERS*
Ezra A. Amsterdam, MD, FACC, Chair†; Nanette K. Wenger, MD, MACC, FAHA, Vice Chair*†;
Ralph G. Brindis, MD, MPH, MACC, FSCAI‡; Donald E. Casey, Jr, MD, MPH, MBA, FACP, FAHA§;
Downloaded from http://circ.ahajournals.org/ by guest on February 25, 2017
Theodore G. Ganiats, MD║; David R. Holmes, Jr, MD, MACC†; Allan S. Jaffe, MD, FACC, FAHA*†;
Hani Jneid, MD, FACC, FAHA, FSCAI†; Rosemary F. Kelly, MD¶;
Michael C. Kontos, MD, FACC, FAHA*†; Glenn N. Levine, MD, FACC, FAHA†;
Philip R. Liebson, MD, FACC, FAHA†; Debabrata Mukherjee, MD, FACC†;
Eric D. Peterson, MD, MPH, FACC, FAHA*#; Marc S. Sabatine, MD, MPH, FACC, FAHA*†;
Richard W. Smalling, MD, PhD, FACC, FSCAI***; Susan J. Zieman, MD, PhD, FACC†
The writing committee gratefully acknowledges the memory of Dr. Francis M. Fesmire (representative of the American College of Emergency Physicians),
who died during the development of this document but contributed immensely to our understanding of non–ST-elevation acute coronary syndromes.
*Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other
entities may apply; see Appendix 1 for recusal information.
†ACC/AHA Representative.
‡ACC/AHA Task Force on Practice Guidelines Liaison.
§American College of Physicians Representative.
║American Academy of Family Physicians Representative.
¶Society of Thoracic Surgeons Representative.
#ACC/AHA Task Force on Performance Measures Liaison.
**Society for Cardiovascular Angiography and Interventions Representative.
††Former Task Force member; current member during the writing effort.
Full-text guideline available at: Circulation. http://circ.ahajournals.org/lookup/doi/10.1161/CIR.0000000000000134.
This document was approved by the American Heart Association Science Advisory and Coordinating Committee and the American College of Cardiology
Board of Trustees in August 2014.
The online-only Comprehensive Relationships Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/
doi:10.1161/CIR.0000000000000133/-/DC1.
The online-only Data Supplement files are available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/
CIR.0000000000000133/-/DC2.
The American Heart Association requests that this document be cited as follows: Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG,
Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ.
2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: executive summary: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:2354–2394.
This article is copublished in the Journal of the American College of Cardiology.
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(Circulation. 2014;130:2354-2394.)
© 2014 by the American Heart Association, Inc., and the American College of Cardiology Foundation.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000133
2354
Amsterdam et al 2014 AHA/ACC NSTE-ACS Executive Summary 2355
ACC/AHA TASK FORCE MEMBERS

Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect;
Nancy M. Albert, PhD, RN, FAHA; Biykem Bozkurt, MD, PhD, FACC, FAHA;
Ralph G. Brindis, MD, MPH, MACC; Lesley H. Curtis, PhD, FAHA; David DeMets, PhD††;
Lee A. Fleisher, MD, FACC, FAHA; Samuel Gidding, MD, FAHA; Robert A. Guyton, MD, FACC††;
Judith S. Hochman, MD, FACC, FAHA††; Richard J. Kovacs, MD, FACC, FAHA;
E. Magnus Ohman, MD, FACC; Susan J. Pressler, PhD, RN, FAHA;
Frank W. Sellke, MD, FACC, FAHA; Win-Kuang Shen, MD, FACC, FAHA;
William G. Stevenson, MD, FACC, FAHA††; Duminda N. Wijeysundera, MD, PhD;
Clyde W. Yancy, MD, FACC, FAHA††
Table of Contents 5. Myocardial Revascularization:

Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . 2369
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2356 5.1. PCI–General Considerations . . . . . . . . . . . . . . . 2369
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2357 5.1.1. PCI–Oral and Intravenous
1.1. Methodology and Evidence Review . . . . . . . . . 2357 Antiplatelet Agents . . . . . . . . . . . . . . . . . 2369

1.2. Organization of the GWC . . . . . . . . . . . . . . . . . 2358 5.1.1.1. PCI–GP llb/llla Inhibitors . . . . . 2370
1.3. Document Review and Approval . . . . . . . . . . . . 2358 5.1.2. Anticoagulant Therapy in Patients
1.4. Scope of the CPG . . . . . . . . . . . . . . . . . . . . . . . . 2358 Undergoing PCI . . . . . . . . . . . . . . . . . . . 2370
2. Overview of Acs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2358 5.2. Timing of Urgent Coronary Artery Bypass
3. Initial Evaluation and Management: Graft in Patients With NSTE-ACS in Relation
Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . 2358 to Use of Antiplatelet Agents . . . . . . . . . . . . . . . 2370
3.1. Clinical Assessment and Initial Evaluation . . . . 2358 6. Late Hospital Care, Hospital Discharge, and
3.2. Emergency Department or Outpatient Posthospital Discharge Care: Recommendations . . . 2371
Facility Presentation . . . . . . . . . . . . . . . . . . . . . . 2358 6.1. Medical Regimen and Use of Medications
3.3. Prognosis–Early Risk Stratification . . . . . . . . . . 2359 at Discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2371
3.4. Cardiac Biomarkers and the Universal 6.2. Late Hospital and Posthospital Oral
Definition of Myocardial Infarction . . . . . . . . . . 2362 Antiplatelet Therapy . . . . . . . . . . . . . . . . . . . . . 2371
3.4.1. Biomarkers: Diagnosis . . . . . . . . . . . . . . 2362 6.3. Combined Oral Anticoagulant Therapy
3.4.2. Biomarkers: Prognosis . . . . . . . . . . . . . . 2363 and Antiplatelet Therapy in Patients With
3.5. Discharge From the ED or Chest Pain Unit . . . . 2363 NSTE-ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2372
4. Early Hospital Care: Recommendations . . . . . . . . . . 2363 6.4. Risk Reduction Strategies for
4.1. Standard Medical Therapies . . . . . . . . . . . . . . . 2363 Secondary Prevention . . . . . . . . . . . . . . . . . . . . 2372
4.1.1. Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . 2363 6.5. Plan of Care for Patients With NSTE-ACS . . . . 2373
4.1.2. Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . 2363 7. Special Patient Groups: Recommendations . . . . . . . . 2373
4.1.3. Analgesic Therapy . . . . . . . . . . . . . . . . . 2364 7.1. NSTE-ACS in Older Patients . . . . . . . . . . . . . . . 2373
4.1.4. Beta-Adrenergic Blockers . . . . . . . . . . . . 2364 7.2. Heart Failure and Cardiogenic Shock . . . . . . . . 2373
4.1.5. Calcium Channel Blockers . . . . . . . . . . . 2365 7.3. Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . 2375
4.1.6. Cholesterol Management . . . . . . . . . . . . 2365 7.4. Post-CABG . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2375
4.2. Inhibitors of the Renin-Angiotensin-Aldosterone 7.5. Perioperative NSTE-ACS Related to
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2365 Noncardiac Surgery . . . . . . . . . . . . . . . . . . . . . . 2375
4.3. Initial Antiplatelet/Anticoagulant Therapy 7.6. Chronic Kidney Disease . . . . . . . . . . . . . . . . . . 2376
in Patients With Definite or Likely 7.7. Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2376
NSTE-ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2365 7.8. Anemia, Bleeding, and Transfusion . . . . . . . . . . 2376
4.3.1. Initial Oral and Intravenous Antiplatelet 7.9. Cocaine and Methamphetamine Users . . . . . . . . 2376
Therapy in Patients With Definite or Likely 7.10. Vasospastic (Prinzmetal) Angina . . . . . . . . . . . . 2376
NSTE-ACS Treated With an Initial Invasive 7.11. ACS With Angiographically Normal
or Ischemia-Guided Strategy . . . . . . . . . 2365 Coronary Arteries . . . . . . . . . . . . . . . . . . . . . . . . 2377
4.3.2. Initial Parenteral Anticoagulant 7.12. Stress (Takotsubo) Cardiomyopathy . . . . . . . . . 2377
Therapy in Patients With Definite 8. Quality of Care and Outcomes For ACS–Use
NSTE-ACS . . . . . . . . . . . . . . . . . . . . . . . 2367 of Performance Measures and Registries:
4.4. Ischemia-Guided Strategy Versus Early Recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2377
Invasive Strategies . . . . . . . . . . . . . . . . . . . . . . . 2367 9. Summary and Evidence Gaps . . . . . . . . . . . . . . . . . . 2377
4.4.1. Early Invasive and Ischemia-Guided References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2378
Strategies . . . . . . . . . . . . . . . . . . . . . . . . . 2367 Appendix 1. Author Relationships With Industry
4.5. Risk Stratification Before Discharge for and Other Entities (Relevant) . . . . . . . . . . 2387
Patients With an Ischemia-Guided Strategy Appendix 2. Reviewer Relationships With Industry
of NSTE-ACS . . . . . . . . . . . . . . . . . . . . . . . . . . 2369 and Other Entities (Relevant) . . . . . . . . . . 2390
2356 Circulation December 23/30, 2014
Preamble treatment regimens, the reader should confirm the dosage with
The American College of Cardiology (ACC) and the American product insert material and carefully evaluate for contraindi-
Heart Association (AHA) are committed to the prevention and cations and possible drug interactions. Recommendations are
management of cardiovascular diseases through professional limited to treatments, drugs, and devices approved for clinical
education and research for clinicians, providers, and patients. use in the United States.
Since 1980, the ACC and AHA have shared a responsibility to Class of Recommendation and Level of Evidence—Once
translate scientific evidence into clinical practice guidelines recommendations are written, the Class of Recommendation
(CPGs) with recommendations to standardize and improve (COR; ie, the strength the GWC assigns to the recommen-
cardiovascular health. These CPGs, based on systematic dation, which encompasses the anticipated magnitude and
methods to evaluate and classify evidence, provide a corner- judged certainty of benefit in proportion to risk) is assigned
stone of quality cardiovascular care. by the GWC. Concurrently, the Level of Evidence (LOE)
In response to published reports from the Institute of rates the scientific evidence supporting the effect of the
Medicine1,2 and the ACC/AHA’s mandate to evaluate new intervention on the basis on the type, quality, quantity, and
knowledge and maintain relevance at the point of care, the consistency of data from clinical trials and other reports
ACC/AHA Task Force on Practice Guidelines (Task Force) (Table 1).4 Unless otherwise stated, recommendations are
began modifying its methodology. This modernization effort presented in order by the COR and then the LOE. Where
is published in the 2012 Methodology Summit Report3 and comparative data exist, preferred strategies take precedence.
2014 perspective article.4 The latter recounts the history of When more than 1 drug, strategy, or therapy exists within
the collaboration, changes over time, current policies, and the same COR and LOE and there are no comparative data,
planned initiatives to meet the needs of an evolving health- options are listed alphabetically.
care environment. Recommendations on value in proportion Relationships With Industry and Other Entities—The
to resource utilization will be incorporated as high-quality ACC and AHA exclusively sponsor the work of GWCs with-
comparative-effectiveness data become available.5 The rela- out commercial support, and members volunteer their time for
tionships between CPGs and data standards, appropriate use this activity. The Task Force makes every effort to avoid actual,
criteria, and performance measures are addressed elsewhere.4 potential, or perceived conflicts of interest that might arise
Intended Use—CPGs provide recommendations appli- through relationships with industry or other entities (RWI).
cable to patients with or at risk of developing cardiovascu- All GWC members and reviewers are required to fully dis-
lar disease. The focus is on medical practice in the United close current industry relationships or personal interests from
States, but CPGs developed in collaboration with other orga- 12 months before initiation of the writing effort. Management
nizations may have a broader target. Although CPGs may be of RWI involves selecting a balanced GWC and requires that
used to inform regulatory or payer decisions, the intent is to both the chair and a majority of GWC members have no rel-
improve the quality of care and be aligned with the patient’s evant RWI (see Appendix 1 for the definition of relevance).
best interest. GWC members are restricted with regard to writing or voting
Evidence Review—Guideline writing committee (GWC) on sections to which their RWI apply. In addition, for trans-
members are charged with reviewing the literature; weighing parency, GWC members’ comprehensive disclosure informa-
the strength and quality of evidence for or against particular tion is available as an online supplement. Comprehensive
tests, treatments, or procedures; and estimating expected health disclosure information for the Task Force is available as an
outcomes when data exist. In analyzing the data and develop- additional supplement. The Task Force strives to avoid bias
ing CPGs, the GWC uses evidence-based methodologies devel- by selecting experts from a broad array of backgrounds repre-
oped by the Task Force.6 A key component of the ACC/AHA senting different geographic regions, sexes, ethnicities, races,
CPG methodology is the development of recommendations on intellectual perspectives/biases, and scopes of clinical prac-
the basis of all available evidence. Literature searches focus tice. Selected organizations and professional societies with
on randomized controlled trials (RCTs) but also include regis- related interests and expertise are invited to participate as
tries, nonrandomized comparative and descriptive studies, case partners or collaborators.
series, cohort studies, systematic reviews, and expert opinion. Individualizing Care in Patients With Associated
Only selected references are cited in the CPG. To ensure that Conditions and Comorbidities—The ACC and AHA recog-
CPGs remain current, new data are reviewed biannually by the nize the complexity of managing patients with multiple condi-
GWCs and the Task Force to determine if recommendations tions, compared with managing patients with a single disease,
should be updated or modified. In general, a target cycle of 5 and the challenge is compounded when CPGs for evaluation
years is planned for full revisions.1 or treatment of several coexisting illnesses are discordant or
Guideline-Directed Medical Therapy—Recognizing interacting.7 CPGs attempt to define practices that meet the
advances in medical therapy across the spectrum of cardiovas- needs of patients in most, but not all, circumstances and do not
cular diseases, the Task Force designated the term “guideline- replace clinical judgment.
directed medical therapy” (GDMT) to represent recommended Clinical Implementation—Management in accordance
medical therapy as defined mainly by Class I measures, gen- with CPG recommendations is effective only when fol-
erally a combination of lifestyle modification and drug- and lowed; therefore, to enhance their commitment to treatment
device-based therapeutics. As medical science advances, and compliance with lifestyle adjustment, clinicians should
GDMT evolves, and hence GDMT is preferred to “optimal engage the patient to participate in selecting interventions on
medical therapy.” For GDMT and all other recommended drug the basis of the patient’s individual values and preferences,
Table 1. Applying Classification of Recommendations and Level of Evidence

A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the clinical practice
guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or
therapy is useful or effective.
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes mellitus, history of prior
myocardial infarction, history of heart failure, and prior aspirin use.
†For comparative-effectiveness recommendations (Class I and Ma; Level of Evidence A and B only), studies that support the use of comparator verbs should involve
direct comparisons of the treatments or strategies being evaluated.
taking associated conditions and comorbidities into consid- 1. Introduction

eration (eg, shared decision making). Consequently, there
are circumstances in which deviations from these guidelines 1.1. Methodology and Evidence Review
are appropriate. The recommendations listed in this CPG are, whenever pos-
The recommendations in this CPG are the official policy sible, evidence based. An extensive evidence review was con-
of the ACC and AHA until they are superseded by a pub- ducted through October 2012, and other selected references
lished addendum, focused update, or revised full-text CPG. published through April 2014 were reviewed by the GWC.
The reader is encouraged to consult the full-text CPG8 for Literature included was derived from research involving human
additional guidance and details about the management of subjects, published in English, and indexed in MEDLINE
patients with non–ST-elevation acute coronary syndrome (through PubMed), EMBASE, the Cochrane Library, Agency
(NSTE-ACS) because the executive summary contains for Healthcare Research and Quality Reports, and other selected
mainly the recommendations. databases relevant to this CPG. The relevant data are included
Jeffrey L. Anderson, MD, FACC, FAHA in evidence tables in the Online Data Supplement. Key search
Chair, ACC/AHA Task Force on Practice Guidelines words included but were not limited to the following: acute
coronary syndrome, anticoagulant therapy, antihypertensives, coronary syndrome (ACS).10 In selecting the initial approach to
anti-ischemic therapy, antiplatelet therapy, antithrombotic care, the term “ischemia-guided strategy” has replaced the pre-
therapy, beta blockers, biomarkers, calcium channel block- vious descriptor, “initial conservative management,” to more
ers, cardiac rehabilitation, conservative management, dia- clearly convey the physiological rationale of this approach.
betes mellitus, glycoprotein Ilb/IIIa inhibitors, heart failure, The task of the 2014 GWC was to establish a contemporary
invasive strategy, lifestyle modification, myocardial infarction, CPG for the optimal management of patients with NSTE-ACS.
nitrates, non-ST-elevation, P2Y12 receptor inhibitor, percuta- It incorporates both established and new evidence from pub-
neous coronary intervention, renin-angiotensin-aldosterone lished clinical trials, as well as information from basic science
inhibitors, secondary prevention, smoking cessation, statins, and comprehensive review articles. These recommendations
stent, thienopyridines, troponins, unstable angina, and weight were developed to guide the clinician in improving outcomes
management. Additionally, the GWC reviewed documents for patients with NSTE-ACS. Table 2 lists documents deemed
related to NSTE-ACS previously published by the ACC and pertinent to this effort and is intended for use as a resource, thus
AHA. References selected and published in this document are obviating the need to repeat extant CPG recommendations.
representative and not all-inclusive. The GWC abbreviated the discussion sections to include an
explanation of salient information related to the recommenda-
1.2. Organization of the GWC tions. In contrast to textbook declaratory presentations, expla-
The GWC was composed of clinicians, cardiologists, inter- nations were supplemented with evidence tables. The GWC
nists, interventionists, surgeons, emergency medicine special- also provided a brief summary of the relevant recommenda-
ists, family practitioners, and geriatricians. The GWC included tions and references related to secondary prevention rather
representatives from the ACC and AHA, American Academy than detailed reiteration. Throughout, the goal was to provide
of Family Physicians, American College of Emergency the clinician with concise, evidence-based contemporary rec-
Physicians, American College of Physicians, Society for ommendations and the supporting documentation to encour-
Cardiovascular Angiography and Interventions, and Society age their application.
of Thoracic Surgeons.
2. Overview of ACS
1.3. Document Review and Approval
ACS has evolved as a useful operational term that refers to
This document was reviewed by 2 official reviewers each
a spectrum of conditions compatible with acute myocardial
nominated by the ACC and AHA; 1 reviewer each from the
ischemia and/or infarction that are usually due to an abrupt
American Academy of Family Physicians, American College of
reduction in coronary blood flow (Figure 1).
Emergency Physicians, Society for Cardiovascular Angiography
and Interventions, and Society of Thoracic Surgeons; and 37 indi-
vidual content reviewers (including members of the American 3. Initial Evaluation and
Association of Clinical Chemistry, ACC Heart Failure and Management: Recommendations
Transplant Section Leadership Council, ACC Cardiovascular 3.1. Clinical Assessment and Initial Evaluation
Imaging Section Leadership Council, ACC Interventional
Section Leadership Council, ACC Prevention of Cardiovascular Class I
Disease Committee, ACC Surgeons’ Council, Association of
1. Patients with suspected ACS should be risk strati-
International Governors, and Department of Health and Human
fied based on the likelihood of ACS and adverse
Services). Reviewers’ RWI information was distributed to the
outcome(s) to decide on the need for hospitalization
GWC and is published in this document (Appendix 2). and assist in the selection of treatment options.40–42
This document was approved for publication by the gov- (Level of Evidence: B)
erning bodies of the ACC and the AHA and endorsed by
the American Association for Clinical Chemistry, Society
3.2. Emergency Department or Outpatient Facility
for Cardiovascular Angiography and Interventions, and the
Presentation
Society of Thoracic Surgeons.
Class I
1.4. Scope of the CPG
1. Patients with suspected ACS and high-risk features
The 2014 NSTE-ACS CPG is a full revision of the 2007
such as continuing chest pain, severe dyspnea, syn-
ACCF/AHA CPG for the management of patients with unsta-
cope/presyncope, or palpitations should be referred
ble angina (UA) and non–ST-elevation myocardial infarc-
immediately to the emergency department (ED) and
tion (NSTEMI) and the 2012 focused update.9 The new title,
transported by emergency medical services when
“Non–ST-Elevation Acute Coronary Syndromes,” emphasizes available. (Level of Evidence: C)
the continuum between UA and NSTEMI. At presentation,
patients with UA and NSTEMI can be indistinguishable and
are therefore considered together in this CPG.
Class IIb
In the United States, NSTE-ACS affects >625 000 patients 1. Patients with less severe symptoms may be considered
annually,* or almost three fourths of all patients with acute for referral to the ED, a chest pain unit, or a facility
capable of performing adequate evaluation depend-
*Estimate includes secondary discharge diagnoses. ing on clinical circumstances. (Level of Evidence: C)
Table 2. Associated CPGs and Statements

Publication
Title Organization Year/Reference
CPGs
Stable ischemic heart disease ACC/AHA/AATS/PCNA/SCAI/STS 201411* 201212
Atrial fibrillation AHA/ACC/HRS 201413
Assessment of cardiovascular risk ACC/AHA 201314
Heart failure ACC/AHA 201315
Lifestyle management to reduce cardiovascular risk AHA/ACC 201316
Management of overweight and obesity in adults AHA/ACC/TOS 201317
ST-elevation myocardial infarction ACC/AHA 201318
Treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults ACC/AHA 201319
Acute myocardial infarction in patients presenting with ST-segment elevation ESC 201220
Device-based therapy ACC/AHA/HRS 1 201321
Third universal definition of myocardial infarction ESC/ACC/AHA/WHF 201222
Acute coronary syndromes in patients presenting without persistent ST-segment elevation ESC 201123
Coronary artery bypass graft surgery ACC/AHA 201124

Hypertrophic cardiomyopathy ACC/AHA 201125
Effectiveness-based guidelines for the prevention of cardiovascular disease in women AHA/ACC 201126
Percutaneous coronary intervention ACC/AHA/SCAI 201127
Secondary prevention and risk reduction therapy for patients with coronary and other AHA/ACC 201128
atherosclerotic vascular disease
Assessment of cardiovascular risk in asymptomatic adults ACC/AHA 201029
Myocardial revascularization ESC 201030
Unstable angina and non–ST-elevation myocardial infarction NICE 201031†
Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care—part 9: AHA 201032
postcardiac arrest care
Seventh report of the joint national committee on prevention, detection, evaluation, and treatment NHLBI 200333
of high blood pressure
Statements
Key data elements and definitions for measuring the clinical management and outcomes of patients ACC/AHA 201334
with acute coronary syndromes and coronary artery disease
Practical clinical considerations in the interpretation of troponin elevations ACC 201235
Testing of low-risk patients presenting to the emergency department with chest pain AHA 201036
Primary prevention of cardiovascular diseases in people with diabetes mellitus AHA/ADA 200737
Prevention and control of influenza CDC 200538
*The full-text SIHD CPG is from 2012. A focused update was published in 2014.
12 11
†Minor modifications were made in 2013. For a full explanation of the changes, see http://publications.nice.org.uk/unstable-angina-and-nstemi-cg94/
changes-after-publication.
AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiology; ADA, American Diabetes Association; AHA, American Heart Association;
CDC, Centers for Disease Control and Prevention; CPG, clinical practice guideline; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; NHLBI, National Heart,
Lung, and Blood Institute; NICE, National Institute for Health and Clinical Excellence; PCNA, Preventive Cardiovascular Nurses Association; SCAI, Society for Cardiovascular
Angiography and Interventions; SIHD, stable ischemic heart disease; STS, Society of Thoracic Surgeons; TOS, The Obesity Society; and WHF, World Heart Federation.
3.3. Prognosis—Early Risk Stratification 2. If the initial ECG is not diagnostic but the patient
See Figure 2 and Table 3 for estimation at presentation of remains symptomatic and there is a high clinical
death and nonfatal cardiac ischemic events. See Table 4 for a suspicion for ACS, serial ECGs (eg, 15- to 30-minute
summary of recommendations from this section. intervals during the first hour) should be performed
to detect ischemic changes. (Level of Evidence: C)
Class I 3. Serial cardiac troponin I or T levels (when a con-
1. In patients with chest pain or other symptoms sug- temporary assay is used) should be obtained at pre-
gestive of ACS, a 12-lead electrocardiogram (ECG) sentation and 3 to 6 hours after symptom onset (see
should be performed and evaluated for ischemic Section 3.4.1, Class I, #3 recommendation if time of
changes within 10 minutes of the patient’s arrival at symptom onset is unclear) in all patients who pres-
an emergency facility.22 (Level of Evidence: C) ent with symptoms consistent with ACS to identify a
Figure 1. Acute Coronary Syndromes. The top half of the figure illustrates the progression of plaque formation and onset and
complications of NSTE-ACS, with management at each stage. The numbered section of an artery depicts the process of atherogenesis
from 1) normal artery to 2) extracellular lipid in the subintima to 3) fibrofatty stage to 4) procoagulant expression and weakening of
the fibrous cap. ACS develops with 5) disruption of the fibrous cap, which is the stimulus for thrombogenesis. 6) Thrombus resorption
may be followed by collagen accumulation and smooth muscle cell growth. Thrombus formation and possible coronary vasospasm
reduce blood flow in the affected coronary artery and cause ischemic chest pain. The bottom half of the figure illustrates the clinical,
pathological, electrocardiographic, and biomarker correlates in ACS and the general approach to management. Flow reduction may
be related to a completely occlusive thrombus (bottom half, right side) or subtotally occlusive thrombus (bottom half, left side). Most
patients with ST-elevation (thick white arrow in bottom panel) develop QwMI, and a few (thin white arrow) develop NQMI. Those
without ST-elevation have either UA or NSTEMI (thick red arrows), a distinction based on cardiac biomarkers. Most patients presenting
with NSTEMI develop NQMI; a few may develop QwMI. The spectrum of clinical presentations including UA, NSTEMI, and STEMI
is referred to as ACS. This NSTE-ACS CPG includes sections on initial management before NSTE-ACS, at the onset of NSTE-ACS,
and during the hospital phase. Secondary prevention and plans for long-term management begin early during the hospital phase.
Patients with noncardiac etiologies make up the largest group presenting to the ED with chest pain (dashed arrow). *Elevated cardiac
biomarker (eg, troponin), Section 3.4. ACS indicates acute coronary syndrome; CPG, clinical practice guideline; Dx, diagnosis; ECG,
electrocardiogram; ED, emergency department; Ml, myocardial infarction; NQMI, non–Q-wave myocardial infarction; NSTE-ACS,
non-ST-elevation acute coronary syndromes; NSTEMI, non–ST-elevation myocardial infarction; QwMI, Q-wave myocardial infarction;
STEMI, ST-elevation myocardial infarction; and UA, unstable angina. Modified with permission from Libby et al.39
Figure 2. Global Registry of Acute Coronary Events Risk Calculator for In-Hospital Mortality for Acute Coronary Syndrome.
Table 3. TIMI Risk Score* for NSTE-ACS is nondiagnostic and who are at intermediate/high
risk of ACS.59–61 (Level of Evidence: B)
All-Cause Mortality, New or Recurrent Ml, or Severe
TIMI Risk Recurrent Ischemia Requiring Urgent Revascularization
Score Through 14 d After Randomization, % Class IIb
0–1 4.7 1. Continuous monitoring with 12-lead ECG may be a
2 8.3 reasonable alternative in patients whose initial ECG
3 13.2 is non–diagnostic and who are at intermediate/high
4 19.9 risk of ACS.62,63 (Level of Evidence: B)
5 25.2
2. Measurement of B-type natriuretic peptide or
N-terminal pro–B-type natriuretic peptide may be
6–7 40.9
considered to assess risk in patients with suspected
*The TIMI risk score is determined by the sum of the presence of 7 variables at ACS.64–68 (Level of Evidence: B)
admission; 1 point is given for each of the following variables: ≥65 y of age; ≥3 risk
factors for CAD; prior coronary stenosis ≥50%; ST deviation on ECG; ≥2 anginal
events in prior 24 h; use of aspirin in prior 7 d; and elevated cardiac biomarkers. 3.4. Cardiac Biomarkers and the Universal
CAD indicates coronary artery disease; ECG, electrocardiogram; Ml, myo Definition of Myocardial Infarction
cardial infarction; NSTE-ACS, non–ST-elevation acute coronary syndromes; and See Table 5 for a summary of recommendations from this
TIMI, Thrombolysis In Myocardial Infarction. section.
Modified with permission from Antman et al.40
3.4.1. Biomarkers: Diagnosis

rising and/or falling pattern of values.22,43–48 (Level of
Class I
Evidence: A)
4. Additional troponin levels should be obtained beyond 1. Cardiac-specific troponin (troponin I or T when a
6 hours after symptom onset (see Section 3.4.1, Class I, contemporary assay is used) levels should be mea-
#3 recommendation if time of symptom onset is sured at presentation and 3 to 6 hours after symp-
unclear) in patients with normal troponin levels on tom onset in all patients who present with symptoms
serial examination when changes on ECG and/or clin- consistent with ACS to identify a rising and/or falling
ical presentation confer an intermediate or high index pattern.22,43–48,70–74 (Level of Evidence: A)
of suspicion for ACS.22,49–51 (Level of Evidence: A) 2. Additional troponin levels should be obtained beyond
5. Risk scores should be used to assess prognosis in 6 hours after symptom onset in patients with normal
patients with NSTE-ACS.40–42,52–57 (Level of Evidence: A) troponins on serial examination when electrocardio-
graphic changes and/or clinical presentation con-
Class IIa fer an intermediate or high index of suspicion for
ACS.22,49–51,75 (Level of Evidence: A)
1. Risk-stratification models can be useful in manage- 3. If the time of symptom onset is ambiguous, the time
ment.40–42,52–58 (Level of Evidence: B) of presentation should be considered the time of
2. It is reasonable to obtain supplemental electrocardio- onset for assessing troponin values.44,45,49 (Level of
graphic leads V7 to V9 in patients whose initial ECG Evidence: A)
Table 4. Summary of Recommendations for Prognosis: Early Risk Stratification

Recommendations COR LOE References
Perform rapid determination of likelihood of ACS, including a 12-lead ECG within 10 min of arrival I C 22
at an emergency facility, in patients whose symptoms suggest ACS
Perform serial ECGs at 15- to 30-min intervals during the first hour in symptomatic patients with initial I C N/A
nondiagnostic ECG
Measure cardiac troponin (cTnI or cTnT) in all patients with symptoms consistent with ACS* I A 22, 43–48
Measure serial cardiac troponin I or T at presentation and 3–6 h after symptom onset* in all patients I A 22, 49–51
with symptoms consistent with ACS
Use risk scores to assess prognosis in patients with NSTE-ACS I A 40–42, 52–57
Risk-stratification models can be useful in management IIa B 40–42, 52–58
Obtain supplemental electrocardiographic leads V7 to V9 in patients with initial nondiagnostic IIa B 59–61
ECG at intermediate/high risk for ACS
Continuous monitoring with 12-lead ECG may be a reasonable alternative with initial nondiagnostic IIb B 62, 63
ECG in patients at intermediate/high risk for ACS
BNP or NT–pro-BNP may be considered to assess risk in patients with suspected ACS IIb B 64–68
*See Section 3.4.1, Class I, #3 recommendation if time of symptom onset is unclear.
ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; COR, Class of Recommendation; cTnl, cardiac troponin I; cTnT, cardiac troponin T;
ECG, electrocardiogram; LOE, Level of Evidence; N/A, not available; NSTE-ACS, non–ST-elevation acute coronary syndromes; and NT-pro-BNP, N-terminal pro–
B-type natriuretic peptide.
Table 5. Summary of Recommendations for Cardiac Biomarkers and the Universal Definition of MI
Diagnosis
Measure cardiac-specific troponin (troponin I or T) at presentation and 3–6 h after symptom onset I A 22, 43–48, 70–74
in all patients with suspected ACS to identify pattern of values
Obtain additional troponin levels beyond 6 h in patients with initial normal serial troponins with I A 22, 49–51, 75
electrocardiographic changes and/or intermediate/high risk clinical features
Consider time of presentation the time of onset with ambiguous symptom onset for assessing I A 44, 45, 49
troponin values
With contemporary troponin assays, CK-MB and myoglobin are not useful for diagnosis of ACS III: No Benefit A 76–82
Prognosis
Troponin elevations are useful for short- and long-term prognosis I B 48, 50, 83, 84
Remeasurement of troponin value once on d 3 or 4 in patients with MI may be reasonable as an IIb B 82, 83
index of infarct size and dynamics of necrosis
BNP may be reasonable for additional prognostic information IIb B 64, 65, 85–89
ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; CK-MB, creatine kinase myocardial isoenzyme; COR, Class of Recommendation; LOE,
Level of Evidence; and Ml, myocardial infarction.
Class III: No Benefit 3. In patients with possible ACS and a normal ECG,
normal cardiac troponins, and no history of coro-
1. With contemporary troponin assays, creatine kinase nary artery disease (CAD), it is reasonable to initially
myocardial isoenzyme (CK-MB) and myoglobin perform (without serial ECGs and troponins) coro-
are not useful for diagnosis of ACS.76–82 (Level of nary computed tomography angiography to assess
Evidence: A) coronary artery anatomy98–100 (Level of Evidence: A)
3.4.2. Biomarkers: Prognosis or rest myocardial perfusion imaging with a techne-
tium-99m radiopharmaceutical to exclude myocar-
Class I dial ischemia.101,102 (Level of Evidence: B)
4. It is reasonable to give low-risk patients who are
1. The presence and magnitude of troponin elevations
referred for outpatient testing daily aspirin, short-act-
are useful for short- and long-term prognosis.48,50,83,84
(Level of Evidence: B) ing nitroglycerin, and other medication if appropriate
(eg, beta blockers), with instructions about activity
level and clinician follow-up. (Level of Evidence: C)
Class IIb
1. It may be reasonable to remeasure troponin once on 4. Early Hospital Care: Recommendations
day 3 or day 4 in patients with a myocardial infarc- See Table 6 for a summary of recommendations from this
tion (Ml) as an index of infarct size and dynamics of section.
necrosis.82,83 (Level of Evidence: B)
2. Use of selected newer biomarkers, especially B-type 4.1. Standard Medical Therapies
natriuretic peptide, may be reasonable to provide
additional prognostic information.64,65,85–89 (Level of 4.1.1. Oxygen
Evidence: B)
Class I
3.5. Discharge From the ED or Chest Pain Unit 1. Supplemental oxygen should be administered to
patients with NSTE-ACS with arterial oxygen satura-
Class IIa
tion less than 90%, respiratory distress, or other high-
1. It is reasonable to observe patients with symptoms risk features of hypoxemia. (Level of Evidence: C)
consistent with ACS without objective evidence 4.1.2. Nitrates
of myocardial ischemia (nonischemic initial ECG
and normal cardiac troponin) in a chest pain unit Class I
or telemetry unit with serial ECGs and cardiac
troponin at 3- to 6-hour intervals.90–94 (Level of 1. Patients with NSTE-ACS with continuing isch-
Evidence: B) emic pain should receive sublingual nitroglycerin
2. It is reasonable for patients with possible ACS who (0.3 mg-0.4 mg) every 5 minutes for up to 3 doses,
have normal serial ECGs and cardiac troponins after which an assessment should be made about the
to have a treadmill ECG93–95 (Level of Evidence: A), need for intravenous nitroglycerin if not contraindi-
stress myocardial perfusion imaging,93 or stress echo- cated.103–105 (Level of Evidence: C)
cardiography96,97 before discharge or within 72 hours 2. Intravenous nitroglycerin is indicated for patients
after discharge. (Level of Evidence: B) with NSTE-ACS for the treatment of persistent
Table 6. Summary of Recommendations for Early Hospital Care

Oxygen
Administer supplemental oxygen only with oxygen saturation <90%, respiratory distress, I C N/A
or other high-risk features for hypoxemia
Nitrates
Administer sublingual NTG every 5 min × 3 for continuing ischemic pain and then assess need for IV NTG I C 103–105
Administer IV NTG for persistent ischemia, HF, or hypertension I B 106–111
Nitrates are contraindicated with recent use of a phosphodiesterase inhibitor III: Harm B 112–114
Analgesic therapy
IV morphine sulfate may be reasonable for continued ischemic chest pain despite maximally tolerated IIb B 115, 116
anti-ischemic medications
NSAIDs (except aspirin) should not be initiated and should be discontinued during hospitalization III: Harm B 117, 118
for NSTE-ACS because of the increased risk of MACE associated with their use
Beta-adrenergic blockers
Initiate oral beta blockers within the first 24 h in the absence of HF, low-output state, risk for cardiogenic I A 119–121
shock, or other contraindications to beta blockade
Use of sustained-release metoprolol succinate, carvedilol, or bisoprolol is recommended for beta-blocker I C N/A
therapy with concomitant NSTE-ACS, stabilized HF, and reduced systolic function
Re-evaluate to determine subsequent eligibility in patients with initial contraindications to beta blockers I C N/A
It is reasonable to continue beta-blocker therapy in patients with normal LV function with NSTE-ACS IIa C 120, 122
IV beta blockers are potentially harmful when risk factors for shock are present III: Harm B 123
CCBs
Administer initial therapy with nondihydropyridine CCBs with recurrent ischemia and contraindications I B 124–126
to beta blockers in the absence of LV dysfunction, increased risk for cardiogenic shock, PR interval
>0.24 s, or second- or third-degree atrioventricular block without a cardiac pacemaker
Administer oral nondihydropyridine calcium antagonists with recurrent ischemia after use of beta I C N/A
blocker and nitrates in the absence of contraindications
CCBs are recommended for ischemic symptoms when beta blockers are not successful, I C N/A
are contraindicated, or cause unacceptable side effects*
Long-acting CCBs and nitrates are recommended for patients with coronary artery spasm I C N/A
Immediate-release nifedipine is contraindicated in the absence of a beta blocker III: Harm B 127, 128
Cholesterol management
Initiate or continue high-intensity statin therapy in patients with no contraindications I A 129–133
Obtain a fasting lipid profile, preferably within 24 h IIa C N/A

*Short-acting dihydropyridine calcium channel antagonists should be avoided.
CCB indicates calcium channel blocker; COR, Class of Recommendation; HF, heart failure; IV, intravenous; LOE, Level of Evidence; LV, left ventricular; MACE, major
adverse cardiac event; N/A, not available; NSAIDs, nonsteroidal anti-inflammatory drugs; NSTE-ACS, non–ST-elevation acute coronary syndromes; and NTG, nitroglycerin.
ischemia, heart failure (HF), or hypertension.106–111 tolerated anti-ischemic medications.115,116 (Level of

(Level of Evidence: B) Evidence: B)
Class III: Harm Class III: Harm

1. Nitrates should not be administered to patients with 1. Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSTE-ACS who recently received a phosphodiester- (except aspirin) should not be initiated and should be
ase inhibitor, especially within 24 hours of sildenafil discontinued during hospitalization for NSTE-ACS
or vardenafil, or within 48 hours of tadalafil.112–114 because of the increased risk of MACE associated
(Level of Evidence: B) with their use.117,118 (Level of Evidence: B)
4.1.3. Analgesic Therapy 4.1.4. Beta-Adrenergic Blockers
Class IIb Class I
1. In the absence of contraindications, it may be reason- 1. Oral beta-blocker therapy should be initiated
able to administer morphine sulfate intravenously to within the first 24 hours in patients who do not have
patients with NSTE-ACS if there is continued isch- any of the following: 1) signs of HF, 2) evidence of
emic chest pain despite treatment with maximally low-output state, 3) increased risk for cardiogenic
shock, or 4) other contraindications to beta block- 4.1.6. Cholesterol Management

ade (eg, PR interval >0.24 second, second- or third-
degree heart block without a cardiac pacemaker, Class I
active asthma, or reactive airway disease).119–121 1. High-intensity statin therapy should be initiated or
(Level of Evidence: A) continued in all patients with NSTE-ACS and no con-
2. In patients with concomitant NSTE-ACS, stabilized traindications to its use.129–133 (Level of Evidence: A)
HF, and reduced systolic function, it is recommended
to continue beta-blocker therapy with 1 of the 3 drugs Class IIa
proven to reduce mortality in patients with HF: sus-
tained-release metoprolol succinate, carvedilol, or 1. It is reasonable to obtain a fasting lipid profile in
bisoprolol. (Level of Evidence: C) patients with NSTE-ACS, preferably within 24 hours
3. Patients with documented contraindications to beta of presentation. (Level of Evidence: C)
blockers in the first 24 hours of NSTE-ACS should be
reevaluated to determine their subsequent eligibility. 4.2. Inhibitors of the Renin-Angiotensin-
(Level of Evidence: C) Aldosterone System
Class IIa Class I
1. It is reasonable to continue beta-blocker therapy in 1. Angiotensin-converting enzyme (ACE) inhibitors should

patients with normal left ventricular (LV) function be started and continued indefinitely in all patients
with NSTE-ACS.120,122 (Level of Evidence: C) with left ventricular ejection fraction (LVEF) less than
0.40 and in those with hypertension, diabetes mellitus,
or stable chronic kidney disease (CKD) (Section 7.6),
Class III: Harm
unless contraindicated.134,135 (Level of Evidence: A)
1. Administration of intravenous beta blockers is poten- 2. Angiotensin receptor blockers are recommended in
tially harmful in patients with NSTE-ACS who have patients with HF or MI with LVEF less than 0.40 who
risk factors for shock.123 (Level of Evidence: B) are ACE inhibitor intolerant.136,137 (Level of Evidence: A)
3. Aldosterone blockade is recommended in post–MI
4.1.5. Calcium Channel Blockers patients who are without significant renal dysfunc-
Class I tion (creatinine >2.5 mg/dL in men or >2.0 mg/dL
in women) or hyperkalemia (K+ >5.0 mEq/L) who
1. In patients with NSTE-ACS, continuing or fre- are receiving therapeutic doses of ACE inhibitor and
quently recurring ischemia, and a contraindication beta blocker and have a LVEF 0.40 or less, diabetes
to beta blockers, a non-dihydropyridine calcium mellitus, or HF.138 (Level of Evidence: A)
channel blocker (CCB) (eg, verapamil or diltiazem)
should be given as initial therapy in the absence of Class IIa
clinically significant LV dysfunction, increased risk
for cardiogenic shock, PR interval greater than 0.24 1. Angiotensin receptor blockers are reasonable in other
second, or second- or third-degree atrioventricular patients with cardiac or other vascular disease who
block without a cardiac pacemaker.124–126 (Level of are ACE inhibitor intolerant.139 (Level of Evidence: B)
Evidence: B)
2. Oral nondihydropyridine calcium antagonists are Class IIb
recommended in patients with NSTE-ACS who have 1. ACE inhibitors may be reasonable in all other
recurrent ischemia in the absence of contraindica- patients with cardiac or other vascular disease.140,141
tions, after appropriate use of beta blockers and (Level of Evidence: B)
nitrates. (Level of Evidence: C)
3. CCBs† are recommended for ischemic symptoms
when beta blockers are not successful, are contrain- 4.3. Initial Antiplatelet/Anticoagulant Therapy in
dicated, or cause unacceptable side effects. (Level of Patients With Definite or Likely NSTE-ACS
Evidence: C) 4.3.1. Initial Oral and Intravenous Antiplatelet Therapy in
4. Long-acting CCBs and nitrates are recommended Patients With Definite or Likely NSTE-ACS Treated With
in patients with coronary artery spasm. (Level of an Initial Invasive or Ischemia-Guided Strategy
Evidence: C) See Table 7 for a summary of recommendations from this section.
Class III: Harm Class I‡

1. Immediate-release nifedipine should not be adminis- 1. Non–enteric-coated, chewable aspirin (162 mg to 325
tered to patients with NSTE-ACS in the absence of mg) should be given to all patients with NSTE-ACS
beta-blocker therapy.127,128 (Level of Evidence: B) without contraindications as soon as possible after pre-
sentation, and a maintenance dose of aspirin (81 mg/d
†Short-acting dihydropyridine calcium channel antagonists should be
avoided. ‡See Section 5.1 for recommendations at the time of PCI.
Table 7. Summary of Recommendations for Initial Antiplatelet/Anticoagulant Therapy in Patients With Definite or Likely NSTE-ACS
and PCI
Dosing and Special
Recommendations Considerations COR LOE References
Aspirin
Non–enteric-coated aspirin to all patients promptly after 162 mg–325 mg I A 142–144, 147, 363
presentation
Aspirin maintenance dose continued indefinitely 81 mg/d–325 mg/d* I A 142–144
P2Y12 inhibitors
Clopidogrel loading dose followed by daily maintenance 75 mg I B 145
75 mg dose in patients unable to take aspirin
P2Y12 inhibitor, in addition to aspirin, for up to 12 mo for patients 300-mg or 600-mg loading dose, I B 143, 146
treated initially with either an early invasive or initial ischemia- then 75 mg/d
guided strategy:
– Clopidogrel 180-mg loading dose, then 90 mg BID 147, 148
– Ticagrelor*
P2Y12 inhibitor therapy (clopidogrel, prasugrel, or N/A ticagrelor) N/A I B 147, 169–172
continued for at least 12 mo in post–PCI patients treated with

coronary stents
Ticagrelor in preference to clopidogrel for patients N/A treated N/A IIa B 147, 148
with an early invasive or ischemia-guided strategy
GP llb/llla inhibitors
GP IIb/IIIa inhibitor in patients treated with an early invasive • Preferred options are eptifibatide IIb B 141, 149, 150
strategy and DAPT with intermediate/high-risk features or tirofiban
(eg, positive troponin)
Parenteral anticoagulant and fibrinolytic therapy
SC enoxaparin for duration of hospitalization or until PCI is • 1 mg/kg SC every 12 h (reduce dose I A 151–153
performed to 1 mg/kg/d SC in patients with CrCl
<30 mL/min)
• Initial 30 mg IV loading dose in
selected patients
Bivalirudin until diagnostic angiography or PCI is performed in • Loading dose 0.10 mg/kg loading I B 146, 147, 154, 155
patients with early invasive strategy only dose followed by 0.25 mg/kg/h
• Only provisional use of GP llb/llla inhibitor
in patients also treated with DAPT
SC fondaparinux for the duration of hospitalization or until PCI • 2.5 mg SC daily I B 156–158
is performed
Administer additional anticoagulant with anti-IIa activity if PCI N/A I B 157–159
is performed while patient is on fondaparinux
IV UFH for 48 h or until PCI is performed • Initial loading dose 60 Ill/kg I B 160–166
(max 4000 IU) with initial infusion
12 lU/kg/h (max 1000 IU/h)
• Adjusted to therapeutic aPTT range
IV fibrinolytic treatment not recommended in patients with NSTE-ACS N/A III: Harm A 167, 168
See Section 5.1 for recommendations on antiplatelet/anticoagulant therapy at the time of PCI and Sections 6.2 and 6.3 for recommendations on posthospital therapy.
*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.144
aPTT indicates activated partial thromboplastin time; BID, twice daily; COR, Class of Recommendation; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; GP,
glycoprotein; IV, intravenous; LOE, Level of Evidence; max, maximum; N/A, not available; NSTE-ACS, non–ST-elevation acute coronary syndromes; PCI, percutaneous
coronary intervention; SC, subcutaneous; and UFH, unfractionated heparin.
to 325 mg/d) should be continued indefinitely.142–144,147,363 to 12 months to all patients with NSTE-ACS without
(Level of Evidence: A) contraindications who are treated with either an early
2. In patients with NSTE-ACS who are unable to take invasive§ or ischemia-guided strategy. Options include:
aspirin because of hypersensitivity or major gastro- • Clopidogrel: 300-mg or 600-mg loading dose, then
intestinal intolerance, a loading dose of clopidogrel 75 mg daily143,146 (Level of Evidence: B)
followed by a daily maintenance dose should be
administered.145 (Level of Evidence: B)
3. A P2Y12 inhibitor (either clopidogrel or ticagrelor) §See Section 4.3.1.2 in the full-text CPG for prasugrel indications in
in addition to aspirin should be administered for up either an early invasive or ischemia-guided strategy.
• Ticagrelor||: 180-mg loading dose, then 90 mg anticoagulation according to the specific hospital
twice daily147,148 (Level of Evidence: B) protocol, continued for 48 hours or until PCI is
performed.160–166 (Level of Evidence: B)
Class IIa
Class III: Harm
1. It is reasonable to use ticagrelor in preference to
clopidogrel for P2Y12 treatment in patients with 1. In patients with NSTE-ACS (ie, without
NSTE-ACS who undergo an early invasive or isch- ST-elevation, true posterior Ml, or left bundle-
emia-guided strategy.147,148 (Level of Evidence: B) branch block not known to be old), intravenous
fibrinolytic therapy should not be used.167,168 (Level
Class IIb of Evidence: A)
1. In patients with NSTE-ACS treated with an early 4.4. Ischemia-Guided Strategy Versus Early
invasive strategy and dual antiplatelet therapy Invasive Strategies
(DAPT) with intermediate/high-risk features (eg, See Figure 3 for the management algorithm for ischemia-
positive troponin), a glycoprotein (GP) llb/llla inhibi- guided versus early invasive strategy.
tor may be considered as part of initial antiplatelet
therapy. Preferred options are eptifibatide or tirofi- 4.4.1. Early Invasive and Ischemia-Guided Strategies
ban.41,149,150 (Level of Evidence: B) For definitions of invasive and ischemia-guided strategies, see
Table 8.
4.3.2. Initial Parenteral Anticoagulant Therapy in Patients
With Definite NSTE-ACS 1. An urgent/immediate invasive strategy (diagnostic
See Table 7 for a summary of recommendations from this angiography with intent to perform revascularization
section. if appropriate based on coronary anatomy) is indi-
cated in patients (men and women¶) with NSTE-ACS
Class I‡ who have refractory angina or hemodynamic or elec-
trical instability (without serious comorbidities or
1. In patients with NSTE-ACS, anticoagulation, in contraindications to such procedures).40,42,173,174 (Level
addition to antiplatelet therapy, is recommended for of Evidence: A)
all patients irrespective of initial treatment strategy. 2. An early invasive strategy (diagnostic angiography
Treatment options include: with intent to perform revascularization if appro-
• Enoxaparin: 1 mg/kg subcutaneous (SC) every 12 priate based on coronary anatomy) is indicated
hours (reduce dose to 1 mg/kg SC once daily in patients in initially stabilized patients with NSTE-ACS
with creatinine clearance [CrCl] <30 mL/min), contin- (without serious comorbidities or contraindica-
ued for the duration of hospitalization or until percu- tions to such procedures) who have an elevated
taneous coronary intervention (PCI) is performed. An risk for clinical events (Table 8).40,42,173–177 (Level of
initial intravenous loading dose of 30 mg has been used Evidence: B)
in selected patients.151–153 (Level of Evidence: A)
• Bivalirudin: 0.10 mg/kg loading dose followed by Class IIa
0.25 mg/kg per hour (only in patients managed
1. It is reasonable to choose an early invasive strategy
with an early invasive strategy), continued until
(within 24 hours of admission) over a delayed inva-
diagnostic angiography or PCI, with only provi-
sive strategy (within 24 to 72 hours) for initially sta-
sional use of GP IIb/IIIa inhibitor, provided the
bilized high-risk patients with NSTE-ACS. For those
patient is also treated with DAPT.146,147,154,155 (Level
not at high/intermediate risk, a delayed invasive
of Evidence: B)
approach is reasonable.173 (Level of Evidence: B)
• Fondaparinux: 2.5 mg SC daily, continued for the
duration of hospitalization or until PCI is per- Class IIb
formed.156–158 (Level of Evidence: B)
• If PCI is performed while the patient is on 1. In initially stabilized patients, an ischemia-guided
fondaparinux, an additional anticoagulant with strategy may be considered for patients with
anti-IIa activity (either UFH or bivalirudin) should NSTE-ACS (without serious comorbidities or
be administered because of the risk of catheter contraindications to this approach) who have an
thrombosis.157–159 (Level of Evidence: B) elevated risk for clinical events.174,175,177 (Level of
Evidence: B)
• UFH IV: initial loading dose of 60 IU/kg (maximum 2. The decision to implement an ischemia-guided strat-
4000 IU) with initial infusion of 12 IU/kg per hour egy in initially stabilized patients (without serious
(maximum 1000 IU/h) adjusted per activated par- comorbidities or contraindications to this approach)
tial thromboplastin time to maintain therapeutic may be reasonable after considering clinician and
||The recommended maintenance dose of aspirin to be used with
patient preference. (Level of Evidence: C)
ticagrelor is 81 mg daily.144
‡See Section 5.1 for recommendations at the time of PCI. ¶See Section 7.7 for additional information on women.
Figure 3. Algorithm for Management of Patients With Definite or Likely NSTE-ACS*. *See corresponding full-sentence recommendations
and their explanatory footnotes. †In patients who have been treated with fondaparinux (as upfront therapy) who are undergoing PCI, an
additional anticoagulant with anti-IIa activity should be administered at the time of PCI because of the risk of catheter thrombosis. ASA
indicates aspirin; CABG, coronary artery bypass graft; cath, catheter; COR, Class of Recommendation; DAPT, dual antiplatelet therapy;
GPI, glycoprotein IIb/IIIa inhibitor; LOE, Level of Evidence; NSTE-ACS, non–ST-elevation acute coronary syndrome; PCI, percutaneous
coronary intervention; pts, patients; and UFH, unfractionated heparin.
Class III: No Benefit revascularization and comorbid conditions are

likely to outweigh the benefits of revascularization.
1. An early invasive strategy (ie, diagnostic angiogra- (Level of Evidence: C)
phy with intent to perform revascularization) is not
recommended in patients with: b. Acute chest pain and a low likelihood of ACS who
a. Extensive comorbidities (eg, hepatic, renal, pul- are troponin-negative (Level of Evidence: C), espe-
monary failure; cancer), in whom the risks of cially women.178 (Level of Evidence: B)
Table 8. Factors Associated With Appropriate Selection 5. Myocardial Revascularization:

of Early Invasive Strategy or Ischemia-Guided Strategy in Recommendations
Patients With NSTE-ACS
5.1. PCI—General Considerations
Immediate invasive Refractory angina
(within 2 h) Class IIb
Signs or symptoms of HF or new or worsening
mitral regurgitation 1. A strategy of multivessel PCI, in contrast to culprit
Hemodynamic instability lesion–only PCI, may be reasonable in patients under-
going coronary revascularization as part of treatment
Recurrent angina or ischemia at rest or with
low-level activities despite intensive medical for NSTE-ACS.169,184–189 (Level of Evidence: B)
therapy 5.1.1. PCI–Oral and Intravenous Antiplatelet Agents
Sustained VT or VF
Ischemia-guided strategy Low-risk score (eg, TIMI [0 or 1],
Class I
GRACE [<109])
1. Patients already taking daily aspirin before PCI
Low-risk Tn-negative female patients should take 81 mg to 325 mg non–enteric-coated
Patient or clinician preference in the absence aspirin before PCI.27,190–192 (Level of Evidence: B)
of high-risk features 2. Patients not on aspirin therapy should be given non–
Early invasive (within 24 h) None of the above, but GRACE risk score >140 entericcoated aspirin 325 mg as soon as possible
Temporal change in Tn (Section 3.4) before PCI.27,190–192 (Level of Evidence: B)

3. After PCI, aspirin should be continued indefinitely
New or presumably new ST depression
at a dose of 81 mg to 325 mg daily.28,142,193 (Level of
Delayed invasive (within None of the above but diabetes mellitus Renal
Evidence: B)
25—72 h) insufficiency (GFR <60 mL/min/1.73 m2
4. A loading dose of a P2Y12 receptor inhibitor should
Reduced LV systolic function (EF <0.40) be given before the procedure in patients undergoing
Early postinfarction angina PCI with stenting.27,147,170,172,194–197 (Level of Evidence:
PCI within 6 mo A) Options include:
Prior CABG a. Clopidogrel: 600 mg170,194–196,198–200 (Level of
GRACE risk score 109–140; TIMI score ≥2 Evidence: B) or
CABG indicates coronary artery bypass graft; EF, ejection fraction; GFR, b. Prasugrel#: 60 mg172 (Level of Evidence: B) or
glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; HF, c. Ticagrelor||: 180 mg147 (Level of Evidence: B)
heart failure; LV, left ventricular; NSTE-ACS, non–ST-elevation acute coronary
syndrome; PCI, percutaneous coronary intervention; TIMI, Thrombolysis 5. In patients with NSTE-ACS and high-risk features
In Myocardial Infarction; Tn, troponin; VF, ventricular fibrillation; and VT, (eg, elevated troponin) who are not adequately pre-
ventricular tachycardia. treated with clopidogrel or ticagrelor, it is useful to
administer a GP llb/llla inhibitor (abciximab, double-
bolus eptifibatide, or high-dose bolus tirofiban) at the
4.5. Risk Stratification Before Discharge for Patients time of PCI.201–204 (Level of Evidence: A)
With an Ischemia-Guided Strategy of NSTE-ACS 6. In patients receiving a stent (bare-metal stent or
drug-eluting stent [DES]) during PCI for NSTE-
Class I ACS, P2Y12 inhibitor therapy should be given for at
least 12 months.169 Options include:
1. Noninvasive stress testing is recommended in low-
and intermediate-risk patients who have been free of a. Clopidogrel: 75 mg daily170,171 (Level of Evidence:
ischemia at rest or with low-level activity for a mini- B) or
mum of 12 to 24 hours.179–183 (Level of Evidence: B) b. Prasugrel#: 10 mg daily172 (Level of Evidence: B) or
2. Treadmill exercise testing is useful in patients able c. Ticagrelor||: 90 mg twice daily147 (Level of Evidence:
to exercise in whom the ECG is free of resting ST B)
changes that may interfere with interpretation.179–182
(Level of Evidence: C) Class IIa
3. Stress testing with an imaging modality should be
used in patients who are able to exercise but have 1. It is reasonable to choose ticagrelor over clopido-
ST changes on resting ECG that may interfere with grel for P2Y12 inhibition treatment in patients with
interpretation. In patients undergoing a low-level NSTE-ACS treated with an early invasive strategy
exercise test, an imaging modality can add prognostic and/or coronary stenting.147,148 (Level of Evidence: B)
information.179–182 (Level of Evidence: B) 2. It is reasonable to choose prasugrel over clopidogrel
4. Pharmacological stress testing with imaging is rec- for P2Y12 treatment in patients with NSTE-ACS who
ommended when physical limitations preclude ade-
quate exercise stress. (Level of Evidence: C)
#Patients should receive a loading dose of prasugrel provided that they
5. A noninvasive imaging test is recommended to evalu- were not pretreated with another P2Y12 receptor inhibitor.
ate LV function in patients with definite ACS.179–182 ||The recommended maintenance dose of aspirin to be used with
(Level of Evidence: C) ticagrelor is 81 mg daily.144
undergo PCI who are not at high risk of bleeding with NSTE-ACS undergoing PCI.154,213–217 (Level of
complications.172,205 (Level of Evidence: B) Evidence: B)
3. In patients with NSTE-ACS and high-risk features 4. An additional dose of 0.3 mg/kg IV enoxaparin
(eg, elevated troponin) treated with UFH and ade- should be administered at the time of PCI to patients
quately pretreated with clopidogrel, it is reasonable with NSTE-ACS who have received fewer than 2
to administer a GP llb/llla inhibitor (abciximab, dou- therapeutic subcutaneous doses (eg, 1 mg/kg SC) or
ble-bolus eptifibatide, or high-bolus dose tirofiban) at received the last subcutaneous enoxaparin dose 8 to
the time of PCI.206–208 (Level of Evidence: B) 12 hours before PCI.152,218–222 (Level of Evidence: B)
4. After PCI, it is reasonable to use 81 mg per day 5. If PCI is performed while the patient is on
of aspirin in preference to higher maintenance fondaparinux, an additional 85 lU/kg of UFH should
doses.170,190,209–212 (Level of Evidence: B) be given intravenously immediately before PCI
5. If the risk of morbidity from bleeding outweighs the because of the risk of catheter thrombosis (60 lU/kg
antici pated benefit of a recommended duration of IV if a GP IIb/IIIa inhibitor used with UFH dosing
P2Y12 inhibitor therapy after stent implantation, ear- based on the target-activated clotting time).27,157–159,223
lier discontinuation (eg, <12 months) of P2Y12 inhibi- (Level of Evidence: B)
tor therapy is reasonable.169 (Level of Evidence: C) 6. In patients with NSTE-ACS, anticoagulant therapy
should be discontinued after PCI unless there is a
Class IIb compelling reason to continue such therapy. (Level of
Evidence: C)
1. Continuation of DAPT beyond 12 months may be

considered in patients undergoing stent implanta- Class IIa
tion. (Level of Evidence: C)
1. In patients with NSTE-ACS undergoing PCI who are
Class III: Harm at high risk of bleeding, it is reasonable to use bivali-
rudin monotherapy in preference to the combination
1. Prasugrel should not be administered to patients of UFH and a GP IIb/IIIa receptor antagonist.154,215
with a prior history of stroke or transient ischemic (Level of Evidence: B)
attack.172 (Level of Evidence: B)
5.1.1.1. PCI—GP IIb/IIIa Inhibitors Class IIb
Class I 1. Performance of PCI with enoxaparin may be reason-

able in patients treated with upstream subcutaneous
1. In patients with NSTE-ACS and high-risk features enoxaparin for NSTE-ACS.27,152,218–221,224,225 (Level of
(eg, elevated troponin) and not adequately pretreated Evidence: B)
with clopidogrel or ticagrelor, it is useful to adminis-
ter a GP IIb/IIIa inhibitor (abciximab, double-bolus Class III: Harm
eptifibatide, or high-dose bolus tirofiban) at the time
of PCI.201–204 (Level of Evidence: A) 1. Fondaparinux should not be used as the sole antico-
agulant to support PCI in patients with NSTE-ACS
Class IIa due to an increased risk of catheter thrombosis.27,157–159
(Level of Evidence: B)
1. In patients with NSTE-ACS and high-risk features
(eg, elevated troponin) treated with UFH and ade- 5.2. Timing of Urgent Coronary Artery Bypass
quately pretreated with clopidogrel, it is reasonable Graft in Patients With NSTE-ACS in Relation to
to administer a GP IIb/IIIa inhibitor (abciximab, Use of Antiplatelet Agents
double-bolus eptifibatide, or high-dose bolus tirofi-
ban) at the time of PCI.206,207 (Level of Evidence: B) Class I
5.1.2. Anticoagulant Therapy in Patients Undergoing PCI 1. Non–enteric-coated aspirin (81 mg to 325 mg daily)
See Table 9 for dosing information on dosing of parenteral should be administered preoperatively to patients
anticoagulants during PCI. undergoing coronary artery bypass graft (CABG).226–228
Class I 2. In patients referred for elective CABG, clopidogrel
and ticagrelor should be discontinued for at least 5
1. An anticoagulant should be administered to patients days before surgery24,229–231 (Level of Evidence: B) and
with NSTE-ACS undergoing PCI to reduce the risk prasugrel for at least 7 days before surgery.9,232 (Level
of intracoronary and catheter thrombus formation. of Evidence: C)
(Level of Evidence: C) 3. In patients referred for urgent CABG, clopidogrel and
2. Intravenous UFH is useful in patients with NSTE- ticagrelor should be discontinued for at least 24 hours to
ACS undergoing PCI. (Level of Evidence: C) reduce major bleeding.9,230,233–235 (Level of Evidence: B)
3. Bivalirudin is useful as an anticoagulant with or 4. In patients referred for CABG, short-acting intrave-
without prior treatment with UFH in patients nous GP IIb/IIIa inhibitors (eptifibatide or tirofiban)
Table 9. Dosing of Parenteral Anticoagulants During PCI

In Patients Who Have Received In Patients Who Have Not Received
Drug* Prior Anticoagulant Therapy Prior Anticoagulant Therapy
Enoxaparin • For prior treatment with enoxaparin, if last SC dose was administered • 0.5 mg/kg-0.75 mg/kg IV loading dose
8–12 h earlier or if <2 therapeutic SC doses of enoxaparin have been
administered, an IV dose of enoxaparin 0.3 mg/kg should be given
• If the last SC dose was administered within prior 8 h, no additional
enoxaparin should be given
Bivalirudin • F or patients who have received UFH, wait 30 min, then give 0.75 mg/kg • 0.75 mg/kg loading dose, 1.75 mg/kg/h IV infusion
IV loading dose, then 1.75 mg/kg/h IV infusion
• F or patients already receiving bivalirudin infusion, give additional
loading dose 0.5 mg/kg and increase infusion to 1.75 mg/kg/h
during PCI
Fondaparinux • For prior treatment with fondaparinux, administer additional IV N/A
treatment with anticoagulant possessing anti-Ma activity, considering
whether GPI receptor antagonists have been administered
UFH • IV GPI planned: additional UFH as needed (eg, 2000–5000 U) to • IV GPI planned: 50–70 U/kg loading dose to achieve ACT of
achieve ACT of 200–250 s 200–250 s
• No IV GPI planned: additional UFH as needed (eg, 2000–5000 U) to •N

o IV GPI planned: 70–100 U/kg loading dose to achieve target
achieve ACT of 250–300 s for HemoTec, 300–350 s for Hemochron ACT of 250–300 s for HemoTec, 300–350 s for Hemochron
*Drugs presented in order of the COR and then the LOE as noted in the Preamble. When more than 1 drug exists within the same LOE, and there are no comparative
data, then the drugs are listed alphabetically.
ACT indicates activated clotting time; COR, Class of Recommendation; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; LOE, Level of Evidence; N/A, not applicable;
PCI, percutaneous coronary intervention; SC, subcutaneous; and UFH, unfractionated heparin.
Modified from Levine et al.27
should be discontinued for at least 2 to 4 hours before myocardial ischemia and Ml and should be given ver-
surgery236,237 and abciximab for at least 12 hours bal and written instructions about how and when to
before to limit blood loss and transfusion.238 (Level of seek emergency care for such symptoms.241 (Level of
Evidence: B) Evidence: C)
4. Before hospital discharge, patients who are post–
Class IIb NSTE-ACS and/or designated responsible caregiv-
ers should be provided with easily understood and
1. In patients referred for urgent CABG, it may be culturally sensitive verbal and written instructions
reasonable to perform surgery less than 5 days after about medication type, purpose, dose, frequency, side
clopidogrel or ticagrelor has been discontinued and effects, and duration of use.241 (Level of Evidence: C)
less than 7 days after prasugrel has been discontin- 5. For patients who are post–NSTE-ACS and have ini-
ued. (Level of Evidence: C) tial angina lasting more than 1 minute, nitroglyc-
erin (1 dose sublingual or spray) is recommended if
6. Late Hospital Care, Hospital angina does not subside within 3 to 5 minutes; call
9-1-1 immediately to access emergency medical ser-
Discharge, And Posthospital Discharge
vices.241 (Level of Evidence: C)
Care: Recommendations 6. If the pattern or severity of angina changes, suggest-
6.1. Medical Regimen and Use of Medications at ing worsening myocardial ischemia (eg, pain is more
Discharge frequent or severe or is precipitated by less effort or
occurs at rest), patients should contact their clinician
Class I without delay to assess the need for additional treat-
ment or testing.241 (Level of Evidence: C)
1. Medications required in the hospital to control isch- 7. Before discharge, patients should be educated about
emia should be continued after hospital discharge modification of cardiovascular risk factors.240 (Level
in patients with NSTE-ACS who do not undergo of Evidence: C)
coronary revascularization, patients with incom-
plete or unsuccessful revascularization, and patients
with recurrent symptoms after revascularization. 6.2. Late Hospital and Posthospital Oral
Titration of the doses may be required.239,240 (Level of Antiplatelet Therapy
Evidence: C) Class I
2. All patients who are post–NSTE-ACS should be given
sublingual or spray nitroglycerin with verbal and 1. Aspirin should be continued indefinitely. The mainte-
written instructions for its use.241 (Level of Evidence: C) nance dose should be 81 mg daily in patients treated
3. Before hospital discharge, patients with NSTE-ACS with ticagrelor and 81 mg to 325 mg daily in all other
should be informed about symptoms of worsening patients.142–144 (Level of Evidence: A)
2. In addition to aspirin, a P2Y12 inhibitor (either clopi- 2. Proton pump inhibitors should be prescribed in
dogrel or ticagrelor) should be continued for up to patients with NSTE-ACS with a history of gastroin-
12 months in all patients with NSTE-ACS without testinal bleeding who require triple antithrombotic
contraindications who are treated with an ischemia- therapy with a vitamin K antagonist, aspirin, and a
guided strategy. Options include: P2Y12 receptor inhibitor.27,242,243 (Level of Evidence: C)
• C lopidogrel: 75 mg daily143,171 (Level of Evidence:
B) or Class IIa
• Ticagrelor||: 90 mg twice daily147,148 (Level of
1. Proton pump inhibitor use is reasonable in patients
Evidence: B)
with NSTE-ACS without a known history of gastro-
3. In patients receiving a stent (bare-metal stent or intestinal bleeding who require triple antithrombotic
DES) during PCI for NSTE-ACS, P2Y12 inhibitor therapy with a vitamin K antagonist, aspirin, and a
therapy should be given for at least 12 months.169 P2Y12 receptor inhibitor.27,242,243 (Level of Evidence: C)
Options include:
• C lopidogrel: 75 mg daily170,171 (Level of Evidence: Class IIb
B) or 1. Targeting oral anticoagulant therapy to a lower
• Prasugrel#: 10 mg daily172 (Level of Evidence: B) or international J normalized ratio (eg, 2.0 to 2.5) may
• Ticagrelor||: 90 mg twice daily147 (Level of be reasonable in patients with NSTE-ACS man-
Evidence: B) aged with aspirin and a P2Y12 inhibitor. (Level of

Evidence: C)
Class IIa
6.4. Risk Reduction Strategies for Secondary
1. It is reasonable to use an aspirin maintenance dose Prevention
of 81 mg per day in preference to higher mainte-
nance doses in patients with NSTE-ACS treated Class I
either invasively or with coronary stent implanta-
tion.27,170,190,209–212 (Level of Evidence: B) 1. All eligible patients with NSTE-ACS should be
2. It is reasonable to use ticagrelor in preference to clop- referred to a comprehensive cardiovascular reha-
idogrel for maintenance P2Y12 treatment in patients bilitation program either before hospital discharge
with NSTE-ACS who undergo an early invasive or or during the first outpatient visit.244–247 (Level of
ischemia-guided strategy.147,148 (Level of Evidence: B) Evidence: B)
3. It is reasonable to choose prasugrel over clopidogrel 2. The pneumococcal vaccine is recommended for
for maintenance P2Y12 treatment in patients with patients 65 years of age and older and in high-risk
NSTE-ACS who undergo PCI who are not at high risk patients with cardiovascular disease.248–250 (Level of
for bleeding complications.172,205 (Level of Evidence: B) Evidence: B)
4. If the risk of morbidity from bleeding outweighs the 3. Patients should be educated about appropriate cho-
anticipated benefit of a recommended duration of lesterol management, blood pressure (BP), smoking
P2Y12 inhibitor therapy after stent implantation, ear- cessation, and lifestyle management.16,17,19 (Level of
lier discontinuation (eg, <12 months) of P2Y12 inhibi- Evidence: C)
tor therapy is reasonable.169 (Level of Evidence: C) 4. Patients who have undergone PCI or CABG derive
benefit from risk factor modification and should
Class IIb receive counseling that revascularization does not
obviate the need for lifestyle changes.251 (Level of
1. Continuation of DAPT beyond 12 months may be Evidence: C)
considered in patients undergoing stent implanta- 5. Before hospital discharge, the patient’s need for treat-
tion. (Level of Evidence: C) ment of chronic musculoskeletal discomfort should
be assessed, and a stepped-care approach should
6.3. Combined Oral Anticoagulant Therapy and be used for selection of treatments. Pain treatment
Antiplatelet Therapy in Patients With NSTE-ACS before consideration of NSAIDs should begin with
acetaminophen, nonacetylated salicylates, tramadol,
Class I or small doses of narcotics if these medications are
1. The duration of triple antithrombotic therapy with not adequate.18,252 (Level of Evidence: C)
a vitamin K antagonist, aspirin, and a P2Y12 recep- 6. It is reasonable to use nonselective NSAIDs, such
tor inhibitor in patients with NSTE-ACS should be as naproxen, if initial therapy with acetaminophen,
minimized to the extent possible to limit the risk of nonacetylated salicylates, tramadol, or small doses of
bleeding. (Level of Evidence: C) narcotics is insufficient.252 (Level of Evidence: C)
#Patients should receive a loading dose of prasugrel provided that they Class IIb
were not pretreated with another P2Y12 receptor inhibitor.
||The recommended maintenance dose of aspirin to be used with 1. NSAIDs with increasing degrees of relative cyclo-
ticagrelor is 81 mg daily.144 oxygenase-2 selectivity may be considered for pain
relief only for situations in which intolerable discom- 7. Special Patient Groups: Recommendations
fort persists despite attempts at stepped-care ther- See Table 10 for summary of recommendations for this
apy with acetaminophen, nonacetylated salicylates, section.
tramadol, small doses of narcotics, or nonselective
NSAIDs. In all cases, use of the lowest effective doses
7.1. NSTE-ACS in Older Patients
for the shortest possible time is encouraged.117,118,252,253
(Level of Evidence: C) Class I
Class III: No Benefit 1. Older patients** with NSTE-ACS should be

treated with GDMT, an early invasive strategy,
1. Antioxidant vitamin supplements (eg, vitamins E, C, and revascularization as appropriate.269–273 (Level
or beta carotene) should not be used for secondary of Evidence: A)
prevention in patients with NSTE-ACS.254,255 (Level of 2. Pharmacotherapy in older patients** with NSTE-
Evidence: A) ACS should be individualized and dose adjusted by
2. Folic acid, with or without vitamins B6 and B12, should weight and/or CrCl to reduce adverse events caused
not be used for secondary prevention in patients with by age-related changes in pharmacokinetics/dynam-
NSTE-ACS.256,257 (Level of Evidence: A) ics, volume of distribution, comorbidities, drug inter-
actions, and increased drug sensitivity.269,274–276 (Level
of Evidence: A)
Class III: Harm
3. Management decisions for older patients** with

1. Hormone therapy with estrogen plus progestin, or NSTE-ACS should be patient centered, considering
estrogen alone, should not be given as new drugs for patient preferences/goals, comorbidities, functional
secondary prevention of coronary events to post- and cognitive status, and life expectancy.269,277–279
menopausal women after NSTE-ACS and should (Level of Evidence: B)
not be continued in previous users unless the ben-
efits outweigh the estimated risks.18,258–260 (Level of Class IIa
Evidence: A)
2. NSAIDs with increasing degrees of relative cyclo- 1. Bivalirudin, rather than a GP IIb/IIIa inhibitor
oxygenase-2 selectivity should not be administered plus UFH, is reasonable in older patients** with
to patients with NSTE-ACS and chronic muscu- NSTE-ACS, both initially and at PCI, given simi-
loskeletal discomfort when therapy with acet- lar efficacy but less bleeding risk.215,280–282 (Level of
aminophen, nonacetylated salicylates, tramadol, Evidence: B)
small doses of narcotics, or nonselective NSAIDs 2. It is reasonable to choose CABG over PCI in older
provide acceptable pain relief.117,118,252,253 (Level of patients** with NSTE-ACS who are appropriate can-
Evidence: B) didates, particularly those with diabetes mellitus or
complex 3-vessel CAD (eg, SYNTAX score >22), with
or without involvement of the proximal left anterior
6.5. Plan of Care for Patients With NSTE-ACS
descending artery, to reduce cardiovascular disease
Class I events and readmission and to improve survival.283–288
1. Posthospital systems of care designed to prevent
hospital readmissions should be used to facilitate
7.2. Heart Failure and Cardiogenic Shock
the transition to effective, coordinated outpatient
care for all patients with NSTE-ACS.261–265 (Level of Class I
Evidence: B)
2. An evidence-based plan of care (eg, GDMT) that 1. Patients with a history of HF and NSTE-ACS
promotes medication adherence, timely follow- should be treated according to the same risk
up with the healthcare team, appropriate dietary stratification guidelines and recommenda-
and physical activities, and compliance with tions for patients without HF.15,40–42,52–58 (Level of
interventions for secondary prevention should be Evidence: B)
provided to patients with NSTE-ACS. (Level of 2. Selection of a speciﬁc revascularization strategy
Evidence: C) should be based on the degree, severity, and extent
3. In addition to detailed instructions for daily exer- of CAD; associated cardiac lesions; the extent of
cise, patients should be given specific instruction on LV dysfunction; and the history of prior revascu-
activities (eg, lifting, climbing stairs, yard work, and larization procedures.15,173,175,177,178,289–292 (Level of
household activities) that are permissible and those Evidence: B)
to avoid. Specific mention should be made of resump- 3. Early revascularization is recommended in suit-
tion of driving, return to work, and sexual activ- able patients with cardiogenic shock due to cardiac
ity.247,266,267 (Level of Evidence: B) pump failure after NSTE-ACS.291,293,294 (Level of
4. An annual influenza vaccination is recommended for Evidence: B)
patients with cardiovascular disease.28,268 (Level of
Evidence: C) **Those ≥75 years of age (see Section 7.1 in the full-text CPG).
Table 10. Summary of Recommendations for Special Patient Groups

NSTE-ACS in older patients
Treat older patients (≥75 y of age) with GDMT, early invasive strategy, and revascularization I A 269–273
as appropriate
Individualize pharmacotherapy in older patients, with dose adjusted by weight and/or CrCl
to reduce adverse events caused by age-related changes in pharmacokinetics/dynamics, I A 269, 274–276
volume of distribution, comorbidity, drug interactions, and increased drug sensitivity
Undertake patient-centered management for older patients, considering patient I B 269, 277–279
preferences/ goals, comorbidities, functional and cognitive status, and life expectancy
Bivalirudin rather than GP IIb/IIIa inhibitor plus UFH is reasonable for older patients (≥75 y of IIa B 215, 280–282
age), given similar efficacy but less bleeding risk
It is reasonable to choose CABG over PCI in older patients, particularly those with DM or IIa B 283–288
multivessel disease, because of the potential for improved survival and reduced CVD events
HF and cardiogenic shock
Treat patients with a history of HF according to the same risk stratification guidelines and I B 15, 40–42, 52–58
recommendations for patients without HF
Select a revascularization strategy based on the extent of CAD, associated cardiac lesions, I B 15, 173, 175, 177, 178, 289–292
LV dysfunction, and prior revascularization
Recommend early revascularization for cardiogenic shock due to cardiac pump failure I B 291, 293, 294
DM
Recommend medical treatment and decisions for testing and revascularization similar to I A 173, 176, 295
those for patients without DM
Post-CABG
Recommend GDMT antiplatelet and anticoagulant therapy and early invasive strategy I B 44, 45, 178, 290, 296, 297
because of increased risk with prior CABG
Perioperative NSTE-ACS
Administer GDMT to perioperative patients with limitations imposed by noncardiac surgery I C 298, 299
Direct management at underlying cause of perioperative NSTE-ACS I C 22, 298–306
CKD
Estimate CrCl and adjust doses of renally cleared medications according to pharmacokinetic I B 307, 308
data
Administer adequate hydration to patients undergoing coronary and LV angiography I C N/A
Invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD IIa B 307–310
Women
Manage women with the same pharmacological therapy as that for men for acute care and I B 311–315
secondary prevention, with attention to weight and/or renally calculated doses of antiplatelet
and anticoagulant agents to reduce bleeding risk
Early invasive strategy is recommended in women with NSTE-ACS and high-risk features I A 178, 292, 316, 317
(troponin positive)
Myocardial revascularization is reasonable for pregnant women if ischemia-guided strategy IIa C 318
is ineffective for management of life-threatening complications
Women with low-risk features (Section 3.3.1 in the full-text CPG) should not undergo early III: No Benefit B 178, 316, 317
invasive treatment because of lack of benefit and the possibility of harm
Anemia, bleeding, and transfusion
Evaluate all patients for risk of bleeding I C N/A
Recommend that anticoagulant and antiplatelet therapy be weight-based where appropriate I B 276, 319, 320
and adjusted for CKD to decrease the risk of bleeding
There is no benefit of routine blood transfusion in hemodynamically stable patients with III: No Benefit B 321–325
hemoglobin levels >8 g/dL
Cocaine and methamphetamine users
Manage patients with recent cocaine or methamphetamine use similarly to those without I C N/A
cocaine- or methamphetamine-related NSTE-ACS. The exception is in patients with signs of
acute intoxication (eg, euphoria, tachycardia, and hypertension) and beta-blocker use unless
patients are receiving coronary vasodilator therapy
(Continued )
Table 10. Continued

It is reasonable to use benzodiazepines alone or in combination with NTG IIa C 326–329

to manage hypertension and tachycardia and signs of acute cocaine
or methamphetamine intoxication
Do not administer beta blockers to patients with recent cocaine or methamphetamine III: Harm C N/A
use who have signs of acute intoxication due to risk of potentiating coronary spasm
Vasospastic (Prinzmetal) angina
Recommend CCBs alone or in combination with nitrates I B 330–335
Recommend HMG-CoA reductase inhibitor, cessation of tobacco use, and atherosclerosis I B 336–340
risk factor modification
Recommend coronary angiography (invasive or noninvasive) for episodic chest pain I C N/A
with transient ST-elevation to detect severe CAD
Provocative testing during invasive coronary angiography* may be considered for IIb B 341–344
suspected vasospastic angina when clinical criteria and noninvasive assessment
fail to determine diagnosis
ACS with angiographically normal coronary arteries
Invasive physiological assessment (coronary flow reserve measurement) may be IIb B 301, 345–348
considered with normal coronary arteries if endothelial dysfunction is suspected
Stress (Takotsubo) cardiomyopathy
Consider stress-induced cardiomyopathy in patients with apparent ACS and I C N/A
nonobstructive CAD
Perform ventriculography, echocardiography, or MRI to confirm or exclude diagnosis I B 349–352
Treat with conventional agents (ACE inhibitors, beta blockers, aspirin, and diuretics) I C N/A
if hemodynamically stable
Administer anticoagulant therapy for LV thrombi I C N/A
It is reasonable to administer catecholamines for symptomatic hypotension in the IIa C N/A

absence of LV outflow tract obstruction
It is reasonable to use IABP for refractory shock IIa C N/A
It is reasonable to use beta blockers and alpha-adrenergic agents for LV outflow IIa C N/A
tract obstruction
Prophylactic anticoagulation may be considered to prevent LV thrombi IIb C N/A
*Provocative testing during invasive coronary angiography (eg, using ergonovine, acetylcholine, methylergonovine) is relatively safe, especially when performed
in a controlled manner by experienced operators. However, sustained spasm, serious arrhythmias, and even death can also occur but very infrequently. Therefore,
provocative tests should be avoided in patients with significant left main disease, advanced 3-vessel disease, presence of high-grade obstructive lesions, significant
valvular stenosis, significant LV systolic dysfunction, and advanced HF.
ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCB, calcium
channel blocker; CKD, chronic kidney disease; COR, Class of Recommendation; CPG, clinical practice guideline; CrCl, creatinine clearance; CVD, cardiovascular disease;
DM, diabetes mellitus; GDMT, guideline-directed medical therapy; GP, glycoprotein; HF, heart failure; lABP, intra-aortic balloon pump; LOE, Level of Evidence; LV,
left ventricular; MRI, magnetic resonance imaging; N/A, not available; NSTE-ACS, non–ST-elevation acute coronary syndrome; NTG, nitroglycerin; PCI, percutaneous
coronary intervention; and UFH, unfractionated heparin.
7.3. Diabetes Mellitus early invasive strategy because of their increased

risk.44,45,178,290,296,297 (Level of Evidence: B)
Class I
7.5. Perioperative NSTE-ACS Related to
1. Medical treatment in the acute phase of NSTE-ACS
Noncardiac Surgery
and decisions to perform stress testing, angiography,
and revascularization should be similar in patients Class I
with and without diabetes mellitus.173,176,295 (Level of
Evidence: A) 1. Patients who develop NSTE-ACS following noncar-
diac surgery should receive GDMT as recommended
7.4. Post-CABG for patients in the general population but with the
modifications imposed by the specific noncardiac sur-
Class I gical procedure and the severity of NSTE-ACS.298,299
(Level of Evidence: C)
1. Patients with prior CABG and NSTE-ACS should 2. In patients who develop NSTE-ACS after noncar-
receive antiplatelet and anticoagulant therapy accord- diac surgery, management should be directed at the
ing to GDMT and should be strongly considered for underlying cause.22,298–306 (Level of Evidence: C)
7.6. Chronic Kidney Disease hemoglobin levels greater than 8 g/dL is not recom-
mended.321–325 (Level of Evidence: B)
Class I
1. CrCl should be estimated in patients with NSTE- 7.9. Cocaine and Methamphetamine Users
ACS, and doses of renally cleared medications should
Class I
be adjusted according to the pharmacokinetic data
for specific medications.307,308 (Level of Evidence: B) 1. Patients with NSTE-ACS and a recent history of
2. Patients undergoing coronary and LV angiogra- cocaine or methamphetamine use should be treated
phy should receive adequate hydration. (Level of in the same manner as patients without cocaine- or
Evidence: C) methamphetamine-related NSTE-ACS. The only
exception is in patients with signs of acute intoxica-
Class IIa tion (eg, euphoria, tachycardia, and/ or hypertension)
and beta-blocker use, unless patients are receiving
1. An invasive strategy is reasonable in patients with coronary vasodilator therapy. (Level of Evidence: C)
mild (stage 2) and moderate (stage 3) CKD.307–310
Class IIa
7.7. Women 1. Benzodiazepines alone or in combination with nitro-
glycerin are reasonable for management of hyperten-

Class I sion and tachycardia in patients with NSTE-ACS and
signs of acute cocaine or methamphetamine intoxica-
1. Women with NSTE-ACS should be managed with the
tion.326–329 (Level of Evidence: C)
same pharmacological therapy as that for men for
acute care and for secondary prevention, with atten-
tion to weight and/or renally-calculated doses of anti- Class III: Harm
platelet and anticoagulant agents to reduce bleeding
1. Beta blockers should not be administered to patients
risk.311–315 (Level of Evidence: B)
with ACS with a recent history of cocaine or metham-
2. Women with NSTE-ACS and high-risk features (eg,
phetamine use who demonstrate signs of acute intoxi-
troponin positive) should undergo an early invasive
cation due to the risk of potentiating coronary spasm.
strategy.178,292,316,317 (Level of Evidence: A)
(Level of Evidence: C)
Class IIa
7.10. Vasospastic (Prinzmetal) Angina
1. Myocardial revascularization is reasonable in preg-
Class I
nant women with NSTE-ACS if an ischemia-guided
strategy is ineffective for management of life-threat- 1. CCBs alone330–334 or in combination with long-acting
ening complications.318 (Level of Evidence: C) nitrates332,335 are useful to treat and reduce the fre-
quency of vasospastic angina. (Level of Evidence: B)
Class III: No Benefit 2. Treatment with HMG-CoA reductase inhibitor,336,337
cessation of tobacco use,338,339 and additional atheroscle-
1. Women with NSTE-ACS and low-risk features rosis risk factor modification339,340 are useful in patients
(see Section 3.3.1 in the full-text CPG) should not with vasospastic angina. (Level of Evidence: B)
undergo early invasive treatment because of the lack 3. Coronary angiography (invasive or noninvasive) is
of benefit178,316,317 and the possibility of harm.178 (Level recommended in patients with episodic chest pain
of Evidence: B) accompanied by transient ST-elevation to rule out
severe obstructive CAD. (Level of Evidence: C)
7.8. Anemia, Bleeding, and Transfusion
Class IIb
Class I
1. Provocative testing during invasive coronary angi-
1. All patients with NSTE-ACS should be evaluated for
ography†† may be considered in patients with sus-
the risk of bleeding. (Level of Evidence: C)
pected vasospastic angina when clinical criteria and
2. Anticoagulant and antiplatelet therapy should be
noninvasive testing fail to establish the diagnosis.341–344
weight-based where appropriate and should be
adjusted when necessary for CKD to decrease the
risk of bleeding in patients with NSTE-ACS.276,319,320 ††Provocative testing during invasive coronary angiography (eg, using
(Level of Evidence: B) ergonovine, acetylcholine, methylergonovine) is relatively safe, especially
when performed in a controlled manner by experienced operators.
However, sustained spasm, serious arrhythmias, and even death can also
Class III: No Benefit occur very infrequently. Therefore, provocative testing should be avoided
in patients with significant left main disease, advanced 3-vessel disease,
1. A strategy of routine blood transfusion in hemo- presence of high-grade obstructive lesions, significant valvular stenosis,
dynamically stable patients with NSTE-ACS and significant LV systolic dysfunction, and advanced HF.
7.11. ACS With Angiographically Normal Coronary CPG,362 many emerging diagnostic and therapeutic strategies
Arteries have posed new challenges. There is general acceptance of
an early invasive strategy for patients with NSTE-ACS in
Class IIb whom significant coronary vascular obstruction has been
1. If coronary angiography reveals normal coronary precisely quantified. Low-risk patients with NSTE-ACS are
arteries and endothelial dysfunction is suspected, documented to benefit substantially from GDMT, but this is
invasive physiological assessment such as coronary often suboptimally used. Advances in noninvasive testing
flow reserve measurement may be considered.301,345–348 have the potential to identify patients with NSTE-ACS who
(Level of Evidence: B) are at intermediate risk and are candidates for invasive ver-
sus medical therapy.
7.12. Stress (Takotsubo) Cardiomyopathy Newer, more potent antiplatelet agents in addition to
anticoagulant therapy are indicated irrespective of initial
Class I treatment strategy. Evidence-based decisions will require
comparative-effectiveness studies of available and novel
1. Stress (Takotsubo) cardiomyopathy should be con-
agents. The paradox of newer and more potent antithrom-
sidered in patients who present with apparent ACS
and nonobstructive CAD at angiography. (Level of botic and anticoagulant drugs that reduce major adverse
Evidence: C) cardiac outcomes but increase bleeding risk occurs with
2. Imaging with ventriculography, echocardiography, or greater frequency in patients with atrial fibrillation. Patients
magnetic resonance imaging should be performed to with atrial fibrillation who develop NSTE-ACS and receive
confirm or exclude the diagnosis of stress (Takotsubo) a coronary stent are the population at risk from triple antico-
cardiomyopathy.349–352 (Level of Evidence: B) agulant/antiplatelet therapy. This regimen has been reported
3. Patients should be treated with conventional agents to be safely modified by elimination of aspirin, a finding that
(ACE inhibitors, beta blockers, aspirin, and diuret- requires confirmation.
ics) as otherwise indicated if hemodynamically sta- Among the most rapidly evolving areas in NSTE-ACS diag-
ble. (Level of Evidence: C) nosis is the use of cardiac troponin, the preferred biomarker
4. Anticoagulation should be administered in patients of myocardial necrosis. Although a truly high- sensitivity
who develop LV thrombi. (Level of Evidence: C) cardiac troponin is not available in the United States at the
time this CPG was prepared, the sensitivity of contemporary
Class IIa assays continues to increase. This change is accompanied by
higher rates of elevated cardiac troponin unrelated to coro-
1. It is reasonable to use catecholamines for patients
with symptomatic hypotension if outflow tract nary plaque rupture. The diagnostic quandary posed by these
obstruction is not present. (Level of Evidence: C) findings necessitates investigation to elucidate the optimal
2. The use of an intra-aortic balloon pump is reason- utility of this advanced biomarker. A promising approach to
able for patients with refractory shock. (Level of improve the diagnostic accuracy for detecting myocardial
Evidence: C) necrosis is measurement of absolute cardiac troponin change,
3. It is reasonable to use beta blockers and alpha-adren- which may be more accurate than the traditional analysis of
ergic agents in patients with outflow tract obstruc- relative alterations.
tion. (Level of Evidence: C) Special populations are addressed in this CPG, the most
numerous of which are older persons and women. More than
Class IIb half of the mortality in NSTE-ACS occurs in older patients,
and this high-risk cohort will increase as our population
1. Prophylactic anticoagulation may be considered
ages. An unmet need is to more clearly distinguish which
to inhibit the development of LV thrombi. (Level of
older patients are candidates for an ischemia-guided strat-
Evidence: C)
egy compared with an early invasive management strategy.
An appreciable number of patients with NSTE-ACS have
8. Quality of Care and Outcomes for angiographically normal or nonobstructive CAD, a group in
ACS—Use of Performance Measures which women predominate. Their prognosis is not benign
And Registries: Recommendation and the multiple mechanisms of ACS postulated for these
Class IIa patients remain largely speculative. Clinical advances are
predicated on clarification of the pathophysiology of this
1. Participation in a standardized quality-of-care data challenging syndrome.
registry designed to track and measure outcomes, A fundamental aspect of all CPGs is that these carefully
complications, and performance measures can be developed, evidence-based documents cannot encompass all
beneficial in improving the quality of NSTE-ACS clinical circumstances, nor can they replace the judgment of
care.353–361 (Level of Evidence: B) individual physicians in management of each patient. The sci-
ence of medicine is rooted in evidence, and the art of medicine
9. Summary and Evidence Gaps is based on the application of this evidence to the individual
Despite landmark advances in the care of patients with patient. This CPG has adhered to these principles for optimal
NSTE-ACS since the publication of the 2007 UA/NSTEMI management of patients with NSTE-ACS.
Presidents and Staff non-ST-elevation myocardial infarction (updating the 2007 guideline and
replacing the 2011 focused update): a report of the American College
American College of Cardiology of Cardiology Foundation/ American Heart Association Task Force on
Practice Guidelines. Circulation. 2012;126:875–910.
Patrick O’Gara, MD, FACC, President 10. Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and Stroke

Shalom Jacobovitz, Chief Executive Officer Statistics-2013 Update: a report from the American Heart Association.
William J. Oetgen, MD, MBA, FACC, Executive Vice Circulation. 2013;127:e6–245.
President, Science, Education, and Quality 11. Fihn S, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/
PCNA/SCAI/STS focused update of the guideline for the diagnosis and
Amelia Scholtz, PhD, Publications Manager, Clinical Policy management of patients with stable ischemic heart disease. Circulation.
and Pathways 2014;130:1749–67.
12. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ AHA/ACP/AATS/
PCNA/SCAI/STS guideline for the diagnosis and management of patients
American College of Cardiology/American Heart with stable ischemic heart disease: a report of the American College
Association of Cardiology Foundation/American Heart Association Task Force on
Lisa Bradfield, CAE, Director, Science and Clinical Policy Practice Guidelines, and the American College of Physicians, American
Emily Cottrell, MA, Quality Assurance Specialist, Science Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions,
and Clinical Policy and Society of Thoracic Surgeons. Circulation. 2012;126:e354–471.
Alexa Papaila, Specialist, Science and Clinical Policy 13. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guide-
line for the management of patients with atrial fibrillation: a report of
the American College of Cardiology/American Heart Association Task
American Heart Association Force on Practice Guidelines and the Heart Rhythm Society. Circulation.
Elliott Antman, MD, FAHA, President 2014;130:e199-267.

Nancy Brown, Chief Executive Officer 14. Goff DC Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline
Rose Marie Robertson, MD, FAHA, Chief Science Officer on the assessment of cardiovascular risk: a report of the American College
of Cardiology/American Heart Association Task Force on Practice
Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice Guidelines. Circulation. 2014;129[suppl 2]:S49–73.
President, Office of Science Operations 15. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA guideline
Marco Di Buono, PhD, Vice President, Science, Research, for the management of heart failure: a report of the American College
and Professional Education, Office of Science Operations of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Circulation. 2013;128:e240–327.
Jody Hundley, Production Manager, Scientific Publications, 16. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on life-
Office of Science Operations style management to reduce cardio vascular risk: a report of the American
College of Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation. 2014;129[suppl 2]:S76–99.
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Appendix 1. Author Relationships With Industry and Other Entities (Relevant)–2014 AHA/ACC Guideline for the Management of
Patients With Non-St-Elevation Acute Coronary Syndromes
Ownership/ Institutional,
Committee Speakers Partnership/ Personal Organizational, Expert Voting Recusals
Member Employment Consultant Bureau Principal Research or Other Financial Benefit Witness by Section*
Ezra A. University of None None None None None None None
Amsterdam California (Davis)
(Chair) Medical Center,
Division of
Cardiology–Professor
Nanette K. Emory University, • Abbott None None • Abbott† None None All sections
Wenger School of • Amgen • Eli Lilly† except 3.1.1, 3.4,
(Vice Chair) Medicine–Professor • AstraZeneca •G ilead 5.2, 6.3.1, 6.3.2,
of Medicine • Gilead Sciences† 6.3.6, 7.5, 7.6, 7.8,
(Cardiology) Sciences† • Merck and 8.
• Janssen • Pfizer†
Pharmaceuticals
• Medtronic
• Merck
• Pfizer
Ralph G. University of None • Volcano None None None None None
Brindis California, San
Francisco Department
of Medicine and the
Phillip R. Lee Institute
for Health Policy
Studies–Clinical
Professor
of Medicine
Donald E. Atlantic Health–Vice None None None None None None None
Casey, Jr President of Health
and Chief Medical
Officer
Theodore G. University of None None None None None None None
Ganiats California, San Diego
School of Medicine–
Executive Director
of Health Services
Research Center
David R. Mayo Clinic– None None None None None None None
Holmes, Jr Consultant,
Cardiovascular
Diseases
Allan S. Mayo Clinic, • Abbott None None None None None All sections
Jaffe Cardiovascular • Alere except 3.1,
Division–Professor • Amgen 3.1.1,3.3, 4.1.2.1-
of Medicine • Beckman- 4.1.2.3, 4.2, 4.3.1,
Coulter 4.3.2, 4.5, 5.1, 5.2,
• Critical 6.2.1, 6.3.1, 6.3.3,
Diagnostics 6.3.6, 7.2.2, 7.5,
• ET Healthcare 7.6, and 8.
• Ortho Clinical
Diagnostic
• Radiometer
• Roche‡
• Thermo-Fishert‡
• Trinity
Hani Jneid Baylor College None None None None None None None
of Medicine–The
Michael E. DeBakey
VA Medical Center–
Assistant Professor
of Medicine
(Continued )
Appendix 1. Continued
Rosemary F. University of None None None None None None None

Kelly Minnesota–
Professor of Surgery;
VA Medical Center–
Chief, Cardiothoracic
Surgery
Michael C. Virginia • Astellas • Astellas None None • Astellas None All sections
Kontos Commonwealth • General Electric • AstraZeneca • Eli Lilly‡
University, Pauley • Ikaria • Merck‡
Heart Center– • Prevencio • Novartis‡
Medical Director, • Sanofi-aventis
Coronary Intensive • Wellpoint/Anthem
Care Unit, and
Associate Professor,
Internal Medicine
Glenn N. Baylor College of None None None None None None None
Levine Medicine–Professor
of Medicine;
Director, Cardiac
Care Unit
Philip R. Rush University None None None None None None None
Liebson Medical Center–
McMullan-Eybel
Chair of Excellence
in Clinical Cardiology
and Professor
of Medicine and
Preventive Medicine
Debabrata Texas Tech None None None None None None None
Mukherjee University
Health Sciences
Center–Chief,
Cardiovascular
Medicine
Eric D. Duke University • Boehringer None None • Eli Lilly† DCRI has numerous None All sections
Peterson Medical Center– Ingelheim • Johnson & grants and contracts
Fred Cobb, MD, • Genentech Johnson† sponsored by industry
Distinguished • Janssen • Janssen that are relevant to the
Professor of Pharmaceuticals Pharmaceuticals† content of this CPG. Dr.
Medicine; Duke • Johnson & Peterson participated in
Clinical Research Johnson discussions but recused
Institute–Director • Merck himself from writing or
voting, in accordance
with ACC/AHA policy.
See comprehensive RWI
table for a complete list
of companies pertaining
to this organization.
(Continued )
Marc S. Brigham and • Amgen None None • A bbott • AstraZeneca† None All sections except
Sabatine Women’s Hospital, • AstraZeneca Laboratories† • Daiichi-Sankyo† 3.1.1, 5.2, 6.3.1,
Chairman–TIMI • Bristol-Myers • Amgen† • Gilead† 6.3.2, 7.5, 7.8,
Study Group, Squibb • AstraZeneca† • J ohnson & and 8.
Division of • Merck •B ristol-Myers Johnson†
Cardiovascular • Pfizer Squibb† • BRAHMS†
Medicine; • Sanofi-aventis •C ritical • Proventys†
Harvard Medical Diagnostics† • Siemens†
School–Professor • Daiichi-Sankyo† • Singulex†
of Medicine • Genzyme†
• GlaxoSmithKline†
• Nanosphere†
•R oche
Diagnostics†
• Sanofi-aventis†
• Takeda†
Richard W. University of • Gilead None None • Cordis • Cordis† None All sections except
Smalling Texas, Health • Maquet • E -valve Abbott • E-valve† 3.1, 3.1.1, 3.3,
Science Center at Vascular 3.4, 3.5.1, 4.1.2.1-
Houston–Professor • E dwards 4.1.2.3, 4.2, 4.3.1,
and Director of Lifesciences 4.3.2, 5.2, 6.2.1,
Interventional • Gilead 6.3.1, 6.3.2, 6.3.3,
Cardiovascular •M aquet 6.3.6, 7.2.2, 7.5,
Medicine; Datascope 7.8, and 8.
James D. Woods
Distinguished Chair
in Cardiovascular
Medicine
Susan J. National Institute None None None None None None None
Zieman on Aging/NIH,
Geriatrics Branch,
Division of Geriatrics
and Clinical
Gerontology–
Medical Officer
This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These
relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the GWC during the document development process. The table
does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents
ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$10 000 of the fair market value of the business entity; or if funds received by
the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for
the purpose of transparency. Relationships in this table are modest unless otherwise noted.
According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property
or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the
document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person’s household, has a reasonable potential for
financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.
*Writing members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Section
numbers pertain to those in the full-text CPG.
†Significant relationship.
‡No financial benefit.
ACC indicates American College of Cardiology, AHA, American Heart Association, BMS, Bristol-Myers Squibb; CPG, clinical practice guideline; DCRI, Duke Clinical
Research Institute; NIH, National Institutes of Health; NYU, New York University; RWI, relationships with industry and other entities; TIMI, Thrombolysis In Myocardial
Infarction; and VA, Veterans Affairs.
Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant)–2014 AHA/ACC Guideline for the
Management of Patients With Non-St-Elevation Acute Coronary Syndromes
Institutional,
Ownership/ Organizational,
Speakers Partnership/ Personal or Other Expert
Reviewer Representation Employment Consultant Bureau Principal Research Financial Benefit Witness
Deepak L. Official VA Boston Healthcare • BMS/Pfizer None None • AstraZeneca* • Medscape None
Bhatt Reviewer–AHA System–Professor • DCRI (BMS/ • Bristol-Myers Cardiology
of Medicine, Harvard Pfizer) Squibb* (Advisory
Medical School; Chief • DCRI (Eli Lilly) • Ethicon* Board)†
of Cardiology • Eli Lilly • The Medicines • WebMD
Company (Steering
• Medtronic* Committee)†
• Sanofi-aventis*
• Takeda†
John E. Official Eastern Virginia None None None None None None
Brush, Jr Reviewer–ACC Medical School–
Board of Professor of Medicine,
Trustees Chief of Cardiology
E. Magnus Official Duke Medicine– • AstraZeneca • Gilead* None • Daiichi-Sankyo* None None
Ohman Reviewer–ACC/ Professor of Medicine • Bristol-Myers • Janssen • Eli Lilly*
AHA Task Force Squibb Pharmaceuticals • Gilead*
on Practice • Gilead*
Guidelines • Janssen
Pharmaceuticals*
• The Medicines
Company
• Merck
• Pozen
• Roche
• Sanofi-aventis
John F. Official Dartmouth-Hitchcock None None None None None • Defendant,
Robb Reviewer–ACC Medical Center– adverse
Board of Director, Interventional drug
Governors Cardiology reaction,
and Cardiac 2012
Catheterization
Laboratories
Sarah A. Official Philadelphia College of • Bristol-Myers None None None None • P laintiff,
Spinier Reviewer–AHA Pharmacy, University Squibb clopidogrel,
of the Sciences • Daiichi-Sankyo 2013
in Philadelphia– • Janssen
Professor of Clinical Pharmaceuticals
Pharmacy • Merck
Gorav Organizational University of • Abbott None None None None None
Ailawadi Reviewer–STS Virginia Health • Atricure
System–Thoracic
and Cardiovascular
Surgery
Srihari S. Organizational Winthrop University None None None None None None
Naidu Reviewer–SCAI Hospital–Director,
Cardiac
Catheterization
Laboratory
Robert L. Organizational Bladen Medical None None None None None None
Rich, Jr Reviewer–AAFP Associates–Family
Physician
Mouaz H. Content King Abdul-Aziz None None None None None None
Al-Mallah Reviewer–ACC Cardiac Center–
Prevention of Associate Professor of
Cardiovascular Medicine
Disease
Committee
(Continued )
Institutional,
John A. Content University of California None None None None None None
Ambrose Reviewer San Francisco Fresno
Department of
Medicine–Professor
of Medicine; Chief of
Cardiology; Program
Director, Cardiology
Fellowship
Giuseppe Content Hospital of University • Bayer* • Merck None None None None
Ambrosio Reviewer-ACC of Perugia School • The Medicines Schering-Plough
Prevention of of Medicine–Medical Company • Pfizer
Cardiovascular Director, Division • Merck
Disease of Cardiology Schering-Plough†
Committee • Sanofi-aventis
H. Vernon Content University of Texas– None None None None • Eli Lilly None
Anderson Reviewer Professor of Medicine,
Cardiology Division
Jeffrey L. Content Intermountain Medical • Sanofi-aventis None None • GlaxoSmithKline None None
Anderson Reviewer–ACC/ Center–Associate • Harvard (DSMB)–
AHA Task Force Chief of Cardiology TIMI -48, -51,
on Practice and -54 Studies
Guidelines
Fred S. Content University of • Abbott None None • Abbott* • Abbott None
Apple Reviewer Minnesota School of Diagnostics • Alere/Biosite* Diagnostics-PI†
Medicine, Hennepin • Alere • Biomerieux* • Alere-PI†
County Medical • Beckman Coulter • Ortho-Clinical
Center–Professor, • T2 Biosystems Diagnostics-PI†
Laboratory Medicine • Ortho-Clinical
and Pathology Diagnostics*
• Radiometer*
• Roche
Laboratories*
• Siemens*
Emmanouil S. Content UT Southwestern • Bridgepoint None None None • Abbott None
Brilakis Reviewer–ACC Medical School– Medical/Boston Vascular
Interventional Director, Cardiac Scientific* • AstraZeneca
Section Catheterization • Janssen • Cordis*
Leadership Laboratory, VA North Pharmaceuticals • Daiichi-Sankyo*
Council Texas Healthcare • Sanofi-aventis • The Medicines
System Company
• Medtronic*
Matthew J. Content Los Angeles None • AstraZeneca† None • General None • Plaintiff,
Budoff Reviewer–ACC Biomedical Research Electric* cardiac
Cardiovascular Institute–Program treatment,
Imaging Director, Division 2013
Section of Cardiology and
Leadership Professor of Medicine
Council
James A. Content Lehigh Valley None None None None None None
Burke Reviewer–ACC Health Network–
Interventional Interventional
Section Cardiologist
Leadership
Council
(Continued )
Institutional,
Robert H. Content University of Maryland • BG Medicine None None • The Medicines • AACC None
Christenson Reviewer–AACC School of Medicine– •C ritical Company (President)†
Professor of Pathology; Diagnostics • Roche
Professor of Medical and • Siemens Medical Diagnostics
Research Technology; Diagnostics (University
Director, Rapid of Maryland
Response Laboratory School of
Medicine)*
Joaquin E. Content Oregon Health and None None None None •C
atheterization None
Cigarroa Reviewer–ACC Science University– and
Interventional Associate Professor of Cardiovascular
Section Medicine Intervention
Leadership (Editorial
Council Board)†
Marco A. Content University Hospital for • Abbott None None • Abbott • Abbott None
Costa Reviewer–ACC Cleveland–Cardiologist Vascular* Vascular* • Cordis
Cardiovascular • Boston • Boston • Medtronic
Imaging Section Scientific Scientific*
Leadership • Medtronic • Cordis*
Council • IDEV
Technology†
• The Medicines
Company
• Medtronic*
• Micell*
• OrbusNeicht
Prakash C. Content University of California • Amgen • Pfizer None None None None
Deedwania Reviewer–ACC San Francisco–Chief of • Pfizer • Takeda
Prevention of Cardiology Pharmaceuticals
Cardiovascular
Disease
Committee
James A. de Content UT Southwestern • Diadexus • AstraZeneca None • A bbott • Daiichi-Sankyo† None
Lemos Reviewer Medical School– • Janssen Diagnostics†
Associate Professor Pharmaceuticals
of Medicine; Director,
Coronary Care Unit and
Cardiology Fellowship
Burl R. Don Content University of California None None None None None None
Reviewer Davis–Professor of
Medicine; Director of
Clinical Nephrology
Lee A. Content University of None None None None None None
Fleisher Reviewer Pennsylvania Department
of Anesthesiology–
Professor of
Anesthesiology
Mary G. Content Centers for Disease None None None None None None
George Reviewer–HHS Control and Prevention–
Senior Medical Officer,
Division for Heart Disease
and Stroke Prevention
Linda D. Content Morristown Medical None None None None None None
Gillam Reviewer–ACC Center–Professor of
Cardiovascular Cardiology; Vice Chair,
Imaging Section Cardiovascular Medicine
Leadership
Council
(Continued )
Institutional,
Robert A. Content Emory Clinic–Professor • Medtronic None None None None None
Guyton Reviewer–ACC/ and Chief, Division
AH A Task Force of Cardiothoracic
on Practice Surgery
Guidelines
Joerg Content Mayo Medical School- None None None None None None
Herrmann Reviewer–ACC Internal Medicine and
Interventional Cardiovascular Disease
Section
Leadership
Council
Judith S. Content New York University • GlaxoSmithKline None None None None None
Hochman Reviewer–ACC/ School of Medicine, • Janssen
AHA Task Force Division of Pharmaceuticals
on Practice Cardiology–Clinical
Guidelines Chief of Cardiology
Yuling Content Centers for Disease None None None None None None
Hong Reviewer–HHS Control and Prevention–
Associate Director
Lloyd W. Content Rush Medical None None None None None None
Klein Reviewer–ACC College-Professor
Interventional of Medicine
Section
Leadership
Council
Frederick G. Content Tulane University School None None None None None None
Kushner Reviewer of Medicine–Clinical
Professor of Medicine;
Heart Clinic of
Louisiana–Medical
Director
Ehtisham Content University of California, • Abiomed • Eli Lilly* None • Abbott Vascular* None None
Mahmud Reviewer–ACC San Diego–Professor • Cordist • Medtronic • Accumetrics*
Interventional of Medicine/Cardiology, • Eli Lilly* •M erck
Section Chief of Cardiovascular • Gilead Schering-Plough
Leadership Medicine; Director, • Johnson & •B oston
Council Interventional Cardiology Johnson Scientific*
and Cardiovascular • Medtronic • Gilead*
Catheterization • T he Medicines
Laboratory Company
• Sanofi-aventis*
Carlos Content Cardiology Society of None None None • AstraZenecat† None None
Martínez- Reviewer–AIG Mexico–President • Eli Lilly†
Sánchez • Sanofi-aventis†
L. Kristen Content Duke University Medical • Johnson & None None • Amylin None None
Newby Reviewer Center–Associate Johnson • AstraZeneca
Professor of Clinical • Daiichi-Sankyo • Bristol-Myers
Medicine Squibb*
• Eli Lilly
• GlaxoSmithKline
• Merck*
Patrick T. Content Brigham and Women’s None None None None None None
O’Gara Reviewer Hospital–Professor
of Medicine, Harvard
Medical School;
Director, Clinical
Cardiology
(Continued )
Institutional,
Narith Ou Content Mayo Clinic– None None None None None None
Reviewer Pharmacotherapy
Coordinator, Pharmacy
Services
Gurusher S. Content George Washington None None None None None None
Panjrath Reviewer–ACC Medical Faculty
Heart Failure and Associates–Assistant
Transplant Section Professor of Medicine;
Leadership Director of Heart Failure
Council and Mechanical Support
Program
Rajan Content Ochsner Clinic None None None None None None
Patel Reviewer–ACC Foundation–
Cardiovascular Interventional
Imaging Section Cardiologist

Leadership
Council
Carl J. Content Shands Hospital • Lilly/Cleveland None None • AstraZeneca* None None
Pepine Reviewer at University of Clinic (DSMB) • Gilead
Florida–Professor Sciences*
and Chief, Division • Park-Davis*
of Cardiovascular • Pfizer*
Medicine • Sanofi-aventis*
Sunil V. Content Duke University Medical • AstraZeneca None None • Sanofi-aventis • Abbott None
Rao Reviewer–ACC Center-Associate • Daiichi-Sankyo Vascular†
Interventional Professor of Medicine • Eli Lilly
Section • Terumo Medical
Leadership • The Medicines
Council Company
Pasala S. Content Reviewer– Oregon Health and None None None None None None
Ravichandran ACC Surgeons’ Science University–
Scientific Council Associate Professor
Michael W. Content Washington University None None None None None None
Rich Reviewer School of Medicine–
Professor of Medicine
Frank W. Content Reviewer- Brown Medical School, None None None None None None
Sellke ACC/AHA Task Rhode Island Hospital–
Force on Practice Professor; Chief of
Guidelines Cardiothoracic Surgery
Alan Wu Content San Francisco General • Abbott None None None None None
Reviewer–AACC Hospital and Trauma • Singulex
Center–Chief, Clinical
Chemistry Laboratory
This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant to
this document. It does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the
interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$10 000 of the fair market value of the business entity; or if
funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. A relationship is considered to be modest if it is
less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in
this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review.
According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property
or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the
document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person’s household, has a reasonable potential for
financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.
*Significant relationship.
†No financial benefit.
AAAHC indicates Accreditation Association for Ambulatory Health Care; AACC, American Association for Clinical Chemistry; AAFP, American Academy of Family
Physicians; AHA, American Heart Association; AIG, Association of International Governors; BMS, Bristol-Myers Squibb; DCRI, Duke Clinical Research Institute; DSMB,
data safety monitoring board; HHS, Health and Human Services; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institutes of Health; SCAI, Society for
Cardiovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; TIMI, Thrombolysis In Myocardial Infarction; and VA, Veterans Affairs.
2014 AHA/ACC Guideline for the Management of Patients With Non−ST-Elevation Acute
Coronary Syndromes: Executive Summary: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines
Ezra A. Amsterdam, Nanette K. Wenger, Ralph G. Brindis, Donald E. Casey, Jr, Theodore G.
Ganiats, David R. Holmes, Jr, Allan S. Jaffe, Hani Jneid, Rosemary F. Kelly, Michael C.
Kontos, Glenn N. Levine, Philip R. Liebson, Debabrata Mukherjee, Eric D. Peterson, Marc S.
Sabatine, Richard W. Smalling and Susan J. Zieman
Circulation. 2014;130:2354-2394; originally published online September 23, 2014;

doi: 10.1161/CIR.0000000000000133
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/130/25/2354
An erratum has been published regarding this article. Please see the attached page for:
/content/130/25/e431.full.pdf
Data Supplement (unedited) at:

http://circ.ahajournals.org/content/suppl/2014/09/23/CIR.0000000000000133.DC2
http://circ.ahajournals.org/content/suppl/2014/09/23/CIR.0000000000000133.DC3
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Correction
In the article by Amsterdam et al “2014 ACC/AHA Guideline for the Management of Patients With
Non–ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines,” which
published online September 23, 2014, and appeared in the December 23/30, 2014, issue of the
journal (Circulation. 2014;130:2354–2394), several corrections were needed.
1. On the title page, the Society for Cardiovascular Angiography and Interventions has been
added to the collaborating organizations line. It now reads, “Developed in Collaboration With
the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic
Surgeons.”
2. On page 2361, in Figure 2A, the “GRACE Risk Model Nomogram,” the footnote read, “To
convert serum creatine level to micromoles per liter, multiply by 88.4.” It now reads, “To convert
serum creatinine level to micromoles per liter, multiply by 88.4.”
3. On page 2365, in the second column, the Class I, Recommendation 3 paragraph read, “…hyper-
kalemia (K >5.0mEq/L)….” It now reads “…or hyperkalemia (K+ >5.0 mEq/L)….”
4. On page 2365, in the second column, the Class I, Recommendation 1 paragraph, the mainte-
nance dose for aspirin has been changed. Additionally, the references shown below, numbered
147 and 363, have been added to the text. The recommendation read, “…and a maintenance dose
of aspirin (81 mg/d to 162 mg/d) should be continued indefinitely.142–144” It now reads, “…and a
maintenance dose of aspirin (81 mg/d to 325 mg/d) should be continued indefinitely.142–144,147,363”
147. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med. 2009;361:1045–57
363. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel
and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary
intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomized factorial
trial. Lancet. 2010;376:1233–43.
5. On page 2366, in Table 7, the third row “Non–enteric-coated aspirin…”, in the fifth column, the
references read, “(142–144).” They now read, “(142–144, 147, 363)”.
6. On page 2366, in Table 7, the fourth row “Aspirin maintenance dose…,” the second column
“Dosing…,” the text regarding aspirin maintenance dosing has been modified. The table entry
now reads, “81 mg/d-325 mg/d.*” The asterisk inserted after “325 mg/d,” refers to text added to
the Table 7 footnote. The additional text in the footnote reads, “*The recommended maintenance
dose of aspirin to be used with ticagrelor is 81 mg daily.” The references shown below, numbered
147 and 363, were added to the fifth column, “References.”
147. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med. 2009;361:1045–57
363. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel
and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary
intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomized factorial
trial. Lancet. 2010;376:1233–43.
The fourth row originally read,

Dosing and Special
Aspirin
• Aspirin maintenance dose 81 mg/d to 162 mg/d I A (142–144)
continued indefinitely
(Circulation. 2014;130:e431-e432.)
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000150
e431
e432 Circulation December 23/30, 2014
The corrected row now reads,

Dosing and Special
Aspirin
• Aspirin maintenance dose 81 mg/d to 325 mg/d* I A (142–144,147,363)
continued indefinitely
7. On page 2366, in Table 7, in the thirteenth row “SC enoxaparin for duration…,” in the second
column “Dosing….,” the second bullet read, “Initial IV loading dose 30 mg.” It now reads,
“Initial 30 mg IV loading dose in selected patients.”
8. On page 2367, in the first column, the Class I, Recommendation 1 paragraph read, “Enoxaparin:
1 mg/kg subcutaneous (SC) every 12 hours (reduce dose to 1 mg/kg SC once daily in patients with
creatinine clearance [CrCl] <30 mL/min), continued for the duration of hospitalization or until PCI
is performed. An initial intravenous loading dose is 30 mg.151–153” It now reads, “Enoxaparin: 1 mg/
kg subcutaneous (SC) every 12 hours (reduce dose to 1 mg/kg SC once daily in patients with cre-
atinine clearance [CrCl] <30 mL/min), continued for the duration of hospitalization or until PCI is
performed. An initial intravenous loading dose of 30 mg has been used in selected patients.151–153”
9. On page 2372, in the first column, the Class IIa, Recommendation 2 paragraph read, “It is rea-
sonable to choose ticagrelor over clopidogrel for maintenance P2Y12 treatment in patients with
NSTE-ACS treated with an early invasive strategy and/or PCI.147,148” It now reads, “It is reason-
able to use ticagrelor in preference to clopidogrel for maintenance P2Y12 treatment in patients
with NSTE-ACS who undergo an early invasive or ischemia-guided strategy.147,148”
These corrections have been made to the print version and to the current online version of the
article, which is available at http://circ.ahajournals.org/content/130/25/2354.
Amsterdam EA, et al.
2014 AHA/ACC NSTE-ACS Guideline
Author Relationships With Industry and Other Entities (Comprehensive)—2014 AHA/ACC Guideline for the Management of Patients With Non-
ST-Elevation Acute Coronary Syndromes (July 2013)
Committee Employment Consultant Speakers Ownership/ Personal Research Institutional, Expert Witness
Member Bureau Partnership/ Organizational or
Principal Other Financial
Benefit
Ezra A. University of None None None  California CABG  American Journal of None
Amsterdam (Chair) California (Davis) Project Cardiology†
Medical Center,  Clinical Cardiology†
Division of  2010 School of
Cardiology—Professor Medicine Research
Award*
 ACC-NCDR
ACTION Registry
Subcommittee -
Research and
Publications
Nanette K. Wenger Emory University,  Abbott None None  Abbott*  ACC Extended None
(Vice Chair) School of Medicine—  Amgen  Eli Lilly* Learning
Professor of Medicine  AstraZeneca  Gilead Sciences*  CCCOA
(Cardiology)  Gilead Sciences*  Merck  Clinical Cardiology
 Janssen  NHLBI* Review Editor
Pharmaceuticals  Pfizer*  Society for
 Medtronic Women’s Health
 Merck Research†
 Pfizer
Ralph G. Brindis University of  Ivivi Health  Volcano Corp. None None  ACC-NCDR(Senior None
California, San Sciences Medical Officer,
Francisco— External Affairs)
Department of  DAPT trial
Medicine and the (Advisory Board)†
Phillip R. Lee Institute  California State
for Health Policy Elective PCI Project
Studies—Clinical (Advisory Board)†
Professor of Medicine  C-PORT Elective
RCT† (DSMB)
 FDA Cardiovascular
Device Panel†
 State of California
Health Dept:
STEMI/PCI Work
Group† (DSMB)
 State of California
OSHPD† (DSMB)
Donald E. Casey, Atlantic Health—Vice None None None None None None
Jr President of Health and
Chief Medical Officer
Theodore G. University of None None None  AHRQ None  Plaintiff, deep
Ganiats California, San Diego  NIH (DSMB) vein
School of Medicine— thrombosis,
Executive Director of 2011
Health Services
Research Center
David R. Holmes, Mayo Clinic— None None None None  Atritech† None
Jr Consultant,
Cardiovascular
Diseases
Allan S. Jaffe Mayo Clinic,  Abbott None None None None None
Cardiovascular  Alere
Division—Professor of  Amgen
Medicine  Beckman-Coulter
 Critical
Diagnostics
 ET Healthcare
 Ortho Clinical
Diagnostic
 Radiometer*
 Roche†
 Trinity
 Thermo Fisher†
Hani Jneid Baylor College of None None None None None None
Medicine—The
Michael E. DeBakey
VA Medical Center—
Assistant Professor of
Medicine
Rosemary F. Kelly University of None None None None None None
Minnesota—Division
of Cardiothoracic
Surgery, Professor of
Surgery
Michael C. Kontos Virginia  Astellas  Astellas None  Mission Lifeline  AHA†  Plaintiff,
Commonwealth  General Electric  AstraZeneca Scientific Committee†  Astellas malpractice
University, Pauley  Ikaria  Society of Chest Pain  Eli Lilly† case with
Heart Center—Medical  Prevencio Centers†  Merck † failure to treat
Director, Coronary  Quest Diagnostics  NIH† properly, 2012
Intensive Care Unit;  Sanofi-aventis  Novartis†
Associate Professor,
 Wellpoint/Anthem
Internal Medicine
Glenn N. Levine Baylor College of None None None None None None
Medicine—Professor
of Medicine; Director,
Cardiac Care Unit
Philip R. Liebson Rush University None None None None None None
Medical Center—
McMullan-Eybel Chair
of Excellence in
Clinical Cardiology
and Professor of
Medicine and
Preventive Medicine
Debabrata Texas Tech University None None None None None None
Mukherjee Health Sciences
Center—Chief,
Cardiovascular
Medicine
Eric D. Peterson Duke University  Boehringer None None  Eli Lilly*  DCRI‡ None
Medical Center—Fred Ingelheim  Johnson & Johnson*
Cobb, MD,  Genentech  Janssen
Distinguished  Janssen Pharmaceuticals*
Professor of Medicine; Pharmaceuticals
Duke Clinical
Research Institute—
Director
Marc S. Sabatine Brigham and Women's  Aegerion None None  Abbott*  AstraZeneca* None
Hospital, Chairman—  Amgen  Amgen*  Athera
TIMI Study Group,  AstraZeneca*  AstraZeneca* Biotechnologies*
Division of  Bristol-Myers  Bristol-Myers Squibb*  Daiichi-Sankyo*

Cardiovascular Squibb  BRAHMS*  Gilead*
Medicine; Harvard  Canadian  Critical Diagnostics*  GlaxoSmithKline*
Medical School— Cardiovascular  Daiichi-Sankyo*  Johnson & Johnson*
Professor of Medicine Society  Eisai*  Merck*
 Creative  Genzyme*  Muljibhai Patel
Educational  GlaxoSmithKline* Society for Research
Concepts  Intarcia* in Nepro-Urology*
 Diasorin  Nanosphere*  Proventys*
 GlaxoSmithKline  NIH*  Siemens*
 Health Sciences  Roche Diagnostics*  Singulex*
Media  Sanofi-aventis*
 Merck  Takeda*
 Pfizer
 Sanofi-aventis
 Vertex
 Vox Media
 WebMD
Richard W. University of Texas,  Gilead None None  Amarin  Cordis* None
Smalling Health Science Center  St Jude Medical  Cordis  E-Valve*
at Houston—Professor  Maquet  E-valve/Abbott  St. Jude
and Director of  Toshiba Vascular
Interventional  Gilead
Cardiovascular  St. Jude Medical
Medicine; James D.  Maquet-Datascope
Woods Distinguished
 Edwards Lifesciences
Chair in
Cardiovascular
Medicine
Susan J. Zieman National Institute on None None None  American Geriatrics None None
Aging/NIH, Geriatrics Society†
Branch, Division of  AHA†
Geriatrics and Clinical  NIH*
Gerontology—Medical
Officer
This table represents all healthcare relationships of committee members with industry and other entities that were reported by authors, including those not
deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the
time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the
business entity, or ownership of ≥$10,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of
the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency.
Relationships in this table are modest unless otherwise noted. Please refer to http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-
Standards/Relationships-With-Industry-Policy.aspx for definitions of disclosure categories or additional information about the ACC Disclosure Policy for
Writing Committees.
*Significant relationship.
†No financial benefit.
‡DCRI has numerous grants and contracts sponsored by industry. These include the following: Aastrom Biosciences; Abbott; Abiomed; Acom Cardiovascular; Adolor Corp;
Advanced Cardiovascular Systems; Advanced Stent Technologies; Adynnx; Aijnomoto; Allergan; Amgen; Alnylam Pharma; Alpharma; Amylin Pharmaceuticals; Anadys;
Anesiva; Angel Medical Systems; ANGES MG; Angiomedtrix; APT Nidus Center; ASCA Biopharma; Astellas Pharma; Asklepios; AstraZeneca; Atritech; Attention
Therapeutics; Aventis; Baxter; Bayer; Berlex; BG Medicine; Biogen; Biolex Therapeutics; Biomarker Factory; Biosite; Boehringer Ingelheim Biogen; Boston Scientific; Bristol-
Myers Squibb; BMS Pfizer; Carbomed; CardioDx; CardioKinetix; Cardiovascular Systems; Cardiovax; Celsion Corp; Centocor; Cerexa; Chase Medical; Conatus Pharmaceuticals;
Conor Medsystems; Cortex; Corgentech; CSL Behring; CV Therapeutics; Daiichi Pharmaceuticals; Daiichi-Sankyo; Daiichi-Sankyo/Lilly; Dainippon; Datascope; Dendreon; Dr.
Reddy’s Laboratories; Eclipse Surgical Technologies; Edwards Lifesciences; Eisai; Endicor; EnteroMedics; Enzon Pharmaceuticals; Eli Lilly; Ethicon; Ev3; Evalve; F2G; Flow
Cardia; Fox Hollow Pharmaceuticals; Fujisawa; Genetech; General Electric; General Electric Co.; General Electric Healthcare; General Electric Medical Systems; Genzyme Corp.;
Genome Canada; Gilead Sciences; GlaxoSmithKline; Guidant Corp.; Heartscape Technologies; Hoffman-LaRoche; Hospira; Idera Pharmaceuticals; Ikaria; Imcor
Pharmaceuticals; Immunex; INFORMD; Inimex; Inspire Pharmaceuticals; Ischemix; Janssen; Johnson and Johnson; Jomed; Juventus Therapeutics; KAI Pharmaceuticals; King
Pharmaceuticals; Kyowa Pharma; Luitpold; Mardil; MedImmune; Medscape; Medtronic Diabetes; Medtronic; Medtronic Vascular; Merck Group; MicroMed Technology;
Millennium Pharmaceuticals; Mitsubishi Tanabe; Momenta; Nabriva; Neuron Pharmaceuticals; NitroMed; NovaCardia Inc; Novartis AG Group; Novartis Pharmaceuticals;
Oncura; Orexigen; Ortho-McNeil-Janssen; OSI Eyetech; OSI Pharmaceuticals; Pfizer; Pharmacyclics; Pharmasset; Pharmos; Phyxius Pharmaceuticals; Pharsight; Pluristen
Therapeutics; Portola Pharmaceuticals; Proventys; Radiant; Regado Biosciences; Rengeneron Pharmaceuticals; Roche Molecular Systems; Roche Group; Roche Diagnostic; Salix
Pharmaceuticals; Sanofi-Pasteur; Sanofi-aventis; Santaris Pharmaceuticals; Schering-Plough; Scios; Siemens; Southwest Oncology Group; Spectranetics; Summit; Sunovion
Pharmaceuticals; TAP Pharmaceutical Products; Tengion; The Medicines Company; Theravance; TherOx; Tethys Bioscience; Theregen; Three Rivers Pharmaceuticals; The
EMMES Corporation; UCB; Valentis; Valleylab; Vertex; Viacor; and Wyeth.
ACC indicates American College of Cardiology; AHA, American Heart Association; AHRQ, Agency for Healthcare Research and Quality; CABG, coronary
artery bypass graft; CCCOA, Council on Cardiovascular Care for Older Adults; C-PORT, Cardiovascular Patient Outcomes Research Team; DAPT, dual
antiplatelet therapy; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; FDA, Food and Drug Administration; MI, myocardial
infarction; NCDR, National Cardiovascular Data Registry; NIH, National Institutes of Health; NHLBI, National Heart, Lung, and Blood Institute; OSHPD;
Office of Statewide Health Planning and Development; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; STEMI, ST-elevation
myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction; and VA, Veterans Affairs.
2014 NSTE-ACS Guideline Data Supplements
(Section numbers correspond to the full-text guideline.)
Data Supplement 1. Clinical Assessment and Initial Evaluation (Section 3.1) ............................................................................................................................................................................................................... 3
Data Supplement 2. Risk Stratification (Section 3.3) ...................................................................................................................................................................................................................................................... 7
Data Supplement 3. Cardiac Injury Markers and the Universal Definition of AMI (Section 3.4) .................................................................................................................................................................................. 8
Data Supplement 4. Cardiac Troponins (Section 3.4.3)................................................................................................................................................................................................................................................. 10
Data Supplement 5. CK-MB, MB Isoforms and Myoglobin, Compared With Troponins (Section 3.4.4) ................................................................................................................................................................... 12
Data Supplement 6. Bedside Testing for Cardiac Biomarkers (Section 3.4.4) .............................................................................................................................................................................................................. 14
Data Supplement 7. Summary Comparison of Injury Markers (Section 3.4.4) ............................................................................................................................................................................................................. 17
Data Supplement 8. Discharge from ED or Chest Pain Unit (Section 3.5.1)................................................................................................................................................................................................................. 20
Data Supplement 9. Nitrates (Section 4.1.2.1) ............................................................................................................................................................................................................................................................... 22
Data Supplement 10. Analgesic Therapy (Section 4.1.2.2) ........................................................................................................................................................................................................................................... 25
Data Supplement 11. Beta-Adrenergic Blockers (Section 4.1.2.3)................................................................................................................................................................................................................................ 26
Data Supplement 12. Calcium Channel Blockers (Section 4.1.2.4) .............................................................................................................................................................................................................................. 29
Data Supplement 13. Other Anti-Ischemic Inverventions (Ranolazine) (Section 4.1.2.5) ............................................................................................................................................................................................ 32
Data Supplement 14. Inhibitors of the Renin-Angiotensin-Aldosterone System (Section 4.2) ..................................................................................................................................................................................... 34
Data Supplement 15. Oral and Intravenous Antiplatelet Therapy in Patients With Likely or Definite NSTE-ACS Treated With Initial Invasive or Conservative Strategy (Section 4.3.1) .................................... 37
Data Supplement 16. Combined Oral Anticoagulant Therapy and Antiplatelet Therapy in Patients With Definite NSTE-ACS (Section 4.3.2) ........................................................................................................ 52
Data Supplement 17. Parenteral Anticoagulant and Fibrinolytic Therapy (Section 4.3.3) ............................................................................................................................................................................................ 57
Data Supplement 18. Comparison of Early Invasive and Initial Conservative Strategy (Section 4.4.4) ....................................................................................................................................................................... 74
Data Supplement 19. Comparison of Early Versus Delayed Angiography (Section 4.4.4.1)........................................................................................................................................................................................ 80
Data Supplement 20. Risk Stratification Before Discharge for Patients With Conservatively Treated NSTE-ACS (Section 4.5)............................................................................................................................... 81
Data Supplement 21. RCTs and Relevant Meta-Analyses of GP IIb/IIIa Inhibitors in Trials of Patients With NSTE-ACS Undergoing PCI (Section 5) .......................................................................................... 83
Data Supplement 22. Studies of Culprit Lesion Versus Multivessel (Culprit and Nonculprit) PCI in Patients with NSTE-ACS (Section 5) ............................................................................................................. 83
Data Supplement 23. Risk Reduction Strategies for Secondary Prevention (Sections 6.3.) .......................................................................................................................................................................................... 84
Data Supplement 24. Older Patients (Section 7.1)......................................................................................................................................................................................................................................................... 86
Data Supplement 25. Heart Failure (Section 7.2) .......................................................................................................................................................................................................................................................... 95
Data Supplement 26. Cardiogenic Shock (Section 7.2.2) ............................................................................................................................................................................................................................................ 101
Data Supplement 27. Diabetes Mellitus (Section 7.3) ................................................................................................................................................................................................................................................. 103
Data Supplement 28. Post-CABG (Section 7.4) .......................................................................................................................................................................................................................................................... 106
Data Supplement 29. Chronic Kidney Disease (Section 7.6) ...................................................................................................................................................................................................................................... 110
Data Supplement 30. Women (Section 7.7) ................................................................................................................................................................................................................................................................. 113
Data Supplement 31. Anemia, Bleeding, and Transfusion-Relationship Between Transfusion and Mortality (Section 7.8) ..................................................................................................................................... 120
Data Supplement 32. Anemia, Bleeding, and Transfusion Studies for Weight-Based and Renally-Adjusted Dosing of Anticoagulants (Section 7.8)............................................................................................. 121
Data Supplement 33. Cocaine and Methamphetamine Users (Section 7.10)............................................................................................................................................................................................................... 122
Additional Data Supplement Tables ............................................................................................................................................................................................................................................................................ 125
Data Supplement A. Other (Newer) Biomarkers ..................................................................................................................................................................................................................................................... 125
© American Heart Association, Inc and American College of Cardiology Foundation 1

Data Supplement B. Other Anticoagulants .............................................................................................................................................................................................................................................................. 127

Data Supplement C. Lipid Management .................................................................................................................................................................................................................................................................. 129
Data Supplement D. Blood Pressure Control........................................................................................................................................................................................................................................................... 132
Data Supplement E. Diabetes Mellitus .................................................................................................................................................................................................................................................................... 133
Data Supplement F. Smoking Cessation .................................................................................................................................................................................................................................................................. 135
Data Supplement G. Weight Management .............................................................................................................................................................................................................................................................. 138
Data Supplement H. Cardiac Rehabilitation ............................................................................................................................................................................................................................................................ 140
References .................................................................................................................................................................................................................................................................................................................... 141

Data Supplement 1. Clinical Assessment and Initial Evaluation (Section 3.1)

Title, Author, Study Aim Study Type/Size (N) Patient Population Endpoints P Values, Adverse Events Study Limitations
Year OR: HR: RR: & 95 CI:
Inclusion Exclusion Criteria Primary Endpoint & Results Safety Endpoint &
Criteria Results
Antman EM et al. Develop a simple Retrospective, Inclusion in Not included in Adverse events defined as new or N/A Event rates <significantly as N/A Regression model developed
2000 scoring system to observational study; TIMI 11B trial or these trials recurrent MI, severe recurrent TIMI risk score <in test cohort in pts with diagnosed ACS
10938172 (1) predict the risk of TIMI 11B pts not ESSENCE trial ischemia requiring urgent revasc, in TIMI 11B and was not designed to be
death and receiving UFH group and death within 14 d of pt (p=001 by ×2 for trend). applied indiscriminately to
ischemic events test cohort (N=1,957); presentation; regression model Pattern of <event rates with undifferentiated chest pain pts
for pts with TIMI 11B pts receiving selected the following 7 significant <TIMI risk score confirmed in
UA/NSTEMI enoxaprin (N=1,953) risk factors: ≥65 y, ≥3 coronary all 3 validation groups
and ESSENCE trial pts risk factors, documented prior (p=001). Slope of <in event
(N=3,171) validation stenosis ≥50%; ST-segment rates with <numbers of risk
cohort deviation on initial ECG, ≥2 factors significantly lower in
anginal events in prior 24 h, use enoxaparin groups in both
of ASA within 7 d of presentation, TIMI 11B (p=0.01) and
and elevated serum markers; ESSENCE (p=0.03) and there
presence of factor was given 1 was significant interaction
point and absence of risk factor between TIMI risk score and
given 0 points; rates of adverse treatment (p=0.02)
events for TIMI score as follows:
0/1: 4.7%; 2: 8.3%; 3:13.2%; 4:
19.9%; 5:26.2%; 6/7: 40.9%
Boersma E et al. Develop a model Retrospective analysis Pts enrolled in Pts not enrolled in 1º outcome: 30-d death; 2º N/A 7 factors most predictive of N/A Regression model developed
2000 for predicting 30- of pts with NSTE-ACS PURSUIT trial PURSUIT trial; pts outcome: composite of 30-d death death: age (adjusted [Χ]2=95), in pts with diagnosed ACS
10840005 (2) d death and enrolled in PURSUIT with STE on initial and myocardial (re)infarction; heart rate ([Χ]2=32), SBP and not designed to be
myocardial trial (N=9,461; 3.6% with ECG More than 20 variables were ([Χ]2=20), ST-segment applied indiscriminately to
(re)infarction in 1º outcome) found to be predictive of 1º and 2º depression ([Χ]2=20), signs of undifferentiated chest pain
pts without STE- outcomes HF ([Χ]2=18), and cardiac pts; difficult to calculate;
ACS markers ([Χ]2=15); C-index for original model requires
the mortality model was 0.814 preexisting programmed
calculator; simplified version
requires print-out of scoring
system for each variable with
corresponding figure to
interpret data
Granger CB et al. Develop a Retrospective Inclusion in Not included in Adverse event defined as in- N/A The discrimination ability of N/A Regression model developed
2003 regression model observational study GRACE or these trials hospital mortality; Regression the simplified model was in pts with diagnosed ACS
14581255 (3) in pts with utilizing pts from GUSTO-IIb trial model identified following 8 excellent with C-statistics of (including STEMI pts) and
diagnosed ACS GRACE (N=11,389; 509 independent risk factors: 0.83 in the derived database, was not designed to be
(including pts with deaths); validation set accounted age, Killip class, SBP, 0.84 in the confirmation applied indiscriminately to
STEMI) for in- included a subsequent ST-segment deviation, cardiac GRACE data set, and 0.79 in undifferentiated chest pain
hospital mortality cohort of 3,972 pts arrest during presentation, serum the GUSTO-IIb database; OR pts; difficult to calculate;
enrolled in GRACES creatinine level, positive initial for the 8 independent risk original model requires pre-
and 12,142 pts enrolled cardiac enzyme findings, and factors were: age (OR: 1.7 per existing programmed
in GUSTO-IIb trial heart rate 10 y), Killip class (OR: 2.0 per calculator; simplified version
class), SBP (OR: 1.4 per 20 requires print-out of scoring
mmHg decrease), ST- system for each variable with
segment deviation (OR: 2.4), corresponding nomogram
cardiac arrest during
presentation (OR: 4.3), serum
creatinine level (OR: 1.2 per 1
mg/dL [88.4 μmol/L]
increase), positive initial
cardiac enzyme findings (OR:
1.6), and heart rate (OR: 1.3
per 30 beat/min increase)
Chase M et al. Validate TIMI Prospective (N=1,354; Pts with chest Pts <30; cocaine 1º outcome composite of death, Increasing TIMI score N/A The incidence of 30-d 15% of pts did not have
2006 score in ED chest 136 with 1º outcome) pain who had use within 7 d MI, PCI, CABG within 30 d of associated with death, AMI, and cardiac marker
16934646(4) pain pts an ECG initial presentation increased rates of revasc according to measurements; pts with
obtained adverse outcome TIMI score is as STEMI included
follows: TIMI 0, 1.7%
(95% CI: 0.42–2.95);
TIMI 1, 8.2% (95% CI:
5.27–11.04); TIMI 2,
8.6% (95% CI: 5.02–
12.08); TIMI 3, 16.8%
(95% CI: 10.91–
22.62); TIMI 4, 24.6%
(95% CI: 16.38–
32.77); TIMI 5, 37.5%
(95% CI: 21.25–
53.75); and TIMI 6,
33.3% (95% CI: 0–
100)
Lyon R et al. Compare GRACE Retrospective analysis Pts with Pts<20 y Recurrent MI, PCI, or death within GRACE score and N/A GRACE AUC-ROC Retrospective; 240 pts from
2007 and TIMI score in of prospective database undifferentiated 30 d of pt presentation (note: pts TIMI score equivalent 0.80 (95% CI: 0.75– initial database of 1,000
17360096(5) risk stratification (N=760; 123 with 1º chest pain with MI on initial presentation in risk stratification of 0.85). TIMI AUC-ROC excluded; Did not count MI on
of undifferentiated endpoint) excluded from outcome) undifferentiated ED 0.79 (95% CI: 0.74– presentation as adverse event
chest pain pts chest pain pts 0.85)
Hess EP et al. Prospectively Prospective; 117 pts Pts presenting Pts with STE-AMI, 1º outcome defined as MI, PCI, Increasing sens of N/A The modified TIMI risk Only 72% of eligible pts
2010 validate a with 1º endpoint to ED with chest hemodynamic CABG, or cardiac death within 30 modified TIMI score score outperformed enrolled; 4.6% of pts without
20370775(6) modified TIMI risk (N=1,017) pain in whom a instability, cocaine d of initial presentation seen with increasing the original with regard 30-d follow-up
score to risk Tn value was use, terminal illness, score; sens and spec to overall diagnostic
stratify ED chest obtained or pregnancy at potential decision accuracy (area under
pain pts; The thresholds were: the ROC curve=0.83
modification of >0=sens 96.6%, spec vs. 0.79; p=0.030;
TIMI score was 23.7%; >1=sens absolute difference
assigning 5 points 91.5%, spec 54.2%; 0.037; 95% CI: 0.004-
if pt had either and >2=sens 80.3%, 0.071)
elevated Tn or spec 73.4%; sens for
ischemic ECG 30-d ACS for a score
findings of 0, 1, 2 was 1.8%,
2.1%, and 11.2%
Lee B et al. 2011 Compared Prospective data Chest pain Pts in which scores 1º outcome composite of death, The TIMI and N/A The AUC for TIMI was Retrospective nature of
21988945(7) GRACE, collection for TIMI score; pts>30 y who were unable to be MI, PCI, or CABG within 30 d of GRACE score 0.757 (95% CI: 0.728- comparison of TIMI score to
PURSUIT, and retrospective had ECG calculated due to presentation outperformed the 0.785); GRACE, 0.728 GRACE and PURSUIT
TIMI scores in determination of obtained and incomplete data PURSUIT score in (95% CI: 0.701-0.755);
risk stratification PURSUIT and GRACE were enrolled in (e.g., no creatinine risk stratification of and PURSUIT, 0.691
of chest pain pts score (N=4,743; 319 pts previous study obtained) ED chest pain pts (95% CI: 0.662-0.720)
with 1º outcome) utilizing TIMI
score in risk
stratification of
chest pain pts
Sanchis J et al. Develop a risk Retrospective (N=646; Chest pain pts Significant STE or N/A 1º endpoint: 1-y N/A Accuracy of score was Small study size; selection
2005 score for ED pts 6.7% with 1º endpoint) presenting to depression on initial mortality or MI; greater than that of the bias towards more healthy pts
16053956(8) with chest pain ED undergoing ECG; abnormal Tn; point); 4 factors were TIMI risk score for the as study population limited to
evaluation for not admitted to found to be predictive 1º (C-index of 0.78 vs. pts admitted to chest pain
ACS who chest pain unit of 1º endpoint and 0.66; p=0.0002) and 2º unit; chest pain component of
subsequently were assigned (C-index of 0.70 vs. score is not easily calculated
were admitted following score: chest 0.66; p=0.1) endpoints
to chest pain pain score ≥10
unit points: 1 point, ≥2
pain episodes in last
24 h: 1 point; age≥67
y: 1 point; IDDM: 2
points, and prior PCI:
1 point; Pts were
classified in 5
categories of risk (0,
1, 2, 3, 4, >4) with
direct correlation of
increasing rates of 1º
outcome with risk
score
Christenson J et Develop a scoring Prospective cohort with Pts presenting <25, traumatic or 1º outcome MI or definite UA Prediction rule: if pt CI for prediction rule not N/A Prediction rule developed
al. 2006 system for retrospective creation of to ED with chest radiologically had normal initial supplied retrospectively; not supplied,
16387209(9) discharge of pts decision rule (N=769; pain between 7 evident cause of ECG, no Hx CAD, but exceed the threshold of
from the ED that 165 with 1º outcome) am-10 pm h CP, enrolled in age<40 y, and allowed 2% miss rate; 2%
would miss <2% study in previous 30 normal baseline CK- miss rate not standard of care
of ACS d, or had terminal MB<3.0 ng/mL, or no in United States
noncardiac illness increase in CK-MB or
Tn at 2 h; 30-d ACS;
prediction rule 98.8%
sens and 32.5% spec
Backus BE et al. Validation of the Retrospective analysis Pts admitted to STE on initial ECG 1º outcome was a composite of Rates of 1º outcome N/A Hx, ECG, and Tn were Retrospective; weighting of
2010 HEART Score of prospective database “cardiology” ED AMI, PCI, CABG, and death seen with increasing independent predictors the elements of HEART Score
20802272(10) which utilizes (N=880; 158 with 1º within 6 wk of initial presentation score: 0–3: 0.1%; 4– of the combined arbitrarily assigned and not
elements of outcome) 6: 11.6%; 7–10: endpoint (p<0.0001). based on likelihood ratio
patient History, 65.2% Avg HEART score in analysis or regression
ECG, Age, Risk the no endpoint group analysis
factors, and was 3.8±1.9; pts with
Troponin to risk at least 1 endpoint 7.2
stratify ED chest ±1.7 (p±0.0001). C–
pain pts stat 0.897
Fesmire et al. Improve upon the Retrospective analysis Pts presenting STE on initial ECG; 1º outcome was 30-d ACS Increasing HEARTS3 N/A HEARTS3 score Retrospective; utilized older-
2012 HEART score in of prospective database to ED with chest chest pain in the defined as MI, PCI, CABG, life- score was associated outperformed the generation Tn
22626816(11) risk stratification (N=2,148; 315 with 1º pain undergoing presence of TAAR, threatening cardiac complications, with increasing risk of HEART score as
of chest pain pts outcome) evaluation for pts with pulmonary or death within 30 d of initial 30-d ACS; likelihood determined by
by incorporating ACS edema, pts with presentation ratio analysis comparison of areas
sex, serial ECG, chest pain deemed revealed significant under the receiver
and serial Tn; not to require any discrepancies in operating
weighting of cardiac workup weight of the 5 characteristic curve for
elements of (obvious individual elements 30-d ACS (0.901 vs.
scoring nonischemic chest shared by the 0.813; 95% CI
determined by pain and absence of HEART and difference in areas,
likelihood ratio risk factors or pre- HEARTS3 score 0.064–0.110)
analysis existing disease that
would prompt
screening workup)
Hess EP et al. Develop a Retrospective analysis Pts presenting Pts with STE-AMI, 1º outcome defined as MI, PCI, Prediction rule N/A Rule was 100% sens Rule developed
2012 prediction rule for of prospective database to ED with chest hemodynamic CABG, or cardiac death within 30 consisted of the (95% CI: 97.2%– retrospectively; only 82% of
21885156(12) pts at low risk of (N=2,718 pts; 336 with pain in whom instability, cocaine d of initial presentation absence of 5 100.0%) and 20.9% eligible pts enrolled
30-d adverse adverse events) Tn value was use, terminal illness, predictors: ischemic spec (95% CI: 16.9%–
cardiac events obtained or pregnancy ECG changes, Hx of 24.9%) for a cardiac
CAD, pain typical for event within 30 d
ACS, initial or 6-h Tn
level > 99th

percentile, and age
<50 y. Pts aged ≤40
y required only a
single Tn evaluation
1º indicates primary; ACS; acute coronary syndrome; AMI, acute myocardial infarction; ASA, aspirin; AUC, area under the curve; BP, blood pressure; CABG, coronary artery bypass graft; CAD, coronary artery disease; CK-MB, creatine kinase-MB; CP, chest pain;
ECG, electrocardiograph; ED, emergency department; ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events; GRACE, Global Registry of Acute Coronary Events; GUSTO, Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries trial; HEART, Healing and Early Afterload Reducing Therapy Trial; HF, heart failure; Hx, history; MI, myocardial infarction; N/A, not applicable; NSTE, non-ST-elevation; NSTE-ACS, non-ST-elevation acute
coronary syndrome; NSTEMI, non–ST-elevation myocardial infarction; Pts, patients; PCI, percutaneous coronary intervention; revasc, revascularization; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina:Receptor Suppression Using Integrilin Therapy; ROC,
receiver operator curve; SBP, systolic blood pressure; Sens, sensitivity/sensitivities; Spec, specificity/specificities; STE, ST-elevation; STE-AMI, ST-elevation acute myocardial infarction; STEMI, ST-elevation myocardial infarction; TAAR, tachyarrhythmia; TIMI,
Thrombolysis In Myocardial Infarction; Tn, troponin; UA, unstable angina; and UFH, unfractionated heparin.
Data Supplement 2. Risk Stratification (Section 3.3)

Study Name, Study Aim Study Type/Size (N) Intervention vs. Patient Population Study Endpoints P Values Study Limitations
Author, Year Comparator (n) Intervention OR: HR: RR: & 95 CI:
Inclusion Criteria Exclusion Primary Endpoint & Secondary

Criteria Results Endpoint &
Results
Antman 2000 Development of original Multisite RCTs, TIMI- N/A Clinical ACS, ECG Planned revasc, N/A All-cause mortality, new or N/A p<2 selected for Biomarkers all
10938172(1) score to risk stratify pts 11 B and ESSENCE changes, and bleeding risks, recurrent MI, severe multivariate modeling, elevated; 65 y pg age
presenting with ACS elevated biomarkers and correctable ischemia leading to revasc then variables scored cutoff
cause for angina
Pollack 2006 Validation in ED Convenience sample N/A Chest Sx and ECG New STE N/A Death/MI/revasc over 30 d In-hospital and Graded relationship Used parts of score to
16365321(13) population with chest N=3,326 without new obtained 14-d events between score and define management
pain STE events
Go 2011 Attempt to add Single center N=798 N/A Ischemic Sx within STEMI N/A CV death, MI, urgent N/A Renal dysfunction Small and only 9%
21691204(14) creatinine to TIMI risk 48 h revasc or Sx, and elevated increased risk, but not with eGFR, 30
score biomarkers enough to add variable to
system
Huynh 2008 Across all ACS Multicenter RCT with N/A NSTE-ACS and N/A N/A 6-mo death and MI N/A 2 mm ST deviation All high-risk pts
19960136(15) spectrum N=1,491 from STEMI increased risk and risk
angiographic arm was less regardless of
score with less
Boersma 2000 N/A Multicenter N/A NSTE-ACS STE N/A Death and MI N/A Similar risk prediction to No biomarkers
10840005(2) RCT-Pursuit TIMI over groups with
many similar variables
Eagle 2004 Original GRACE Registry N=17,141 N/A All ACS N/A N/A 6-mo all-cause mortality N/A p<0.25 into multivariate Registry data, 200 pts
15187054(16) validation model without 6-mo follow-up

Granger 2003 Validation in NSTE-ACS 11,389 from registry N/A NSTE-ACS N/A N/A All-cause mortality during N/A p<0.25 into multivariate Only high-risk pts
14581255(3) as training set and then and then testing in hospitalization model
test set in registry with 3,872 from GRACE
validation in RCT and 12,142 from
GUSTO IIb
Eggers 2010 Incremental prognostic Single center trial of NT-proBNP, Possible ACS N/A Biomarkers at All-cause mortality at 6 mo NT-pro BNP not ROC analysis Small, but 92 deaths
20598977(17) value of multiple 453 chest pain pts cystatin presentation additive, cystatin
biomarkers in NSTE- GDF-15 minimally and
ACS GDF-15 helpful
Abu-Assi 2010 Does GRACE score still MASCARA national N/A Confirmed ACS N/A LVEF included In-hospital and 6-mo LVEF did not add N/A Registry data, but
21095268(18) work with modern registry N=5,985 mortality to GRACE score contemporary
management management
Meune 2011 Question as to whether 370 pts from APACE Hs-cTnT and NT- Non-STE-ACS N/A N/A Hospital and 1-y mortality No additive N/A All pts likely had
21444339(19) hs-cTn or NT-proBNP trial with 192 MIs pro added to benefit elevated hs-cTnT
influence prediction GRACE score
ACS indicates acute coronary syndrome; APACE, Advantageous Predictors of Acute Coronary Syndromes Evaluation trial; BNP, B-type natriuretic peptide; CV, cardiocvascular; ECG, electrocardiograph; ED, emergency department; ESSENCE, Efficacy and Safety of
Subcutaneous Enoxaparin in Non-Q wave Coronary Events; eGFR, estimated glomerular filtration rate; GDF,growth and differentiation factors; GRACE, Global Registry of Acute Coronary Events; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries trial; hs-cTn, high sensitivity cardiac troponin; hs-cTnT, high sensitivity cardiac troponin T; LVEF, left ventricular ejection fraction; MASCARA, Manejo del Síndrome Coronario Agudo. Registro Actualizado national registry; MI,
myocardial infarction; N/A, not applicable; NSTE, non-ST-elevation; NSTE-ACS, non-ST-elevation acute coronary syndrome; Pts, patients; NT-pro, N-terminal pro; NT-proBNP, N-terminal pro-brain natriuretic peptide revasc, revascularization; RCT, randomized
controlled trial; ROC, receiver operating characteristic; STE, ST-elevation; STEMI, ST-elevation myocardial infarction; Sx, symptom; and TIMI, Thrombolysis In Myocardial Infarction.
Data Supplement 3. Cardiac Injury Markers and the Universal Definition of AMI (Section 3.4)
Study Name, Study Aim Study Type/Size Intervention vs. Patient Population Study Endpoints P Values, Study Limitations
Author, Year (N) Comparator (n) Intervention OR: HR: RR: & 95 CI:
Inclusion Exclusion Criteria Primary Endpoint & Secondary Endpoint &
Criteria Results Results
Thygesen 2012 Definition of MI Guideline N/A N/A N/A N/A N/A N/A N/A N/A
22958960(20)
Roger 2006 Prospective Prospective Identification of MI County residents Lower TrT values N/A Identification of MI 538 Clinician Dx mentioned MI 74% increase Participation rate of MIs
16908764(21) Evaluation of new community based using TrT vs. CK- with TrT ≤0.03 MI with TrT; 327 with in only 42% of TrT-based TrT vs. CK (95% CI: was only 80% but similar
criteria for Dx of MI epidemiologic MB and CK ng/mL identifying CK; 427 with CK-MB criteria (diagnosing UA in 69%–79%) 41% inc TrT to median of similar
study compared with MI many) vs. 74% using vs. CK-MB participation studies
WHO and ARIC previous criteria p<0.001 (95% CI: 37%–46%)
criteria
Hamm 2000 Classification of UA Reclassification N/A Angina at rest N/A N/A 30-d risk of death N/A N/A N/A
10880424(22) based on Tr levels within 48-h Class 20% in IIIB Tr+, <2% in
IIIB into Tr+ and IIIB Tr +
Tr-

Kavsak 2006 Impact of new Retrospective TrI vs. CK-MB Dx 2 SPSS CK-MB, N/A 2 specimens AMI prevalence TrI-vs. CK-MB cTnI Exclusion of
16824840(23) classification of MI analysis using CK- based on MONICA TrI ≥20% change CK-MB, TrI MONICA CK-MB 19.4% p<0.001 for increase MI 35.7% (30.1–41.7) nonischemic diseases
MB vs. TnI or AHA definition using 99% TrT drawn at least AHA 19.8%. definition using TnI Relative increase 84% causing Tr elevation
analysis for MI of MI cutoff 6 h apart TnI to 35.7%
defined by 258 pts
with ACS
Eggers 2009 Effects of new Retrospective Evaluation of Stable community Evidence of clinical 1 cTnI Community N/A N/A N/A
19231317(24) UDMI on evaluation of single Tr in stable population. instability Sample; 0.6%
misdiagnosis with stable community population Stable 3-mo post- MI by UDMI
single evaluation of sample (995) and MI pts Stable post-MI; 6.7% MI
Tr post-AMI pts by UDMI
(1380) with
TrI≥99th percentile
Goodman 2006 Diagnostic and Multicenter Use of CK and Tn >18 y with NS comorbity, CK Tn+ levels demonstrate In entire population, Tn+ Hospital fatality rates 34% in GRACE registry
16504627(25) prognostic impact of observational neg 16,797 vs. possible ACS trauma, surgery, CK-MB higher in-hospital and 6- status vs. CK status 6-mo. higher with Tn+ vs. CK+: excluded because of
new UDMI prospective CK-MB and Tn with ECG lack of 1 biomarker Tn mo mortality rates than mortality:1.6 (1.4–1.9) 2.2 (95% CI: 1.6–2.9) use of 1 biomarker only
Registry (GRACE) 10,719 for hospital. abnormal or CAD Follow up for 6 higher CK levels with Tn+/CK-MB-: 2.1
26,267 pts with fatality, 14,063 vs. history. CK, CK- mo (95% CI: 1.4-3.2)
ACS 8,785 for 6-mo MB. Tn.
mortality
Eggers 2011 Clinical implications Retrospective UDMI with N/A cTnI <99th cTnI levels Peak cTnl level ≥99th N/A All 160 pts had Analysis of assay could
20869357(26) of relative change in study of 454 pts prespecified cTnI percentile percentile positive significant raised not be validated by hs-Tr
cTnI levels with with ACS within 24 changes from change ≥20% in 160 mortality assay.
chest pain h of admission with ≥20%, 50%, 100% pts. 25 pts had no AMI HR 2.5 (95% CI: 1.7– No review of pts records
5.8-y follow-up by ESC/ACC criteria 3.8) Higher TnI deltas for type I or 2 AMI
were not associated with No long-term risk
higher mortalities assessment
Mills 2012 Evaluation of ACS Retrospective Study groups: cTnI Noncardiac chest cTnI values 1-y outcomes based on Compared with ≥0.050, Tr p<0.001 for 1-y outcome Not a prospective study.
22422871(27) pts by using cTnI cohort study with cTnI <0.012, ACS pain, cTnI subgroups: 0.012–0.049 had a higher of 0,012–0.049 vs. Tn levels of 0.012-0.049
diagnostic threshold 1-y follow-up of 0.012–0.049, and tachyarrhythmia, 0.012–0.049 had higher risk profile, but less likely to <0.012 were considered
and ≤99th percentile 2,092 consecutive ≥0.50 (99th anemia. Severe mortality and re-MI than be investing for AMI “normal” and not
on Dx and risk for pts with suspected percentile) with C Valve HD, HOCM, <0.012 (13% vs. 3%) repeated. Possible
future events ACS of V ≥20% vs. pericarditis, Increase in Dx of MI myocardial ischemia due
previous cocaine use based on new criteria by to noncardiac illness.
diagnostic criteria 47%
TRITON-TIMI 38 Association Prospective cohort Follow-up of Types 1, 2, 3, 4, 5 Cardiogenic shock Tn used Risk of death at 6 mo N/A p<0.001 for death after Association of MI with
Bonaca 2012 between new and analysis of 13,608 recurrent MI vs. no MI or any condition preferentially after follow-up MI: MI at recurrent MI vs. no death not necessarily
22199016(28) recurrent MI using pts with ACS follow-up MI and that was for recurrent follow-up 6.5% vs. 1.3% recurrent MI related to causality.
new UDMI undergoing PCI risk of death at 6 associated with MI and CK-MB and by subtypes p<0.001 for difference Confounders could
classification TRITON-TIMI 38 mo decreased survival for peri-PCI MI with each of 5 subtypes explain relationship.
system and risk of study over 15 mo Standard Cox
death regression may bias
results
ACC indicates American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; AMI, acute myocardial infarction; ARIC, Atherosclerosis Risk in Communities; CAD, coronary artery disease; C of V, coefficient of variation; CK,
Creatine Kinase; CK-MB, Creatine kinase-MB; cTnl, Cardiac troponin I; Dx, diagnosis; ECG, electrocardiograph; Elev, elevation; ESC, European Society of Cardiology; GRACE, Global Registry of Acute Coronary Events; HD, heart disease; Hs-Tn, high-sensitivity
Troponin; HOCM, Hypertrophic Obstructive Cardiomyopathy; MB, myocardial band; MI, myocardial infarction; MONICA, Multinational MONItoring of trends and determinants in CArdiovascular disease; N/A, not applicable; NSTEMI, non-ST segment elevation
myocardial infarction; pt, patient; PCI, percutaneous coronary intervention; SPSS; STEMI, ST elevation MI; TIMI, thrombolysis in myocardial infarction; Tn, Troponin; Tn+, positive troponin, Tn-, negtative troponin; Tr, Troponin; TRITON, Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel; TrT, Troponin T; TrI, Troponin I; UA, Unstable angina; UDMI, Universal Definition of MI; and WHO, World Health Organization.
Data Supplement 4. Cardiac Troponins (Section 3.4.3)

Study Name, Study Aim Study Type/Size Intervention vs. Patient Population Study Intervention Endpoints P Values, Study Limitations
Author, Year (N) Comparator (n) OR: HR: RR: & 95 CI:
Inclusion Criteria Exclusion Criteria Primary Endpoint & Secondary Endpoint &
Results Results
Apple 2009 Dx, accuracy of Prospective cohort VITROS Tnl-ES Sx suggestive of No 2nd Tn level Tn assay at Sens and spec for MI Risk stratification Sens admission Difficulty in
19299542(29) cTnI for early study 381 with assay 2× vs. clinical ACS in ED admission and 6 h from admission and improved by 30^ cTnI for AMI ascertaining time of
detection of AMI possible ACS Dx of AMI later for delta delta change (see p Delta to initial cTnI >99th 69% (95% CI: 55%– initial Sx.
and risk prediction change values) percentile. 81%) Problems with
for adverse events Sens increased from Risk of death/follow-up Spec 78% (95% CI: getting 2nd sample at
admission to 6-h cTnI MI within 60 d 73%–82%) 6h
and ROC from 0.82– 6-h cTnI Question of false
0.96 (p<0.001) Sens 94% (95% CI: 84– +cTnI
99) Initial rather than
Spec 81% (95% CI: discharge sampling
77%–85%) may have biased
Deltas >30% evaluation of risk at
Sens 75% (95% CI: 60 d
6%–86%)
Spec 91% (95% CI:
87%–94%)
Delta cTnI added to
initial or follow-up cTnI
improved risk
stratification p<0.001
Px implication.of Prospective multi + or – hs-cTnI NST-ACS Shock ,ST- Baseline cTnI with +cTnI higher risk of Pts with low-level Risk of death 12 mo vs. Does not address all
Bonaca 2010 low-level inclusion study 99th percentile for elevation, revasc cutpoint at 99th death/MI at 30 d than - increases <0.04 ug/L pts with nontraumatic
20447535(30) in Hs-cTnI in 4,513 with NST- death/MI in 30 d before random percentile cTnI 0.04-1.0 at <risk than 6.4% vs. 2.4%; p=0.005 chest pain
possible ACS ACS 6.1% vs. 2.0% cutpoint of 0.04 (5.0%
p<0.001 vs. 2.0%); p=0.001
Kontos 2010 NSTEMI with +Tn Post hoc data Tr+ MB- vs. Tr+ MB+ Present within 24 h No STEMI Biomarkers on Treatment and in- MB- were older and had In-hospital mortality: No central core lab in
21095267(31) but -CK-MB in base analysis of Sx with NSTEMI admission, Tr and hospital outcomes. more comorbidities. MB+ 4.9 vs. 3.8 MB− multi-institutional
treatment and 16,064 with CK-MB In-hospital mortality p<0.01 and fewer p<0.02 study
outcomes NSTEMI lower in MB pts intervals
Tr+ and MBCK -

Lindahl 2010 Hs-cTnT Prospective cohort Effect of + by both Pts with ACS No coronary Both cTnT collected +Hs-TnT same 1-y For death or AMI at 30 +Hs-TnT 1-y mortality Pts with higher
20691825(32) comparison with 1,452 assays vs. only 1 angiography within 48 h after mortality. Whether + or - d 9,2% vs. 1.6%; p=0.001 pretest risk than
std cTnT for risk assay 12 h randomization with St-TnT + only for Hs-TnT had For – by both typical chest pain pts
assessment interim risk assays in ED
Giannitsis 2010 Dx, performance of Retrospective Baseline UA or NSTEMI with Immediate PCI or Hs-cTnT baseline, Hs-cTnt Dx 61% at Doubling of hs-TnT with Delta changes and Admission to chest
20167697(33) Hs-cTnT for cohort analysis concentrations and initial –cTnT kidney dysfunction 3, 6 h baseline to 100% at 6 h. initial 99% + positive ROC optimized values pain unit more
detection of 57 with UA and serial concentrations delta change Dx increase by 34% predicted value 100% − spec 100% with sens selective than typical
NSTEMI in ACS evolving NSTEMI at 3 h and 6 h >20%,or ROC above std cTnT predicted value 88% 69% and 76% ED admissions
optimized value
>117% 3 h, or
246% 6 h
Giannitsis 2008 Serial TnT Retrospective AMI with TnT and STEMI and Lack of biomarkers TnT at admission Except for admission Estimation of infarct cTnT at d 4 showed Possible poor timing
18206741(34) measurements vs. cohort analysis MRI NSTEMI with MRI at any of 5× up to and daily to 96 h. values, all TnT at mass on d 4 was lower highest correlation and of sampling with
MRI infarct mass 31 STEMI and 30 before discharge 96 h from various times correlated for NSTEMI than performed as well as NSTEMI and
NSTEMI admission with infarct size STEMI peak cTnT and AUC visualization
r=0.75 STEMI r=0.66 vs. r=0.65 vs. problems with MRI in
r=0.36 NSTEMI r=0.69 NSTEMI vs. STEMI
Keller 2011 Diagnostic Prospective Hs-TnI and St-TnI Suspected ACS Major surgery or Hs-TnI and St-TnI Both Hs-Tnl and St-TnI 3 h after admission. Hs-TnI at admission Final Dx of AMI by in
22203537(35) performance of hs- multicenter trauma within 4 wk, at baseline and 3 h at 99th percentile at Sens 98.2% and – sens 82.3%,−pred house Tn, biasing
cTnI with analysis pregnancy, drug serial changes admission and 3 h had predicted value 99.4% value 94.7% biomarker assays
continued. cTnI for 1,818 with abuse similar sens and spec for both assays. St Tnl sens 79.4% toward Tn
serial changes suspected ACS, High proportion of MI
413 with AMI vs. other studies
Younger 2007 72-h TnI estimate Prospective cohort TnI correlation with STEMI, NSTEMI, Prior AMI Admission and 12-h 72h Tn similar to CK for Correlation of 12-h TnI 72 h TnI vs. MRI 12 and 72-h TnI
17540686(36) with MRI for infarct analysis MRI LBBB contraindication to TnI and CK infarct size estimate with microvascular R=0.62 p<0.0001 available only on 37
size 93 MI 1st MI MRI previous MRI average 3.7 d and superior to 12-h TnI obstruction was NS 12-h TNI pts and 64 pts.
19 NSTEMI TnI revasc, PCI before from admission p=0.16 R=0.56 p=0.0003 Only 19 NSTEMI.
CK MRI Compared with peak Peak CK Data larger than on
MRI CK r=0.44 R=0.75 p<0.0001 previous studies of
72-h TnI r=0.46 Tn MRI correlations.
p=0.0002
Apple 2012 Diagnostic Prospective cohort cTnI at admission and Possible ACS with N/A cTnI at 0-, 6-, 24-h Cardiac events and Sens and Specs: AUC Diagnostic Long period needed
22465126(37) accuracy and risk study up to 24 h for follow-up for 60 d for optimum % death in 60 d. Optimal Absolute value: accuracy of absolute to evaluate deltas.
stratification of 371 optimum deltas using change, absolute % value of change was 89.8-93.7 value of change 0.96 Further studies need
cTnI-ultra assay ROC analysis change, change, absolute value of Change: (0.94, 0.98). to determine whether
absolute value of change delta 67.5-99.0 Change 0.76 2–3-h changes can
change Absolute value of % Absolute value of % provide adequate Dx
change: change 0.88 and prognostic
75.5-85.7 % change 0.77 information
% change:
71.4-89.7
Reichlin 2011 Diagnostic Prospective Absolute value Sx suggesting AMI STEMI, terminal Hs-TnT and cTnI ROC at 2-h higher for ROC absolute cutoff 2 h ROC absolute change Observation cannot
21709058(38) accuracy of multicenter relative changes in kidney failure ultra at admission absolute than relative 0.007 ug/L hs and Hs-TnT quantify clinical
absolute value 836 with ACS cTn and 1 h and 2 h changes 0.020 ug/L for ultra 0.95 (95% CI: 0.92– benefit of results
relative changes in 0.98) vs. relative
cTn change 0.76 (95% CI:
0.70–0.83) p<0.001
Aldous 2012 Early means of hs- Prospective cohort NSTE-ACS with NSTE-ACS STEMI Hs-TnT and Dx of MI on admission Mortality at 1 y Hs TnT 95% CL for MI Blood samples not
22291171(39) TnT vs. 909, and 205 with conventional and hs- <18 y, unable to conservative TnT at at 2 h Hs superior to Dx at 2 h taken beyond 2 h.
conventional cTnT AMI TnT assays follow-up admission, 2 h and Hs-sens 92.2% and conventional Sens (95% CI: 88.1%– Used cTnI as gold
in NSTE-ACS 6-12 h spec of 79.7% Death 5.4 (95% CI: 2.7– 95.0%) spec (95% CI: standard for Dx of MI
10.7) and HF 27.8 (95% 78.6–80.5)
CI: 6.6–116.4)
Mueller 2012 Kinetic changes on Prospective cohort Pts with ACS with hs ACS with 2nd blood STEMI or LBBB Hs-TnT-ACS and Absolute delta vs. +Predicted value of ROC for absolute Relative changes
22134520(40) hs-cTnT in ACS 784 TnT vs. non-ACS with draw within 6-h non-ACS with relative delta absolute change 82.8% change added value for confined to 6 h, not
and non-ACS NSTEMI 165 hs-TnT above 99th Non-ACS with 2 elevated hs-TnT2 ROC-optimized value -predicted 93.0% entire ACS cohort vs. 24 h.
percentile blood draws blood draw within 6 6.9 ng/L was sup to rel relative change. Not all pts received
h change p<0.0001 angiography
≥20%
ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; ASA, aspirin; AUC, area under the curve; CK, Creatine Kinase; CKD, chronic kidney disease; CK-MB, creatine kinase-MB; cTnT, cardiac troponin T; cTn, cardiac troponin; cTnl, cardiac troponin
l; Dx, diagnosis; ED, emergency department; Hs, high sensitivity; hs-cTnI, high-sensitivity cardiac troponin I; hs-cTnT, high-sensitivity cardiac troponin T; hs-TnT, high-sensitivity troponin T; LBBB, left bundle-branch block; MBCK, MB Isoenzyme of Creatine Kinase; MI,
myocardial infarction; MRI, magnetic resonance imaging; N/A, not applicable; NST-ACS, non-ST acute coronary syndrome; NSTE, Non-ST-elevation; NSTEMI, Non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; Pts, patients; Px,
prognosis; ROC, Receiver Operating Curves; Sens, sensitivity/sensitivities; Spec, specificity/specificities; Std TnI, standard troponin I; Std cTnT, standard cardiac troponin T; STEMI, ST-elevation myocardial infarction; Sx, symptom; Tn, troponin; TnT, troponin T; TnI,
troponin I; and UA, unstable angina.
Data Supplement 5. CK-MB, MB Isoforms and Myoglobin, Compared With Troponins (Section 3.4.4)
Inclusion Exclusion Primary Endpoint & Secondary Endpoint &
Criteria Criteria Results Results
Apple 1999 Use of triage panel of Multicenter Comparison of Pts in ED with N/A Triage panel Concordance Sens/Spec ROC values Does not address
9931041(41) TrT, CK-MB, and prospective study myoglobin, TnI and ACS biomarkers to for detection or rule-out TnI: 98/100 TnI: 0.97 reinfarction or AMI
myoglobin for AMI 192 CK-MB for sens and evaluate ROC for of MI CK-MB: 95/91 CK-MB: 0.905 presenting after 72 h
detection spec AMI pred TnI >89% Myoglobin: 81/92 Myoglobin: 0.818
CK-MB >81% diff p<0.05
Myoglobin >69%
TACTICS-TIMI 18 CK-MB vs. TnT to Multicenter CK-MB elevated in 1st 24 h of chest N/A Invasive or CV events 30 d/180 d No evidence of OR benefit of invasive Small group
Kleiman 2002 predicted cardiac risk prospective study 826. With CK-MB-, pain conservative strategy Event rates 2× as high interaction between CK- strategy analysis–hypothesis
12354426(42) and benefit in AMI 2,220 TnT elevated in 361 with CK-MB and TrT with CK-MB+ value −. MB elevation and CK-Tr+ generating
invasive strategy for 30-d and 180-d benefit in invasive with strategy on 30-d and 30 d: 0.13 (95% CI:
risk. Tr+, but CK- 180-d endpoints 0.04–0.39)
180 d: 0.29 (95% CI:
0.16–0.52)
Aviles 2002 Long term Px Retrospective All CK-MB- and TnI+ Clinical UA N/A Using TrI with normal 2-y all-cause mortality N/A 2-y mortality Tr >0.5 Study did not
12372578(43) in UA with elevated cohort including Class CK and CK-MB for 2- 20% with Tn>0.5 ug/L, vs. <0.5 evaluate serial ECGs
TnI and normal CK- 724 IIIa y risk evaluation 8% with <0.5 ug/L HR 2.59 (95% CI: for dynamic changes
MB and CK 1.66–4.05); p<0.001
Sallach 2004 Sens Prospective Myoglobin and TnI Possible AMI with Incomplete Myoglobin Dx of MI Increase myoglobin of 20 Combination sens Change Myoglobin Relatively small
15464666(4) of myoglobin with multicenter normal TrI (27) biomarker panel with normal TnI ng/mL from 0-90 min change myoglobin+ TnI >20 number of AMIs.
normal TnI in AMI 817 or noncardiac max diagnostic utility with at 90 min 90 min Predetermined
–myoglobin and-TnI at 97.3% Sens: 83.3%, 88.6% values of myoglobin
admission spec: 99.5% – not evaluated
Predicted value for
AMI
Eggers 2004 Value of adding Prospective cohort TnI and CK-MB Chest pain >15 STE TnI and Myoglobin TnI highest sens of all TnI 0.07 ug/L cutoff TnI sens 93% spec Relatively small
15459585(44) myoglobin to TnI to 197 min in past 24 h for exclusion of MI markers at all-time pts. sens: 81% at 2-h group.
exclude AMI 30 min=93%, 2 h=98%, CK-MB 79% Relatively long delay
3 h=100% Myoglobin 67% time from pain to
admission
Storrow 2006 Associated among Multicenter Discordant CK-MB/Tn Possible ACS Transfer CK-MB and Tr with OR for AMI vs. Tr-/CK- CK-MB+/CK- CK-MB/Tn+: N/A
17112930(45) discordant Tn, CK, prospective 113 or ECG for evaluation of MB-both positive: 26.6 5.7 (95% CI: 4.4–7.4) 26.6 (95% CI: 18.0–
and CK-MB chest registry includes MB with routine purposes significance. of Tn+ 4.8 CKMN+/CK+ 39.3) Tn+/CK-MB-:
pain evaluation 1,614 normal CK 239 discordant values CK-MB+ 2.2 4.36 (95% CI: 3.6–5.2) 4.8 (95% CI: 3.4–6.8)
Ref: vs. CK-MB- Tn-/CK-MB+:
2.2 (95% CI: 1.7–2.8)
CRUSADE Frequency and Multicenter 22,687 Tn+ High-risk NSTE- N/A CK-MB and Tr during Adjusted OR for hospital In-hospital mortality CK-MB+/Tn+: Used individual labs
Newby 2006 implications of prospective 20,506 CK-MB+ ACS 1st 36 h of ACS to mortality both−: 2.7% 1.53 (95% CI: 1.18– for ULN.
16412853(46) discordant CK-MB 29,357 3,502 both – evaluate discordance CK-MB+/Tn +: 1.53 both+: 5.9% 1.98) No account for timing
and Tn in ACS 2,988 only CK+ CK-MB-/Tn+: 1.15 Only CK-MB+: 3.0% CK-MB-tn+: of positive markers
5,349 only Tn + CK-MB+/Tn- 1.02 Only Tn: 4.5% 1.15 (95% CI: 0.86–
1.54) NS
CK-MB+/Tn-:
1.02 (95% CI: 0.75–
1.38) NS
Kavsak 2007 Effect of Tn on Retrospective CK-MB isoforms, Possible ACS N/A CK-MB , myoglobin Clinical sens for AMI: N/A WHO MI def: Insufficient time
17306781(47) myoglobin and CK- cohort myoglobin and Accu and TrI to compare For both myoglobin and sen >90% elapse before
MB isoforms in ACS 228 TnI utility in R/O MI <6 h CK-MB Dec. in ESC/ACC def: remeasuring TnI
assays ESC/ACC Both sen<70%
MI def Using TnI assay
Jaffery 2008 Myoglobin and TnI Retrospective TnI, myoglobin, and Possible ACS N/A TnI, Myoglobin, and +TnI and +Myoglobin, N/A +TnI: Single center. TnI
19061710(9) pred of long-term cohort CK-MB CK-MB at but not +CK-MB 1.7 (95% CI: 1.3–2.3) assay no longer in
mortality in ACS 951 presentation with Pred. 5-y all-cause +Myoglobin: use.
ACS mortality 1.6 (95% CI: 1.2–2.1) No peak levels of
+MB: NS markers recorded
Di Chiara 2010 Pred value of TnI vs. Prospective 55 STEMI and 5 AMI + reperfusion No pacemakers, TnI and CK-MB at Tn at 72 h most accurate N/A TnI: Blood samples every
20588136(10) CK-MB for infarct cohort NSTEMI with CMR within 7 clips, peak admission and estimate of predischarge 0.84 (95% CI: 0.75– 6 h could be too
size with CMR 60 TnI, CK-MB d markers on serially up to 96 h infarct volume 0.91) sparse.
admission from Sx onset CK-MB: Could miss
0.42 (0.19–0.62) biomarker peak
p<0.02
ACTION-GWTG Prognostic value of Retrospective Peak CK-MB and TnI AMI in data Peak values Peak CK-MB and TnI Both peak CK-MB and N/A Peak CK-MB Registry only collects
Registry CK-MB vs. Tn in AMI registry registry with below lab ULN for in-hospital TnI are independently C-statistic 0.831 in-hospital outcomes.
Chin 2012 26,854 biomarkers mortality associated with hospital Peak TnI Participation in
22434769(48) mortality CK-MB >TnI C-statistic 0.824 registry voluntary
p=0.001
Ilva 2005 Novel TnI in early risk Prospective cohort Standard TnI novel TnI Biomarkers at 0 Absence of 1 or Comparison of 3 Positivity of novel TnI MI within 3 h of Novel TnI+ in 27.5%, Use a 1st generation
15667582(12) stratification in ACS 531 myoglobin h, 1-12 h and 24 more biomarkers biomarkers at times assay for AMI in higher presentation: 50% by standard TnI in 17.5%, TnI assay with low
h after admission indicated percent than other novel TnI and only (p<0.010) and analytic limits
biomarkers 11.5% by reference TnI myoglobin+ in 24.1%
assay, (p<0.001) (p=0.067)
44% by myoglobin ROC: novel TnI 0.937,
(p=NS) ref TnI 0.775,
myoglobin 0.762
(p<0.001)
Volz 20012 Can Tn alone be Retrospective TrT and CK-MB All pts with TrT in Initial CK-MB+ with TnT- to None with Tn- but CK- N/A Rate of true +CK MB No evaluation of CK-
21129891(13) used for initial AMI cohort ED with nonnegative Tn determine value on MB+ with Tn- : MB in pts with
screening with 11,092 correspond CK- AMI screening Judged to have AMI 0% (95% CI: 0–0.04%) intermed or Tn+.
elimination of CK-MB MB No follow-up with -
CK-MB or Tn.
Lim 2011 CK-MB vs. Tn in Dx Prospective cohort TnI and CK-MB PCI and CMR N/A CK-MB and TnI after Only small min of +Tn Percent changes in ROC for detection of Small sample size.
21292125(49) of AMI after PCI 32 imaging baseline PCI to determine Dx had CMR abnormal CK- inflamed markers new MI No evaluation of
and 7 d of AMI MB+ closely approximate corresponded with CK- CK-MB: 0.97 inflammed markers
CMR injury MB, but not TnI levels TnI: 0.985 after 24 for TNF
for CRP and SAA NS, but poor alpha
TnI specific
22% TnI
93% CK-MB
ACC indicates American College of Cardiology; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CK, creatine kinase; CK-MB, creatine kinase MB; CK-Tr+, creatine kinase troponin positive; CMR, cardiovascular magnetic resonance; CRP, C-reactive
protein; CV, cardiovascular; Dx, diagnosis; ECG, electrocardiograph; ED, emergency department; ESC, European Society of Cardiology; MI, myocardial infarction; Myo, myoglobin; N/A, not applicable; NSTE-ACS, Non-ST elevation acute coronary syndrome; NS, not
significant; NSTEMI, non-ST segment myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; Pred, predicted; pts, patients; Px, prognosis; ROC, receiver operator curve; SAA, serum amyloid A protein; Sens, sensitivity/sensitivities; Spec,
specificity/specificities; STEMI, ST segment elevation MI; Tn, troponin; Tn+, positive troponin, Tn-, negtative troponin; TNF, tumor necrosis factor; TnI, troponin I; TnT, troponin T; TrT, troponin T; UA, unstable angina; ULN, upper limit normal; and WHO, World Health
Organization.
Data Supplement 6. Bedside Testing for Cardiac Biomarkers (Section 3.4.4)

Study Name, Author, Study Aim Study Type/ Intervention vs. Patient Population Study Intervention Endpoints P Values, Study Limitations
Year Size (N) Comparator (n) OR: HR: RR: & 95
CI:
Inclusion Exclusion Primary Safety Secondary

Criteria Criteria Endpoint & Endpoint & Endpoint &
Results Results Results
Hamm 1997 Bedside evaluation Prospective TnT vs. TnI for Dx Acute chest STE or AMI Bedside tests of TrT AMI N/A Event rates for – 30-d event All pts with +TnT
9385123(50) of TnT and TnI in cohort of MI and 30-d pain <12 h within 2 wk and TrI 2×, arrival and TrI sens: 100% tests: TrT 26 (10–49) admitted so event
acute chest pain 773 events without STE >4 h TrT sens: 94% 1.1% TnT TrI 61 (15–512) rate may be lower
+TnT 123 0.3% TnI than that with
+TnI 171 conventional decision
making
Van Domburg Long-term Prospective TnT, CK-MB, Suspected MI within Blood specimen at 0 h, 29%+ on N/A Early myoglobin +TROPT risk for 3-y Detection limit of TnT
2000 prognostic cohort myoglobin ACS previous wk 3 h, 6 h, 12 h, 24 h, 48 admission predict 3-y mortality: higher than 2nd
10980212(51) significance of 163 98 TnT + <12 h h, 72 h, 96 h 60%+ in 12 h mortality 4.3 (95% CI: 1.3– generation Tn
bedside TnT 48 + baseline Bedside assay TROPT 3.7 (95% CI: 14.0)
50 positive 3-12 h and quantitative assay 1.0–12.0) Quantitative assay
2 positive 12-96 h sample up to 12-h 2.9 (95% CI: 1.0–8.6)
effect on mortality
prediction
Amodio POC TnI at 99th Retrospective Higher vs. lower Suspected STE-ACS or Bedside TrI Best clinical N/A Sens of Tn Sens at 99th No info on outcomes
2007 percentile cutoff for cohort TnI cutoffs and Dx angina or AMI LBBB Stratus CS for AMI Dx cutoff at 99th myoglobin at 2 percentile 77.3% Long median delay
17429291(52) diagnostic accuracy 516 of AMI using different cutoffs percentile 0.03 cutoffs (68.3–84.7) time from pain onset
of MI 70 TnI+ 0.03–0.07 ug/L 36.4% and 49% 0.03>0.07 to admission
p<0.005 No consideration of
muscle trauma or
renal insufficiency
DISPO-ACS POC length of stay Multi-institute Bedside Tn testing Suspected Tachyarrhythmia POC markers vs. lab POC discharge N/A Transfer to inpt Turnaround at Possible Hawthorne
Ryan 2009 in ED prospective study + central lab ACS with or ECG AMI markers Home 4.5 h POC 5.4 h baseline effect bias in testing
18691791(53) 2,000 Central lab only biomarkers Lab discharge Lab 5.5 h POC 0.30 h areas.
1,000 in each arm Home Lab 1.07 h Different interinstitute
4.6 h sampling times.
CRUSADE Use patterns of POC Retrospective POC with Tn+ vs. POC Tn in Death within 24 h Hospital and pt Higher POC had N/A ED length of +POC results Sample size relatively
Takakuwa testing for Tn in multi-institutional Tn- NSTE-ACS Hospital with 30 characteristics shorter ED stay, stay (h) associated with limited.
2009 NSTE-ACS 12,604 6,185 +POC result pts. In-hospital events and less likely to use No POC 4.2 expedited and higher No record of type of
19743496(54) 6,419 negative Infrequent care variables drug IV (2.9–6.5) use of anti-ischemic bedside marker test.
POC result percentage use Hospital using POC High POC therapy. No std. for + or − test
of bedside Tn testing >50% vs. <50% 3.9 (2.6–6.0) p<0.0001
testing p<0.0001
Birkhahn 2011 POC vs. core lab Prospective POC and core lab Suspected STE, ECG, or POC (TnT) CK-MB, 6.5 h saved N/A POC pathway POC benefited 60% Time of 2nd blood test
20825823(55) testing for time cohort testing of TnT ACS with 2 lack of serial myoglobin vs. central using POC and had 32% false (95% CI: 52–68) of varied widely
saving and 151 TnT+ in 12 pts TnT 6 h apart biomarkers lab testing (TnI) relative sens of positives pts with cost of $7.40
cost/benefit baseline +2h 100%. POC sens (95% CI: $6.40–
vs. baseline +6 h p<.00001 100%, spec 65% $8.70) per direct pt
Accuracy 68% care h saved.
Scharnhorst 2011 Sens and spec of Prospective POC evaluation Suspected STE on AD POC Tn values At T2 Sens: 87% N/A Use of 30% 2-h sens and spec of Low number of pts.
21350097(56) bedside Tn cohort Tn, CK-MB, NSTEMI ambulance to T0–T12 h and Spec: 100% Diff T2-T0 myoglobin and CK- No subgroup
compared with CK- 137 myoglobin, for hospital sens/spec +PV: 100% without absolute MB lower than Tn analysis. Broad 95%
MB and myoglobin rapid detection of for MI at 99% −PV: 96% included above Myoglobin: 50/92 CI.
+test cutoff 99th percentile CK-MB: 48/96
37+ ACS: Sens: 100%
7 UA Spec: 87%
26 NSTEMI
4 STEMI
ASPECT Validate safety of Multicenter POC evaluation Suspected STE ACS, ADP use of POC Tn, Major CV events ADP class. For 30-d events For 30-d events Low specificity.
Than 2011 predefine 2 h prospective Tn, CK-MB, ACS Noncoronary CK-MB, and myoglobin at 30 d 9.8% low risk. TIMI + ECG ADP Sens: 99.3% Atypical Sx not
21435709(57) protocol (ADP) for observation study Myoglobin chest pain with 30-d follow-up ADP Major adverse Sens: 98.1% (95% CI: 07.9–99.8) included
ACS 3,582 3260 ADP+ Sens 99.3% event in only Spec: 14.6% Spec: 11% (10–12.2)
270 ADP– 0.9% -PV: 98.3% −PV: 99.1% (97.3–
3,582 30-d follow- 99.8)
up
GUSTO-IV Comparison of POC Prospective 2 POC vs. 2 All pts in ED N/A Tn assays with 99th 99th percentile N/A Central lab 99th percentile No attempts to relate
Venge 2010 vs. laboratory cohort central laboratory with Tn assays percentile URL cutoffs cutoffs: identified more POC 1 vs. central lab results to Dx of MI,
21095269 (58) assays of Tn 1,069 assays central lab who died of CV 1: 20% vs. 39% only outcome
cTnI cutoffs identified disease up to 3 POC 2 vs. central predictions
more pts with mo: lab:
high cTnI and 88% vs. 50% 2:27% vs. 74%
predicted higher 1: 81% vs. 54% p<0.001 for each
% deaths 2
[RATPAC] Variation in Multicenter POC vs. central Suspected, but Proven MI by POC or std care with Difference in N/A The cost per pt OR varied from 0.12 1° outcome based
Bradburn 2012 outcomes and costs prospective lab assays at 6 not proven ECG, high-risk CK-MB, myoglobin, proportion of pts varied from (95% CI: 0.01–1.03) upon 1° effectiveness
21617159(10) in different hospitals analysis hospitals AMI at 6 ACS, known and Tn biomarkers successfully £214.49 <control to 11.07 (05% CI: outcome rather than
using POC 2,243 hospitals. CAD, serious discharged. POC group to 6.23–19.66) with economic measures.
noncoronary led to higher £646.57 more significant Response rate was
pathology, proportion in 4, expensive with heterogeneity only 70% so possible
recurrent chest lower in 1 and weak evidence between hospitals responder bias
pain equivocal in 1. of heterogeneity
among centers
p=0.08
[RATPAC] Cost effectiveness of Multicenter Std care 1,118 Suspected, but Proven MI by POC or std care with POC associated N/A Probability of std Mean costs per pt 1° outcome based on
Fitzgerald 2011 POC biomaker prospective POC 1,125 not proven ECG, high-risk CK-MB, myoglobin, with higher ED care being $1,987.14 with POC 1° effectiveness
21569168(59) assay analysis AMI at 6 ACS, known and Tn biomarkers costs, coronary dominant 0.888 vs. $1,568.64 with outcome rather than
2,243 hospitals CAD, serious care costs, and POC dominant std care p=0.056 economic measures.
noncoronary cardiac 0.004 Response rate 70%
pathology, intervention so possible responder
recurrent chest costs, but lower bias.
pain general pts costs
1º indicates primary; ACS, acute coronary syndrome; ADP, adenosine diphosphate; AMI, acute myocardial infarction; CAD, coronary artery disease; CK-MB, creatine kinase MB; cTnI, cardiac troponin I; CV, cardiovascular; Dx, diagnosis; ECG, electrocardiograph; ED,
emergency department; IV, intravenous; Lab, laboratory; LBBB, left bundle-branch block; MI, myocardial infarction; Myo, myoglobin; NSTE ACS, non-ST elevation acute coronary syndrome; NSTEMI, Non-ST-elevation MI; POC, point of care; pts, patients; +PV, positive
predictive value; -PV, negative predictive value; Sens, sensitivities; Spec, specificities; Std, standard; STE, ST-elevation; STE ACS, ST-elevation acute coronary syndrome; STEMI, ST-elevation MI; Sx, symptom; TIMI, thrombolysis in MI; TnI, Troponin I; TnT, troponin
T; TrI, troponin I; TROPT, Troponin T rapid test; TrT, troponin T; and UA, unstable angina.
Data Supplement 7. Summary Comparison of Injury Markers (Section 3.4.4)

Study Name, Study Aim Study Type / Intervention vs. Patient Population Study Endpoints P Values, Study Limitations
Author, Year Size (N) Comparator (n) Intervention OR: HR: RR: & 95 CI:
Inclusion Exclusion Primary Endpoint & Secondary Endpoint &
Criteria Criteria Results Results
FRISC Multiple biomarkers Multi-institution TnT UA or possible Increased risk Biomarker Cardiac death at 37 mo Highest tertile of CRP Multivariate analysis: No evaluation of LV
Lindahl 2000 as long-term risk prospective 917 CRP MI within 72 h of bleeding samples at 0 h, Multivariate analysis significant for mortality. High TnT: function.
11036119(60) predictors for CV Fibrinogen (dalteparin 12 h, 24 h TnT and CRP Lowest 2 tertiles NS 10.8 (95% CI: 2.6–44.6) Use of death certificates
death trial) independently predicted difference High CRP may misclassify.
of mortality p=0.001 3rd vs. 2nd tertile 2.3 (95% CI: 1.3–4.0)
Fibrinogen NS
TACTICS-TIMI18 Use of multiple Multi-institution TnI, CRP, BNP in Possible ACS Age <18 y 3 biomarkers at Death/MI/HF at 6 mo 30-d mortality 1 Biomarker+:2.1 Using binary cutpoints of
Sabatine 2002 biomarkers to predict prospective combination vs. each within 72 h pregnancy, enrollment Number of elevated RR p=0.006 biomarkers rather than
11956114(61) MACE in NSTE-ACS 450 alone significant biomarkers include 0 Biomarker+: 1 2 Biomarker+:3.1 higher levels.
(OPUS-TIMI comorbidities, prediction of outcome 1 Biomarker+: 1.8 p<0.001 Very insensitive cTn assay
16) bleeding 2 Biomarker+: 3.5 3 Biomarker+: 3.7
1,635 tendency 3 Biomarker+: 6 p=0.001
(TACTICS-18) p=0.014 (6 mo)
HOPE 9 Biomarkers to Multicenter Evaluation of CRP Hx of CAD, HF, low LVEF, 9 biomarkers on Combined events 4.5 y Only inclusion of BNP HR: BNP 1.721<0.001 Only baseline
Blankenberg evaluate improved prospective fibrinogen, IL-6, TNF stroke, PAD, nephropathy enrollment Significant relations: provided info above that sIAM 1.46=0.0003 measurements; later
2006 CV risk in a 2nd d 3,199 1, 2, sIAM-1, s-IAM-1, diabetes MI, or stroke 4 BNP, sIAM, from traditional risk Microalbuminuria analysis on frozen
16831981(62) prevention population BNP, IL-1 wk before Microalbuminuria, s- factors 1.55=0.0004 specimens; for our
RA microalbuminuria, enrollment IRA-1, fibriongen sIAM1.46=0.0003 purposes, not an ACS study
individually for MACE Fibriogenen 1.31=0.02
McCann 2008 Role of novel Multicenter Multiple biomarker Chest pain <24 Transfer from Biomarkers on Dx of AMI only H-FABP -PV Sens H-FABP: 73% Only single measure of
18682444(63) biomarkers in AMI Dx prospective 664 comparisons including h to 2 CCUs other hospital entry challenged cTnT and H-FABP 75% Sens cTnT: 55% biomarker.
cTnT, H-FABP, BNP, thrombolytics combined approach cTnT–90% On admission p=0.043.
hs-CRP, D-dimer, or improved -PV Either–97% Combined improved sens:
MPO, MMP-9, PAPP- anticoagulant (95% CI: 91%–99%) 85%; p≤0.04 vs. individual
A, sCD40L values
FRISC Eggers Risk predicted by Multicenter Evaluated: cTnI, BNP, NSTE-ACS Bleeding risk, Biomarkers at 5-y follow-up BNP: BNP 1.7 (95% CI: 1.3–2.1); Outcomes before more
2009 multiple biomarkers retrospective CRP, estimated GFR high creatinine, enrollment, 6 BNP strongest predictor 6 wk: 1.5 p<0.001 p<0.00 1 5 y advanced 2º previous
(64) in NST-ACS analysis PCI in previous wk, and 6 mo for mortality 6 mo: 1.4 p=0.001 only 6 wk BNP showed measures.
1960803464) 877 6 mo, decision significant increments to Preselected population
for PCI before established risk factors C-
randomization statistic 0.69; p=0.03
ARCHIPELAGO Multiple biomarkers Multicenter Evaluated 9 NSTE-ACS STE-ACS, Biomarkers at Biomarkers for IL-6 AUC significant IL-6: 1.69 (95% CI: 1.2–2.3) Post-hoc analysis;
Beygui 2010 for risk in NSTE-ACS prospective trial biomarkers: planned randomization Ischemia/HF at 2 mo improved model for BNP :3.2 (95% CI: 2.0–5.0) Only 2-mo follow-up
20723640(65) Post hoc CRP, IL-6, MPO, PL- corresponding IL-6 corresponding with ischemia, 3 biomarkers + Aldo: 1.57 (95% CI: 1.1–2.6) Select group of pts.
analysis 22, MMP-9, IMA, interval, CHF, Ischemia BNP, for HF improved MMP-9: 0.64 (95% CI: 0.46– No indication of severity
440 sCD40L, BNP, hypotension, aldosterone MMP-9 for performance models for 0.88) of HF.
aldosterone, cTnI low creatinine HF HF
Cl
Manhenke 2011 Elucidating complex Multicenter 37 biomarkers AMI Not Stated Biomarkers 2 sets of biomarkers Natriuretic peptides Of 5 sets of biomarkers only Limited number pts
22197217 (66) interactions between prospective trial complicated by median 3 d after corresponded with risk among others provided 2 sets showed significant Relatively small number
circulated biomarkers 236 HF AMI Dx for death and combined significant contribution to prediction events. Blood Time frame 1
following AMI death/reinfarction risk assessment d–10 d post- MI
Bhardwaj 2011 Assess role of 5 Prospective Evaluated: Possible ACS Multiple Biomarkers at Compared with cTnT, +PV Sens and –PV: Small sample size
21835288(67) biomarkers in Dx in cohort BNP, IMA, H-FABP, including presentation diagnostic information cTnT: 65% BNP: 73%, 90% Incomplete biomarker
ACS 318 hs-TnI, FFAu vs. cTnT ESRD, increased with BNP, hs-TnI: 50% Hs-TnI: 57%, 89% Data. Dichotamous
thrombolytic FFAu, hs-TnI, but not FFAu: 40% FFAu: 75%, 92% cutpoints rather than
agents, IMA and H-FABP BNP: 28% (Highest) multiple cutpoints
noncardiac IMA: 17% Increased C-statistic for
chest pain H-FABP: 26% cTnT :
BNP 0.09
Hs-TnI 0.13
FFAu 0.15
All p≤0.001
MERLIN-TIMI Incremental Multicenter cTI Possible STE-ACS Biomarkers at Including all biomarkers Addition of biomarkers to Addition of biomarkers to LV function incomplete.
Scirica 2011 prognostic value of prospective BNP ACS ESRD presentation only BNP and cTnI reference for CV reference for CV Death: No serial evaluations of
21183500(68) multiple biomarkers 4,352 CRP CV Shock associated with 12-mo death/HF: cTnI: 0.805 biomarkers, not
in NSTE-ACS MPO Short life CV death cTnI: 0.776 BNP: 0.809 generalizable to overall
expectancy Only TnI with BNP: 0.790Ref: 0.749 p<0.001 population.
reinfarction Ref: 0.784
CAPTURE Predictive value of 7 Multicenter Hs-CRP Possible Ischemia >48 h Biomarkers after 4-y MI/death TnT: 1.8 (95% CI: 1.2– Admission levels of +TnT: Not adjudicated data for MI
Oemrawsingh Biomarkers in NSTE- prospective MPO NSTE-ACS from last episode of A multimarker 2.6) HR 1.8 Dx
2011 ACS 1,090 sCD40L enrollment angina model of TnT, IL-10, IL10: 1.7 (95% CI: 1.1– +IL-10:HR: 1.7 No info on long-term
21558475(69) IL-10 MPO, and PIGF 2.6) +PIGF:HR: 1.9 medications
TnT predicted 4-y rates: PIGF: 1.9 (95% CI: 1.3– +Myoglobin:HR: 1.5
PIGF 6.0% (all normal) 35.8% 2.8) Significant prediction for
PAPP-A (3+ abnormal) CRP: 1.0 NS outcomes in multivariate
sCD40L: 1.2 NS analysis
MPO :1.5 (95% CI: 1.1–
2.1)
PAPP-A: 1.1 NS
FAST II Predictive of MI with Retrospective Hs-TnT + NSTEMI STEMI Biomarkers at Hs-TnT greater No increase in C-statistic C-statistics Retrospective, small
FASTER I Eggers multiple biomarkers cohort h-FABP (retrospective enrollment accuracy in Dx of AMI for hs-TnT by combining Hs-Tnt: 0.84 sample, from 2 different
2011 Combines with hs- 360 copeptin Classification) than H-FABP and with H-FABP 0.85 or H-FABP: 0.80 studies.
22456003(70) TnT copeptin copeptin 0.84 p=0.04 No serial biomarkers
Copeptin: 0.62
p<0.001
Meune 2012 Multimarker Retrospective cTnT- ACS with Detectable Biomarkers At mean follow-up 668 Sens/spec for death/MI ROC AUC for death/MI: Subgroup analysis
22507551(71) evaluation in multi-institution 15 biomarkers undetectable cTnT >6 h from d for death/MI hs-TnT, (%) Hs-TnT: 0.73 (95% CI: 0.6– Relatively low cardiac
suspected AMI with 325 with Including CK-MB and cTnT at 0 h enrollment MR-Pro ADM and PDF- Hs-TnT: 43,86 0.8) events in follow-up
undetectable cTn undetectable MPO and 6 h. ESRD 15 showed increased MR-Pro ADM: 43,76 MR-Pro ADM: 0.71 (95% CI:
levels cTnT risk GDF-15: 95,55 0.6–0.8)
GDF-15: 0.78 (95% CI:
0.71–0.86)
Schaub 2012 Markers of plaque Prospective Multimarkers: Possible ACS ESRD Biomarkers at Diagnostic accuracy for AUC for combination with ROC (AUC): Biomarkers linked to factors
22057876(72) instability use in AMI multicenter Hs-cTnT presentation all non-TnT biomarkers hs-TnT: MPO: 0.63 related to morbidity:
Dx and risk 398 cTnT was low using ROC MPO: 0.95 MRP8/14: 0.65 potentially confusing.
MPO AUC MRP-8/14: 0.95 PAPP-A: 0.62 No info on avoiding adverse
PAPP-A PAPP-A: 0.95 CRP: 0.59 outcomes
CRP CRP: 0.95 cTnT: 0.88
MRP 8/14 (NS change) hs-TnT: 0.96
Weber 2008 Prognosis. value of Retrospective BNP vs. TnT Cohorts PCI within 6 Biomarkers at Among TnT-pts ROC Mortality rate TnT+ vs. Kaplian-Meier Retrospective study. No
18355657(73) BNP with normal TnT multicenter different, 1 mo, or C and entry analysis yielded an TnT-: analysis of risk for death by serial measurements
in ACS 2,614 higher risk for reperfusion optimal cutoff of BNP Registry 1: BNP: Registry 1:
From 2 center (1,131) and the cancer, that was able to 8.2 vs. 3.8% Log-rank: 19.01
registries other lower risk autoimmune discriminate pts at p=0.009 p<0.001
1,131 and (1,483) inflammatory higher risk for death at Registry 2: Adjusted HR: 9.56 (95% CI:
1,483 analyzed disease 6 mo 8.6 vs. 2.8% 2.42–37.7)
separately p=0.009 p=0.001
Registry 2:
Log rank: 23.16
p<0.001
HR: 5.02 (95% CI: 2.04–
12.33)
p<0.001
Wiviott 2004 Gender and Multicenter Multiple biomarker Women with No criteria for Biomarkers at Women more likely had Women with +Tn were Women more likely to have Cutpoints rather than
14769678(74) biomarkers in ACS prospective trial analysis ACS with PCI entry: TnT elevated CRP and BNP. more likely to have elevated hs-CRP continuum.
off 1,865 pts in Men vs. women criteria for PCI. TnI Men more likely had recurrent 6-mo MI 1.49 (95% CI: 1.16-1.92) and N/A to atypical chest pain.
TACTICS-TIMI Randomized to CK-MB elevated CK-MB and Tn whether TnI or TnT elevated BNP 1.33 (95% CI: Not designed to answer
18, 34% were invasive vs. CRP 1.02-1.75) pathophysiological
women conservative BNP questions
strategies
ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; AUC, area under the curve; BNP, B-type natriuretic peptide; CAD, coronary artery disease; CHF, congestive heart failure; CRP, C- reactive protein; cTn, cardiac troponin; cTnI, cardiac troponin
I; cTnT, cardiac troponin T; CCU, cardiac care unit; CV, cardiovascular; Dx, diagnosis; ESRD, end stage renal disease; FFAu, unbound free fatty acids; GDF-15, growth differentiation factor-15; GP-BB, glycogen phosphorylase-BB; GRF, growth hormone releasing
factor; H-FABP, heart type fatty acid binding protein; HF, heart failure; Hs, high sensitivity; Hs-CRP, high sensitivity C-reactive protein; Hs-TnI, high sensitivity troponin I; Hs-cTnt, high sensitivity cardiac troponin T; Hx, history; IL, interleukin; IL-1 RA, interleukin-1
receptor antagonist; IMA, ischemia-modified albumin; LV, left ventricle; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; MMP-9, matrix metalloproteinase- 9; MPO, myeloperoxidase; MRP 8/14,
myeloid related protein 8/14; MR-pro-ADM, midregional pro-adrenomedullin; N/A, not applicable; NS, not significant; NST-ACS, non-ST- segment acute coronary syndrome; NSTE-ACS, Non-ST-Segment-Elevation Acute Coronary Syndrome; OPUS-TIMI, orbofiban in
patients with unstable coronary syndromes; PAD, Peripheral Artery Disease; PAPP-A, pregnancy- associated plasma protein-A; PCI, percutaneous coronary intervention; PIGF, placenta growth factor; PL-22, sectretory type II phospholipase-22; pts, patients; PV,
predictive value; RA, rheumatoid arthritis; ROC, receiver operating curve; RR, relative risk; sCD40L, soluble CD40; Sens, sensitivities; sIAM, solube intercellular adhesion molecule-1; sIRA, soluble intercellular adhesion molecule- 1; Spec, specificities; STEMI, ST-
elevation myocardial infarction; TACTICS, Thrombolysis and Counterpulsation to Improve Cardiogenic Shock Survival; TIMI, Thrombolysis In Myocardial Infarction; Tn, troponin; TnI, troponin I; TnT, troponin T; and UA, unstable angina.
Data Supplement 8. Discharge from ED or Chest Pain Unit (Section 3.5.1)

Study Name, Aim of study Study Type Study Study Study Patient Population Study Study Endpoints P Values, Study Limitations
Author, Year Size (N) Interventi Comparat Intervention Comparator OR: HR: RR & & Adverse Events
on Group or Group 95% CI:
(n) (n)
Criteria Criteria Endpoint Endpoint and Endpoint and
(efficacy) and Results Results
Results
CHEER, Evaluate utility Single- 424 212 212 Intermediate MI, instability 6-h CPU Routine No significant Same as 1º CPU pts: No significant diff in Relatively small
Farkouh,1998 of CPU center, risk, UA marked ST observation hospital diff in early (30 endpoint Fewer follow- early 30-d/late 6-mo single-center,
9862943(75) management prospective changes followed by admission d) and late (6 up ED visits, cardiac events. tertiary care with
of low-risk pts RCT pre-D/C ETT mo) MI, death, cardiac tests Fewer repeat ED extensive
with CP or Ex-MPI CHF, CVA, (p<0.003). visits, cardiac tests expertise/resource
with early D/C card arrest in- (Also, median (p<0.003) s; Pts 95% white.
if negative hospital LOS in CPU No. ETT/Nuc pts
admission vs. 9.2 h) not given. Study
CPU pts not blinded
ROMIO Test rapid Single- 100 50 N/A CP low-risk for <30 y, >7% MI Rapid rule-out Routine No diff in low No MI missed Echo substudy: Admission vs. rapid Small single center
Gomez, 1996 R/O MI to center, MI (Goldman), prob MI protocol in hospital adm 30-d cardiac low rule-out: LOS 14 h study, not blinded,
8752791(76) ↓time/$ prospective stable, (Goldman), ED: Serial events. ITT incremental vs. 27 h; p<0.0001; shorter follow-up,
RCT nonischemic ECG, ischemia, ECGs and analysis: LOS value in rapid Initial cost: $2,089 hospital charges,
ECG; injury VT, AV Bl, new CK-MB q 3-h shorter, $ less rule-out vs. $1,108; and costs not
marker data not BBB, BP x 4. If in ED rule-out patients with p>0.0001; equivalent
required >220/120, negative, PD- pts with MI MI 30-d cost: $2,253
unstable ETT vs. $1,237
Amsterdam, Utility of Observation 1,000 1,000 N/A Nontraumatic Abnormal Immediate N/A Negative ETT No adverse No MACE at 6 N/A ETT performed by
2002 immediate al, single- CP, negative ECG, positive ETT, Max/Sx/ in 64% pts effects of ETT. mo in pts who specially trained
12106928(77) ETT in triage center ECG, marker, marker, Sign limited enabled direct No deaths at 30 did not have MDs
of ED CP pts no arrhythmia, clinically discharge from d. ACS at index (Noncardiologist),
stable, Hx CVD unstable ED, 30-d visit. Approx 40 7 d/12 h function.
not excluded follow-up: NPV min total time Limitation: Includes
98.3%. for scan and only pts able to do
Non-Dx: 23% interpret. ETT
pts, 7 revasc
predischarge;
positive: 13%,
4 NSTEMI at
30 d
Udelson, 2002 Does addition Prospective 2,475 1,215 N/A Suspected Hx of MI, non- Rest SPECT Usual ED MPI: Admission No adverse MPI: See 1º/ 2° endpoint May not be
12460092(78) of rest MPI Multicenter acute ischemia Dx ECG Tc 99m strategy in rate <UC (RR: effects of MPI ↓unnecessary columns generalizable to
improve ED (n=7) RCT (CP or sestamibi, each 0.87; 95% CI: except radiation admission rate small hospitals;
triage of low- equivalent) results to ED institution's 0.81-0.93; and longer time to 42% (10% performed during
risk CP pts to present within for use in ED p<0.001) to discharge absolute ↓); daytime. LOS
admission or ≤3 h, clinical from ED in RR: 0.84; 95% MPI>UC (5.3 vs.
D/C from ED nonischemic decision- negative scan CI: 0.77–0.92; 4.7 h; p<0.001)
ECG, ≥30 y making pts. p<0.001. 30-d
cardiac event
rate was
related to MPI
data; p<0.001
Trippi, 1997 Evaluate utility Prospective, 173 139 N/A ROMI, negative No Hx CAD, DSE by nurse N/A 3-mo follow-up: 54.7% Sx with 72.0% pts See 1º/2° endpoints No control group.
9283518(79) of DSE single- screened, markers, NL screened for & NPV for ACS DSE: test D/C'd directly Method not
telemedicine center, DSE 139 ECG, No Hx exclusions by sonographer 98.5%, PPV terminated for from ED in generalizable,
triage of low- by nurse and eligible CVD. Initially: nurse (not Card present; 51.5%. PVCs=6.3%; phase 4. DSE highly
risk pts with sonographer and pts obs'v'd 12 h; specified) (LV later cardiol Agreement CP, nausea, report to ED in developed/speciali
CP in ED received later. neg DSE: wall motion available by TeleEcho/conv SOB common 2.5 h from zed personnel
DSE (24 direct D/C from abnormal = phone, ED ential Echo Sx request. ED
no DSE ED exclusion) MDs present. kappa 0.78; MDs adm
d/t LV DSE 95% CI: 0.65– some pts
wall telemetry to 0.90 despite neg
motion Card, Dx to DSE.
abnormal ED. Follow-up
) confirm, ECG
Bholasingh, Study Prospective 377 of 377 N/A ≥18 y, non-Dx Arrhythmias, DSE after 12- N/A 6-mo follow-up: All DSE Revasc: Pos See 1°/2° endpoints No control group.
2003 prognostic single- 557 ECG, present HF, severe h observation, 1º endpoints: completed DSE 3/26 pts, Pts discharged DSE not performed
12598071(80) value of DSE center, eligible within 6 h of CP, HTN, serious 6.9% (26/377) Neg DSE 4% within 24 h of Neg DSE d/t poor window in
in low-risk CP blinded. ED pts neg cTt. noncard pts had Pos (1 death), Pos admission; 7/351 pts ~5X 5.7% pts.
pts MDs blinded received disease DSE DSE 30.8% (1 follow-up 100%; greater in neg
to DSE DSE. No death); OR 19.9% protocol DSE
results. DSE: 119 10.7; 95% CI: terminated d't
ACS, 34 4.0–28.8; ECG changes,
other p<0.0001) CP, arrhythmia,
serious severe HTN,
Dis., 24 hypotension.
rest LV
abn.
ROMICAT, Utility of Observation 368 368 N/A CP, neg initial Hx CAD: stent CCTA before N/A Pts without 1 ACS in No MACE at 6 See 1° endpoint Single center, wkd
Hoffman, 2009 CCTA in al cohort Tn, nonischemic or CABG, renal admission, CAD: NPV for absence of + mo in pts who column h, underrepresent
19406338(81) acute CP pts study ECG discharge results not ACS at 6 CCTA showing did not have of elderly d/t
(blinded) disclosed, sig mo=98% (95% coronary plaque ACS at index exclusion of CAD,
stenosis: CI: 98%–100%; visit. ~40 min renal dis. May not
>50% PPV=35% total time for be generalizable to
(95% CI: 24%– scan & smaller hospitals,
48%) interpret radiation
Litt, 2012 CCTA vs UC Prospective 1370, 2:1 908 462 ≥30 y, Noncard sx, NL CTA was 1st Traditional No MI/death at No MI or death CTA: higher See 1º/2° endpoint All exclusions to
22449295(82) to assess low- multictr (n=5) ratio to nonischemic angio within 1 test in CTA care 6 mo in pts with at 60 d in the rate of D/C columns CCTA not noted,
risk CP pts in RT CTA and ECG, TIMI 0-2 y, contraind to group. In neg CTA 640 pts with neg from ED: 50% young study group
ED traditional CTA, CrCl <60 traditional (<50% CTA vs. 23%, 95% (age 50 y),
care care pts stenosis): 0% CI 21-32; radiation
clinicians (95% CI 0- shorter LOS:
decided 1st 0.57) (100%) 18 h vs. 25 h,
tests p<0.001;
higher ID of
CAD: 9.0 % vs.
3.5%, 95% CI
0-11.
ROMICAT II, CCTA vs UC Prospective 1000 501 499 CP, 40-74 y, CAD, ischemic CTA Traditional LOS: CCTA 23 28-d follow-up: Direct D/C from See 1º and 2° Wkd, daytime,
Hoffman, 2012 to assess low- multictr (9) NSR ECG, +Tn, Cr care h vs. UC 31 h no missed ACS; ED: CTA 47% endpoint columns radiation. May not
22830462(83) risk CP pts in RCT >1.5, instability, (p<0.001) no difference in vs. 12%, be generalizable to
ED allergy to MACE at 28 d p<0.001; no smaller hospitals
contrast, BMI difference in
>40, asthma downstream
care
1°indicates primary; 2°, secondary; ACS, acute coronary syndrome; BBB, bundle branch block; BMI, body-mass index; BP, blood pressure; CAD, coronary artery disease; CABG, coronary artery bypass graft; CCTA, coronary computed tomographic angiography; CTA,
computed tomographic angiography; CHF, congestive heart failure; CK, creatine kinase; CP, chest pain; CPU, chest pain unit; Cr, creatinine; CrCl, creatinine clearance; CTA, computed tomography angiography; CVA, cardiovascular accident; CVD, cardiovascular
disease; D/C, discharge; diff, difference; DSE, dobutamine stress echocardiography; Dx, diagnosis; ECG, echocardiograph; ED, emergency department; pts, patients; ETT, exercise treadmill testing; HF, heart failure; HR, hazard ratio; HTN, hypertension; Hx, history;
ITT, intention to treat; LOS, length of stay; MACE, major adverse cardiac events; MI, myocardial infarction; MPI, myocardial perfusion imaging; NPV, net present value; NSR, normal sinus rhythm; PPV, positive predictive value; PVC, premature ventricular contractions;
R/O, rule out; RCT, randomized controlled trial; ROMI, rule out myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction; and UA, unstable angina.
Data Supplement 9. Nitrates (Section 4.1.2.1)

Study Aim of Study Study Study Study Study Patient Population Study Study Endpoints P Values, OR: Study
Name, Type Size (N) Intervention Comparator Intervention Comparat HR: RR & Limitations &
Author, Group (n) Group (n) or 95% CI: Adverse Events
Year
(efficacy) and Results Results
Results
Ambrosio Investigate Multicenter 52,693 10,555 42,138 (80%) Clinical history of Pts with non-CV Chronic Nitrate- Chronic nitrate N/A Antecedent nitrate Chronic nitrate Registry data–
G., 2010 whether registry (20%) pts on (nitrate-naïve ACS, causes for the nitrates on naïve use was use was use remained No data on dose
19903682 antecedent (GRACE) chronic pts) accompanied by clinical admission associated with associated with independent or duration of
(84) nitrate nitrates on at least 1: ECG presentation were a shift away significantly lower predictor of antecedent Rx
therapy admission complete with excluded, as from STEMI in levels of peak CK- NSTE-ACS:
affords ischemia, serial were pts in whom favor of NSTE- MB and Tn (OR: 1.36; 95%
protection increases in initial Dx of ACS ACS. (p<0.0001 for all) CI: 1.26–1.46;
toward acute cardiac markers, was not Chronic nitrate (in both STEMI p<0.0001)
ischemic documented CAD confirmed at use remained and NSTEMI)
events discharge independent
predictor of
NSTE-ACS:
(OR: 1.36; 95%
CI: 1.26–1.46;
p<0.0001)
Mahmarian, Investigate Multicenter 291 214 77 Pts surviving a A- Exclusion criteria: Intermittent PC 1º endpoint: Cardiac event The beneficial Both ESVI and No associated
1998 the long-term RCT QMI severe CHF, NTG patch Change in ESVI rates were not effects seen EDVI were clinical or survival
9610531 (6 mo) persistent therapy was significantly significantly primarily in pts with significantly advantage
(85) efficacy of hypotension, initiated reduced with 0.4 different baseline LVEF reduced with associated with
NTG patches sustained VT, or within 1 wk mg/h NTG between PC ≤40% (delta ESVI, 0.4 mg/h NTG the beneficial
on LV high-degree AVB, after AMI patches and active -31 mL/m2; delta patches (-11.4 remodeling
remodeling in UA, significant and treatment EDVI, -33 mL/m2; mL/m2 and - effects. Gated
pts surviving noncardiac continued for groups both p<0.05) and 11.6 mL/m2, radionuclide
a AMI illness, or either a 6 mo only at the 0.4 p<0.03) angiography used
requirement for or (0.4, 0.8, mg/h dose to assess
known and 1.6 changes in LVEF
intolerances mg/h) and cardiac
volumes –no
TTE, and as such
unable to address
other aspects of
LV remodeling.
Higher NTG
doses prevented
LV remodeling to
a lesser degree
(NTG tolerance
may be limiting
efficacy at the
higher doses).
ISIS-4, Examine the RCT 58,050 29,018 28,539 Within 24 h of Sx Contraindications 1 mo of oral PC NS difference in Greater effect No effect on any 5-wk mortality: Hypotension
1995 effect of oral onset of at the clinician’s controlled- 5-wk mortality early after subgroup studied (mononitrate 17.4% vs. 14.4%,
7661937 controlled- suspected AMI discretion (e.g., release (mononitrate vs. starting (age, sex, previous vs. PC) p<0.0005
(86) release with no clear conditions mononitrate PC): treatment MI, ECG on 7.34% vs. (mononitrate vs.
mononitrate indications for, or associated with a (30 mg initial 7.34% vs. (deaths on d presentation, HF at 7.54%, p=NS PC)
on early contraindications high risk of dose titrated 7.54%; p=NS 0–1: 514 entry, early after 50%-60% had
mortality (4 to, any 1 of the adverse effects, up to 60 mg [1.77%] Sx onset, etc) open label nitrate
wk) study treatments such as qd) mononitrate vs. No difference in therapy.
cardiogenic 628 [2.16%] 12-mo mortality Contraindications
shock, persistent PC; p<0.001). were specified
severe not by the
hypotension, protocol, but by
evidence of the responsible
severe fluid clinician
depletion, etc.)
Or conditions
associated with
only a small
likelihood of
worthwhile benefit
GISSI-3, Assess the Multicenter 19,394 N/A N/A AMI pts within 24 N/A Nitrates (IV PC (open No effect of Systematic The trend toward 6-wk mortality: No excess of
1994 effects of RCT h of Sx onset and for the 1st 24 label) nitrate on 6-wk combined reduction in GTN vs. PC: unfavorable
7910229 lisinopril and no clear h, then mortality: OR: administration cardiac events with OR: 0.94; 95% clinically-relevant
(87) transdermal indications for or transdermal 0.94 (95% CI: of lisinopril and nitrate therapy CI: 0.84–1.05 events in the
glyceryl against the study GTN 10 mg 0.84–1.05) GTN produced reached statistical Combined treated groups
trinitrate treatments daily) No effect of significant significance outcome: GTN was reported. 2D
alone and nitrates on the reductions in among the elderly vs. PC: echo data were
their combined overall and women. OR: 0.94; 95% available only for
combination outcome mortality (OR: Significant CI: 0.87–1.02 14,209 pts (73%)
on 6-wk measure of 0.83; 95% CI: reductions in 6-wk 50%–60% had
mortality and mortality and 0.70–0.97) and mortality and open label nitrate
LVEF after severe in the combined outcome therapy.
AMI ventricular combined with lisinopril.
dysfunction. endpoint (OR:
0.85; 95% CI:
0.76–0.94)
Yusuf, 1988 Examine the Meta- 2,000 N/A N/A AMI pts– Exclusions of Nitrate PC 35% reduction The greatest Both NTG and NS reduction Publication bias
2896919 effect of IV analysis inclusions of individual trials (SD 10) in the reduction in nitroprusside after the 1st wk Baseline risk
(88) nitrates on (10 RCTs) individual trials odds of death mortality reduced mortality, of follow-up heterogeneity
mortality in (2p<0.001; 95% occurred the reduction being Different
AMI CI of predominantly NS greater with definitions of
approximately during the 1st NTG than with clinical endpoints
0.166-0.50) wk of follow-up nitroprusside across the
various studies
1º indicates primary; 2D, two-dimensional; ACS, acute coronary syndrome; AMI, acute myocardial infarction; A-QMI, acute Q-myocardial infarction; AVB, auriculoventricular block; CAD, coronary artery disease; CHF, congestive heart failure; CK-MB, creatine kinase-
MB; CV, cardiovascular; Dx, diagnosis; ECG, electrocardiogram; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; GTN, glyceryl trinitrate; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; IV, intravenous; LV, left ventricular;
LVEF, left ventricular ejection fraction; MI, myocardial infarction; NS, nonsignificant; NTG, intermittent transdermal nitroglycerin; NSTE-ACS, non-STE-elevation acute myocardial infarction; PC, placebo; pts, patients; qd, daily; RCT, randomized controlled trial; Rx,
prescription; SD, standard deviation; STEMI, non-ST-elevation myocardial infarction; Sx, symptoms; Tn, troponin; TTE, transthoracic echocardiography; UA, unstable angina; and VT, ventricular tachycardia.
Data Supplement 10. Analgesic Therapy (Section 4.1.2.2)

Study Aim of Study Type Study Study Study Patient Population Study Study Endpoints P Values, OR: Study
Name, Study Size (N) Intervention Comparator Intervention Comparator HR: RR & 95% Limitations &
Author, Group (n) Group (n) CI: Adverse Events
Year
Inclusion Exclusion Primary Safety Endpoint Secondary
Criteria Criteria Endpoint and Results Endpoint and
(Efficacy) and Results
Results
Iakobishvili, Determine Observational 2,336 218 (9.3%) 2,118 (90.7%) Consecutive N/A IVM No IVM IM associated IVM increased in- Using IVM had higher Pts with IVM
2011 the impact registry pts with ADHF with higher hospital mortality adjustment with adjusted OR for were more likely
21627393 of IVM on participating in unadjusted propensity in-hospital to have ACSs
(89) outcomes of a national HF (11.5% vs. matched death: 2.0; 95%
pts with survey 5.0%) and analysis, IVM CI: 1.1-3.5;
ADHF with adjusted in- was not p=0.02) using
and without hospital associated with logistic
ACSs mortality using increased in- regression
logistic hospital death analysis
regression (OR: 1.2; 95%
adjustment CI: 0.6–2.4;
p=0.55)
Iakobishvili, Assess the Multicenter 993 pts 97 (9.8%) 896 (90.2%) Consecutive Pts IVM No IVN No diff in 30-d N/A Using propensity Using logistic Retrospective
2010 30-d retrospective with pts presenting transferred to mortality with analysis, of 249 regression On-site
20346305 outcomes analysis from NSTE- with ACS to another IVN use. matched STEMI analysis, there catheterization
(90) stratified by the ACSIS ACS any of 26 CCU institution Using pairs, 30-d were no diff in and bypass
IVNs use 2008 database and cardiology propensity death was lower 30-d mortality surgery facilities
among pts wards in Israel adjustment (95 in pts receiving among NSTE- were available in
enrolled in a matched NSTE- IVN; this trend ACS (OR: 0.56; 22 and 10 of the
national ACS pairs): 30-d persisted after 95% CI: 0.14- centers only.
survey of death rate (2.2% logistic 2.33; p=0.43) Relatively small
pts with for pts receiving regression cohort. No data
STEMI and IVNs vs. 6.3%; analysis (OR: regarding the
NSTE-ACS p=0.16) 0.40; 95% CI: exact timing of
0.14-1.14; IVN use or the
p=0.09) cumulative dose
administered. Did
not specify the
types of IVN
used.
Only a minority of
pts were treated
with IVN
Meine, Compare Observational 57,039 17,003 40,036 (70%) Pts presenting Pts who were Morphine No morphine Higher adjusted Increased Relative to those In-hospital Nonrandomized,
2005 outcomes in registry, (30%) with NSTE- transferred within 24 h at risk of in- adjusted OR of receiving NTG, death: morphine retrospective,
15976786 pts who GRACE ACS at 443 out to another of presentation hospital death in in-hospital death pts treated with vs. no morphine: observational
(91) received hospitals institution presentation pts treated with in all subgroups morphine had a adjusted (OR: data
IVM vs. across the US were morphine (including pts with higher adjusted 1.48; 95% CI: Only a minority of
those who from 01/2003– excluded, compared with CHF, ST OR of death: 1.33-1.64) pts were treated
did not 06/2003 because data no morphine depression, <75 1.50; 95% CI: Using propensity with IVM
receive IVM Pts included in could not be (OR: 1.48; 95% y, positive 1.26-1.78 score matching,
the CRUSADE collected CI: 1.33-1.64) biomarkers, morphine use
initiative have nonhypotensive was associated
ischemic Sx at pts) with increased
rest within 24 h Also, increased in-hospital
prior to adjusted OR of mortality (OR:
presentation in-hospital 1.41; 95% CI:
and high-risk adverse 1.26-1.57)
features outcomes
including ST- (death/MI; CHF;
segment postadmission
depression, MI; cardiac
transient ST- shock)
segment
elevation,
and/or positive
cardiac
markers.
ACS indicates acute coronary syndrome; ADHF, acute decompensated heart failure; CCU, cardiac care unit; CHF, congestive heart failure; CRUSADE, Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation
of the American College of Cardiology/American Heart Association Guidelines; diff, differences; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; IVM, intravenous morphine; IVN, intravenous narcotics; MI, myocardial infarction; NSTE-ACS, non-
ST-elevation acute coronary syndrome; NTG, intermittent transdermal nitroglycerin; pts, patients; STEMI, ST-elevation myocardial infarction; Sx, symptoms; and US, United States.
Data Supplement 11. Beta-Adrenergic Blockers (Section 4.1.2.3)

Study Study Aim Study Type/ Intervention Patient Population Study Endpoints P Values, Adverse Study Limitations
Name, Size (N) vs. Intervention OR: HR: RR: & 95 CI: Events
Author, Comparator
Year (n)
Inclusion Exclusion Criteria Primary Endpoint Safety Endpoint Secondary
Criteria & Results & Results Endpoint &
Results
TIMI-IIB Immediate vs. Prospective Immediate IV AMI treated Implanted IV metoprolol as Global LVEF at time No diff in Lower incidence of Resting EF: immediate NS diff in deaths Complexity of
Roberts, deferred BB multicenter group with invasive pacemaker; resting soon as rt-PA of discharge using mortality in both reinfarction 51.0% vs. 50.1% at 6 wk or 1 y interventions other
1991 therapy 1,434 720 vs. HR <55; SBP <100 was started radionuclide groups. In low- (2.7% vs. 5.1%; delayed p=0.22 with immediate than BB
1671346 Deferred group conservative mm Hg; pulmonary followed by oral ventriculography. risk group there p=0.02) at 6 d in NS diff invasive or vs. delayed BB administration may
(92) 714 strategy. edema; advanced 1st metoprolol or LVEF 50.5% at were 7 deaths in the immediate conservatives strategy treatment. More have affected
Susceptible to degree or higher oral metoprolol discharge was 6 wk in deferred group and less in EF comparisons intracranial results.
BB therapy. heart block; asthma beginning on d 6 virtually the same in group vs. none in recurrent chest hemorrhage in
or COPD. both groups immediate group pain (18.8% vs. the delayed
24.2%; p<0.02) group
Ryden, Occurrence of Prospective Metoprolol Sx suggestive Contraindications for Metoprolol IV Significant No increase in BB did not VF: 6 in BB group, 17 in NS adverse Use of a beta-1-
1983 ventricular multicenter 698 of AMI beta-blockade; need than po or PC ventricular significant heart influence PVCs or PC group events with BB blocker precludes
6828092 tachyarrhythm 2,395 PC for beta-blockade’s with admission tachyarrhythmias: block with BB short bursts of VT (0.9% vs. 2.4%) vs. PC assessment with
(93) ias in 697 “administrative to CCU More cases of VF in in 1st 24 h. 3-mo p<0.01 other type BB. No
suspected considerations.” the PC group mortality lower in Requirement for indication of
AMI with BB. BB group (5.7% vs. lidocaine less in BB whether deferred
8.9%) p<0.03 group 16 vs. 38 BB would have
p<0.01 affected results.
Al Reesi, Effect of BB Meta-analysis BB vs. PC or RCT of MI with No information on 6- Beta-1 or 6-wk mortality: N/A Subgroup analysis 6-wk mortality N/A Publication bias as
2008 use within 72 18 studies 74 no control BB vs. PC wk mortality. nonselective BB Adding a BB had no that excluded high- Reduction BB vs. with all meta-
19019272 h of MI on 6- 643 group within 72 h of Treatment started or PC within 72 effect compared risk pts showed control: 0.95 (95% CI: analyses. No
(94) wk mortality 1966–2007 Roughly 50% AMI after 72 h. Non- h of MI. Follow- with control mortality benefit of 0.90–1.01) NS evaluation of other
vs. PC each English speakers up for 6 wk BB: 0.93 [0.88– With high quality outcomes or
0.99] studies only: 0.96 (95% adverse events.
CI: 0.91–1.02) NS Mixed beta-1 and
nonselective BB.
Janosi, BB effects in Multi-institute 950 metoprolol MI >0.28 d AMI or UA <28 d Metoprolol or PC BB reduced total Withdrawal of BB Reduced CV death, Total mortality Death from Only 68% of post-
2003 post-MI with prospective 976 PC before. Contraindicated to for 1 y. mortality by 40%, vs. PC NS. MI by 45%, SCD by p=0.0004, MACE worsening HF MI pts ideal
14564329 CHF trial BB. combined MACE by 50% p<0.0001 educed 49% vs. candidates for BB
(95) 1,926 31%. PC
Hjalmarson Meta-analysis >55 RCT of Over 38,000 AMI Contraindicate to BB, BB vs. PC Total deaths 13% Lipophilic BBs N/A Total mortality N/A N/A
1997 of early BB over 73,000 BB sever HF, heart reduction. prevent vs. p<0.0001
9375948 trials in MI pts Over 35,000 block. Short-term SCD fibrillation after SCD reduction
(96) PC 34% reduction. MI <0.0001
Emery, Use of early Registry of 96 5,422 early BB NSTEMI STEMI Early BB therapy BB therapy showed N/A Hospital Mortality Hospital mortality 0.58 N/A Observational
2006 BBs in hospital pts 1,684 None Ccontraindications to or none lower hospital Killip II/III (95% CI: 0.42–0.81) No adjustment for
17161045 NSTEMI admitted for BB therapy beginning <24 h mortality 6-mo 0.39 (95% CI: 6-mo mortality 0.75 confounders. No
(97) ACS Transfer pts with Hx mortality also lower 0.23–0.68) (95% CI: 0.56–0.997) indication of dose
retrospective of CHF or brand
7,106 Cardiac arrest on
admission
Freemantle BBs in short- Meta - 82 randomized BB in MI in PC N/A BB/PC or Short-term: small N/A N/A Short-term risk for Usually Multiple BB
, 1999 term Rx in MI regression trials or alternative alternative Rx and NS reduction of death bradycardia or brands, varied
10381708 and in longer analysis of Short-term: Rx in controlled begun at any risk for death 0.96 (95% CI: 0.85– hypotension follow-up, diff
(98) term trials with 29,260 trials stage of AMI Long-term: 0.98) times of initiation
secondary acute or past Long-term: significant reduction Long-term: and withdrawal.

preview AMI 24,974 0.77 (95% CI: 0.69–
54,234 pts 0.85)
Dargie, Outcomes of Multicenter Carvedilol 975 AMI with <18 y, use of 6.25 mg BB to Death or hospital N/A All-cause mortality 1º endpoint N/A Insignificant power
2001 carvedilol in randomized PC 984 LVEF≤40%, diuretics or inotropes 25 mg bid or PC admission for CV alone 0.92 (95% CI: 0.80– to detect a diff in
11356434 AMI with LV PC controlled use of ACE followed until problem no Lower in BB group 1.07) all-cause mortality
(99) dysfunction 1,959 inhibitors requisite number difference 0.77 (0.60–0.98)
of endpoints p=0.03
Chen, 2005 Effect of Multicenter Metoprolol <24 h of ACS Scheduled for PCI, IV then po, BB, Death/reinfarction/ 11/1,000 more Less vs. fibrillation MACE for BB: More cardiac Different
16271643 adding BB to randomized 22,929 with STEMI, hypotension, or PC for up to 4 cardiacarrest with BB having with BB p=0.001 0.96 (95% CI: 0.90– shock with BB (d population groups
(100) current std PC controlled PC NSTEMI, or bradycardia, heart wk NS cardiac shock Less reinfarct 1.01); p=0.1 0–1) at centers
therapies in 45,852 22,923 LBBB block, shock during d 0–1 of p=0.001 NS
AMI admission
Ellis, 2003 BB therapy in Pooled date 1,939 BB MI or UA within Pts presenting within BB vs. control 30-d, 6-mo MACE N/A NS diff recurrent MI Death 30-d NA 1° comparison not
14562669 ACS from 5 RCTs 955 No BB 48 h 24 h with ECG through hospital BB decreased Death or MI BB vs. no BB randomized. Diff pt
(101) PCI 2,894 change /UA stay death during both 0.6% vs. 2.0% populations. No
± abciximab PCI periods p=0.017 uniform definition
Death 6 mo of ACS
1.7% vs. 3.7%
p=0.01
McMurray, Effect of BB in Multicenter 975 carvedilol 3–21 d after MI Not stated Carvedilol of PC Arrhythmias over 2 N/A Malignant vs. Atrial arrhythmias: AT, atrial flutter, Not prespecified
2005 reducing PC controlled 984 follow-up 1.3 y for duration of y, atrial and arrhythmias: 0.41 (95% CI: 0.25– atrial fibrillation, analysis. ECG
15708698 arrhythmias 1,959 PC study (average ventricular 0.9% BB 0.68); p=0.0003 vs. vs. tachm, vs. confirmation not
(102) added to Post hoc 1.3 y) arrhythmias lower in 3.9% PC arrhythmias fibrillation available
ACEI analysis of BB group 0.24 (95% CI: 0.34 (95% CI: 0.11–
arrhythmias 0.11–0.49) 0.49); p<0.0001
p<0.0001
Miller, 2007 Impact of Multi- 82.5% received Acute ischemia Hospital transfer, no BB vs. no BB Lower in-hospital N/A Acute BB Hospital mortality: N/A Undocumented
17679127 early use of institutional acute BB vs. <24 h, NSTE, +cardiac markers, no mortality, associated with 0.66 (95% CI: 0.60– contraindicated to
(103) BB in ACS retrospective no BB contrary to BB acute medications reinfarction, shock more invasive 0.72) BB use, hospital
analysis recorded with BB. procedures and Reinfarction actively seeking to
72,054 at 509 No diff in CHF other acute therapy 0.80 (95% CI: 0.72– improve
hospitals 0.89) performance
Shock
0.76 (95% CI: 0.67–
0.87)
Brandler, Literature Meta-analysis Early BB 18+ y, ACE Contraindications to Early BB vs. no No diff in in-hospital N/A In largest study In-hospital mortality N/A Single outcome
2010 review to of RCTs 36,173 pts within 24-h BB BB mortality (45,852) higher 0.95 (95% CI: 0.90– variable. No long-
20078433 determine BB 72,249 with/without pain onset, BB ± PC cardio shock in BB 1.01) term evaluation.
(104) effects on 18 articles PC 36,076 within 8 h of 5.0% vs. control Heterogeneous pt
outcome in presentation 3.9% population
ACS p<0.0001
Kontos, Registry of NCDR 291 hospitals BB within 24 h Contraindications to BB only: early Very early BB use Evidence of NS diff between Early vs. late use Cardiogenic Oral or IV?
2011 BB use in ACTION- 2007–2008 of ACS BB vs. late use increased increased early or late use in cardiogenic shock: shock with use No infomation on
21570515 ACS GWTG 21 822 BB Missing data cardiogenic shock cardiogenic death alone 1.54 (95% CI: 1.26– of BB in ED type of BB or dose.
(105) registry and death or shock shock with early 1.88); p<0.001 No information on
34,661 pts use (<24 h) of BB Death or shock: arrhythmias.
with NSTEMI 1.23 (95 % CI: 1.08–
21 822 1.40); p=0.0016
1º indicates primary; ACS, acute coronary syndrome; ACE, angiotensin- converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; ACTION, Acute Coronary Treatment and Intervention Outcomes Network Registry; AMI, acute myocardial infarction; AT, atrial
tachycardia; BB, beta blocker; CCU, cardiac care unit; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; diff, difference; ECG, electrocardiograph; ED, emergency department; EF, ejection fraction; GWTG, Get With the
Guidelines; HF, heart failure; Hx, history; IV, intravenous; LBBB, left bundle-branch block; LV, left ventricular; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; NCDR- National Cardiovascular
Data Registry; NCDR ACTION-GWTG, National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry- Get With the Guidelines; NS, no/t significant; NSTE, non-ST-elevation; NSTEMI, non-ST-elevation MI; PC, PC; PCI,
percutaneous coronary intervention; pt, patient; PVCs, premature ventricular contractions; RCT, randomized controlled trial; Rt-PA, recombinant tissue plasminogen activator; Rx, prescription; SBP, systolic blood pressure; SCD, sudden cardiac death; std, standard;
STEMI, ST-elevation MI; UA, unstable angina; VF, ventricular fibrillation; and VT, ventricular tachycardia.
Data Supplement 12. Calcium Channel Blockers (Section 4.1.2.4)

Study Aim of Study Study Type Study Study Study Patient Population Study Study Endpoints P Values, OR: Study Limitations
Name, Size (N) Intervention Comparator Interventio Comparator HR: RR & 95% & Adverse Events
Author, Group (n) Group (n) n CI:
Year
(Efficacy) and Results Results
Results
Gibson, Effect of Multicenter 576 Diltiazem PC NQMI >30 m Q waves or Diltiazem PC 14-d reinfarction No increased Refractory Reinfarction: Only 4.8%
1986 diltiazem on double-blind 287 289 Ischemic conduction 24–72 h 9.3% in PC mortality with angina 51.2%(90% CI: withdrawn because
3526151 NQMI. randomized pain or ST disturbances AV from 5.2% in Diltiazem CCB reduced by 7%–67%); of adverse effects.
(106) changes block admission Reduced by Tolerated well diltiazem p=0.0297 No diff vs. PC in LV
Bradycardia Up to 14 d diltiazem with BB Refractory angina failure, shock, AV
Cardio shock 49.7% (90% CI: block, severe
6%–73%); bradycardia, or
p=0.0345 hypotension
Lubsen, Efficacy of BB Multicenter 338 Combination PC UA not AMI Nifediipine, PC Ischemia or No increased Starting a BB Rate ratio for Equal numbers on
1987 and CCB in PC control of nifedipine previously on metoprolol, progression to MI mortality with plus nifedipine CCB: BB alone or
2887097 UA in a CCU and BB or in 48 h. Only CCB. showed no pretreated with combination
(107) metoprolol combination pretreatment with benefit from BB: developed AMI or
BB showed BB initiation 0.68 (0.47, 0.97) reversible ischemia.
favorable effects alone vs. PC. Not on BB:
with nifedipine. 1.51 (0.87, 2.74)
vs. PC
Gibson, Px effect of Multicenter 576 Diltiazem PC Confirmed Q waves or Diltiazem PC Incidence of early N/A N/A CCB red of N/A
1987 dilriazem on double-blind 287 289 NQMI conduction 24-72 h recurrent ischemia:
3303886 recurrent disturbances from ischemia 28% (95% CI:
(108) ischemia AV block admission decreased by 9.3%–53.8%);

Bradycardia Up to 14 d CCB p=0.0103
Cardio shock 15.7% vs. 24.2%
Held, 1989 CCB effect on Meta-analysis 19,000 8,870 CCB 8,889 control MI 22 trials CHF CCB usually Control Risk of death, No increase in Results Mortality: CCB vs. Usual limitation of
2513047 events of 28 trials UA 6 trials Hypotension early in ACS infarct size, or reinfarction or similar in UA PC meta-analysis
(109) AV block reinfarction. No infarct size vs. trials 1.06 (95% CI: heterogeneity of
(most common) effect by CCB vs. PC by CCB 0.96–1.18) in populations and
PC in MI trials. MI trials various agents.
Adverse effects not
addressed per se
Moss, 1991 Diltiazem and Multicenter 2,464 No HTN Hypertension MI treated CHF Diltiazem at PC for same 1st recurrent +pulmonary Significant CCB benefit Retrospective
1872266 long-term PC control Diltiazem: Diltiazem: with diltiazem Hypotension ACS for 12- time period cardiac event: congestion; reduction in hyperension analysis. Post-hoc
(110) outcome 760 471 with or AV block 52 mo CCB benefit only CCB increased BP and HR without analysis of HTN
PC: 762 PC: 471 without in hypertensives Risk: with CCB pulmonary effect. Adverse
hypertension with no Hypertension/ though small. congestion effect of pulmonary
pulmonary No 0.67 (95% CI: congestion on
congestion. hypertension 0.47–0.96) diltiazem outcome
1.32 (95% CI:
0.83-2.10)
1.63 (0.99,
2.69) vs. PC
Furberg, Meta-analysis Meta-analysis 8,350 Nifedipine Control Nifedipine 2º No Nifedipine PC Effect on Increased Total mortality Total mortality Heterogeneity of
1995 of nifedipine of 16 studies 4,171 4,183 prevention randomization 12 AMI mortality sympathy stim Low dose 1.16 (95% CI: clinical trial
7648682 trials on trials with 3 UA Nifedipine and active of 1.06 (95% CI: 1.01-1.33); populations
(111) outcome mortality data 1 SA increased RAAS 0.89-1.27) p=0.01
Short-acting mortality by 16% High dose
Dose related 2.83 (95% CI:
1.35–5.93)
Rengo, Effect of Multicenter 1,073 Verapamil PC Dx of AMI Contraindication Long acting PC For 24 Total mortality No safety Verapamil Total mortality No diff in
1996 verapamil on prospective 531 542 to verapamil Verapamil mo and CV deaths. issues group had verapamil vs. PC discontinuation of
8602564 mortality after trial Hx of severe HF 7-21 d after No diff between lower 30 vs. 29 NS therapy due to
(112) AMI AMI groups reinfarction Cardiac deaths adverse reactions.
360 mg qd rates (NS) 21 vs. 22 NS Death rate and
for 24 mo 39 vs. 49 number of pts
Significantly recruited were
less angina lower than
OR: 0.8 (95% expected and pts
CI: 0.5-0.9) were relatively
young decreasing
the power of study

Smith, 1998 Long-term Retrospective 247 Diltiazem BB At discharge MI or stroke Monotherap Monotherap Deaths in 51 mo N/A Adjusted: for Deaths: CCB Compliance issues.
9809940 outcome cohort 188 59 with UA Dx during y CCB for 1- y BB for 1-7 No diff between CCB vs. BB No infomation on
(113) BB + CCB in hospitalization 7y y BB and CCB NS increase in 1.1 (95% CI: follow-up treatment.
UA CAD 0.49-2.4) Relatively small
rehospitalization/ number of BB users
death
1.4 (95% CI:
0.8–2.4)
Pepine, Safety of CCB Meta-analysis 4,000 Verapamil PC Randomized No randomization Verapamil PC Outcomes with Data too No diff verapamil Combined No evidence of
1998 in CV disease 14 person y studies of or control group CCBs after MI: limited for pts vs. PC in angina death/reinfarcti harm with CCB in
9755379 randomized verapamil vs. PC with pts on: angina.
(114) parallel group and PC from No diff in deaths hypertension 0.82 (95% CI:
studies AMI Decreased No evidence 0.70–0.97);
nonfatal for increased p=0.016
MI harm with Death: 0.93
Decreased verapamil (95% CI: 0.78–
death/reinfarction 1.1)
Reinfarction:
0.79 (95% CI:
0.65–0.97);
p=0.024
DAVIT 6 mo and 12 Multicenter 3,498 Verapamil PC roughly AMI HF, AV block, Verapamil PC for 6 mo NS diff in 6-mo or Higher number 6-mo 6-mo mortality: Dosage of
Danish mo mortality prospective roughly 50% 50% severely 120 tid for 6 12-mo mortality of AV block in reinfarctions: 12.8% verapamil caused
study, 1984 after AMI with study disabling mo rate verapamil verapamil verapamil 7% verapamil significantly
6383832 verapamil diseases, vs. PC group not PC 8.3 % 13.9% PC increased AV block
(115) treatment with associated with NS NS in 1st wk
BB or CCB increased 12-mo More HF in
mortality. NS mortality: verapamil group
decreased in 15.2% p<0.005
vs. fibrillation in verapamil
verapamil 16/4% PC
group. NS
DAVIT II 18 mo Multicenter 1,775 Verapamil PC AMI HF, AV block, Verapamil PC for same Long-term Significant diff In pts without HF 18-mo Minor discrepancies
Danish mortality rates prospective 878 897 severely 360 mg qd period treatment with in reasons for in CCU mortality: between resulting
study, 1990 and major CV trial disabling from 2nd wk verapamil permanently 18-mo mortality: verapamil vs. confidence limits
2220572 events with diseases, of AMI and decreased major stopping verapamil vs. PC PC: and p values from
(116) verapamil treatment with up to 18 mo CV events verapamil vs. 7.7% vs. 11.8% 11.1% vs. the Tarone-Ware
after AMI BB or CCB without PC: p=0.02 13.8%; p=0.11 tests occurred
significant effect 2nd or 3rd 0.64 (95% CI: 0.80 (95% CI: because HR are
on mortality degree AV 0.44–0.94) 0.61–1.05) based on
block , sinus Major CV event Major CV proportional
bradycardia, rates: events: hazards
abdominal 14.6% vs. 18.0% vs. assumption, not the

pain, 19.7%; p=0.01 21.6%; p=0.03 case for the
constipation 0.70 (95% CI: 0.80 (95% CI: Tarone-Ware test
0.52–0.93) 0.64–0.99)
In HF, NS diff in
mortality or
major CV events
2º indicated secondary; ACS, acute coronary syndrome; AMI, acute myocardial infarction; AV, atrioventricular; BB, beta-blocker; BP, blood pressure; CAD, coronary artery disease; CCB, calcium channel blocker; CCU, cardiac care unit; CHF, congestive heart failure;
CV, cardiovascular; diff, difference(s); Dx, diagnosis; HF, heart failure; Hx, history; HTN, hypertension; LV, left ventricular; MI, myocardial infarction; NQMI, Non-Q Wave myocardial infarction; NS, no/t significant; PC, placebo; pts, patients; Px, prognosis; qd, once daily;
RAAS, Renin-Angiotensin-Aldosterone System; SA, stable angina; t.i.d., three times daily; and UA, unstable angina.
Data Supplement 13. Other Anti-Ischemic Inverventions (Ranolazine) (Section 4.1.2.5)

Study Name, Aim of Study Study Type Study Study Study Patient Population Study Study Endpoints P Values, OR: Study
Author, Year Size (N) Intervention Comparator Intervention Comparator HR: RR & 95% Limitations &
Group (n) Group (n) CI: Adverse Events
Results
Wilson SR, Evaluate the Substudy 3,565 1,789 1,776 Pts with Cardiogenic Ranolazine PC 1º endpoint Symptomatic Composite 1º endpoint: Substudy of a
2009 efficacy and from a NSTE-ACS shock, (CV death, MI, documented endpoint driven ranolazine vs. PC RCT that did not
19389561 safety of multinational within 48 h of persistent STE, recurrent arrhythmias by significant HR: 0.86; 95% meet its 1º
(117) ranolazine in RCT ischemic Sx successful ischemia) was (2.9% vs. 2.9%; reduction in CI: 0.75-0.97; endpoint
pts with prior (between Oct revasc before less frequent p=0.92) and recurrent p=0.017 (exploratory)
chronic SA 2004–Feb randomization, with ranolazine total mortality ischemia (HR: Randomization
2007) clinically (HR: 0.86; 95% (6.2% vs. 6.4%; 0.78; 95% CI: was not stratified
Eligibility significant CI: 0.75–0.97; p=0.96) were 0.67–0.91; by Hx of prior
criteria: ≥18 hepatic disease, p=0.017) similar with p=0.002). angina, small diffs
y; Sx of ESRD requiring (Follow-up was ranolazine or Ranolazine in clinical
myocardial dialysis, a median of PC. reduced characteristics
ischemia; at treatment with 350 d) CV death or MI worsening angina between those
least 1 agents known to did not differ (p=0.048) and randomized to
moderate- prolong the QT between intensification of ranolazine or PC
high-risk interval, ECG treatment antianginal exist.
indicator abnormal levels groups (HR: therapy (p=0.005)
interfering with 0.97; 95% CI: Exercise duration
Holter 0.80–1.16; at 8 mo greater
interpretation, p=0.71) with ranolazine
life expectancy (p=0.002)
<12 mo
Scirica, 2007 Assess the Sub-study 6,351 3,162 3,189 Pts with Cardiogenic Ranolazine PC Ranolazine (numerically, but Lower incidence VT ≥8 beats Substudy of a
17804441 potential from a NSTE-ACS shock, was associated not statistically, of pauses ≥3 s (5.3% vs. 8.3%; RCT that did not
(118) antiarrhythmic multinational within 48 h of persistent STE, with fewer lower incidence with ranolazine p<0.001) meet its 1º
actions of RCT ischemic Sx successful episodes of VT of sudden (3.1% vs. 4.3%; SVT (44.7% vs. endpoint
ranolazine after (between Oct revasc before ≥8 beats (5.3% cardiac death in p=0. 01) 55.0%; p<0.001), (exploratory)
ACS 2004–Feb randomization, vs. 8.3%; pts treated with New-onset AF
2007) clinically p<0.001), SVT ranolazine over (1.7% vs. 2.4%;
Eligibility significant (44.7% vs. the entire study p=0.08)
criteria: ≥18 hepatic disease, 55.0%; period)
y; Sx of ESRD requiring p<0.001), or
myocardial dialysis, new-onset AF
ischemia; at treatment with (1.7% vs.
least 1 agents known to 2.4%; p=0.08)
moderate- prolong the QT (Continuous
high-risk interval, ECG ECG [Holter]
indicator abnormal levels recording was
interfering with performed for
Holter the 1st 7 d after
interpretation, randomization)
life expectancy
<12 mo
Morrow, 2007 Determine the Multinational 6,560 3,279 3,281 Pts with Cardiogenic Ranolazine PC 1º efficacy No diff in total No diff in the 1º efficacy Given the
17456819 efficacy and RCT NSTE-ACS shock, (initiated IV endpoint mortality with major 2º endpoint endpoint statistically NS
(119) safety of within 48 h of persistent STE, followed by (composite of ranolazine vs. (CV death/MI/ (ranolazine vs. result for the 1º
ranolazine ischemic Sx successful oral CV PC (HR: 0.99; severe recurrent PC): endpoint, all
during long- (between Oct revasc before ranolazine death/MI/recurr 95% CI: 0.80– ischemia), or in HR: 0.92; 95% additional efficacy
term treatment 2004 and Feb randomization, extended- ent ischemia): 1.22) the composite of CI: 0.83–1.02 analyses,
of pts with 2007) clinically release 1000 21.8% in the No diff in QTc CV death/MI. although
NSTE-ACS Eligibility significant mg 2× daily) ranolazine prolongation Ranolazine was prespecified,
criteria: ≥18 hepatic disease, group vs. requiring dose associated with should be
y; Sx of ESRD requiring 23.5%, p=0.11 reduction: 0.9% reduced recurrent considered as de
myocardial dialysis, Follow-up was in pts receiving ischemia: 13.9% facto exploratory
ischemia; at treatment with a median of ranolazine vs. vs.16.1%; HR: 915 and 736 pts
least 1 mod- agents known to 350 d 0.3% in PC, p 0.87; 95% CI: discontinued the
high-risk prolong the QT NS 0.76–0.99; study Rx in the
indicator interval, ECG No difference in p=0.03). ranolazine and
abnls interfering symptomatic PC arms,
with Holter arrhythmias respectively.
interpretation, (ranolazine:
life expectancy 3.0% vs. PC:
<12 mo 3.1%; p=0.84)
1º indicates primary; 2º, secondary; ACS, acute coronary syndrome; AF, atrial fibrillation; CV, cardiovascular; diff, difference; ECG, electrocardiograph; ESRD, end-stage renal disease; Hx, history; IV, intravenous; MI, myocardial infarction; NS, no/t significant; NSTE,
non-ST-elevation; NSTE-ACS, non-ST-elevation acute coronary syndrome; pts, patients; RCT, randomized controlled trial; revasc, revascularization; Rx, prescription; SA, stable angina; STE, ST-elevation; Sx, symptoms; SVT, sustained ventricular tachycardia; and VT,
ventricular tachycardia.
Data Supplement 14. Inhibitors of the Renin-Angiotensin-Aldosterone System (Section 4.2)

Study Name, Aim of Study Type Study Study Study Patient Population Study Study Endpoints P Values, OR: HR: Study Limitations &
Author, Year Study Size (N) Intervention Comparato Intervention Comparator RR & 95% CI: Adverse Events
Group (n) r Group (n)
Results
SAVE Captopril on Multi- 2,231 Captopril PC 3 d after Contraind. to Captopril for PC All-cause No prospective Reduction of All-cause mortality Adverse: dizziness,
Pfeffer, 1992 events in institute 1,115 1,116 AMI ACEI 42 mo mortality safety CV death by reduction by ACEI dysgeusia, cough,
1386652 AMI with LV prospective LVEF≤4% Creatinine >2.5 reduced in evaluators ACEI 19% (95% CI: 3%– diarrhea. Exclusion of
(120) dysfunction 21–79 y. mg/dL captopril group 37% 32%); p=0.019 pts with symptomatic
vs. PC Reduction of MACE: HF
(20% vs. 25%) severe HF by 21% (95% CI: 5–35);
Reduction of 22% p=0.014
MACE by 21% Reduction of CV deaths
recurrent MI by 37% (95% CI: 20–50);
25% p<0.001
Recurrent MI:
25%:(95% CI: 5–40);
p=0.015
Ambrosioni, ACEI for Multi- 1,556 Zofenopril PC CCU with Contraindication ACEI for 6 PC 6-wk death or N/A 1-y death rate 6-wk death reduction: Side effects: 6.8% PC,
1995 short-term institute 772 784 AMI to ACEI wk severe HF reduced by 34% (95% CI: 8%– 8.6% ACEI
7990904 events prospective reduced by 34% ACEI 54%); p=0.018 No use of initial IV ACI
(121) with ACEI 29%; p=0.011 MACE: to see beneficial or
46% (95% CI: 11–71); adverse effects.
p=0.018
CONSENSUS Long-term Multi- 6,090 Enalapril PC <24 h after BP <100/60; Enalapril for PC 1- and 6-mo Death due to HF Change in Mortality; p=0.26 Early hypotension
II Swedberg, reduction in institute 3,044 3,046 onset of need for 6 mo mortality 4.3% ACEI therapy due to 12% ACEI and 3% PC
1992 mortality prospective chest pain vasopressors, unchanged with 3.2% PC HF increased p<0.001
1495520 with ACEI with ECG/ severe heart enalapril vs. PC p=0.06 in PC group. Lack of ACEI benefit
(122) enzyme block, valvular 7.2% vs. 6.3% 1 p<0.006 possibly due to low
changes disease, mo NS diff in dose of ACEI
contraindication 11.0% vs. reinfarctions or
to ACEI, TIA 10.2% 6 mo rehospitalizatio
n due to HF
ACEI MI Coll. Use of ACEI Meta- 98,496 ACEI PC roughly AMI-early Smaller trials, no ACEI from PC 30-d mortality Hypotension Absolute 30-d mortality Significant increase in
Group in early AMI analysis of 4 roughly 1/2 1/2 short-term control group 28–42 d reduction 7% by less common in benefit highest reduction cardiac shock and
1998 clinical trials trials>1,000 ACEI ACEI vs. in Killip 2, 3 7% (95% CI: 2%– renal dysfunction with
9631869 pts controls anterior MI 11%); p<0.004 ACEI
(123) 9.3 vs. 17.6% HF reduction Higher 2nd-3 d AV
14.6% vs. 15.2% block.
2p=0.01
AIREX Cumulative Multi- 603 in Ramipril PC AMI with Clinical Ramipril PC for 15 15-mo mortality N/A N/A 15-mo mortality: Mortality benefit only
Hall, 1997 Mortality 3 y institute initial 302 301 evidence of instability, beginning 2- mo, then 3-y reduced with 16.9% ACEI in 1st 24 mo after study
9167457 after end of prospective- AIRE trial HF contraindication 9 d after follow-up ACEI and 3-y 22.6% PC ended. Possibly
(124) AIRE trial of of 15 mo to ACEI, HF of admission follow-up 27% (95% CI: 11–40); because more
MI with HF valvular or and up to 15 mortality also p=0.002 severally ill PC pts
congenital HD, mo with 3-y reduced 3-y post-AIRE died before 24 mo
need for open follow-up mortality: leaving a relatively
label ACEI. poststudy 27.5% ACEI healthy post-PC
38.9% PC population.
36% (95% CI: 15–52);
p=0.002
Reduction with ACEI.
Squire, 2010 Benefit of Observation 1,725 ACEI in all Various ACS in Resident pts ACEI or NT-pro-BNP MACE: only in ACEI treatment. Death or HF: Decreased MACE in Observational only.
20478862 BNP in use al cohort or ARB in levels of CCU outside health ARB median values by top quartile of Had survival reduced risk in top quartile of BNP: Possible residual
(125) of ACEI in study some cases BNP 44% NSTE- authority area. 528 d follow- quartiles BNP was ACEI benefit only in top quartile of HR: 0.613 (0.46,0.82); confounding of
ACS retrospective ACS up. associated with pts without BNP: 0.498 p=0.001 variables.
reduction of diabetes mellitus (0.31, 0.80); Demographic diff in
MACE. NS or hypertension. p=0.004 BNP. Single center,
benefit in other NS reduction of but 2 hospitals.
BNP quartiles death in top
BNP quartile.
Pfeffer, 2003 Effect of Multicenter 14,703 Valsartan 3-way AMI 0.5–10 Low BP ACE, ARB 3-way Total mortality: Valsartan: Noninferiority Total mortality: Significant adverse
14610160 ACEI and prospective 4,909 comparison d Creatinine >2.5 or comparison NS diff among 3 hypotension, of valsartan vs. valsartan vs. captopril events: hypotension,
(126) ARB trial Captopril HF and/or combination groups renal captopril for 1.00 (97.5% CI: 0.90– renal causes,
combination 4,909 LVEF Median 24.7 abnormalities death 1.11) hyperkalemia, cough,
in AMI with Both <0.35 by mo more common. Combined vs. rash, dysgeusia,
HF/LV 4,885 echo or Captopril: captopril angioedema.
Dysfunction <0.40 by cough, rash, 0.98 (97.5% CI: 0.89– Significant greater
RN dysgeusia more 1.09) adverse events with
common. combination vs.
valsartan alone.
9.0% vs. 5.8% for
permanent
discontinuation of
drug.
Pitt, 2003 Effect of Multicenter 6,632 Eplerenone PC 3-14 d after K+ sparing Eplerenone PC Total and CV BP increase less Reduction in Total deaths: Low rate of D/C of EP
12668699 eplerenone prospective 3,319 3,313 AMI diuretics use; mean follow- death in eplerenone sudden death 0.85 (95% CI: 0.75– for adverse events. No
(127) in AMI with trial LVEF Creatinine >2.5 up 16 mo Total deaths and than PC 0.79 (95% CI: 0.96); p=0.008 gynecomastia.
LV ≤0.40 K+>5 meq/L CV deaths increase in 0.64–0.97); CV deaths: However, increased
dysfunction CHF on decreased by creatinine p=0.03 0.83 (95% CI: 0.72– incidence of serious
ACEI, BB, eplerenone vs. EP>PC; 0.94); p=0.005 hyperkalemia
diuretics PC p<0.001 CV Death or Hospital: 5.5% vs. 3.9%;

Increase in K+ 0.87 (95% CI: 0.79– p=0.002
greater in EP 0.95); p=0.02
Gheorghiade, Effect of Retrospectiv 6,632; Eplerenone PC Rehospitali No Eplerenone PC Reduction of d In NS effect of Total d in hospital for In subset
2009 eplerenone e analysis of 827 3,319 3,313 zation for rehospitalization 16-mo of rehospitalization geographic HF; (reduction) rehospitalized: No
19699868 on prospective with HF from original follow-up rehospitalization pts: region on 3.6 (13.3–16.9) deaths from
(128) readmission multicenter subseque 827 group by eplerenone K+>6.0 in 10.1% results p=0.0006 vs. PC hyperkalemia, 2-fold
hospital stay trial nt hospital 5,805 EP vs. reduction of
after MI with readmissi 5.8% PC hypokalemia,
LV on p=0.02 impotence was rare
dysfunction
Weir, 2009 MRI study to Prospective 100 Eplerenone PC AMI 1-14 d Clinical HF, DM, Eplerenone PC Change in LV NS diff between Diastolic Systolic volume 3 eplerenone pts died,
19464421 evaluate cohort study 50 50 LVEF <040 preexisting, LV 24 wk systolic volume eplerenone and volume fell EP decreased with vs. fibrillation, stroke,
(129) eplerenone dysfunction, after covariate PC in HR, BP vs. PC EP vs. PC: p=0.027 recurrent AMI, NS
effects on elevated adjusted volume changes 7.5±3.4 mL/m2 change in creatinine or
LV after MI creatinine, K+> fell by 6.1± 2.7 2/50 EP pts p=0.031 eGFR. Need for
mmol/L mL/m2 vs. PC developed Increased covariate adjustment;
K+ bet, 5.6 and MMP LVEF changes
5.9 -9 and between screening
decreased TTE and MRI.
MMP-2
Rossignol Mechanism Retrospectiv 6,080 Eplerenone PC 3-14 d after K+ sparing Eplerenone PC Interaction Decreased rate EP vs. PC EP decreased total Post-hoc analysis
2011, of e analysis of 3,055 3,025 overall AMI; diuretic 1-mo between diuretic of CV death due Reduced mortality, CV death/ Short-term evaluation
22032706 eplerenone multicenter LVEF Creatinne >2.5 evaluation effects and K+ to K+ sparing weight <0.0001 hospitalization and of K+ and diuretic
(130) benefit in study ≤0.40 K+>5 meq/L sparing effects effect of EP vs. Plasma volume hospitalization for HF effects only
AMI CHF on of eplerenone PC p=0.047 independent of K+
ACEI, BB, and benefit of Increased K+ and diuretic effects
diuretics CV outcome p<0.0001
Rossignol, Eplerenone Retrospectiv 5,792 Eplerenone PC 3-14 d after K+ sparing Eplerenone PC Serial changes Most salient: Early decline in Decline >20% eGFR Post-hoc analysis and
2012 effects on e analysis of 2,918 2,874 AMI; diuretic 24 mo in eGFR early decline in eGFR by>20% 1st mo: included
22128223 renal multicenter LVEF Creatinine>2.5 follow-up EP had a eGFR by EP vs. associated with 16.9% EP vs. 14.7% nonprespecified
(131) function after study ≤0.40 K+>5 meq/L decline in eGFR PC worse CV PC subgroups
AMI CHF, on from 1st mo and outcomes OR: 1.15 (95% CI: Changes focused only
ACEI, BB, persisted independent of 1.02–1.30); p=0.017 on a 1-mo timepoint
diuretics throughout study baseline eGFR At this timepoint,
and use of deaths in eplerenone
eplerenone were already lower
than PC
GISSI-3, 1994 Effect of Multicenter 18,895 Lisinopril, Open In CCU Severe HF Lisinopril 10 PC Deaths and Rates of Rates of Overall 6-wk mortality Relatively low dosage
7910229(87) ACEI on prospective 9,435 control within 24 h requiring study mg qd for 6 combined hypotension and reinfarction, reduction: OR: 0.88 of lisinopril, many
mortality and trial 9,460 of chest treatment, wk deaths and LV renal cardiogenic (95% CI: 0.79–0.99) elderly and women
LV function pain, ECG hemodynamic dysfunction dysfunction shock, and Overall reduction in excluded
after MI changes deterioration, Lisinopril higher with ACEI stroke did not death plus decreased. Concern about slightly
and no bilateral renal reduced differ LV dysfunction: increased creatinine
contraindic artery stenosis, mortality and 0.90 (0.84-0.98) and hypotension with
ations to other life combined ACEI
study med threatening outcome
disorders
ISIS-4, 1995 Effect of Multicenter 58,050 Captopril PC In CCU Hypotension, Captopril 50 PC 5-wk mortality Rates of Somewhat 5-wk mortality:7.19% Possible contending
7661937(86) ACEI on 5- prospec trial 29,028 29,022 within 24 h cardiogenic mg bid for lower with ACE hypotension fewer deaths ACI vs. 7.69% PC effects of magnesium
wk mortality of chest shock, fluid 28 d inhibitor increased with 1st 2 d of 2p=0.02 and nitrates in regard
after AMI pain depletion ACEI, renal treatment with to results
dysfunction ACEI vs. PC
No excess of
deaths with
lower BPs on
ACEI
ACS indicates acute coronary syndrome; ACEI, angiotensin-converting enzyme inhibitor; AIRE Trial, Acute Infarction Ramipril Efficacy Trial; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; AV,block, atrioventricular block; BB, beta blocker; bid,
twice a day; BNP, B-type Natriuretic Peptide; BP, blood pressure; CCU, cardiac care unit; CHF, congestive heart failure; CV, cardiovascular; diff, diference(s); D/C, discharge; ECG, electrocardiograph; eGFR, estimated glomerular filtration rate; EP, eplerenone; HD,
heart disease; HF, heart failure; IV, intravenous; LV, left ventricular; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac events; MI, myocardial infarction; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; MRI, magnetic
resonance imaging; NS, no(t) significance; NSTE, non-ST-elevation; NSTE-ACS, non-ST-elevation-acute coronary syndrome; NT-pro-BNP, N-terminal pro-brain natriuretic peptide; PC, placebo; pts, patients; RN, radionuclide; and TTE, transthoracic echocardiography.
Data Supplement 15. Oral and Intravenous Antiplatelet Therapy in Patients With Likely or Definite NSTE-ACS Treated With Initial Invasive or Conservative Strategy (Section 4.3.1)
Study Study Aim Study Type / Intervention Patient Population Study Endpoints P Values, Adverse Events Study
Name, Size (N) vs. Intervention OR: HR: RR: & Limitations
Author, Comparator 95 CI:
Year (n)
Inclusion Criteria Exclusion Criteria Primary Endpoint & Safety Secondary
Results Endpoint & Endpoint & Results
Results
Baigent Low-dose ASA Meta-analysis ASA vs. no 1º or 2º prevention 1º prevention trials ASA or no ASA Serious vascular events Major bleeds 2º prevention trials p=0.0001 N/A N/A
2009 is of definite N=95,000 pts at ASA trials eligible only if excluded individuals (MI, stroke, or vascular 0.10% vs. ASA allocation
19482214 and substantial low avg risk they involved with any Hx of death) 0.07% per y; yielded greater
(132) net benefit for randomized occlusive disease at 0.51% vs 0.57% p<0.0001 absolute reduction in
people who comparison of ASA entry serious vascular
already have vs. no ASA (with no events (6.7% vs.
occlusive other antiplatelet 8.2% per y;
vascular drug in either group). p<0.0001) with NS
disease. increase in
Assessed the haemorrhagic stroke
benefits and but reductions of
risks in 1º about a 1/5 in total
prevention. stroke (2.08% vs.
2.54% per y;
p=0.002) and in
coronary events
(4.3% vs 5.3% per y;
p<0.0001).
CURE Compare Randomized, Clopidogrel Pts were eligible for Contraindications to Clopidogrel (300 Death from CV causes, Pts with 1st1º outcome or p<0.001 Clopidogrel was N/A
Yusuf efficacy and double-blind, PC vs. PC in study if they had antithrombotic or mg immed nonfatal MI, or stroke major refractory ischemia RR: 0.80 not associated with
2001 safety of the trial N=12,562 addition to been hospitalized antiplatelet therapy, followed by 75 9.3% vs 11.4% bleeding 16.5% vs 18.8% RR: CI: 0.72–0.90 excess rate of any
11519503 early and long- pts ASA within 24 h after high risk for bleeding mg od) vs. PC in 3.7% vs. 0.86; CI: 0.79–0.94; other type of
(133) term use of onset of Sx and no or severe HF, taking addition to ASA 2.7%; p<0.001 adverse event that
clopidogrel plus STE oral anticoagulants, p=0.001 Percentage of pts necessitated
ASA with those had undergone RR: 1.38 with in-hospital discontinuation of
of ASA alone in coronary revasc in refractory or severe study drug
pts with ACS the previous 3 mo or ischemia, HF, and
and no STE received IV GP revasc procedures
IIb/IIIa receptor were significantly
inhibitors in the lower with
previous 3 d clopidogrel.
PLATO Prespecified Observed Reasons for N/A N/A 2 independently Large number of N//A Pts taking low-dose N/A N/A N/A
Mahaffey subgroup regional the interaction performed subgroup analyses maintenance ASA,
2011 analysis interaction were explored analyses performed and result ticagrelor associated
21709065 showed driven by independently identified numerically favoring with better outcomes
(134) significant interaction of by 2 statistical statistical clopidogrel in at least 1 compared with
interaction randomized groups. interaction with of the 4 prespecified clopidogrel, with
between treatment with ASA regions could occur statistical superiority
treatment and 78% of NA pts in maintenance with 32% probability. in the rest of the
region US compared dose as possible More pts in US (53.6%) world and similar
(p=0.045), with with ROW pts explanation for than in the rest of the outcomes in US
less effect of (p=0.01 vs. regional world (1.7%) took cohort.
ticagrelor in NA p=0.045 for difference. median ASA dose ≥300
than in ROW. interaction using Lowest risk of CV mg qd. Of 37 baseline
Exploratory NA). Analyses death, MI or and postrandomization
analyses focus on stroke with factors explored, only
performed to comparison of ticagrelor ASA dose explained
identify US and ROW, compared with substantial fraction of
potential with Canadian clopidogrel is the regional interaction.
explanations for pts included in associated with
observed ROW group. low-maintenance
region-by- dose of
treatment concomitant ASA
interaction.
Gremmel Investigate age Prospective Clopidogrel Pts on dual Known LD of 300 mg ADP-inducible platelet N/A N/A p=0.003 for LTA N/A Lack of clinical
2010 dependency of observational and age antiplatelet therapy acetylsalicylic acid or (n=116; 60.7%) reactivity increased and p<0.001 for outcome data,
19818001 clopidogrel study after angioplasty and clopidogrel or 600 mg (n=50; linearly with age after the VerifyNow the relatively
(135) mediated N=191 pts stenting for CVD intolerance (allergic 26.2%) of adjustment for CV risk P2Y12 assay small number of
platelet reactions and clopidogrel prior factors, type of patients on
inhibition gastrointestinal intervention intervention, chronic
bleeding), therapy followed by 75 medication, CRP and clopidogrel
with VKA (warfarin, mg of clopidogrel renal function [using therapy and pts
phenprocoumon and od LTA 0.36% of maximal were not
acenocoumarol), Pts received daily aggregation per y, 95% studied again
treatment with acetylsalicylic CI: 0.08–0.64%; under
ticlopidine, acid therapy (100 p=0.013; using the maintenance
dipyridamol or mg qd). VerifyNow P2Y12 assay therapy with
NSAID, a family or 3.2 clopidogrel.
personal Hx of P2Y12 reaction units
bleeding disorders, (PRU) per y, 95% CI:
malignant 1.98–4.41 PRU;
paraproteinemias, p<0.001. ADP-inducible
myeloproliferative platelet reactivity
disorders or significantly higher in
heparininduced pts 75 y or older
thrombocytopenia, compared with younger
severe hepatic pts (p=0.003 for LTA
failure, known and p<0.001 for
qualitative defects in VerifyNow P2Y12
thrombocyte assay). High on-
function, a major treatment residual ADP-
surgical procedure inducible platelet
within 1 wk before reactivity significantly
enrollment, a platelet more common among
count <100, 000 or pts 75 y or older
>450, 000 lL-1 and (p=0.02 for LTA and
hematocrit <30%. p<0.001 for VerifyNow
P2Y12 assay).
CAPRIE Assess Randomized N=9577 Ischaemic stroke Severe cerebral Clopidogrel (75 Pts treated with There were N/A p=0.043 Reported adverse N/A
1996 potential benefit N=19,185 pts clopidogrel (including retinal deficit likely lead to mg od) clopidogrel had annual no major RR reduction of experiences in the
8918275 of clopidogrel (75 mg od) origin and lacunar pts being bedridden ASA (325 mg od) 5.32% risk of ischaemic differences in 8.7% in favor of clopidogrel and
(136) compared with plus PC infarction); MI; or demented; stroke, MI, or vascular terms of clopidogrel ASA groups judged
ASA in n=9,566 ASA Atherosclerotic PAD Carotid death compared with safety Cl: 0.3–16.5 to be severe
reducing risk of (325 mg od) endarterectomy after 5.83% with ASA. included rash
ischaemic plus PC qualifying stroke; Significant (p=0.043) (0.26% vs. 0.10%),
stroke, MI, or Qualifying stroke relative-risk reduction of diarrhoea (0.23%
vascular death induced by carotid 8.7% in favor of vs. 0.11%), upper
in pts with endarterectomy or clopidogrel (95% Cl: gastrointestinal
recent angiography; Pts 0.3-16.5). discomfort (0.97%

ischaemic unlikely to be Corresponding on- vs. 1.22%),
stroke, recent discharged after treatment analysis intracranial
MI, or PAD. qualifying event; yielded RR reduction of haemorrhage
Severe comorbidity 9.4%. (0.33% vs. 0.47%),
likely to limit pts life and gastrointestinal
expectancy to less haemorrhage
than 3 y, (0.52% vs. 0.72%).
Uncontrolled 10 pts (0.10%) in
hypertension, clopidogrel group
Scheduled for major with significant
surgery, reductions in
Contraindications to neutrophils (<1.2 x
study drugs; Women 10(9)/L) and 16
of childbearing age (0.17%) in ASA
not using reliable group.
contraception,
Currently receiving
investigation drug;
Previously entered in
other clopidogrel
studies.
Gollapudi Provide Literature review N/A N/A N/A N/A Prevalence of ASA- N/A N/A N/A N/A N/A
2004 diagnostic exacerbated respiratory
15613671 strategy for tract disease
(137) evaluating and approximately 10% and
treating pts with for ASA-induced
ASA sensitivity, urticaria prevalence
with additional varies 0.07% to 0.2% of
consideration general population.
for issues ASA sensitivity most
specific to pts often manifested as
with CAD. rhinitis and asthma or
urticaria/angioedema
induced by cross-
reacting NSAID that
inhibit cyclooxygenase
1. 1º mechanism of
sensitivity less often
related to drug-specific
IgE antibody production
leading to
urticaria/angioedema
and rarely to
anaphylaxis. Most pts
with acetylsalicylic acid
sensitivity are able to
undergo desensitization
therapy safely and
successfully except in
cases of chronic
idiopathic urticaria.
Experience with
acetylsalicylic acid
desensitization in pts
with CAD very limited.
TRITON – Compare N=13,608 pts Prasugrel Pts with UA NSTEMI, Increased risk of Prasugrel or Death from CV causes, Major Stent thrombosis p<0.001 More pts treated N/A
TIMI 38 regimens of with ACS with n=6813 TIMI risk score ≥3, bleeding, anemia, clopidogrel nonfatal MI, or nonfatal bleeding- and composite of HR: 0.81 with prasugrel
Wiviott prasugrel and scheduled PCI (60 mg LD either ST-segment thrombocytopenia, a stroke TIMI major death from CV CI: 0.73 - 0.90 2.5% vs. 1.4%
2007 clopidogrel and 10 mg qd deviation of 1 mm or Hx of pathologic 12.1% clopidogrel vs bleeding not causes, nonfatal MI, clopidogrel;
17982182 maintenance more or elevated intracranial findings, 9.9% prasugrel related to nonfatal stroke, or p<0.001
(138) dose) or levels of a cardiac or use of any rates of MI CABG, non- rehospitalization due discontinued the
Clopidogrel biomarker of thienopyridine within 9.7% clopidogrel vs. CABG to a cardiac ischemic study drug owing to
n=6795 (300 necrosis. Pts with 5 d before 7.4% prasugrel; related TIMI event. adverse events
mg LD and 75 STEMI could be enrollment. p<0.001) life Rate of MI with related to
mg qd enrolled within 12 h urgent target-vessel threatening subsequent death hemorrhage; rate
maintenance after onset of Sx if 1º revasc 3.7% vs. 2.5%; bleeding, and from CV causes of serious adverse
dose), for 6- PCI was planned or p<0.001 TIMI major or 0.7% vs. 0.4% HR: events not related
15 mo within 14 d after stent thrombosis minor 0.58; CI:0.36 - 0.93; to hemorrhage was
receiving medical 2.4% vs. 1.1%; p<0.001 bleeding p=0.02 similar 22.5% vs
treatment for STEMI 2.4% 22.8%
prasugrel vs. p=0.52
1.8%
clopidogrel
HR: 1.32;
95% CI:
1.03–1.68;
p=0.03
rate of life-
threatening
bleeding
1.4% vs.
0.9%; p=0.01
including
nonfatal
bleeding
1.1% vs.
0.9%;
HR: 1.25;
p=0.23
fatal bleeding
0.4% vs.
0.1%;
p=0.002
PLATO Determine N=18,624 pts Ticagrelor Hospitalized for ACS Any contraindication Ticagrelor or Composite of death Major MI alone p<0.001 Discontinuation of Geographic
Wallentin whether with ACS with or n=9333 (180 with or without STE; against the use of clopidogrel from vascular causes, bleeding 5.8% vs. 6.9%, HR: 0.84 the study drug due differences
2009 ticagrelor is without STE mg LD, 90 mg with an onset of Sx clopidogrel, MI, or stroke 9.8% of 11.6% vs p=0.005 CI: 0.77-0.92 to adverse events between
19717846 superior to bid thereafter) during the previous fibrinolytic therapy pts receiving ticagrelor 11.2%, Death from vascular 7.4% ticagrelor vs populations of
(139) clopidogrel for or clopidogrel 24 h. Pts who had within 24 h before vs 11.7% clopidogrel p=0.43 causes 6.0% clopidogrel pts or practice
the prevention (n=9291) ACS NSTE at least 2 randomization, a (HR: 0.84; 95% CI: ticagrelor 4.0% vs. 5.1%, p<0.001 patterns
of vascular (300-600 mg of the following 3 need for oral 0.77–0.92; p<0.001). was p=0.001 Dyspnea 13.8% vs. influenced the
events and LD, 75 mg criteria had to be anticoagulation associated Stroke alone 1.5% 7.8%; effects of the
death in broad daily met: ST changes on therapy, an with a higher vs. 1.3%, p=0.22 Higher incidence of randomized
population of thereafter) ECG indicating increased risk of rate of major The rate of death ventricular pauses treatments
pts presenting ischemia; positive bradycardia, and bleeding not from any cause in 1 wk but not at
with ACS. test of biomarker, concomitant therapy related to 4.5% vs. 5.9%, 30 d in ticagrelor
indicating myocardial with a strong CABG 4.5% p<0.001 group than
necrosis; one of cytochrome P-450 vs. 3.8%, clopidogrel group
several risk factors 3A inhibitor or p=0.03),
(age≥60 y; previous inducer including
MI or CABG; CAD more
with stenosis of instances of
≥50% in at least 2 fatal
vessels; previous intracranial
ischemic stroke, TIA, bleeding and
carotid stenosis of at fewer of fatal
least 50% or cerebral bleeding of
revasc; DM; PAD; other types
chronic renal
dysfunction, defined
as a creatinine
clearance of <60
ml/min per 1.73 m2
of body surface area
with STE the
following 2 inclusion
criteria had to be
met: persistent STE
of at least 0.1 mV in
at least 2 contiguous
leads or a new left
bundle-branch block,
and the intention to
perform 1º PCI.
Mehta Clopidogrel and N=25,086 pts Pts randomly ≥18 yand presented Increased risk of 2×2 factorial Time to CV death, MI, Major Composite of death p=0.30 N/A Nominally
2010 ASA are widely assigned to with a NSTE, ACS or bleeding or active design. Pts were or stroke whichever bleeding from CV causes, MI, HR=0.94 significant
20818903 used for pts double-dose STE MI. Either ECG bleeding and known randomly occurred 1st, up to 30 d. occurred in stroke, or recurrent CI=0.83–1.06 reduction in 1º
(140) with ACS and clopidogrel changes compatible allergy to clopidogrel assigned in Primary outcome 2.5% of pts in ischemia; the outcome was
those received 600 with ischemia or or ASA double blind occurred in 4.2% of pts double-dose individual associated with
undergoing mg LD elevated levels of fashion to assigned to double- group and components of 1º use of higher-
PCI. However, followed by cardiac biomarkers; double-dose dose clopidogrel 2.0% in outcome; death from dose clopidogrel
evidence-based 150 mg od d coronary regimen of compared with 4.4% standard- any cause; Definite in subgroup of
guidelines for 2-7. Pts angiographic clopidogrel or assigned to standard- dose group or probable stent 17,263 study
dosing have not assigned to assessment, with standard-dose dose clopidogrel HR: 1.24; thrombosis. Double- participants who
been standard- plan to perform PCI regimen. In the HR: 0.94, 95% 95% CI: dose clopidogrel underwent PCI
established for dose as early as possible 2nd component of CI: 0.83-1.06 1.05–1.46; associated with after
either agent. clopidogrel but no later than 72 h factorial design p=0.30 p=0.01 significant reduction randomization
received 300 after randomization pts were NS difference between NS difference in 2º outcome of (69%). Test for
mg LD before randomly higher-dose and lower- between stent thrombosis interaction
angiography assigned in open dose ASA respect to 1º higher-dose among the 17,263 between pts
followed by label fashion to outcome and lower- pts who underwent who underwent
75 mg od higher-dose ASA 4.2% vs. 4.4% dose ASA PCI (1.6% vs. 2.3%; PCI and those
days 2-7. D 8- or lower-dose HR: 0.97: 95% CI: 0.86- with respect HR: 0.68; 95% CI: who did not
30 both ASA. –1.09; p=0.61 to major 0.55–0.85; p=0.001). undergo PCI
double-dose bleeding (p=0.03) did not
and standard- (2.3% vs. meet
dose groups 2.3%; HR: prespecified
received 75 0.99; 95% CI: threshold of
mg of 0.84-1.17; p<0.01 for
clopidogrel p=0.90). subgroup
od. Pts interactions. 13
randomly prespecified
assigned to subgroup
lower-dose analyses were
ASA received performed for
75-100 mg the clopidogrel
daily on d 2- dose
30. Those comparison; this
randomly result could

assigned to have been due
higher-dose to the play of
ASA received chance.
300 to 325
mg daily d 2-
30.
Plato Evaluate Randomized Ticagrelor Admitted to hospital Contraindication to ticagrelor or CV death, MI, and Incidence of Overall mortality p=0.04 N/A N/A
James efficacy and N=5216 pts n=2601 vs. with STE ACS clopidogrel, clopidogrel stroke; their individual total major 6.1% vs. 8.2% HR: HR: 0.85
2011 safety clopidogrel scheduled for PCI or fibrinolytic treatment components; and bleeding 0.75; 95% CI: 0.61– 95% CI: 0.73–
21685437 outcomes in pts n=2615 NSTE-ACS, with within 24 h, need for PLATO defined major 11.9% vs. 0.93; p=0.01 1.00
(141) in PLATelet onset of Sx during oral anticoagulation bleeding during 1 y 10.3%, HR:
inhibition and the previous 24 h. At treatment, need for 12.0% (n=295) 1.17; 95% CI:
pts outcomes least two of the dialysis, and ticagrelor vs. 14.3% 0.98–1.39;
(PLATO) trial following three clinically important (n=346) clopidogrel HR p=0.08
who at criteria were required anaemia or 0.85, 95% CI 0.73 to non-CABG
randomization for NSTE-ACS: STE thrombocytopenia 1.00; p=0.04). related major
were planned depression or bleeding
for a non- transient elevation of 4.0% vs.
invasive at least 1 mm in ≥2 3.1%; HR:
treatment contiguous leads; a 1.30; 95% CI:
strategy. positive biomarker 0.95–1.77;
indicating myocardial p=0.10
necrosis; and 1
additional risk
indicator, including
age >60 y, previous
MI or CABG, CAD,
previous ischaemic
stroke. TIA, carotid
stenosis, cerebral
revasc, DM, PAD, or
chronic renal
dysfunction
ISAR- Assess whether Randomized Abciximab High-risk ACS pts STE-AMI Abciximab (0.25 Death, MI or UTVR at NS N/A p=0.03 N/A Cannot exclude
REACT 2 abciximab is N=2,022 pts n=1012 vs undergoing PCI mg/kg bolus, 30 d differences RR: 0.75 possibility that
Kastrati associated with PCn=1010 followed by a 8.9% vs. 11.9% between 2 95% CI: 0.58– greater benefit
16533938 clinical benefit 0.125- groups 0.97 from abciximab
(142) in high-risk pts microg/kg/min regarding risk might have
with ACS max, 10 of major and been present
undergoing PCI mcg/min) infusion minor had therapy
after for 12 h plus bleeding as been initiated
pretreatment heparin, 70 U/kg well as need earlier prior to

with 600 mg of or PC (PC bolus for the cath lab
clopidogrel and infusion of transfusion.
12 h, plus
heparin bolus,
140 U/kg). All pts
received
clopidogrel 600
mg at least 2 h
prior to
procedure as well
as 500 mg oral or
IV ASA
PURSUIT Inhibition of Double blind Bolus and Pts who had Persistent STE of Eptifibatide or PC Composite of death and Bleeding Mortality from all p=0.04 Bleeding was more N/A
Trial platelet N=10,948 pts infusion of presented with more than 1 mm, bolus dose of nonfatal MI occurring complications causes within 30 d common in
2010 aggregation eptifibatide or ischemic chest pain active bleeding or a 180 mcg/kg of up to 30 d after index More red-cell after the index event, eptifibatide group,
9705684 with eptifibatide PC n=1487 within previous 24 h Hx of bleeding body weight, event compared with transfusions a 1st for recurrent MI although there was
(143) would have low-dose and who had either diathesis, followed by PC group. Eptifibatide among the within 30 d, no increase in the
incremental eptifibatide ECG changes gastrointestinal or infusion of 1.3 group had 1.5% pts treated composite endpoint incidence of
benefit beyond group n=4722 indicative of ischemia genitourinary mcg/kg/min or absolute reduction in with (death or nonfatal hemorrhagic
that of heparin high-dose (but not persistent bleeding within 30 d bolus dose of incidence of 1º endpoint eptifibatide MI) at 96 h and 7 d stroke.
and ASA in eptifibatide STE) or high serum before enrollment, 180 mcg/kg (14.2% vs. 15.7% in PC 11.6% vs.
reducing group concentrations of systolic blood followed by group; p=0.04) Effect 9.2%; RR:
frequency of n=4739 PC CK-MB isoenzymes pressure above 200 infusion of 2.0 was consistent in most 1.3; 95% CI:
adverse group mmHg or diastolic mcg/kg/min or major subgroups except 1.1-1.4
outcomes in pts blood pressure bolus and for women (odds ratios Study would
with ACS who above 110 mmHg, a infusion of PC for death or nonfatal MI, be stopped in
did not have Hx of major surgery 0.8 (95% CI: 0.7-0.9) in lower-dose
persistent STE. within the previous 6 men and 1.1 (95% CI: group after
wk, a Hx of 0.9-1.3) in women independent
nonhemorrhagic DSMB
stroke within conducted
previous 30 d or any interim
Hx of hemorrhagic review of
stroke, renal failure, safety data,
pregnancy, the provided the
planned higher dose
administration of had
platelet GP IIb/IIIa acceptable
receptor inhibitor or safety profile.
thrombolytic agent, After 3,218
or receipt of pts been
thrombolytic therapy randomly

within previous 24 h assigned to
treatment
groups,
committee
recommende
d dropping to
lower dose
PRISM- Evaluate Double-blind Tirofiban, Prolonged anginal STE lasting more Tirofiban, Death, MI, or refractory Study was Death, MI, or Tirofiban plus Major bleeding N/A
PLUS tirofiban, a N=1915 pts heparin, or pain or repetitive than 20 min, heparin, or ischemia within 7 d stopped refractory ischemia heparin vs. occurred in 3.0% of
1998 specific inhibitor tirofiban plus episodes of angina at thrombolysis in tirofiban plus lower among pts who prematurely within 48 h and 30 d heparin alone pts receiving
9599103 of platelet GP heparin rest or during previous 48 h, heparin. Study received tirofiban plus for group after randomization, p=0.004 heparin alone and
(144) IIb/IIIa receptor, minimal exercise in coronary angioplasty drugs were heparin than among receiving the three RR=0.68 4.0% of pts
in treatment of previous 12 h and within previous 6 m infused for mean those who received tirofiban components of this CI=0.53–0.88 receiving
UA and non–Q- new transient or or bypass surgery (±SD) of 71.3±20 heparin alone (12.9% alone end point as combination
wave MI persistent ST-T within previous mo, h, during which vs. 17.9%; RR: 0.68; because of separate measures, therapy p=0.34
ischemic changes on angina caused by time coronary 95% CI: 0.53–0.88; excess and composite of
ECG, or elevation of identifiable factors, a angiography and p=0.004). mortality at 7 death and MI.
plasma levels of CK Hx of a platelet angioplasty were d (4.6%,
and CK-MB fraction disorder or performed when compared
thrombocytopenia, indicated after 48 with 1.1% for
active bleeding or a h pts treated
high risk of bleeding, with heparin
and stroke within alone
previous y. Pts who
had serum creatinine
values above 2.5
mg/dL (220 μmol/L)
or a platelet count
below 150,000/m3
EARLY Determine Randomized Early, routine Pts N/A Early, routine Composite of death, MI, Major Rate of death or MI p=0.23 N/A Convergence of
ACS optimal timing N=9492 pts administration ACS NSTEMI administration of recurrent ischemia bleeding at 30 d 11.2% vs. OR=0.92 use of
Giugliano for initiation of of Eptifibatide undergoing invasive Eptifibatide or requiring urgent revasc Pts in early 12.3%; OR=0.89; 95% CI=0.80– eptifibatide
2009 treatment with n=4722 vs. strategy delayed or occurrence of eptifibatide 95% CI: 0.79–1.01; 1.06 during PCI in 2
19332455 GP IIb/IIIa delayed Eptifibatide after thrombotic complication group had p=0.08 study groups
(145) inhibitors in pts Eptifibatide angiography but during PCI at 96 h significantly probably
who have ACS n=4684 before the pts 9.3% vs. 10.0% higher rates reduced the
without STE underwent PCI of bleeding. difference in
and undergoing There was efficacy. Could
invasive NS difference not assign pts to
procedures between 2 strict PC group
groups in since guidelines
rates of at time of
severe planning trial
bleeding or strongly
nonhemorrha endorsed use of
gic serious GP IIb/IIIa
adverse inhibitors during
events. PCI
ACUITY Assess Randomized n=2561 Pts undergoing PCI Included - STE AMI Heparin 30-d endpoints of N/A N/A Composite N/A Randomization
subgroup anticoagulation N=7789 pts heparin after angiography, or shock; bleeding (unfractionated or composite ischemia ischemia occurred before
analysis with the direct (unfractionate new ST-segment diathesis or major enoxaparin) plus (death, MI, or p=0.16; angiography,
Stone thrombin d or depression; raised bleeding episode GP IIb/IIIa unplanned revasc for major bleeding study drugs
2007 inhibitor enoxaparin) TnI, TnT, or CK-MB within 2 wk; inhibitors, ischemia), major p=0.32; were
17368152 bivalirudin plus GP isozyme; known thrombocytopenia; bivalirudin plus bleeding, and net net clinical administered at
(146) during PCI in IIb/IIIa CAD; or all 4 other CrCl <30 mL/min GP IIb/IIIa clinical outcomes outcomes p=0.1 median of 4 h
individuals with inhibitors UA risk criteria defi inhibitors, or (composite ischemia or before PCI. PCI
moderate- and n=2609 ned by TIMI study bivalirudin alone major bleeding) subgroup
high-risk ACS bivalirudin group Bivalirudin plus GP represents
plus GP IIb/IIIa inhibitors vs. subset of 56%
IIb/IIIa heparin plus GP IIb/IIIa of all pts
inhibitors inhibitors - composite enrolled in
n=2619 ischemia 9% vs. 8%; ACUITY, and
bivalirudin major bleeding 8% vs. randomization
alone 7%; net clinical was not
outcomes 15% vs. 13% stratified by
treatment
assignment
BRILINTA BRILINTA is N/A N/A N/A N/A N/A N/A Daily N/A N/A N/A N/A
™ indicated to maintenance
(ticagrelor) reduce rate of dose of ASA,
tablets thrombotic CV coadminister
AstraZene events in pts ed with
ca LP with ACS, UA, BRILINTA,
(147) NSTEMI or should not
STEMI exceed 100
mg
Increased
risk of
bleeding
Decreased
efficacy with
BRILINTA
(ticagrelor) in
combination
with ASA
doses
exceeding
100 mg
GUSTO Investigate long Randomized n=2590 Pts with ACS without N/A Abciximab for 24- Death (of any cause) or N/A N/A 24-hour N/A N/A
IV-ACS term effects of N=7800 pts abciximab for persistent STE h (0.25 mg/kg MI within 30 d abciximab HR:
Ottervange GP IIb/IIIa 24 h including NSTEMI bolus followed by Follow-up data obtained 1.1; 95% CI:
r inhibitor n=2612 and UA. < 21 y and 0.125 up to 1 y for 7746 pts 0.86–1.29), and
2003 abciximab in abciximab for should have had 1≥ mcg/kg/min (99.3%). Overall 1-y 48-h abciximab
12551868 pts with ACS 48 h episodes of angina infusion up to mortality rate 8.3% (649 HR: 1.2; 95%
(148) without STE n=2598 PC lasting at least 5 min max of 10 pts). 1-y mortality was CI: 0.95–1.41
who were not within 24 h before mcg/min for 24 7.8% PC, 8.2% in the
scheduled for admission. Either h), followed by 24-h abciximab, and
coronary abnormal cardiac 24-h PC infusion; 9.0% in 48-h abciximab
intervention TnT or TnI test or at abciximab for 48
least 0.5 mm of h (same bolus
transient or and infusion for
persistent ST- total duration of
segment depression. 48 h); matching
PC (bolus and
48-h infusion)
PCI-CURE Find out Randomized clopidogrel N/A N/A Clopidogrel vs. Composite of CV death, At follow-up, N/A p=0.03 N/A N/A
Mehta whether in N=2658 pts (n=1313) or PC MI, or urgent target- there was NS RR: 0.70
2001 addition to ASA PC (n=1345) vessel revasc within 30 difference in 95% CI: 0.50–
11520521 pretreatment d of PCI. major 0.97
(149) with clopidogrel 4.5% vs. 6.4% bleeding
followed by Long-term between
long-term administration of groups
therapy after clopidogrel after PCI p=0.64
PCI is superior associated with a lower
to strategy of rate of CV death, MI, or
no pretreatment any revasc (p=0.03),
and short-term and of CV death or MI
therapy for only (p=0.047). Overall
4 wk after PCI (including events before
and after PCI) there
was 31% reduction CV
death or MI (p=0.002).
Less use of GP IIb/IIIa
inhibitor in clopidogrel
group (p=0.001)
Petersen Systematically Systematic N/A All 6 RCTs N/A N/A Enoxaparin is more NS difference N/A 10.1% vs 11.0% N/A Systematic
2004 evaluate end overview comparing effective than UFH in found in OR: 0.91 overviews do
18056526 points of all- N=21946 pts enoxaparin and UFH preventing combined blood CI: 0.83–0.99 not replace
(150) cause death ESSENCE, A to in NSTE ACS were endpoint of death or MI transfusion RCTs but
and nonfatal Z, and selected for analysis NS difference found in (OR: 1.01; provide
MI, transfusion, SYNERGY, TIMI death at 30 d for 95% CI: important
and major 11B, ACUTE II, enoxaparin vs UFH 0.89-1.14) or insights through
bleeding and INTERACT (3.0% vs. 3.0%; OR: major analyses of
observed in the Performed using 1.00; 95% CI: 0.85- bleeding totality of data.
6 randomized a random- 1.17). (OR: 1.04; Trial
controlled trials effects empirical Statistically significant 95% CI: populations are
comparing Bayes model reduction in combined 0.83–1.30) 7 not identical
enoxaparin and endpoint of death or d after with respect to
UFH in nonfatal MI at 30 d randomizatio baseline
treatment of observed for n characteristics,
ACS enoxaparin vs. UFH in duration of
overall trial populations study treatment,
(10.1% vs 11.0%; OR: time to revasc,
0.91; 95% CI: 0.83- or use of
0.99). concomitant
Statistically significant medical
reduction in combined therapies in
endpoint of death or MI management of
at 30 d observed for UA/NSTEMI
enoxaparin in ACS.
populations receiving Imprecision
no prerandomization exists in
antithrombin therapy frequency of
(8.0% vs 9.4%; OR: events as
0.81; 95% CI: 0.70– protocols for
0.94). data collection
and definitions
of efficacy and
safety events
varied among
studies. Not
having the
individual pt
data from all
trials precluded
more
sophisticated
statistical
analyses.
PRINCIPL Compare Randomized, Prasugrel ≥18 y and scheduled Planned PCI for Prasugrel 1º endpoint of LD phase N/A Pts with PCI entered p<0.0001 N/A LTA requires
E-TIMI 44 prasugrel with double-blind, 2- compared to undergo cardiac immediate treatment compared with (prasugrel 60 mg vs. the maintenance CI: 38.0–48.4 very precise
Wiviott higher than phase crossover with high- catheterization with of MI, any high-dose clopidogrel 600 mg) dose phase, a 28-d sample
2007 currently study dose planned PCI for thienopyridine within clopidogrel was IPA with 20 crossover conditions and
18056526 approved 300- N=201 subjects clopidogrel in angina and at least 5 d, GP IIb/IIIa mumol/L ADP at 6 h comparison of processing.
(150) mg LD and 75- pts one of the following: inhibitor within 7 d or IPA at 6 h significantly prasugrel 10 mg/d Significant
mg/d MD of coronary planned use (bailout higher in subjects vs. clopidogrel 150 proportion of
clopidogrel angiography within was permitted), high receiving prasugrel mg qd with a 1º samples did not
14 d with at least 1 risk of bleeding, (mean±SD; endpoint of IPA after meet
lesion amenable to thrombocytopenia, 74.8±13.0%) compared 14 d of either drug. prespecified
PCI, a functional or anemia. with clopidogrel IPA with 20 mumol/L conditions and
study within 8 wk (31.8±21.1%; ADP was higher in were excluded
with objective p<0.0001). subjects receiving from analyses.
findings of ischemia, prasugrel Absence of a
or prior PCI or CABG (61.3±17.8%) washout period
surgery compared with between MD
clopidogrel treatments also
(46.1±21.3%; could be
p<0.0001). Results considered
were consistent limiting.
across all key 2º
endpoints; significant
differences emerged
by 30 min and
persisted across all
time points
TRILOGY Evaluate Double-blind, ASA ACS consisting of UA Hx of TIA or stroke, Prasugrel or Death from CV causes, Rates of Prespecified P=0.21 Higher frequency N/A
ACS whether ASA randomized trial prasugrel (10 or MI without STE. PCI or CABG within clopidogrel. MI, or stroke among pts severe and analysis of multiple Prasugrel of HF in clopidogrel
Roe plus prasugrel N=7243 pts <75 mg daily) vs. Pts were eligible if the previous 30-d, Prasugrel (10 mg <75 y occurred in intracranial recurrent ischemic group, group
2012 is superior to y clopidogrel selected for final renal failure daily) adjusted to 13.9% of prasugrel bleeding events (all HR: 0.91
22920930 ASA plus N=2083 pts >75 (75 mg qd). treatment strategy of requiring dialysis, (5 mg qd) pts group and 16.0% of the similar in 2 components of 1º 95% CI: 0.79–
(151) clopidogrel for y Low dose 5 medical management and concomitant >75 y. clopidogrel group (HR groups in all endpoint) suggested 1.05
long term mg of without revasc within treatment with an Clopidogrel (75 prasugrel group: 0.91; age groups. lower risk for
therapy in pts prasugrel 10 d after index oral anticoagulant mg/d) 95% CI: 0.79–1.05; NS between prasugrel among pts
with UA or MI versus 75 mg event. Pts required to p=0.21). group <75 y (HR: 0.85;
without STE of clopidogrel have at least one of differences in 95% CI: 0.72–1.00;
who were <75 y four risk criteria: an frequency of p=0.04).
age ≥60 y, presence nonhemorrha
of DM, previous MI, gic serious
or previous revasc adverse
with either PCI or events.

CABG.
PLATO Determine the Randomized, Ticagrelor Pts admitted to N/A Ticagrelor oral PLATO major bleeding Fatal Procedure related PLATO major N/A N//A
Trial rate, clinical double-blind, n=9235 or hospital with either LD of 180 mg, (11.6 vs. 11.2%; bleeding and bleeding rates were bleeding p=0.43
Becker impact, and active control clopidogrel STE or NSTE-ACS followed by 90 p=0.43), TIMI major transfusion also similar. Non- TIMI major
2011 predictors of N=18,624 pts n=9186 in mg bid bleeding (7.9 vs. 7.7%, rates did not CABG major bleeding
22090660 major and fatal addition to Clopidogrel 300 p=0.56) and GUSTO differ bleeding (4.5 vs. p=0.56)
(152) bleeding ASA mg oral LD severe bleeding (2.9 vs. between 3.8%, p=0.02) and GUSTO severe
complications followed by 3.1%, p=0.22) groups nonprocedure bleeding p=0.22
in the PLATO maintenance related major
study dose of 75 mg bleeding (3.1 vs.
daily. All pts 2.3%, p=0.05) were
received ASA at more common in
dose of 75–100 ticagrelor treated
mg daily pts, primarily after 30
d on treatment.
Valgimigli To perform a Meta analysis 12,874 Pts undergoing N/A N/A Tirofiban associated at N/A N/A N/A N/A Heterogenity in
2010 thorough and 31 studies comparing treatment for various 30 d with significant pt populations,
19755402 updated involving 20,006 tirofiban vs. CAD conditions reduction in mortality different study
(153) systematic pts heparin plus compared with PC (OR: drug regimens,
review of PC or 0.68; 95% CI: 0.54– and variable
randomized bivalirudin 0.86; p=0.001) and endpoint
clinical trials alone, and death or MI (OR: 0.69; definitions
comparing 7132 vs. 95% CI: 0.58–0.81; across studies
tirofiban vs. PC abciximab p<0.001)
or vs. Compared with
abciximab. abciximab, mortality at
30 d did not differ (OR:
0.90; 95% CI: 0.53–
1.54; p=0.70)
In overall group
tirofiban tended to
increase the composite
of death or MI
(OR=1.18; 95% CI:
0.96–1.45; p=0.11)
ACUITY To determine Randomized Routine Moderate- and high- Included STE AMI or Routine Composite ischemic N/A Noninferiority or p=0.044 for N/A Open label
Stone optimal strategy N=9207 pts upstream risk ACS pts shock; bleeding upstream or events (death, MI, or superiority of major noninferiority; design of the
2007 for use of GP (n=4605) undergoing invasive- diathesis or major deferred unplanned revasc for bleeding and net p=0.13 for trial, a result of
17299194 IIb/IIIa inhibitors deferred treatment strategy bleeding within 2 wk; selective GP ischemia) at 30 d clinical outcomes superiority RR: the logistic
(154) in pts with selective thrombocytopenia; IIb/IIIa inhibitor 7.1% vs. 7.9% (composite ischemia 1.12 complexities of
moderate and (n=4602) GP CrCl <30 mL/min administration or major bleeding). 95% CI: 0.97– the study
high-risk ACS IIb/IIIa 30-d rates of major 1.29 design,

undergoing an inhibitor bleeding 6.1% vs. introducing the
early invasive administration 4.9% potential for
treatment p<.001 for bias.
strategy noninferiority; p=009
for superiority
Net clinical
outcomes (11.7% vs.
11.7%; p<.001 for
noninferiority; p=0.93
for superiority).
1º indicates primary; 2º, secondary; A to Z, AGGRASTAT to ZOCOR; ACS, acute coronary syndrome; ACUTEAcute Catheterization and Urgent Intervention Triage strategy; ADP, adenosine diphosphate; ASA, aspirin; bid, twice daily; CABG, coronary artery bypass
graft; CAD, coronary artery disease; CI, confidence interval; CK, creatine kinase; CK-MB, creatine kinase-MB; CRP, C-reactive protein; ;DM, diabetes mellitus; DSMB, Data and Safety Monitoring Board; ECG, electrocardiography; ESSENCE, Efficacy and Safety of
Subcutaneous Enoxaparin in Non–Q wave Coronary Events; GP, glycoprotein; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HF, heart failure; HR, hazard ratio; Hx, history; IgE, Immunoglobin E;
INTERACT, Intensive blood pressure reduction in acute cerebral haemorrhage trial; IPA; IV, intravenous; LD, loading dose; pts, patients; LTS, ;MI, myocardial infarction; OD, once daily; NA, North America; NS, no(t) significant; NSAID, nonsteroidal anti-inflammatory
drugs; NSTE, non-ST elevation; NSTEMI, non-ST-elevation myocardial infarction; PAD, peripheral arterial disease; PC, placebo; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes; qd, daily; Revasc, revascularization; ROW,
rest of the world; RR, relative risk; STE, ST elevation; STEMI, ST-elevation myocardial infarction; SYNERGY, Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors; Sx, symptoms; TIA, transient ischemic attack; TIMI,
thrombolysis in MI; TnI, troponin I; TnT, troponin T; UA, unstable angina; US, United States; UTVR, Urgent Target Vessel Revascularization; and VKA, vitamin K antagonist.
Data Supplement 16. Combined Oral Anticoagulant Therapy and Antiplatelet Therapy in Patients With Definite NSTE-ACS (Section 4.3.2)
Study Study Aim Study Type/ Intervention vs. Patient Population Study Intervention Endpoints P Values, Adverse Study
Name, Size (n) Comparator (n) OR: HR: RR: & Events Limitations
Author, 95 CI:
Year
Inclusion Criteria Exclusion Criteria Primary Endpoint Safety Endpoint Secondary
& Results & Results Endpoint & Results
CURE Compare the Randomized Clopidogrel vs. Pts were eligible Contraindications to Clopidogrel Death from CV Pts with major 1º outcome or p<0.001 Clopidogrel not N/A
Yusuf 2001 efficacy and , double- PC in addition to for the study antithrombotic or (300 mg causes, nonfatal MI, bleeding 3.7% vs. refractory ischemia RR: 0.80 associated with
(133) safety of early blind, PC- ASA hospitalized within antiplatelet therapy, immediately or stroke 2.7% p=0.001 16.5% vs. 18.8% 95% CI: 0.72 — excess rate of
11519503 and long-term controlled 24 h after the high risk for followed by 75 mg RR: 1.38 RR: 0.86; 0.90 any other type
use of clopidogrel trial onset of Sx and bleeding or severe once daily) vs. PC 9.3% vs. 11.4% 95% CI: 0.79–0.94; of adverse
plus ASA with 12,562 pts did not have STE HF, taking OACs, in addition to ASA p<0.001 event that
those of ASA had undergone % of pts with in- necessitated
alone in pts with coronary revasc in hospital refractory or discontinuation
ACS and no STE the previous 3 mo severe ischemia, HF, of study drug
or had received IV and revasc
GP IIb/IIIa receptor procedures were also
inhibitors in the significantly lower
previous 3 d with clopidogrel
ASPECT-2 Investigate Randomized LDASA n=336, Men or non- Established LDASA, high 1st occurrence of MI, Major bleeding N/A ASA vs. N/A N/A
van Es whether ASA or N=999 pts Coumadin-high pregnant women indications for intensity OAC, or stroke, or death 1% ASA, 1% on coumadin HR:
2002 OACs is more intensity OAC admitted with treatment with OAC, combined LDASA 9% vs. 5% vs. 5% OAC 0.55; 95% CI:
(155) effective in the n=325, AMIMI or UA within contraindications for and moderate ASA vs. coumadin (HR: 1·03; 95% 0.30-1.00;
12126819 long term after combined preceding 8 wk the study drug, intensity OAC HR: 0.55; 95% CI: 0·21-5·08; p=0.0479
ACS, and LDASA and planned revasc CI=0.30-1,00; p=1.0), and 2% ASA vs.
whether the coumadin- procedure, serious p=0.0479 on combination combined HR:
combination of moderate comorbidity, ASA vs. combined therapy HR: 2.35; 0.50; 95% CI:
ASA and OAC intensity OAC increased risk of HR=: 0.50; CI: 0.27- 95% CI: 0.61- 0.27-0.92;
offers greater n=332 bleeding, abnormal 0.92; p=0.03 9.10; p=0.2 p=0.03
benefit than either blood platelets or
of these agents erythrocytes,
alone, without anemia, Hx of
excessive risk of stroke, and inability
bleeding to adhere to the
protocol
Karjalainen Determine the Retrospectiv IAC group; All consecutive pts N/A IAC vs. UAC Major bleeding, N/A N/A N/A Major bleeding, Inherent
2008 safety and e analysis UAC group on warfarin therapy access-site stroke, access- limitations of a
(156) efficacy of various n=523 pts referred for PCI in complications, and site retrospective
18346963 periprocedural 4 centers with a MACE (death, MI, complications study including
antithromboticstra main policy to IAC target vessel individual risk-
tegies in pts on before PCI and in revasc, and stent based decision
long-term OAC 3 centers with a thrombosis) making in the
with warfarin long experience on Major bleeding treatment
undergoing PCI UAC during PCI 5.0% vs. 1.2%, choices;
to assess the p=0.02 and after outcome
safety of the adjusting for assessment
simplistic UAC propensity score was not
strategy OR: 3.9; 95% CI: blinded;
1.0-15.3; p=0.05) sample size
Access-site may not be
complications sufficient to
11.3% vs. 5.0%, cover small,
p=0.01 but clinically
After adjusting for significant diff
propensity score in bleeding and
OR: 2.8; 95% CI: thrombotic
1.3-6.1; p=0.008 complications
BAAS Study the N=530 pts ASA plus Pts who were N/A ASA (300 mg LD; Thrombotic events - Bleeding N/A N/A N/A N/A
ten Berg intensity and the coumarins prospectively then 100 mg qd) death, MI, target complications -
2001 duration of AC as randomized to the and coumarins lesion revasc, and hemorrhagic
(157) predictors of use of coumarins (acenocoumarol or thrombotic stroke stroke, major
11319192 thrombotic and as part of the Sintrom at 6 mg on 17 early thrombotic extracranial
bleeding events BAAS study 1 d, 4 mg on 2 d, 2 events (3.2%), 7 bleeding, and
mg on 3 d and after early bleeding false aneurysm
until intervention) episodes (1.3%), Late bleeding

started 1 wk before and 10 false episodes (1.4%)
intervention aneurysms (1.9%) lowest in pts in
Target INR 2.1-4.8 61 late thrombotic the target range
during angioplasty events occurred
and 6 mo follow-up (11.6%)
INR was measured Optimal AC was an
on the morning independent
before PTCA and predictor of late
daily thereafter until thrombotic events
discharge (RR: 0.33; 95% CI:
0.19-0.57) and was
associated with a
0.21 mm (95% CI:
0.17-0.42) larger
vessel lumen 6 mo
ACCF/ACG Not a study but a N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
/AHA report report with
Bhatt 2008 recommendations
(158)
19017521
Ruiz-Nodar Evaluate the Retrospectiv DES (n=207) vs. Pts with AF who N/A DES or BMS All bleeding Major bleeding N/A N/A N/A Limited by its
2009 safety and e cohort BMS (n=207) had undergone episodes, was higher in the registry design
(159) efficacy of use of study PCI with stent thromboembolism, DES group (2.26 and as well as
19246502 DES vs. BMS in a N=604 pts and MACE; i.e. vs. 1.19/10,000 d being the
cohort of pts with death, AMI, TVF. of exposure, experience of
AF Incidence density of p=0.03) only 2
MACE as well as Rate of definitive European
the incidence of all- and probable centers; study
cause mortality in thrombosis was may not be
both groups was similar in both adequately
similar. Higher DES and BMS powered
incidence of major groups (0.43 vs. enough to
bleeding in DES 0.06/10,000 d of detect diff in
group (2.26 vs. exposure, clinical
1.19/10,000 d of p=0.09) outcomes; the
exposure; p=0.03) retrospective
design of the
study could
explain an
underreporting
of minor
bleeding; the
exact length of
triple treatment
in BMS and
DES groups
Lip 2010 Not a study but a N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
(160) summary report
20447945 Full consensus
document
comprehensively
reviews published
evidence and
presents
consensus
statement on
‘best practice’
antithrombotic
therapy guideline
for management
of antithrombotic
therapy in AF pts
WARSS Investigate Multicenter, Warfarin (dose Pts were 30-85 y, Baseline INR above Warfarin (dose Combined recurrent Major N/A p=0.25 HR:1.13 N/A N/A
Mohr 2001 whether warfarin, double-blind, adjusted INR of considered normal range (>1.4), adjusted INR 1.4- ischemic stroke or hemorrhage 95% CI: 0.92-
(161) which is effective randomized 1.4-2.8) acceptable stroke that was due 2.8) vs. ASA (325 death from any 2.22 per 100 pt-y 1.38
11794192 and superior to n=1,103 candidates for to procedure or mg qd) cause within 2 y vs. 1.49 per 100
ASA in the vs. ASA (325 warfarin therapy, attributed to high- Death or recurrent pt-y
prevention of mg qd) n=1,103 had ischemic grade carotid ischemic stroke
cardiogenic stroke within stenosis which 17.8% vs. 16.0%
embolism, would previous 30 d, and surgery was p=0.25; HR: 1.13;
also prove had scores of ≥3 planned, or stroke 95% CI: 0.92-1.38
superior in the on GOS associated with an
prevention of inferred
recurrent cardioembolic
ischemic stroke in source
pts with a prior
noncardioembolic
ischemic stroke
CARS N/A Commentary Fixed low-dose N/A N/A Fixed low-dose Reinfarction, stroke, N/A N/A N/A N/A N/A
Peverill warfarin (1-3 warfarin (1-3 mg) or CV death.
1997 mg) combined combined ASA (80 Provides no
(162) ASA (80 mg) mg) reduction in
15687136 reinfarction beyond
that achievable with

160 mg ASA
Rossini Assess long-term N=102 Triple Pts undergoing Pts requiring OAC Triple antiplatelet Bleeding N/A MACE N/A N/A N/A
2008 outcomes antiplatelet coronary stenting therapy because of therapy ASA and 10.8% vs. 4.9%, 5.8% vs. 4.9%, p=0.7
(163) associated with therapy ASA treated with dual mechanical valve clopidogrel and p=0.1
19064015 the use of triple- and clopidogrel antiplatelet therapy prosthesis OAC or control INR values were
therapy in pts and OAC also requiring OAC group: dual higher in pts with
undergoing n=102 antiplatelet therapy bleeding (2.8+1.1
coronary stenting Control group: ASA and clopidogrel vs. 2.3+0.2,
and evaluate how dual antiplatelet INR targeted to p=0.0001)
these may be therapy ASA lower therapeutic INR values within
affected by and clopidogrel range (2.0-2.5) target range risk of
targeting INR n=102 bleeding was lower
values to the compared with pts
lower therapeutic who did not (4.9 vs.
range 33%, p=0.00019)
and in control group
(4.9%)
Sarafoff Investigate the N=515 pts n=306 pts Pts on chronic N/A Clopidogrel and Composite of death, Major bleeding 2 N/A N/A N/A Lack of
2008 efficacy and continued OAC OAC who ASA MI, stent thrombosis y 1.4% (n=4, randomization;
(164) safety of 2 (triple therapy) underwent DES or stroke triple therapy) vs. diff regarding
18624903 regimens of and n=209 pts implantation During SRAT 13 pts 3.1% (n=6, dual indication for
antithrombotic AC discontinued in group with triple therapy, p=0.34) OAC amongst
therapy in pts OAC (dual therapy vs. 15 pts in both groups;
who present for therapy) they the group with dual study may be
DES implantation received therapy underpowered
whilst on OAC antiplatelet Kaplan–Meier
therapy with estimates 4.2% and
clopidogrel and 7.2%, OR: 0.61,
ASA 95% CI: 0.29-1.28;
p=0.19.
2 y follow-up, 35 pts
triple therapy vs. 36
pts dual therapy
(Kaplan–Meier
estimates 14.1%
and 18.0%, OR:
0.76, 95% CI: 0.48-
1.21; p=0.25).
1º indicates primary; AC, anticoagulants; ACS, acute coronary syndrome; AF, atrial fibrillation; AMI, acute myocardial infarction; ASA, aspirin; BAAS, Balloon Angioplasty and Anticoagulation Study; BMS, bare metal stents; CV, cardiovascular; DES, drug-eluting stents;
diff, difference(s); GOS, Glascow Outcome Scale; GP, glycoprotein; HF, heart failure; Hx, history; IAC, interrupted anticoagulation; INR, internationalized normalized ratio; IV, intravenous; LDASA, low-dose aspirin; MACE, major adverse cardiac events; MI, myocardial

infarction; N/A, not applicable; NSTE, non-ST-segment elevation; OAC, oral anticoagulant(s); OR, odds ratio; PC, placebo; PCI, percutaneous coronary intervention; PTCA, percutaneous coronary angioplasty; pt, patient; revasc, revascularization; RR, relative risk;
STE, ST-segment elevation; SRAT, stent-related antithrombotic treatment; Sx, symptoms; TVF, target vessel failure; UA, unstable angina; and UAC, uninterrupted anticoagulation.
Data Supplement 17. Parenteral Anticoagulant and Fibrinolytic Therapy (Section 4.3.3)
Study Study Aim Study Type / Intervention vs. Patient Population Study Endpoints P Values, Adverse Study
Name, Size (N) Comparator (n) Intervention OR: HR: RR: & Events Limitations
Author, 95 CI:
Year
Inclusion Criteria Exclusion Criteria Primary Endpoint & Safety Secondary
Results Endpoint & Endpoint &
Results Results
PLATO Prespecified Observed Reasons for N/A N/A Regional Cox regression N/A Both Cox N/A N/A N/A
Mahaffey subgroup regional interaction interaction could analyses performed to regression with
2011 analysis interaction explored arise from quantify how much of median
(134) showed driven by independently by chance alone. regional interaction maintenance dose
21709065 significant interaction of 2 statistical Results of 2 could be explained by and landmark
interaction randomized groups. independently pt characteristics and techniques showed
between treatment with performed concomitant pts taking low-dose
treatment and 78% of North analyses treatments, including maintenance ASA,
region American pts identified ASA maintenance ticagrelor
(p=0.045), in US underlying therapy. Landmark associated with
with less effect compared with statistical Cox regressions at 8 better outcomes
of ticagrelor in the ROW pts interaction with timepoints evaluated compared with
North America (p=0.01 vs. ASA association of clopidogrel with
than in rest of p=0.045 maintenance selected factors, statistical
world. interaction dose as possible including ASA dose, superiority in ROW
Additional using NA), explanation for with outcomes by and similar
exploratory analyses focus regional treatment. Systematic outcomes in US
analyses on comparison difference. errors in trial conduct cohort.
performed to of US and rest Lowest risk of CV ruled out. Given large
identify of world with death, MI, or number of subgroup
potential Canadian pts stroke with analyses performed
explanations included in the ticagrelor and that result
for observed rest of world compared with numerically favoring
region by group. clopidogrel clopidogrel in at least
treatment associated with 1 of 4 prespecified
interaction. low maintenance regions could occur
dose of with 32% probability,
concomitant chance alone cannot
ASA. be ruled out. More pts
in US (53.6%) than
rest of world (1.7%)
took median ASA

dose ≥300 mg qd.
Only ASA dose
explained substantial
fraction of regional
interaction in 37
baseline and
postrandomization
factors explored.
PLATO Determine N=18,624 Ticagrelor Hospitalized for ACS, Contraindication Ticagrelor or Composite of death Major bleeding MI alone p<0.001 Discontinuatio Geographic
Wallentin whether Pts with ACS (n=9333) with or without STE, with against use of clopidogrel from vascular causes, 11.6% vs. 5.8% vs. 6.9%, HR=0.84 n of study differences
2009 ticagrelor is with or without (180-mg LD, 90 onset of Sx during the clopidogrel, MI, or stroke 11.2%, p=0.005 95% CI=0.77- drug due to between
(139) superior to STE mg bid after) or previous 24 h. fibrinolytic therapy 9.8% pts receiving p=0.43 Death from 0.92 adverse populations of pts
19717846 clopidogrel for clopidogrel Pts who had ACS within 24 h before ticagrelor vs. 11.7% Ticagrelor vascularcauses events 7.4% or practice
prevention of (n=9291) (300- NSTE, at least two of randomization, need clopidogrel (HR: 0.84; associated 4.0% vs. 5.1%, ticagrelor vs. patterns
vascular 600 mg LD, 75 following three criteria for oral 95% CI: 0.77–0.92; with higher p=0.001 6.0% influenced effects
events and mg daily after) had to be met: ST anticoagulation p<0.001). rate of major Stroke alone 1.5% clopidogrel of the randomized
death in broad changes on ECG therapy, increased bleeding not vs. 1.3%, p=0.22 p<0.001 treatments
population of indicating ischemia; risk of bradycardia, related to Rate of death from Dyspnea was
pts presenting positive test of and concomitant CABG 4.5% any cause 4.5% vs. 13.8% vs.
with ACS biomarker indicating therapy with strong vs. 3.8%, 5.9%, p<0.001 7.8%
myocardial necrosis; or cytochrome P-450 p=0.03, Higher
one of several risk 3A inhibitor or including more incidence of
factors (age ≥60 y; prev inducer instances of ventricular
MI or CABG; CAD with fatal pauses in 1
stenosis of ≥50% at intracranial wk but not at
least 2 vessels; prev bleeding and 30 d in
ischemic stroke, TIA, fewer fatal ticagrelor
carotid stenosis ≥50%, bleeding of group than in
or cerebral revasc; DM; other types clopidogrel
PAD; chronic renal group
dysfunction, defined as
CrCl of <60 mL/min per
1.73 m2 of body surface
area).
With STE following two
inclusion criteria had to
be met: persistent STE
≥0.1 mV at least 2
contiguous leads or new
LBBB, and intention to
perform 1º PCI.
Mehta Clopidogrel 25,086 pts Pts randomly ≥18 y and presented Increased risk of 2×2 factorial Time to CV death, MI, Major bleeding Composite of death p=0.30 N/A Nominally
2010 and ASA assigned to with NSTE ACS or bleeding or active design pts or stroke, whichever occurred in from CV causes, HR: 0.94 significant
(140) widely used double-dose STEMI. ECG changes bleeding and known randomly occurred 1st, up to 30 2.5% of pts in MI, stroke, or CI: 0.83–1.06 reduction in 1º
20818903 for pts with clopidogrel compatible with allergy to clopidogrel assigned in d. Primary outcome double dose recurrent ischemia; outcome
ACS and received LD of ischemia or elevated or ASA double-blind occurred in 4.2% of group and in individual associated with
those 600 mg 1 d levels of cardiac fashion to pts assigned to 2.0% in components of 1º use of higher-
undergoing followed by 150 biomarkers; coronary double-dose double dose standard-dose outcome; death dose clopidogrel
PCI. mg od on 2-7 d. angiographic regimen of clopidogrel as group (HR, from any cause; in subgroup of
Evidence- Pts assigned to assessment, with plan to clopidogrel or to compared with 4.4% 1.24; 95% CI: Definite or probable 17,263 study
based standard-dose perform PCI early as standard-dose assigned to standard- 1.05–1.46; stent thrombosis. participants who
guideline for clopidogrel possible but no later regimen. 2nd dose clopidogrel (HR: p=0.01). Double-dose underwent PCI
dosing not received 300 mg than 72 h after component of 0.94; 95% CI: 0.83– No significant clopidogrel after
been LD 1 d before randomization factorial design, 1.06; p=0.30). difference associated with randomization
established for angiography pts were No significant between significant (69%). Test for
either agent. followed by 75 randomly difference between higher-dose reduction in 2º interaction
mg od 2-7 d. 8- assigned in open higher-dose and and lower- outcome of stent between pts who
30 d both label fashion to lower-dose ASA with dose ASA with thrombosis among underwent PCI
double-dose and higher-dose ASA respect to 1º outcome respect to the 17,263 pts who and those who
standard-dose or lower-dose (4.2% vs. 4.4%; HR: major bleeding underwent PCI did not undergo
groups received ASA. 0.97; 95% CI: 0.86– (2.3% vs. (1.6% vs. 2.3%; PCI (p=0.03) did
75 mg of 1.09; p=0.61) 2.3%; HR: HR: 0.68; 95% CI: not meet
clopidogrel od. 0.99; 95% CI: 0.55–0.85; prespecified
Pts randomly 0.84–1.17; p=0.001). threshold of
assigned to p=0.90). p≤0.01 for
lower-dose ASA subgroup
received 75 to interactions since
100 mg daily 2-7 13 prespecified
d and those subgroup
randomly analyses were
assigned to performed for
higher-dose ASA clopidogrel dose
received 300- comparison,
325 mg daily on result could have
d 2-30. been due to play
of chance.
ACUITY Assess Randomized n=2561 Pts undergoing PCI after Included - STE AMI Heparin 30-d endpoints of N/A N/A Composite N/A Randomization
subgroup anticoagulatio n=7789 pts Heparin angiography, ST or shock; bleeding (unfractionated or composite ischemia ischemia occurred before
analysis n with direct (unfractionated depression; raised TnI, diathesis or major enoxaparin) plus (death, MI, or p=0.16; major angiography,
Stone thrombin or enoxaparin) TnT, or CK-MB isozyme; bleeding episode GP IIb/IIIa unplanned revasc for bleeding study drugs were
2007 inhibitor plus GP IIb/IIIa known CAD; or all 4 within 2 wk; inhibitors, ischemia), major p=0.32; net administered at
(146) bivalirudin inhibitors other UA risk criteria as thrombocytopenia; bivalirudin plus bleeding, and net clinical median of 4 h
17368152 during PCI in n=2609 defined by TIMI study CrCl <30 mL/min GP IIb/IIIa clinical outcomes outcomes p=0.1 before PCI. PCI
individuals Bivalirudin plus group inhibitors, or (composite ischemia subgroup

with moderate- GP IIb/IIIa bivalirudin alone or major bleeding) represents subset
and high-risk inhibitors, or bivalirudin plus GP of 56% of all pts
ACS. n=2619 IIb/IIIa inhibitors vs. enrolled in
bivalirudin alone. heparin plus GP ACUITY,
IIb/IIIa inhibitors - randomization not
composite ischemia stratifi ed by
9% vs. 8%; major treatment
bleeding 8% vs. 7%; assignment.
net clinical outcomes
15% vs. 13%
Petersen Systematically Systematic N/A All 6 RCT comparing N/A N/A Combined endpoint of NS difference N/A 10.1% vs. N/A Systematic
2004 evaluate overview enoxaparin and death or MI was found in 11.0% overviews do not
(165) endpoints of N=21946 pts unfractionated heparin in enoxaparin more blood OR: 0.91 replace RCT but
15238596 all-cause ESSENCE, A NSTE ACS selected for effective than UFH in transfusion CI: 0.83-0.99 provide important
death nonfatal to Z, and analysis preventing combined (OR: 1.01; insights through
MI, SYNERGY, endpoint of death or 95% CI: 0.89– analyses of
transfusion, TIMI 11B, MI. NS difference 1.14) or major totality of the
and major ACUTE II, and found in death at 30 d bleeding (OR, data. Trial
bleeding INTERACT for enoxaparin vs 1.04; 95% CI: populations are
observed in 6 performed UFH (3.0% vs 3.0%; 0.83–1.30) at not identical with
RCT using random OR: 1.00; 95% CI: 7 d after respect to
comparing effects 0.85–1.17). randomization baseline
enoxaparin empirical Statistically significant characteristics,
and UFH in Bayes model reduction in combined duration of study
treatment of endpoint of death or treatment, the
ACS nonfatal MI at 30 d time to revasc or
observed for the use of
enoxaparin vs. UFH in concomitant
overall trial medical therapies
populations (10.1% in management of
vs. 11.0%; OR, 0.91; UA/NSTEMI
95% CI, 0.83-0.99). ACS. Some
Statistically significant imprecision exists
reduction in combined in frequency of
endpoint of death or events as
MI at 30 d also protocols for data
observed for collection and
enoxaparin in definitions of
populations receiving efficacy and
no prerandomization safety events
antithrombin therapy varied among
(8.0% vs. 9.4%; OR: studies. Not

0.81; 95% CI: 0.70– having individual
0.94) pt data from trials
precluded more
sophisticated
statistical
analyses.
Hochman Evaluate Nonrandomize Heparin Pts admitted with UA Exclusion criteria Standard (group Proportion of pts N/A Proportion of pts Significantly No major Pts not randomly
1999 regimens that d Group 1 n=23 and NSTEMI included Hx of 1) non weight achieving a target achieving a target higher complications assigned, and the
(166) reduced N=80 pts Group 2 n=19 bleeding, Coumadin adjusted 5000-U aPTT at 6 h. Pts aPTT at 24 h and proportion of pts in any group 2 weight adjusted
10426845 heparin Group 3 n=38 or thrombolytic IV bolus/1000 treated with lower number of times above target regimens were
dosage for low therapy, and failure U/hr infusion. dose of weight heparin dose range in groups not concurrently
body weight to comply exactly 2 weight adjusted adjusted heparin adjusted within 1st 1 (95%) and 2 tested. At
on weight with dosing regimen heparin regimens group 3 more often 24 h. 52% pts in (84%) versus initiation of 2nd
adjusted basis group 2 within the target range group 1 within group 3 (47%) weight-adjusted
in prospective, 70 U/kg IV bolus; for aPTT at 6 h (34% target range (p<0.0005) nomogram the
nonrandomize 15 U/kg/h pts vs. 5% vs. 0%) compared with 79% target aPTT
d cohort pts <70 kg and a required fewer in group 2 and 74% changed to 45-70
with UA and fixed 5000-U IV heparin infusion in group 3 s from 50-75 s
MI who did not bolus/1000 U/hr changes (1.0 ± 1.0 vs. significantly fewer
receive for pts who 1.9 ± 1.0 vs. 2.0 ± changes in infusion
thrombolytic weighed >70 kg) 0.9) within 1st 24 h rate required over
agents (group 3) compared with other 24 h period in
60 U/kg IV bolus, regimens. Pts in group 3 compared
12 U/kg/hr groups 1 and 2 above with other regimens
infusion pts <70 target range at 6 h (1.05 ± 1.0 for
kg and capped (95% and 84% group 3 vs. 2 ± 0.9
4000-U IV bolus; compared with 48% in for group 1 vs. 1.9
900 U/hr infusion group 3) ± 1.0 in group 2;
pts >70 kg. p<0.001).
Garcia Pharmacology Parenteral N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
2012 of approved Anticoagulants
(167) parenteral Evidence-
22315264 anticoagulants Based Clinical
including Practice
indirect Guidelines
anticoagulants
, UFH, LMWH,
fondaparinux,
and
danaparoid,
and direct
thrombin
inhibitors
hirudin,
bivalirudin,
and
argatroban.
TIMI 11B Test benefits Randomized UFH n=1957 vs. Pts with UA/NQMI Planned revasc UFH >3 d Composite of all- Major Individual elements 8d Stroke (1.0% N/A
Antman of strategy of N=3910 pts enoxaparin ischemic discomfort of within 24 h, treatable followed by cause mortality, hemorrhage, of 1º endpoint and p=0.048 vs. 1.2%), TIA
1999 extended n=1953 >5 min duration at rest; cause of angina, subcutaneous recurrent MI, or urgent bleed in composite of death OR=0.83 (0.3% vs.
(168) course of Hx of CAD (abnormal evolving Q-wave MI, PC injections or revasc at 8 d 14.5% retroperitoneal or nonfatal MI 95% CI: 0.69- 0.3%), or
10517729 uninterrupted coronary angiogram, Hx of CABG surgery enoxaparin (30 vs. 12.4% OR: 0.83; , intracranial, 1.00 at 43 d thrombocytop
antithrombotic prior MI, CABG surgery, within 2 mo or PTCA mg IV bolus 95% CI: 0.69–1.00; or intraocular p=.048 enia (2.1%
therapy with or PTCA), ST deviation, within 6 mo, followed by p=0.048 at 43 d location; OR= 0.85 vs. 1.9%)
enoxaparin or elevated serum treatment with injections of 1.0 19.7% vs. 17.3% hemoglobin 95% CI= 0.72–
compared with cardiac markers continuous infusion mg/kg every 12 OR: 0.85; 95% CI: drop of >3 1.00
standard of UFH for >24 h h) 0.72–1.00; p=0.048 g/dL;
treatment with before enrollment, Outpatient phase requirement of
UFH for Hx of heparin- (injections every transfusion of
prevention of associated 12 h of 40 mg pts >2 U blood 72
death and thrombocytopenia <65 kg, 60 mg h no difference
cardiac with or without >65 kg)
ischemic thrombosis, and
events in pts contraindications to
with UA/NQMI anticoagulation
OASIS-5 Study reports Double-blind, n=1,414 Pts with UA or NSTEMI; Contraindication to Fondaparinux or Rates of major Catheter N/A p<0.00001 N/A Randomized
trial Mehta prospectively randomized subcutaneous at least 2 of following low molecular weight enoxaparin total bleeding and efficacy thrombus HR: 0.46 treatments may
2007 planned 20,078 pts fondaparinux criteria: age >60 y, heparin, of 12,715 pts by evaluating more common have influenced
(169) analysis of pts 2.5 mg od or positive cardiac hemorrhagic stroke underwent heart composite of death, in pts receiving which pts
17964037 with ACS who n=1,420 biomarkers, or ECG within last 12 mo, catheterization MI, or stroke at 9, 30, fondaparinux underwent PCI.
underwent subcutaneous changes compatible with indication for during the initial 180 d (0.9%) than Types of pts
early PCI in enoxaparin 1 ischemia. anticoagulation other hospitalization, Fondaparinux vs. enoxaparin undergoing PCI
the OASIS-5 mg/kg bid than ACS, revasc and 6,238 pts enoxaparin reduced alone (0.4%), and number and
trial procedure already underwent PCI. major bleeding by but largely timing of PCI
performed for >0.5 (2.4% vs. 5.1%; prevented by procedures
qualifying event, and HR: 0.46, p<0.00001) using UFH at similar in 2
severe renal at 9 d with similar the time of PCI randomized
insufficiency rates of ischemic without treatment groups.
events resulting in increase in Number of pts
superior net clinical bleeding who received
benefit (death, MI, open-label UFH
stroke, major before PCI in
bleeding: 8.2% vs. OASIS-5 trial
10.4%; HR: 0.78, modest.

p=0.004).
Fondaparinux
reduced major
bleeding 48 h after
PCI irrespective of
whether PCI was
performed <6 h of the
last enoxaparin dose
(1.6% vs. 3.8%; HR:
0.42, p<0.0001) or >6
h when UFH was
given (1.3% vs. 3.4%;
HR: 0.39, p<0.0001).
OASIS-5 Compare the Randomized, n=10,057 Pts with UA or NSTEMI; Contraindications to Fondaparinux Death, MI, or Rate of major Death, MI, or HR: 1.01 N/A N/A
Yusuf efficacy and double-blind, fondaparinux vs. ≥60 y, elevated level of low molecular weight (2.5 mg d) or refractory ischemia at bleeding at 9 d refractory ischemia; CI: 0.90-1.13
(170) safety of double-dummy n=10,021 troponin or CK-MB heparin, recent enoxaparin (1 9d markedly and individual
16537663 fondaparinux trial enoxaparin isoenzyme, or ECG hemorrhagic stroke, mg/kg od) for 1º outcome events lower with components of
and N=20,078 pts changes indicative of indications for mean of 6 d similar in 2 groups fondaparinux composite
enoxaparin in ischemia. anticoagulation other (5.8% (579 events) than with outcomes at 30 d
high-risk pts than ACS or serum with fondaparinux vs. enoxaparin and at end of study
with UA or creatinine level of ≥3 5.7% (573 events) (217 events) NS trend toward
NSTEMI mg/dL (265 μmol/L) enoxaparin HR=1.01; 2.2% vs. 412 lower value in
95% CI, 0.90-1.13); events 4.1%; fondaparinux group
composite of 1º HR: 0.52; at 30 d (805 vs.
outcome and major p<0.001 864, p=0.13) and at
bleeding at 9 d end of study (1222
favored fondaparinux vs. 1308, p=0.06).
(737 events) 7.3% vs. Fondaparinux
(905 events) 9.0%; associated with
HR=0.81; p<0.001. significantly
reduced number of
deaths at 30 d (295
vs. 352; p=0.02)
and at 180 d (574
vs. 638; p=0.05).
FUTURA/ Compare Double-blind Low-dose UFH Pts undergoing PCI <21 y; IV low-dose UFH, Composite of major Major bleeding Composite of major p=0.27 Catheter FUTURA still
OASIS-8 safety of 2 randomized n=1024 vs. within 72 h contraindications to 50 U/kg , bleeding, minor or minor bleeding at 48 h OR: 0.80 thrombus underpowered to
Steg UFH regimens parallel group standard-dose Hx consistent with new UFH or regardless of use bleeding, or major bleeding 5.8% vs. 3.9%; OR: 95% CI: 0.54- 0.5% vs. conclusively rule
2010 during PCI in N=2,026 pts UFH n=1002 or worsening ischemia, fondaparinux; of GpIIb-IIIa vascular access-site Major bleeding 1.51; 95% CI: 1.19 0.1% out moderate, but
(171) high-risk pts occurring at rest or with contraindications for inhibitors or complications up to 48 no difference 1.00–2.28; p=0.05 p=0.15 important,
20805623 with NSTE minimal activity; angiography; pts standard-dose h after PCI minor bleeding death, MI, or target reductions in
acss initially enrollment within 48 h of requiring urgent UFH, 85 U/kg (60 4.7% vs. 5.8% 0.7% vs. 1.7% vessel revasc bleeding from use
treated with most recent Sx; planned coronary U/kg with GpIIb- OR: 0.80; 95% CI: ; within 30 d of low-dose UFH.
fondaparinux coronary angiography, angiography due to IIIa inhibitors), 0.54–1.19; p=0.27 OR: 0.40; 95% 4.5% vs. 2.9%; Based on
with PCI if indicated, refractory or adjusted CI: 0.16–0.97; OR: 1.58; 95% CI: observed 5.8%
within 72 h; at least 2 of recurrent angina by blinded ACT p=0.04) 0.98–2.53; p=0.06 event rate of 1º
following criteria: >60 y, associated with endpoint, a
TnT or TnI or CK-MB dynamic ST sample size of
above upper limit of changes, HF, life- 11, 542 pts
normal; ECG changes threatening needed to have
compatible with arrhythmias, 80% power to
ischemia hemodynamic detect 20% RR
instability; treatment reduction
with other injectable
anticoagulants
hemorrhagic stroke
within 12 mo;
indication for
anticoagulation other
than acss; women
pregnant,
breastfeeding, or of
childbearing
potential not using
contraception; life
expectancy <6 mo;
receiving
experimental
pharmacological
agent; revasc
procedure for
qualifying event
already performed;
creatinine clearance
< 20 mL/min.
Grosser Determine N=400 Group 1 (n=40) Healthy, nonsmoking N/A Single oral dose Pharmacological N/A Pseudoresistance, N/A N/A N/A
2013 commonality received regular, volunteers (aged 18–55 of 325-mg resistance to ASA is reflecting delayed
(172) of immediate y) immediate rare; study failed to and reduced drug
23212718 mechanisticall release ASA release ASA or identify single case of absorption,
y consistent, response was enteric coated true drug resistance. complicates enteric
stable, and assessed 8 h ASA Variable absorption coated but not
specific after dosing. caused high immediate release
phenotype of Group 2 (n=210) frequency of apparent ASA
true received enteric resistance to single

pharmacologic coated ASA dose of 325 mg
al resistance response was enteric coated ASA
to ASA—such measured 8 h (up to 49%) but not to
as might be after dosing. immediate release
explained by Group 3 (n=150) ASA (0%).
genetic received enteric
causes coated ASA,
response was
assessed at 4 h
FUTURA/ Evaluate International 4,000 high-risk UA or NSTEMI; be Age <21 y; N/A Composite of peri-PCI Major and Composite of peri- N/A N/A N/A
OASIS 8 safety of 2- prospective pts treated with enrolled within 48 h of contraindication to major bleeding, minor minor PCI major bleeding
Steg dose regimens cohort study fondaparinux as the onset of most recent UFH or bleeding, or major bleeding; with death, MI, or
(173) of adjunctive N=4,000 initial medical episode of Sx; planned fondaparinux; vascular access site major vascular target vessel
21146654 IV UFH during therapy coronary angiography contraindication for complications access site revasc at 30 d.
PCI in high- Within cohort, with PCI if indicated angiography or PCI; complications
risk pts with 2,000 pts within 72 h of enrolment; subjects requiring
NSTE-ACS undergoing PCI at least 2 of following: urgent (<120 min)
initially treated enrolled into age ≥60 y, TnT or TnI or coronary
with double-blind CK-MB above upper angiography
fondaparinux international limit of normal; ECG because of
and referred randomized changes compatible with refractory or
for early parallel-group ischemia. recurrent angina
coronary trial evaluating associated with
angiography. standard ACT dynamic ST
guided doses of changes, HF, life-
IV UFH versus a threatening
non-ACT-guided arrhythmias, and
weight-adjusted hemodynamic
low dose. instability; subjects
already receiving
treatment with other
injectable
anticoagulants for
treatment of
qualifying event,
unless the last dose
was ≥8 h for LMWH,
≥60 min for
bivalirudin, ≥90 min
for UFH;
hemorrhagic stroke
within last 12 mo;

indication for
anticoagulation other
than ACS;
pregnancy, women
who are
breastfeeding or
childbearing
potential who are not
using effective
method of
contraception;
comorbid conditions
with life expectancy
<6 mo; currently
receiving an
experimental
pharmacologic
agent; revasc
procedure for
qualifying event
already performed;
and severe renal
insufficiency
ACUITY Examine Randomized n=4603 UFH or Pts with Sx of UA lasting MI associated with UFH or Composite ischemia N/A N/A N/A N/A Logistic
Stone usefulness of N=13,819 pts enoxaparin plus ≥10 min within acute STE or shock; enoxaparin plus endpoint (death, MI, complexities of
2006 bivalirudin as a GP IIb/IIIa preceding 24 h eligible bleeding diathesis or a GP IIb/IIIa or unplanned revasc trial necessitated
(174) part of early inhibitor for enrollment if one or major bleeding inhibitor, for ischemia), major an open-label
17124018 invasive n=4604 more following criteria episode within 2 wk bivalirudin plus a bleeding, and net design,
strategy with bivalirudin plus were met: new ST- before episode of GP IIb/IIIa clinical outcome, introduced
optimal GP IIb/IIIa segment depression or angina; inhibitor, or defined as potential for bias;
antiplatelet inhibitor transient elevation of at thrombocytopenia; a bivalirudin alone combination of 59% of study
therapy in pts n=4612 least 1 mm; elevations in calculated creatinine composite ischemia or cohort presented
with acss bivalirudin alone the TnI, TnT, CK-MB clearance rate of major bleeding. with NSTEMI.
levels; known CAD; or <30 mL/min; recent Bivalirudin plus GP Significant
all four other variables administration of IIb/IIIa inhibitor, as proportion of pts
for predicting TIMI risk abciximab, warfarin, compared with pretreated with
scores for UA. fondapar inux, heparin plus GP either UFH or
fibrinolytic agents, IIb/IIIa inhibitor, LMWH before
bivalirudin, ≥2 doses associated with randomization;
of LMWH; and noninferior 30-d rates 25% noninferiority
allergy to any study of composite ischemia margin used may
drugs or to iodinated endpoint (7.7% and be considered

contrast medium that 7.3%, respectively), wide
could not be major bleeding (5.3%
controlled in and 5.7%), and net
advance with clinical outcome
medication. endpoint (11.8% and
11.7%). Bivalirudin
alone, compared with
heparin plus GP
IIb/IIIa inhibitor,
associated with
noninferior rate of
composite ischemia
endpoint (7.8% and
7.3%, respectively;
p=0.32; RR=1.08;
95% CI=0.93-1.24)
significantly reduced
rates of major
bleeding (3.0% vs.
5.7%; p<0.001;
RR=0.53; 95%
CI=0.43-0.65) net
clinical outcome
endpoint (10.1% vs.
11.7%; p=0.02;
RR=0.86; 95%
CI=0.77-0.97).
Fibrinolytic Systematic Collaborative N=58600 pts All trials of fibrinolytic N/A Streptokinase, Deaths during 1st 5 wk N/A Benefit in 45,000 N/A Fibrinolytic N/A
Therapy overview of overview therapy vs. control that anistreplase, tPA, and major adverse pts presenting with therapy
Trialists' effects of randomized >1000 pts urokinase events occurring STE or BBB associated
(FTT) treatment on with suspected AMI during hospitalization irrespective of age, with 4 extra
Collaborati mortality and GISSI-1, ISAM, AIMS, 10.5% deaths sex, blood strokes per
ve Group on major ISIS-2, ASSET, USIM, 1.0% strokes pressure, HR, or 1000 during
1994 morbidity in ISIS-3, EMERAS, LATE 0.7% major non- previous MI or D 0-1 d
(175) various pt cerebral bleeds greater earlier
7905143 categories in 9 Fibrinolytic therapy treatment began
trials designed excess of deaths Relation between
to randomize during 0-1 d benefit and delay
>1000 pts with (especially among pts from Sx onset
AMI between presenting >12 h after indicated highly
fibrinolytic Sx and in the elderly) significant absolute
therapy and Much larger benefit mortality reductions

control – during 2-35 d – 30 per 1000
GISSI-1, within 0-6 h; 20 per
ISAM, AIMS, 1000 presenting 7-
ISIS-2, 12 h; statistically
ASSET, USIM, uncertain benefit 10
ISIS-3, per 1000 within 13-
EMERAS, 18 h
LATE
TIMI IIIB TIMI III Randomized Compare TPA Pts seen within 24 h of Treatable cause of TPA versus PC TPA-PC comparison N/A Endpoint for p=NS 4 intracranial N/A
1994 focused on UA using 2×2 vs. PC as initial ischemic chest UA, experienced MI Early invasive (death, MI, or failure comparison of the hemorrhages
(176) and NQMI. factorial design therapy and an discomfort at rest, within preceding 21 strategy vs. early of initial therapy at 6 two strategies occurred in
8149520 Determine by N=1473 Pts early invasive considered to represent d, undergone conservative wk) occurred in 54.2% (death, MI, or TPA-treated
coronary strategy (early UA or NQMI. coronary strategy of the TPA-treated pts unsatisfactory Sx- group vs.
arteriography coronary arteriography within and 55.5% of PC- limited exercise none in PC
the incidence arteriography 30 d, PTCA within 6 treated pts (p=NS). stress test at 6 wk) treated group
of coronary followed by mo, CABG anytime, Fatal and nonfatal MI occurred in 18.1% (p=.06).
thrombi in revasc when or if, at enrollment, after randomization of pts assigned to
these anatomy was were in pulmonary (reinfarction in NQMI early conservative
conditions and suitable) vs. edema, had SBP pts) occurred more strategy and 16.2%
response of early >180 mm Hg or DBP frequently in TPA- of pts assigned to
these thrombi conservative >100mm Hg, treated pts (7.4%) the early invasive
to 0.8 mg/kg strategy contraindication to than in PC-treated pts strategy (p=NS).
dose (max 80 (coronary thrombolytic therapy (4.9%, p=0.04,
mg) of TPA. arteriography or heparin, LBBB, a Kaplan-Meier
Determine followed by coexistent severe estimate).
effects of revasc if initial illness, woman of
thrombolytic medical therapy child-bearing
therapy and failed). potential, receiving
early invasive oral anticoagulants.
strategy on
clinical
outcome (TIMI
IIIB). Provide
further
understanding
of natural Hx
of UA and
NQMI
Eikelboom Systematic Meta-analysis UFH or LMWH Trials had to be Studies were UFH or LMWH or Composite of death or 1º safety 2º outcomes of N/A N/A Large numbers of
2000 overview of 12 trials, or PC randomized; include pts excluded: PC MI at 7 d (OR: 0.53 outcome major interest were pts randomized to
(147) randomized n=17,157 pts with UA or NQMI; and Randomized 95% CI: 0.38–0.73; bleeding recurrent angina receive short-
trials to assess include ASA-treated pts comparison heparin p=0.0001) Long-term and need for term therapy who
effect of UFH randomly assigned to vs. ASA, heparin Short term LMWH vs LMWH revasc. did not continue
and LMWH on UFH or LMWH or to PC plus ASA vs. UFH (OR: 0.88; 95% OR=2·26, therapy long term
death, MI, and or untreated control combined CI: 0.69–1.12; 95% CI=1.63– may have
major antiplatelet therapy, p=0·34). Long-term 3.14, reduced power of
bleeding. or heparin vs. non- LMWH (up to 3 mo) p<0.0001 studies to detect
ASA control; vs PC or untreated significant
nonrandomized control (OR: 0·98; difference. Pts
comparison 95% CI: 0.81–1.17; who did not
reported; dose- p=0·80 receive long-term
ranging uncontrolled LMWH were
study; pts alternately those at highest
allocated to LMWH risk for recurrent
or UFH therapy; lack events.
of clarity as to
whether study was
properly
randomized.
ACCF/ ACCF/ACG/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
ACG/ HA 2008
AHA Expert
report Consensus
Bhatt Document on
2008 Reducing the
(158) Gastrointestin
19017521 al Risks of
Antiplatelet
Therapy and
NSAID Use
Karjalainen Determine Retrospective IAC and UAC All consecutive pts on N/A IAC vs. UAC Major bleeding, N/A N/A N/A Major Inherent
2008 safety and analysis group warfarin therapy referred access-site bleeding, limitations of
(156) efficacy of n=523 pts for PCI in four centers complications, and stroke, retrospective
18346963 various with a main policy to IAC major adverse cardiac access-site study including
periprocedural before PCI and in three events (death, MI, complications individual risk-
antithrombotic centers with a long target vessel revasc, based decision
strategies in experience on UAC and stent thrombosis) making in
pts on long- during PCI. Major bleeding 5.0% treatment
term OAC with vs. 1.2%, p=0.02 and choices; outcome
warfarin after adjusting for assessment not
undergoing propensity score blinded; sample
PCI. Assess (OR:3.9, 95% CI: 1.0– size may not be
safety of 15.3, p=0.05) sufficient to cover
simplistic UAC Access-site small but clinically

strategy. complications (11.3% significant
vs. 5.0%, p=0.01) differences in
After adjusting for bleeding and
propensity score thrombotic
(OR=2.8, 95% CI: complications
1.3–6.1, p=0.008)
BAAS Study intensity N=530 pts ASA plus Pts who were N/A ASA (LD, 300 Thrombotic events - Bleeding N/A N/A N/A N/A
ten Berg and duration coumarins prospectively mg; then 100 mg Death, MI, target Complications,
2001 of randomized to use of qd) and lesion, revasc, and hemorrhagic
(157) anticoagulatio coumarins as part of coumarins thrombotic stroke stroke, major
11319192 n as predictors BAAS study (acenocoumarol 17 early thrombotic extracranial
of thrombotic or Sintrom at 6 events (3.2%), 7 early bleeding, and
and bleeding mg 1 d, 4 mg on bleeding episodes false
events 2 d, 2 mg on 3 d (1.3%), and 10 false aneurysm
and after until aneurysms (1.9%). Late bleeding
intervention) 61 late thrombotic episodes
started 1 wk events occurred (1.4%) lowest
before (11.6%). Optimal in pts in target
intervention anticoagulation an range.
Target INR was independent predictor
2.1-4.8 during of late thrombotic
angioplasty and events (RR: 0.33;
6-mo follow-up 95% CI: 0.19-0.57)
INR measured on and associated with
morning before 0.21 mm (95% CI:
PTCA and daily 0.17-0.42) larger
after until vessel lumen at 6 mo
discharge
RE-DEEM Evaluate the Double-blind, Dabigatran vs. Pts age ≥18 y, Ongoing or planned Dabigatran Composite of major or N/A Indicators of p<0.001 for 14(3.8%) pts N/A
Oldgren safety and PC-controlled, PC hospitalized with treatment with VKAs, initially one of clinically relevant efficacy such as linear trend died, had a
2011 indicators of dose- NSTEMI or STEMI severe disabling two lower doses minor bleeding during reduction in D- HR 1.77 (95% MI or stroke
(177) efficacy of four escalation trial within last 14 d, and stroke within (50 mg bid n=369 6 mo treatment dimer levels and CI: 0.70–4.50) in PC group
21551462 dose regimens N=1861 pts receiving treatment with previous 6 mo or any and 75 mg bid) period.Composite of incidences of CV for 50 mg; compared
of dabigatran dual antiplatelet therapy stroke within n=368 major or clinically ischaemic events. HR=2.17 (95% with 17
etexilate (ASA and clopidogrel or previous 14 d, vs. PC n=371 relevant minor D-dimer CI: 0.88–5.31) (4.6%) in 50
compared with another thienopyridine). conditions N=406 110 mg bleeding events 3.5, concentrations for 75 mg; mg, 18 (4.9%)
PC when ≥1 risk factor for associated with dose in 2nd stage 4.3, 7.9, and 7.8% in reduced in all HR=3.92 (95% in 75 mg, 12
given in subsequent CV increased risk of n=347 150 mg respective 50, 75, dabigatran dose CI: 1.72–8.95) (3.0%) in 110
addition to complications: age >65 bleeding such as dosegroup in 110, and 150 mg groups by an for 110 mg; and mg, and 12
dual y, DM on treatment, major surgery third stage dabigatran groups, average of 37 and HR=4.27 (95% (3.5%) in the
antiplatelet previous MI, LBBB, (including bypass compared with 2.2% 45% at wk 1 and 4, CI: 1.86–9.81) 150 mg
treatment in congestive HF requiring surgery) in previous in the PC group, respectively for 150 mg. dabigatran
pts with recent treatment or LVEF 40%, mo, Hx of severe p<0.001 for linear (p<0.001). groups
STEMI or PAD, moderate renal bleeding, trend. 96 1º outcome
NSTEMI at insufficiency (CrCl ≥30– gastrointestinal events, compared
high risk of 60 mL/min), or no haemorrhage with in with PC a dose
new ischaemic revasc for the index past y, dependent increase
CV events. event. gastroduodenal ulcer with dabigatran, HR
in previous 30 d, 1.77 (95% CI: 0.70–
fibrinolytic agents 4.50) for 50 mg;
within 48 h of study HR=2.17 (95% CI:
entry, uncontrolled 0.88–5.31) for 75 mg;
hypertension, HR=3.92 (95% CI:
haemoglobin ,10 1.72–8.95) for 110
g/dL or platelet mg; and HR=4.27
count ,100 × 109/L, (95% CI: 1.86–9.81)
normal coronary for 150 mg.
arteries at Compared with PC,
angiogram for index D-dimer
event, congestive concentrations
HF New York Heart reduced in all
Association Class dabigatran dose
IV, and severe renal groups by average of
impairment (CrCl ,30 37 and 45% at wk 1
mL/min). and 4, respectively
(p=0.001).
Uchino Systematically Meta-analysis N/A Searched PubMed, N/A Fixed-effects M- Dabigatran was N/A N/A p=.03 N/A Dominant effect
2012 evaluated risk Seven trials Scopus, and Web of H used to significantly ORM-H, 1.33 of RE-LY trial on
(178) of MI or ACS were selected Science for randomized evaluate the associated with higher CI=1.03-1.71 results of meta-
22231617 with use of N=30,514 controlled trials of effect of risk of MI or ACS than analysis. Other 6
dabigatran. dabigatran that reported dabigatran on MI seen with agents used trials had cohort
on MI or ACS as 2º or ACS. in control group sizes of 515-3451
outcomes. Expressed (dabigatran, 237 of 20 with durations of
associations as 000 [1.19%] vs. ≤6mo. In RE-LY,
OR and 95% CIs. control, 83 of 10 514 18,113
[0.79%]; ORM-H, 1.33; participants
95% CI: 1.03-1.71; monitored for
p=.03). median of 2 y.
Owing to sample
size and duration
of study, RE-LY
comprised 59% of
the cohort and
74% of the
events.
Alexander Determine Randomized, n=3705 ACS (MI, NSTEMI, N/A Apixaban 5 mg CV death, MI, or Major bleeding N/A P=0.51 N/A N/A
2011 whether in double-blind, apixaban, 5 mg STEMI, or UA) within bid PC, in ischemic stroke according to HR=0.95
(179) high-risk pts PC-controlled bid vs. n=3687 previous 7 d, Sx of MI addition to Median follow-up of TIMI definition CI=0.80-1.11
21780946 with ACS N=7392 PC lasting 10 mo or more standard 241 d occurred in
benefit of with pt at rest plus either antiplatelet 7.5% pts assigned to 1.3% pts who
apixaban in elevated levels of therapy apixaban received
reducing cardiac biomarkers or 7.9% assigned to PC apixaban and
ischemic dynamic ST-segment HR=0.95; 95% CI: in 0.5% pts
events depression or elevation 0.80-1.11; p=0.51 who received
outweigh of ≥0.1 mV. 2 or more of PC
increased risk the following high-risk HR=2.59; CI,
of bleeding. characteristics: age ≥65 1.50-4.46;
y, DM, MI within p=0.001.
previous 5 y, Greater
cerebrovascular number of
disease, peripheral intracranial
vascular disease, clinical and fatal
HF or LVEF of <40% in bleeding
association with index events
event, impaired renal occurred with
function with calculated apixaban than
creatinine clearance <60 PC.
ml/min and no revasc
after index event.
Mega N/A Double-blind, bidbid doses of Within 7 d after hospital N/A bid doses of Composite of death Compared bid 2.5-mg dose of p=0.008 Rates of N/A
2012 PC-controlled either 2.5 mg or admission for ACS. either 2.5 mg or 5 from CV causes, MI, with PC, rivaroxaban HR=0.84 adverse
(180) trial 5 mg of Condition of pts needed mg of or stroke. rivaroxaban reduced rates of CI=0.74-0.96 events that
22077192 N=15,526 pts rivaroxaban or to be stabilized before rivaroxaban or Rivaroxaban increased death from CV were not
PC enrollment with initial PC compared with PC, rates of major causes (2.7% vs. related to
management strategies 8.9% and 10.7% (HR bleeding not 4.1%, p=0.002) and bleeding
(e.g., revasc) completed in rivaroxaban group, related to from any cause similar in
0.84; 95% CI: 0.74- CABG (2.1% (2.9% vs. 4.5%, rivaroxaban
0.96; p=0.008), vs. 0.6%, p=0.002), and PC
significant p<0.001) and groups
improvement for both intracranial
bid 2.5-mg dose hemorrhage
(9.1% vs. 10.7%, (0.6% vs.
p=0.02) and bid 5 mg 0.2%,
dose (8.8% vs. p=0.009),
10.7%, p=0.03). without
significant
increase in
fatal bleeding
(0.3% vs.
0.2%, p=0.66)
or other
adverse
events. bid
2.5-mg dose
resulted in
fewer fatal
bleeding
events than
bid 5-mg dose
(0.1% vs.
0.4%, p=0.04).
Warkentin Report Single patient N/A N/A N/A N/A Pts developed N/A N/A N/A N/A N/A
2012 timeline of case massive postoperative
(181) bleeding, bleeding resulting
22383791 hemostatic from elective cardiac
parameters, surgery performed
and with therapeutic
dabigatran dabigatran levels.
plasma levels This illustrates
(by HPLC) in importance of
response to adjusting the number
emergency of d off dabigatran
management before surgery
with rFVIIa according to current
and renal function.
hemodialysis.
Eerenberg Evaluated Randomized, Rivaroxaban 20 Twelve healthy male N/A Rivaroxaban 20 Rivaroxaban induced N/A N/A N/A No major or Small size of
2011 potential of double-blind, mg bid (n=6) or subjects mg bid (n=6) or significant clinically study population
(182) PCC to PC-controlled dabigatran 150 dabigatran 150 prolongation of relevant accounting for
21900088 reverse N=12 mg bid(n=6) mg bid. (n=6) for prothrombin time bleeding variation in
anticoagulant 2.5 d followed by (15.8+1.3 vs. complications results of a few
effect of either single 12.3+0.7 s at occurred coagulation tests.
rivaroxaban bolus 50 IU/kg baseline; p<0.001) during No
and PCC or similar that was immediately treatment, no measurements
dabigatran volume of saline. and completely serious performed
After washout reversed by PCC adverse between 6-24 h
period procedure (12.8+1.0; events. after infusion of
repeated with p<0.001). PCC or PC. If

other Endogenous thrombin PCC had any
anticoagulant potential inhibited by effect of reversal
treatment. rivaroxaban (51+22%; for dabigatran it
baseline, 92+22%; may have been
p<0.002) normalized missed; any
with PCC (114+26%; rebound effect on
p<0.001), saline had anticoagulant
no effect. Dabigatran activity of
increased activated rivaroxaban in
partial thromboplastin that same period
time, ECT, and could not be
thrombin time. observed.
Administration of PCC
did not restore these
coagulation tests.
1º indicates primary; 2º, secondary; ACCF, American College of Cardiology Foundation; ACS, acute coronary syndrome; ACT, activated clotting time; ACUITY, Acute Catheterization and Urgent Intervention Triage strategY; ACUTE II, Assessment of Cardioversion
Using Transesophageal Echocardiography; ADP, adenosine diphosphate; AGC, ; AHA, American Heart Association; AIMS, APSAC Intervention Mortality Study; aPTT, Activated Partial Thromboplastin Time; ASA, aspirin; ASSET, Anglo-Scandinavian Study of Early
Thrombolysis; BID, twice daily; CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; CK, creatine kinase; CK-MB, creatine kinase-MB; CRP, C-reactive protein; DBP, diastolic blood pressure; DM, diabetes mellitus; ECG,
electrocardiography; ECT, ecarin clotting time; EMERAS, Estudio Multicentrico Estreptoquinasa Republicas de America del Sur; ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q wave Coronary Events; FUTURA, The Fondaparinux Trial With
Unfractionated Heparin During Revascularization in Acute Coronary Syndromes ; GISSI-1, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico acuto-1; GP, glycoprotein; HF, heart failure; HR, hazard ratio; Hx, history; IAC, Interrupt anticoagulation;
IgE, Immunoglobin E; ISAM, Intravenous Streptokinase in Acute Myocardial Infarction; ISIS, International Study of Infarct Survival; INTERACT, Intensive blood pressure reduction in acute cerebral haemorrhage trial; ISAM, Intravenous Streptokinase in Acute
Myocardial Infarction; IV, intravenous; LATE, Late Assessment of Thrombolytic Efficacy Study; LBBB, left bundle-branch block; LD, loading dose; LMWH, low molecular weight heparins; LVEF, left ventricular ejection fraction; MH, Mantel-Haenszel test; MI, myocardial
infarction; NQMI, non–Q-wave myocardial infarction; NS, not significant; NSAID, nonsteroidal anti-inflammatory drugs; NSTE, non-ST elevation; NSTEMI, non-ST-elevation myocardial infarction; OAC, Oral anticoagulation; OASIS, Organization for the Assessment of
Strategies for Ischemic Syndromes; OD, once daily; OR, odds ratio; PAD, peripheral arterial disease; PC, placebo; PCC, prothrombin complex concentrate, PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes trial; pts, patients;
RCT, randomized clinical trials; Revasc, revascularization; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy Trial; ROW, rest of the world; RR, relative risk; SBP, systolic blood pressure; STE, ST elevation; STEMI, ST-elevation myocardial
infarction; Sx, symptoms; TIMI, thrombolysis in MI; TnI, troponin I; TnT, troponin T; TPA, ; UA, unstable angina; UAC, Uninterrupted anticoagulation; UFH, unfractionated heparin; US, United States; and USIM, Urochinasi per via Sistemica nell'Infarto Miocardico.
Data Supplement 18. Comparison of Early Invasive and Initial Conservative Strategy (Section 4.4.4)
Study Study Aim Study Type / Intervention Patient Population Study Intervention Study Endpoints P Values, Study Limitations
Name, Size (n) vs. Comparator OR: HR: RR: & & Adverse Events
Author, Comparator 95 CI:
Year (n)
Inclusion Criteria Exclusion Criteria Primary Safety Secondary
Endpoint & Endpoint & Endpoint &
TIMI IIIB, To determine RCT 1,473 Intervention: Chest discomfort at Pts were excluded if The protocol called for Pts randomized Death, None Analyses for 1º endpoint Significant
1994 the effects of 740; rest caused by they had a treatable pts assigned to the early to the early postrandomization differences and occurred in crossover with
8149520 an early Comparator: ischemia that lasted cause of UA, had invasive strategy to conservative MI, or an interactions in the 16.2% of the 64% in the
(176) invasive 733 >5 min but <6 h. The experienced a MI have cardiac strategy were to unsatisfactory results of invasive pts randomized conservative arm
strategy on discomfort must within the preceding catheterization, LVA, have ETT performed at vs. conservative to the early undergoing
clinical have occurred within 21 d, had undergone and coronary angiography the time of the 6- strategies for death invasive angiography by 42
outcome 24 h of enrollment coronary arteriography 18-48 h carried out only wk visit or MI were carried strategy vs. d
and accompanied by arteriography within after randomization after failure of out on several 18.1% of those
objective evidence 30 d, PTCA within 6 initial therapy prespecified assigned to the
of ischemic HD, i.e., mo, CABG at any subgroups early
either new or time, or if, at conservative
presumably new enrollment, they strategy (p=NS)
ECG evidence of were in pulmonary
ischemia in at least edema, had a
2 contiguous leads systolic arterial
or documented CAD pressure >180
mmHg or a diastolic
pressure >100
mmHg, a
contraindication to
thrombolytic therapy
or heparin. LBBB, a
coexistent severe
illness, were a
woman of child-
bearing potential, or
were receiving OAC.
MATE, 1998 To determine RCT 201 Intervention: Pts 18 y and older Exclusion criteria Subjects randomized to Subjects Composite None 2º endpoints The composite High crossover
Mccullogh et if early 201; who presented to were Sx lasting for triage angiography were randomized to endpoint of all including LOS and endpoint of all rate (60%). No
al, revasc Comparator: the ED with an acute more than 24 h or an taken as soon as the conservative recurrent ischemic hospital costs recurrent long-term benefit
(183) favorably 90 chest pain syndrome absolute indication possible directly to the arm were events or death ischemic events in cardiac
9741499 affects consistent with AMI or contraindication to catheterization admitted to a or death outcomes
clinical cardiac laboratory from the ED. monitored bed occurred in 14 compared with
outcomes in catheterization All triage angiography and received (13%) and 31 conservative
pts with pts underwent continued (34%), yielding medical therapy
suspected catheterization within 24 medical therapy a 45% risk with revasc
AMI h of arrival to the and noninvasive reduction (95% prompted by
hospital evaluation CI 27-59%, recurrent ischemia
encouraged by p=0.0002)
the protocol
VANQWISH, To compare RCT 920 Intervention: Eligible pts had to Pts were excluded if Pts assigned to the Pts assigned to Death or nonfatal Major Overall mortality A total of 152 1º The trial was
Boden et al an invasive 462; have evolving AMI, a they had serious early invasive strategy the early MI procedural endpoint events conducted before
1998 with a Comparator: level of (CK-MB coexisting underwent coronary conservative complications occurred in the coronary stents or
(184) conservative 458 isoenzymes that was conditions, ischemic angiography as the strategy after invasive- platelet GP IIb/IIIa
9632444 strategy in more than 1.5× the complications that initial diagnostic test underwent RNV coronary strategy group, receptor
pts with ULN for the hospital, placed them at very soon after to assess LV angiography as did 139 antagonists were
acute NQMI and no new high risk while in the randomization. function as the or myocardial cardiac events widely available
abnormal Q waves CCU (persistent or Thereafter, the initial noninvasive revasc in the
(or R waves) on recurrent ischemia at management guidelines test; this was conservative-
serial rest despite intensive of the TIMI IIIB for followed before strategy group
electrocardiograms medical therapy or revasc were followed discharge by a (p=0.35) during
severe HF that Sx-limited an average of
persisted despite treadmill exercise 23 mo of follow-
treatment with IV test with thallium up
diuretics, scintigraphy
vasodilators, or both
FRISC II, To compare Prospective, Intervention: Pts were eligible for Exclusion criteria The direct invasive Non-invasive Composite Bleeding Total death, MI, Sx There was a Revasc window of
1999 an early randomized, 1,222; inclusion if they had were raised risk of treatments were treatment endpoint of death of angina, need for significant 7 d longer than
(185) invasive with multicenter trial Comparator: Sx of ischaemia that bleeding episodes, coronary angiography included coronary and MI after 6 mo late coronary 22.0% relative actual
10475181 a non- 2,457 1,235 were increasing or anaemia, or within a few d of pts with refractory angiography and and 2.7% contemporary
invasive occurring at rest, or indication for or enrollment, aiming for or recurrent Sx, revasc, bleeding absolute practice
treatment that warranted the treatment in the past revasc within 7 d of the despite max episodes, and decrease in
strategy in suspicion of AMI, 24 h with start of open-label medical stroke death and MI in
UCAD with the last episode thrombolysis, treatment treatment, or the invasive
within 48 h angioplasty in the severe ischaemia compared with
past 6 mo, being on on a Sx-limited the non-
a waiting list for exercise test invasive group
coronary revasc, before discharge after 6-mo RR:
other acute or 0.78 (95% CI:
severe CD, renal or 0.62–0.98),
hepatic insufficiency, p=0.031
known clinically
relevant
osteoporosis, other
severe illness,
hypersensitivity to
randomized drugs,
anticipated
difficulties with
cooperation or
participation in this
or another clinical
trial
TACTICS - To compare Prospective, Intervention: Pts ≥18 y if they had Persistent STE, 2º Pts assigned to the Pts assigned to Combined Bleeding Death, death or MI, At 6 mo, the Study excluded pts
TIMI 18, an early randomized, 1,114 vs. had an episode of angina, a Hx of PCI early invasive strategy the early incidence of fatal or nonfatal MI, rate of the 1º with severe
Cannon et al invasive multicenter trial Comparator: angina (with an or CAB grafting were to undergo conservative death, nonfatal reshospitaliztion endpoint was comorbid
2001 strategy to a 2,220 1,106 accelerating pattern within the preceding coronary angiography strategy were MI, and for MI 15.9% with use conditions or other
(186) more or prolonged [>20 6 mo, factors between 4 h and 48 h treated medically rehospitalization of the early serious systemic
11419424 conservative min] or recurrent associated with an after randomization and and, if their for an ACS at 6 invasive illness
approach episodes at rest or increased risk of revasc when condition was mo strategy and
with minimal effort) bleeding, LBBB or appropriate on the basis stable, underwent 19.4% with use
within the preceding paced rhythm, of coronary anatomical an exercise- of the
24 h, were severe CHF or findings tolerance test conservative
candidates for cardiogenic shock, (83% of such strategy (OR:
coronary revasc, serious systemic tests included 0.78; 95% CI:
and had at least 1 of disease, a serum nuclear perfusion 0.62–0.97;
the following: a new creatinine level of imaging or p=0.025).
finding of ST- <2.5 mg/dL (221 echocardiography
segment depression μmol/L), or current performed
of at least 0.05 mV, participation in according to the
transient (<20 min) another study of an protocol of the
STE of at least 0.1 investigational drug institution) before
mV, or T-wave or device being discharged
inversion of at least
0.3 mV in at least 2
leads; elevated
levels of cardiac
markers; or coronary
disease, as
documented by a Hx
of catheterization,
revasc, or M
VINO, To compare RCT 131 Intervention: Rest ischaemic Unstable post- 1st d Conservative Composite of None Length of the initial The primary Small sample size,
Spacek et al 1st d 64 vs. chest pain, lasting infarction angina angiography/angioplasty treatment death or nonfatal hospitalization and endpoint interventions were
2002 angiography/ Comparator: <20 min, within the pectoris resistant to treatment strategy strategy RMI 6 mo after the number of (death/ done in only one
(120) angioplasty 67 last 24 h before maximal guidelines were guidelines were the randomization subsequent reinfarction) at high volume
11792138 vs. early randomization; ECG pharmacotherapy; characterized by a characterized by hospitalizations for 6 mo occurred tertiary center
conservative evidence of AMI cardiogenic shock; coronary angiogram as initial medical UAP in 6.2% vs.
therapy of without STE (ST- acute LBBB or soon as possible after treatment with 22.3%
evolving MI segment RBBB or STE 2 mm randomization followed coronary (p<0.001). 6 mo
without depressions in 2 leads; QMI or IV by immediate coronary angiography and mortality in the
persistent minimally 0.1 mm in thrombolysis >1 mo; angioplasty of the culprit subsequent 1st d
STE at least 2 contiguous coronary angioplasty coronary lesion + stent revasc only in the angiography/
leads and/or or bypass surgery >6 implantation whenever presence of angioplasty
negative T waves or mo; any concomitant suitable recurrent group was 3.1%
documented old disease which may myocardial vs. 13.4% in the
LBBB/RBBB; CK- have possible ischaemia conservative
MB higher than 1.5× influence on 1-y Px; group (p<0·03).
X ULN and/or lack of pt
positive TnI assay cooperation
RITA -2, Fox To compare RCT 1,810 Intervention: Pts were eligible for All those with Pts assigned to the Pts assigned to The coprimary Bleeding Death, MI, At 4 mo, 86 Primary endpoint
et al, 2002 interventional 895 vs. inclusion if they had probable evolving interventional treatment the conservative trial endpoints refractory angina (9.6%) of 895 driven by reduction
(187) strategy and Comparator: suspected cardiac MI, including those strategy were managed strategy were were: a combined as individual pts in the of refractory
12241831 conservative 915 chest pain at rest for whom reperfusion with optimum managed with rate of death, endpoints intervention angina with no
strategy in and had therapy was antianginal and antianginal and nonfatal MI, or group had died difference in hard
pts with documented indicated, were antiplatelet treatment antithrombotic refractory angina or had a MI or clinical endpoints
unstable evidence of CAD ineligible. Those in (as for the conservative medication at 4 mo; and a refractory
CAD with at least 1 of the whom new group), and enoxaparin combined rate of angina,
following: evidence pathological Q 1 mg/kg subcutaneously death or nonfatal compared with
of ischaemia on waves developed, or 2× for 2-8 d. The MI at 1 y 133 (14.5%) of
ECG (ST-segment those with CK or CK- protocol specified that 915 pts in the
depression, transient MB concentrations coronary arteriography conservative
STE, LBBB 2× the ULN before should be done as soon group (RR:
[documented randomization, were as possible after 0.66; 95% CI:
previously], or T- excluded. Also randomization and 0.51–0.85;
wave inversion); excluded were those ideally within 72 h p=0.001).
pathological Q with MI within the
waves suggesting previous mo, PCI in
previous MI; or the preceding 12 mo,
arteriographically or CABG at any
proven CAD on a time.
previous arteriogram
ICTUS, de To compare RCT 1,200 Intervention: Eligible pts had to Exclusion criteria Pts assigned to the Pts assigned to The primary Bleeding Percentage of pts The estimated Revasc rates were
Winter et al, an early 604 vs. have all 3 of the were an age >18 y or early invasive strategy the selectively endpoint was a free from anginal cumulative rate high in the 2
2005 invasive Comparator: following: Sx of <80 y, STEMI in the were scheduled to invasive strategy composite of Sx of the primary groups in our study
(188) strategy to a 596 ischemia that were past 48 h, an undergo angiography were treated death, RMI, or endpoint was (76% in the early-
16162880 selectively increasing or indication for primary within 24-48 h after medically. These rehospitalization 22.7% in the invasive-strategy
invasive occurred at rest, with PCI or fibrinolytic randomization and PCI pts were for angina within 1 group assigned group and 40% in
strategy for the last episode therapy, when appropriate on the scheduled to y after to early invasive the selectively-
pts who have occurring no more hemodynamic basis of the coronary undergo randomization management invasive-strategy
ACS without than 24 h before instability or overt anatomy angiography and and 21.2% in group during the
STE and with randomization; an CHF, the use of oral subsequent the group initial
an elevated elevated cTnT level anticoagulant drugs revasconly if they assigned to hospitalization,
cTnT level (≥0.03 μg/L); and in the past 7 d, had refractory selectively and 79% and 54%,
either ischemic fibrinolytic treatment angina despite invasive respectively, within
changes as within the past 96 h, optimal medical management 1 y after
assessed by ECG PCI within the past treatment, (RR: 1.07; 95% randomization
(defined as ST- 14 d, a hemodynamic or CI: 0.87-1.33;
segment depression contraindication to rhythmic p=0.33).
or transient STE treatment with PCI or instability, or
exceeding 0.05 mV, GP IIb/IIIa inhibitors, clinically
or T-wave inversion recent trauma or risk significant
of ≥0.2 mV in 2 of bleeding, ischemia on the
contiguous leads) or hypertension despite predischarge
a documented Hx of treatment (i.e., exercise test.

CAD as evidenced systolic pressure
by previous MI, >180 mmHg or
findings on previous diastolic pressure
coronary >100 mmHg), weight
angiography, or a <120 kg, or inability
positive exercise test to give informed
consent
Italian Trial J To determine RCT 313 Intervention: Eligible were pts Excluded were pts Pts enrolled in the trial IC therapy, in The primary Bleeding Individual The 1outcome The main limitation
Am Coll the risk vs. 154 vs. with NSTE-ACS and with 2º causes of were randomly assigned which case pts endpoint was the components of the occurred in 43 of this study is its
Cardiol Intv bebefut ratio Comparator : an age of ≥75 y, myocardial ischemia, to either: 1) an EA had to be composite of primary endpoint pts (27.9%) in relative lack of
2012;5:906- of an EA 159 with cardiac ongoing myocardial strategy of coronary managed with death, MI, the EA group power, because
16) approach in ischemic Sx at rest ischemia or HF angiography within 72 h medical therapy, disabling stroke, and 55 (34.6%) our original sample
(189) elderly pts within 48 h before despite optimized and, when indicated, and coronary and repeat in the IC group size was amended
22995877 with NSTE- randomization, therapy, PCI or coronary revasc by angiography hospital stay for (HR: 0.80; 95% due to slow
ACS together with CABG within 30 d either PCI or CABG during index CV causes or CI: 0.5– 1.19; enrollment
ischemic ECG before according to coronary hospital stay was severe bleeding p=0.26)
changes and/or randomization, anatomy, pt preference, allowed in the within 1 y
elevated levels of serum creatinine and local skills; or 2) IC case of refractory
either Tn or CK-MB >2.5 mg/dL, a therapy ischemia,
cerebrovascular myocardial
accident within the (re)infarction, HR
previous mo, recent of ischemic
transfusions, origin, or
gastrointestinal or malignant
genitourinary ventricular
bleeding within 6 wk arrhythmias
before
randomization,
platelet count 90,000
cells/ l, ongoing oral
anticoagulation,
severe obstructive
lung disease,
malignancy, or
neurological deficit
limiting follow-up
1º indicates primary; 2º, secondary; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAB, coronary artery bypass; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCU, cardiac care unit; CD, cardiac disease; CHF, congestive
heart failure; CK, creatine kinase; CK-MB, creatine kinase-MB; cTnT, cardiac troponin T; CV, cardiovascular; EA, early invasive; ECG, electrocardiograph; ETT; exercise treadmill test; GP, glycoprotein; HD, heart disease; HF, heart failure; Hx, history; IC, initially
conservative; IV, intravenous; LBBB, left bundle branch block; LOS, length of stay; LV, left ventricular; LVA, left ventricular angiography; MI, myocardial infarction; NQMI, Non Q-wave myocardial infarction; NS, no(t) significant; OAC, oral anticoagulants; PCI,
percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; pts, patients; Px, prognosis; QMI, Q-wave myocardial infarction; RBBB, right bundle branch block; RCT, randomized controlled trial; revasc, revascularization; RMI; recurrent
MI;RNV, radionuclide ventriculogram; STE, ST-segment elevation; Sx, symptom(s); TIMI, thrombolysis in MI; TnI, troponin I; UA, unstable angina; UAP, unstable angina pectoris; UCAD, unstable coronary artery disease; and ULN, upper limits of normal.
Data Supplement 19. Comparison of Early Versus Delayed Angiography (Section 4.4.4.1)
Study Name, Study Aim Study Intervention Patient Population Study Study Comparator Endpoints P Values, Study
Author, Year Type/ vs. Comparator Intervention OR: HR: RR: & 95 Limitations &
Size (N) (n) CI: Adverse Events
Inclusion Criteria Exclusion Criteria Primary Safety Endpoint Secondary
Endpoint & & Results Endpoint &
Results Results
ISAR-COOL, To test the RCT Intervention: Pts with AP at rest or Pts with evidence of With the early With the prolonged Composite Bleeding, Death, nonfatal 1º endpoint was Small sample
Neumann et al hypothesis that 410 207 vs. with minimal large MI, including intervention antithrombotic 30-d thrombocytopenia MI reached in 11.6% size
2003 prolonged Comparator: exertion, with the last STE of at least 1 mV strategy pretreatment incidence of (3 deaths, 21
14506118 antithrombotic 203 episode occurring in 2 or more investigators strategy, large nonfatal infarctions) of the
(190) pretreatment ≥24 h before study contiguous leads or performed investigators MI or death group receiving
improves the entry elevation of the coronary continued from any prolonged
outcome of catalytic activity of angiography as pretreatment for at cause antithrombotic
catheter creatine kinase and its soon as possible, least 3 d, to a max of pretreatment and in
intervention in MB isoenzyme to ≤3× at least within 6 5 d, after which all 5.9% (no deaths,
pts with acute the ULN; those with h, during which pts underwent 12 infarctions) of
unstable hemodynamic time coronary the group receiving
coronary instability; those with antithrombotic angiography early intervention
syndromes contraindications to pretreatment was (RR: 1.96; 95% CI:
compared with study medication; or instituted 1.01–3.82; p=0.04)
early intervention those unable to
provide written
informed consent for
participation
TIMACS, To study efficacy RCT Intervention: Presentation to a Pt who is not a Among pts who Pts who were Composite of Bleeding 1st occurrence At 6 mo, 1º The trial may
Mehta et al, of an early 3,031 1,593 vs. hospital with UA or suitable candidate for were randomly assigned to the death, MI, or of the outcome (death, have been
2009 invasive strategy Comparator: MI without STE revasc assigned to the delayed-intervention stroke at 6 mo composite of new MI, or stroke) relatively
(191) (within 24 h of 1,438 within 24 h after early-intervention group underwent death, MI, or occurred in 9.6% of underpowered.
19458363 presentation) onset of Sx and if 2 group, coronary coronary refractory pts in the early- Heterogeneity
compared with of the following 3 angiography was angiography after a ischemia and intervention group, was observed in
delayed invasive criteria for increased to be performed min delay of 36 h the composite as compared with the 1º endpoint,
strategy (anytime risk are present: age as rapidly as after randomization of death, MI, 11.3% in the with pts in the
36 h after ≥60 y, cardiac possible and stroke, delayed- highest tertile
presentation) biomarkers above within 24 h after refractory intervention group experiencing a
ULN, or results on randomization ischemia, or (HR: 0.85; 95% CI: sizeable risk
ECG compatible with repeat 0.68-1.06; p=0.15) reduction and
ischemia (i.e., ST- intervention at 6 suggesting a
segment depression mo potential
≥1 mm or transient advantage of
STE or T-wave early revasc in

inversion >3 mm) this high-risk
subgroup
ABOARD, To determine if RCT Intervention: Presence of at least Hemodynamic or An immediate An invasive strategy Primary Bleeding 2º endpoints The primary Immediate (at a
Montalescot et immediate 352 175 vs. 2 of the following: arrhythmic instability invasive strategy scheduled on the endpoint was were composite endpoint did not median of 70 min)
al intervention on Comparator: ischemic Sx, ECG requiring urgent next working d peak Tn value of death, MI, ordiffer between the 2 vs. delayed (at a
(192) admission can 177 abnormalities in at catheterization, during urgent revasc atstrategies (median median of 21 h)
19724041 result in least 2 contiguous chronic oral hospitalization 1-mo follow-up [IQR] TnI value, 2.1 angiography and
reduction of MI leads, or positive Tn, anticoagulation, or [0.3-7.1] ng/mL vs. revasc in UA/
vs. delayed TIMI risk score 3 thrombolytic therapy in 1.7 [0.3-7.2] ng/mL NSTEMI pts
intervention the preceding 24 h in the immediate conferred no
and delayed advantage with
intervention groups, regard to the
respectively; primary endpoint
p=0.70)
1º indicates primary; 2º, secondary AP, angina pectoris; ECG, electrocardiograph; IQR, interquartile range; MB, myocardial band; MI, myocardial infarction; non-ST-elevation myocardial infarction; pts, patients; RCT, randomized controlled trial; revasc, revascularization;
RR, relative risk; STE, ST- segment elevation; Sx, symptom(s); TIMI; thrombolysis in myocardial infarction; Tn, troponin; TnI, troponin I; UA, unstable angina; and UA/NSTEMI, unstable angina/ non-ST-elevation MI.
Data Supplement 20. Risk Stratification Before Discharge for Patients With Conservatively Treated NSTE-ACS (Section 4.5)
Study Name, Study Aim Study Intervention Patient Population Study Study Endpoints P Values, Study Limitations &
Author, Year Type/ Size vs. Intervention Comparator OR: HR: RR: & 95 CI: Adverse Events
(n) Comparator
(n)
Inclusion Criteria Exclusion Primary Safety Secondary
Criteria Endpoint & Endpoint Endpoint &
Results & Results Results
DANAMI, To test the Post hoc N/A In the DANAMI-2 N/A N/A N/A 1º endpoint was a N/A N/A ST-depression was predictive of Post hoc analysis.
Valeur et al prognostic subgroup study, pts with composite of the clinical outcome (RR: 1.57 Exercise capacity was
2004 importance of analysis of STEMI were death and re- [1.00- 2.48]; p<0.05) in a strong prognostic
(193) predischarge a RCT randomized to 1º infarction multivariable analysis, there was predictor of death and
15618067 maximal Sx- 1,164 angioplasty (PCI) or a significant association re-infarction
limited ET fibrinolysis between ST-depression and irrespective of
following AMI in outcome in the fibrinolysis group treatment strategy,
the era of (RR: 1.95 [1.11- 3.44]; p<0.05), whereas the prognostic
aggressive but not in the 1º PCI group (RR: significance of ST-
reperfusion 1.06 [0.47-2.36]; p=NS). depression seems to be
However, the p-value for strongest in the
interaction was 0.15. fibrinolysis-treated pts.
INSPIRE, To test whether Cohort N/A The study cohort N/A Event rates were Pt risk and Composite of N/A N/A Total cardiac events/death and Investigators did not
Mahmarian et gated ADSPECT study consisted of 728 assessed within subsequent death, MI, or reinfarction significantly track the percentage of
al 2006 could accurately 728 pts stabilized pts 18 y of prospectively therapeutic stroke at 6 mo increased within each INSPIRE eligible pts who were
(194) define risk and age who had either defined INSPIRE decision risk group from low (5.4%, enrolled in the INSPIRE
17174181 thereby guide QAMI or NQAMI and risk groups based making were 1.8%), to intermediate (14%, trial so there may be
therapeutic were prospectively on the prospectively 9.2%), to high (18.6%, 11.6%) selection bias. The
decision making enrolled adenosine- defined by (p<0.01). Event rates at 1 y perfusion results
in stable induced LV specific were lowest in pts with the significantly improved
survivors of AMI perfusion defect ADSPECT smallest perfusion defects but risk stratification
size, extent of variables. Pts progressively increased when beyond that provided
ischemia, and EF with a small defect size exceeded 20% by clinical and EF
(<20%) (p<0.0001). variables. The low-risk
ischemic PDS INSPIRE group,
were classified comprising 1/3 all
as low risk and enrolled pts, had a
most had a shorter hospital stay
LVEF of 35% with lower associated
(96%) and an costs compared with
ischemic PDS the higher-risk groups
of <10% (p<0.001).
(97%).
COSTAMI -II, To compare in a RCT Intervention: 262 pts from 6 Exclusion Pharmacological Maximum Sx 1º endpoint was N/A 2º endpoints No complication occurred during Early pharmacological
Decidari et al prospective, 262 132; participating centers criteria were stress limited exercise cost effectiveness were either stress echocardiography stress
randomized, Comparator: with a recent age >75 y, echocardiography ECG of the diagnostic composite of or exercise ECG. At 1-y follow- echocardiography and
(195) multicenter trial 130 uncomplicated MI serious strategies. The 2º death, MI, or up there were 26 events (1 conventional
15657220 the relative merits were randomly arrhythmias endpoint was urgent death, 5 nonfatal reinfarctions, predischarge Sx limited
of predischarge assigned to early (d (VF, SVT, or quality of life revasc at 1- 20 pts with UA requiring exercise ECG have
exercise ECG 3-5) fixed 2nd or 3rd evaluation. Pts mo follow-up hospitalization) in pts randomly similar clinical outcome
and early pharmacological degree AV were seen at 1 assigned to early stress and costs after
pharmacological stress blocks), LBBB, and 6 mo and 1 y echocardiography and 18 uncomplicated
stress echocardiography pericarditis, after discharge. events (2 reinfarctions, 16 UA infarction. Early stress
echocardiography (n=132) or insufficient Cardiac events, requiring hospitalization) in the echocardiography may
concerning risk conventional acoustic use of resources, group randomly assigned to be considered a valid
stratification and predischarge (d 7-9) window, and costing, and exercise ECG (NS). The alternative even for pts
costs of treating maximum Sx limited poor short-term quality of life were negative predictive value was with interpretable
pts with exercise ECG (n Px because of recorded. 92% for stress baseline ECG who can
uncomplicated =130) concomitant echocardiography and 88% for exercise.
AMI disease exercise ECG (NS). Total costs
of the two strategies were
similar (NS).
1º indicates primary; 2º, secondary; ADSPECT, adenosine Tc-99m sestamibi single-photon emission computed tomography; AMI, acute myocardial infarction; AV, atrioventricular; DANAMI-2, Danish Multicenter Study of Acute Myocardial Infarction 2; ECG,
electrocardiograph; EF, ejection fraction; ET, exercise test; INSPIRE, Investigating New Standards for Prophylaxis in Reduction of Exacerbations; LBBB, left bundle branch block; LV, left ventricular; LVEF, left ventricular ejection fraction; NS, non/t significant; NQAMI,
non-Q-wave myocardial infarction; PCI, percutaneous coronary intervention; PDS, perfusion defect size; pts, patients; Px, prognosis; QAMI, Q-wave myocardial infarction; RCT, randomized controlled trial; revasc, revascularization; STEMI, ST-elevation myocardial
infarction; SVT, sustained ventricular tachycardia; Sx, symptom (s); UA, unstable angina; and VF, ventricular fibrillation.

Data Supplement 21. RCTs and Relevant Meta-Analyses of GP IIb/IIIa Inhibitors in Trials of Patients With NSTE-ACS Undergoing PCI (Section 5)
Trial Study Drug / Population Primary Endpoint Results Statistics Comments
Comparator
Elective (stable) and urgent (ACS) patients enrolled (without routine clopidogrel pretreatment)
EPILOG Abciximab vs. PC 2,792 pts with stable ischemia or Death, MI or UTVR at 30 d 5.2% vs. 11.7% 95% CI: (0.30-0.60); p<0.001 N/A
(196) UA HR: 0.43
9182212
ACS/high risk (without routine clopidogrel pretreatment)
CAPTURE Abciximab 1,265 pts with “refractory UA” Death, MI or UTVR at 30 d 11.3% vs. 15.9% p=0.012 Significant reduction in MI rate both before and during PCI with
(197) (administered for 18-24 undergoing PCI 18-24 h after abciximab therapy. No diff in 6-mo composite endpoint
10341274 h before PCI) vs. PC diagnostic catheterization
EPIC Abciximab vs. PC Pts at high risk for abrupt vessel Death, MI, UTVR, IABP, or Bolus only: 11.4% p=0.009 overall; N/A
(198) closure unplanned stent placement Bolus + infusion: 8.3% p=0.008 for bolus + infusion vs.
8121459 at 30 d PC: 12.8% PC
RESTORE Tirofiban (std dose) vs. 2,139 pts with ACS undergoing Death, NFMI, UTVR, or 10.3% vs. 12.2% p=0.160 Composite endpoint was statistically lower at 2 and 7 d follow-up
(199) PC PTCA or DCA stent placement at 30 d (but not at the 30-d 1º endpoint)
9315530
ACS/high risk or mixed study population (with routine clopidogrel pretreatment)
ISAR-REACT 2 Abciximab vs. PC 2,022 “high-risk” ACS pts Death, MI or UTVR at 30 d 8.9% vs. 11.9% p=0.03 RR: 0.71 in +Tn pts; RR: 0.99 in -Tn pts
(142) undergoing PCI RR: 0.75 95% CI: 0.58–0.97
16533938
ADVANCE Tirofiban (high-dose) 202 pts undergoing elective or Death, NFMI, UTVR or 20% vs. 35% p=0.01 Pts pretreated with either ticlopidine or clopidogrel
(200) vs. PC urgent PCI (1/3 with stable angina; bailout GPI therapy at HR: 0.51 95% CI: 0.29–0.88 Death/MI/TVR at 6-mo lower (HR: 0.57; 95% CI: 0.99-0.33;
15234398 1/2 with ACS) median of 185 d p=0.48)
Pannu GP IIb/IIIa vs. PC 5,303 pts undergoing PCI Death, MI or TVR OR: 0.84 95% CI: 0.58–1.22; N/A
Meta-analysis p=0.35
(201)
18458661
1º indicates primary; ACS, acute coronary syndrome; DCA, directional coronary atherectomy; diff, difference; GP, glycoprotein; GPI, glycoprotein IIb/IIIa inhibitors; IABP, intraaortic balloon pump; MI, myocardial infarction; NFMI, nonfatal myocardial infarction; PC,
placebo; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; pts, patients; RR, relative risk; std, standard; Tn, troponin; +Tn, positive troponin; -Tn, negative troponin; TVR, target vessel revascularization; UA, unstable
angina; and UTVR, urgent target vessel revascularization.
Data Supplement 22. Studies of Culprit Lesion Versus Multivessel (Culprit and Nonculprit) PCI in Patients with NSTE-ACS (Section 5)
Study Aim of Study Type of Study Study Size Patient Primary Endpoint Outcome
Population
Brener SJ, 2008 To compare outcomes of culprit Post hoc database 105,866 pts NCDR database Multiple endpoints Procedural success: 91% culprit PCI vs. 88% multivessel PCI (p<0.001)
(202) only PCI to multivessel PCI in analysis analyzed In-hospital mortality: 1.3% culprit PCI vs. 1.2% multivessel PCI (p=0.09; adjusted OR: 1.11; 95% CI:
18082505 NSTE-ACS pts 0.97–1.27)
Shishehbor MH, 2007 Examination of the safety and Post hoc database 1,240 pts NSTE-ACS pts in Death, MI or TVR Multivessel PCI associated with lower death/MI/TVR rate; adjusted HR: 0.80 (95% CI: 0.64–0.99;
(203) efficacy of nonculprit multivessel analysis institutional Median follow-up 2.3 y p=0.04); propensity matched analysis HR: 0.67 (95% CI: 0.51–0.88; p=0.004)
17320742 PCI with culprit-only PCI in pts database Lower revasc rate with multivessel PCI drove endpoint differences
with NSTE-ACS
Zapata GO, 2009 To investigate MACE at 1-y Post hoc database 609 pts NSTE-ACS pts in MACE at 1 y MACE lower with multivessel PCI than culprit vessel PCI (9.45% vs.16.34%; p=0.02; no OR given)
(204) follow-up in pts with NSTE-ACS analysis institutional Revasc lower with multivessel PCI than culprit vessel PCI (7.46 vs. 13.86%; p=0.04; no OR given)
19515083 and multivessel CAD who database No diff in death or death/MI between groups
underwent either culprit vessel
PCI or multivessel PCI
Palmer ND, 2004 Compare short and medium- Retrospective 151 pts NSTE-ACS pts Multiple endpoints Compared to multivessel PCI, culprit lesion only PCI resulted in:
(205) term outcomes of complete database review treated at a tertiary analyzed More pts with residual angina (22.8% vs. 9.9%; p=0.041; no OR given)
15152143 revasc PCI vs. culprit revasc in with additional pt care institute More pts required further PCI (17.5% vs. 7.0%; p=0.045; no OR given)
NSTE-ACS pts follow-up Trend towards more readmissions for UA
Greater use of long-term antianginal medications (52.6% vs. 38.0%; p=0.043; no OR given)
Brener, 2002 To compare 30-d and 6-m Post hoc trial 427 pts NSTE-ACS pts in In-hospital and 6-mo NS diff between the 3 groups at either 30-d or 6-mo follow-up for any of the endpoints: death; MI; and
(206) outcome in NSTE-ACS pts analysis TACTICS-TIMI 18 MACE MACE
12231091 undergoing PCI with (1) 1 VD
and culprit PCI; (2) multivessel
disease and culprit PCI; and (3)
multivessel disease and
multivessel PCI
ACS indicates acute coronary syndrome; CAD, coronary artery disease; diff, difference(s); MACE, major adverse coronary events; MI, myocardial infarction; NCDR, National Cardiovascular Data Registry; NS, no(t) significance; NSTE, non-ST-elevation; NSTE-ACS,
non-ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; pts, patients; revasc, revascularization; TACTICS, Treat Angina with Tirofiban and Determine Cost of Therapy with an Invasive or Conservative Strategy; TACTICS-TIMI, Treat
Angina with Tirofiban and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction; TIMI, Thrombolysis In Myocardial Infarction; UA, unstable angina; VD, vascular disease; and TVR, target vessel revascularization.
Data Supplement 23. Risk Reduction Strategies for Secondary Prevention (Sections 6.3.)
Study Aim of study Study Study Study Study Patient Population Study Study Endpoints P Values, Study Limitations &
Name, Type Size Intervent Comparat Intervention Comparator OR: HR: RR & Adverse Events
Author, (n) ion or Group 95% CI:
Year Group (n)
(n)
Inclusion Exclusion Criteria Primary Safety Secondary
Criteria Endpoint Endpoint Endpoint and
(efficacy) and Results
and Results Results
6.3.1 Physical activity
Munk, 2009 To evaluate high RCT 40 20 20 Had PCI with History of MI or High- Usual care, Restenosis was N/A Peak oxygen Unknown Limitations: small sample
(207) intensity interval implantation CABG, significant intensity no exercise smaller in the uptake increased size and large interquartile
19853690 training on in- of a stent valvular heart interval intervention treatment group by 16.8% (T) and ranges; heterogeneity of
stent restenosis disease, >80 y, training (0.10 mm) 7.8% (C) (p<0.01). stents implanted.
following PCI for inability to give program compared to the Flowmediated There were no serious
stable or UA informed consent, control group dilation improved training-related adverse
inability to (0.39) p-value by 5.2% (T) and - events.
participate in (0.01) 0.1% (C) (p=0.01).
regular training, any Levels of high-sens

known chronic C-reactive protein
inflammatory decreased by -0.4
disease other than mg/L (T) and
atherosclerosis, or increased by 0.1
planned surgery in mg/L (C) (p=0.03
next 6 mo. for trend)
Depression and other psychological conditions
Tisminetzky To ID Sx profiles Randomiz 79 45 34 Age 35+, Mental healthcare 4-6 30 min Booklet on 26% of treatment N/A N/A N/A Limitations: findings do not
2011 of depression and ed trial hospitalized in prior 3 mo, cognitive coping with Sx improved vs. apply to high-risk
(208) anxiety in pts with with ACS, psychoactive drug behavioral cardiac 10% in control individuals because they
22409097 ACS and examine mild/medium use in past y, Dx therapy illness, and group were excluded from study,
changes over anxiety substance abuse in sessions told to short duration of follow-up
time and/or past y contact PCP and small sample size.
depression if depressed
6.3.4 Nonsteroidal anti-inflammatory drugs
Lee, 2007 To compare the Adjusted APPR APPROV APPROVe History of None mentioned APPROVe: PC N/A There N/A RR (95% CI) p- Limitations: interpretation of
(209) use of celecoxib indirect OVe=2 e=1287 =1299 colorectal 25 mg were NS value adjusted indirect
17051359 and rofecoxib on compariso ,586 APC=685 APC=679 neoplasia/ rofecoxib for differenc Celecoxib vs. comparison should be done
CV risk n of 2 APC= (200 mg adenomas 3y es in CV 200mg rofecoxib with caution
published 2,035 group) APC: Either events 0.74-1.38
RCTs 671 (400 200mg or (0.96)
(APPROV mg 400mg of Celecoxib vs.
e and group) celecoxib for 400mg rofecoxib
APC 3y 1.09 0.81 — 1.45
trials) (0.57)
6.3.6 Antioxidant vitamins and folic acid
Galan, To determine if Double 2,501 G1=622 626 Personal Hx <45 or >80 y; ill Vitamin B: Double PC 1st major CV N/A Significant 2º Vitamin B: Limitations: number of
2010 vitamin B & blind RCT (Vitamin of MI, UA, or defined Dx of CV 560 mg 5 event, NS for endpoints: Vitamin HR: 0.9 participants, short duration
(210) omega 3 fatty B + PC) ischaemic disease; inability methyltetrah Vitamin B or B use associated 95% CI: 0.66- (4.7 y) to provide statistical
21115589 acids can prevent stroke or unwillingness to ydrofolate, 3 Omega 3 with fewer strokes 1.23 (0.5) power to detect effects on
CV events in pts G2 = comply with study g B-6, 20 (HR: 0.57; 95% CI: Omega 3: major vascular events.
with Hx of heart 633 treatment mcg B-12 0.33-0.97; p=0.04); HR: 1.08
disease or stroke. (omega 3 Omega 3: and a higher risk of 95% CI: 0.79-
+ PC) 600 mg of death from any 1.47 (0.6)
eicosapenta cause (HR: 1.55;
G3 = noic acid and 95% CI: 1.07–2.25;
620 docosahexa p=0.02)
(vitamin enoic acid at
B+ a ratio of 2:1
omega 3)

Imasa, To determine the RCT 240 116 124 UA or Hemodynamic 1 mg folic PC Re-hospitalization N/A N/A RR (95% CI), p Limitations: small sample
2009 effect of folic acid NSTEMI in instability, liver acid, and composite of value all-cause size; compliance rate=60%;
(211) supplementation previous 2 disease, renal 400mcg B12, death, nonfatal mortality 1.18 adverse events in
19515873 on prevention of wk disease, <18 y, 10 mg B6 ACS, and re- (0.68- 2.04), 0.54 treatment group: skin
ACS pregnant, daily hospitalization Nonfatal ACS irritation, dyspnea,
Hemoglobin <10 were significantly 1.28 (0.64-2.54), dizziness
g/dL, high-output increased in the 0.5
failure, inability to treatment group Re-hospitalization
provide adequate 5.11 (1.14-23.0),
self-care, 0.016
malignancy or any Composite
terminal illness, and endpoint 1.20
geographic location (1.00-1.44), 0.04
ACS indicates acute coronary syndrome; APC, Adenoma Prevention with Celecoxib trial; APPROVe, Adenomatous Polyp Prevention on Vioxx trial; CABG, coronary artery bypass graft; CV, cardiovascular; Dx, diagnosis; ID, identification; MI, myocardial infarction; N/A,
not applicable; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PCP, primary care physician; Pts, patients; RCT, randomized controlled trials; and UA, unstable angina.
Data Supplement 24. Older Patients (Section 7.1)

Study Name, Aim of Study Study Study Study Patient Population Study Study Endpoints P Values, Study Limitations
Author, Year study Type Size (N) Interventio Comparator Interventio Comparator OR: HR: RR & Adverse Events
n Group (n) Group (n) n & 95% CI:
Criteria Criteria Endpoint Endpoint Endpoint
(efficacy) and Results and Results
and Results
Alexander Summarize Summary or Clinical N/A N/A Clinical trial and Clinical trial and Clinical trial Clinical trial Too numerous Serum Summarizes Too Not a trial but an
2007 evidence on 5 pooled Trials registry registry specific specific specific to list creatinine available numerous to important paper on
(212) pt NSTE-ACS n=34266 specific- pooled inadequately evidence of list understanding mgt of
17502590 heterogeneit clinical trials (18.1% (VIGOUR) assesses age- presentation, older pts. Older
y, clinical and 3 large ≥75 y); included related renal treatment and NSTE-ACS are
presentation NSTE-ACS Registries GUSTO IIb, function outcomes of underrepresented in
, and registries to n=114572 PARAGON A decline- CrCl OA in RCTs clinical trials and are
treatment of assess and 7 (38.3% and B, should be and younger and have
NSTE-ACS grade ≥75 y) PURSUIT, calculated in all registries. less comorbidities vs.
in relation to evidence GUSTO IV-ACS older NSTE- older pts in registries
age (65-74, and provide Registries=NR ACS pts. (and likely ‘real
75-84, and descriptive MI 2-4, Excess world’) warranting
85 y) finding and CRUSADE, bleeding cautious
compare pts GRACE related to extrapolation of
in clinical excess AP/AT results.
trials vs dose
those not

included
Gale 2012 Assess Mixed- N=616 N/A N/A ACS pts in Missing data or N/A N/A Compared to N/A Too Inpatient Diverse sample of
(213) difference in effects 011 ACS National Audit follow-up younger NSTE- numerous to mortality from hospital in United
22009446 risk factors, regression pts: age registry with ACS pts, older list include 2003-2010 Kingdom but less in
presentation analysis <55 outcomes pts had sig effect of age across all age Wales- not all pts
, using data y=23%;55 linked to higher in-pt on presenting groups entered into MINAP.
managemen from MINAP - national mortality rates, symptoms, including pts Approx. 4% missing
t and registry in 64y=20%; database. Pts longer rates of comorbidities, ≥85 y age: data.
outcomes United 65-74 included if met stay and were use of GDMT, OR, 95% CI:
across age Kingdom. y=40%; ACS definition prescribed less PCI, 2004: 0.94,
groups and Comparison 75-84 on admission GDMT (med outcome, and 0.88–1.01;
trends over across older y=39%; (diagnosis was and procedures) trends over 2010: 0.52,
7 y in MI pts age groups ≥85 adjudicated but despite same or time. 0.44–0.61;
in United and over 7 y y=29% did not exclude better efficacy 75–84 y age:
Kingdom pt if not ACS). vs. young. 2004: 0.98,
These age 0.93–1.03;
discrepancies 2010: 0.52,
have decreased 0.45–0.60,
over time. and pts ,55 y
age: 2004:
0.94, 0.79–
1.13; 2010:
0.64, 0.44–
0.93
Devlin 2008 Determine Retrospectiv N=18466 Data In-hospital GRACE registry Pts with non-CV Pts who Medical In NSTE-ACS N/A Elderly and Revasc vs. Although study
(214) whether e multiple NSTE- assessed by and 6-mo pts meeting causes for the underwent therapy types pts, revasc vs. very elderly no revasc 6- reports benefit of
18387940 increasing logistic ACS pts use of GDMT outcomes criteria for clinical revasc during were medical therapy pts less likely mo MACE early invasive
age impacts regression (27% 70- and early compared for NSTE-ACS who presentation initial specifically sig lowered 6- than younger <70 yo therapy, pts who
in-hosp and analyses on 80 y invasive age group had data during such as trauma, hospitalizatio recorded for mo MACE pts to receive OR=0.69, underwent
6-mo NSTE-ACS ‘elderly’;1 treatment and by hospitalization surgery, or n classified comparison. (stroke, death, GDMT 95% CI 0.56– PCI/CABG during
outcome of pts in 6% >80 y (cath with intervention and 6 mo after aortic aneurism, under revasc Age and MI) and 6-mo 0.86; 70-80 y admission were
revasc GRACE very approp discharge. were excluded. included high- intervention mortality. Older OR=0.60, included including
therapy in registry by elderly’) revasc) by 3 (STEMI data risk pts with strategy were NSTE-ACS pts 95% CI 0.47– those who underwent
high-risk age groups age groups also reported dynamic ECG compared. were sig less 0.76; >80 y revasc >24 h after
NSTE-ACS but omitted changes or likely to undergo OR=0.72,95 admission and high-
pts here) recurrent revasc (and % CI,0.54– risk pts were also
ischemia- GDMT) than 0.95 included (including
regardless of younger pts. Revasc vs. dynamic ST changes,
timing of no revasc 6- recurrent ischemia)
revasc mo mortality:
strategy <70 y
OR=0.52,
95% CI 0.37–
0.72; 70-80
OR=0.38,95
%CI 0.26–
0.54; >80 y
OR=0.68,9%
CI 0.49–0.95
Damman 2012 To assess Meta- N=5467 Early Selective Pts enrolled in Those with Routine Initial medical Routine invasive In-hosp The benefits Routine Trials had different
(215) the impact analyses of NSTE- Invasive: invasive (EC): FRISC II, missing data for invasive treatment strategy sig bleeding rates were smaller Invasive vs. time windows for
21930723 of early FRISC II, ACS pts <65 y=1383 <65 y =1424 ICTUS and specific strategy with card reduced 5-y sig higher in for women Selective routine invasive
invasive vs. ICTUS and (51.3% 65-75 y=901 65-75 y=920 RITA-3 with analyses defined as angio and MACE older pts: <65 than for men Invasive on 5- strategy (up to 7 d in
early RITA-3 <65 y, ≥75 y=437 ≥75 y=402 follow-up data card cath revasc only if (death/MI) in 65- y=1.7%; 65-74 but sample y death/MI: FRISC II) and other
conservative studies 33.3% were included. within 24-48 h refractory 74 and ≥75 y y=2.2%; ≥75 size small <65 y (HR between trial
stragety on 65-74 y, in ICTUS trial, angina but not in those y=6.1% (esp ≥75) 1.11, 95% CI heterogeneity exists
long term 15.3% within 72 h in despite OMT, <65 y. (p<0.001 for underpowere 0.90 to 1.38),
outcomes (5 ≥75 y) RITA-3 trial hemodynamic trend). d for gender 65-74 y (HR
y) in older and within 7 d instability or Bleeding rates and age 0.72, 95% CI
NSTE-ACS with positive higher in each analyses 0.58-0.90);
pts subsequent stress age group with ≥75 y (HR
revasc when (ICTUS and Routine 0.71, 95% CI
appropriate. FRISC II) invasive vs. 0.55-0.91)
Selective
Invasive
strategy but all
p>0.1
Bach 2004 To assess Prespecified N=2220 Early Early Pts with NSTE- Persistent STE; Coronary Pt received Among pts ≥75 Major bleeding Sig reduction NSTE-ACS TACTICS-TIMI 18
(216) impact of subgroup NSTE- Invasive: Conservative: ACS eligible for 2º angina; PCI angiography ASA 325 mg, y, Early Invasive rates higher in 30-d pts ≥75 y excluded pts with
15289215 age and analyses by ACS pts: <65 y=623 <65 y=635 card or CABG within 4-48 h after UFH and vs. Initial with Early outcomes of Early Invasive multiple co-
early age strata of <65 ≥65 y=491 ≥65 y=471 cath/revasc previous 6 mo; randomizatio tirofiban, Conservative Invasive vs. MI, death/MI, vs. Initial morbidities and
invasive vs. TACTICS y=1258 contain to AP n and have treated strategy Initial ACS Rehosp Conservative marked renal
initial TIMI 18, a ≥65 and GP meds. revasc when medically conferred an Conservative and MACE 6-mo dysfunction (included
conservative RCT y=962 Stroke/TIA; appropriate and, if stable, absolute strategy in pts for NSTE- outcomes: older pts with mild
strategy on evaluating LBBB or paced All pts underwent reduction ≥75y (16.6% ACS pts ≥75 Death/MI: renal dysfunction by
outcomes in Early rhythm, CHF or received ASA ETT before (10.8% vs. vs. 6.5%; y (none were RR=0.61 CrCl). Underpowered
NSTE-ACS Invasive vs. cardiogenic 325 mg, UFH discharge. 21.6%; p=0.016) p=0.009); Sig sig for pts (0.41–0.92) for many
pts Initial shock; clinically and tirofiban. Card angio in and relative higher minor <65 y) MI: 0.49 comparisons in older
Conservativ important pts w failure reduction of bleeding rates (0.29–0.81) pts. Additional age
e strategy in systemic of OMT or 56% in death or and trasfusions Death: group beyond single
NSTE-ACS disease; SCr stress- MI at 6 mo. w Early RR=0.88 65-y stratification
pts >2.5 mg/dL) induced RR=0.61 in Invasive vs. (0.51–1.53) were not prespecified
ischemia death/MI at 6 Initial ACS Rehosp: and done post hoc
mo for Early Conservative RR=0.75
Invasive vs. in ≥75 y (0.50–1.11)

Initial MACE
Conservative in RR=0.75
NSTE-ACS pts (0.54–1.03)
≥65 y but no sig None of 6 mo
diff in 6-mo outcomes sig
outcome seen in in NSTE-ACS
pts <65 y pt <65 y
Yourman Assess Extensive N=21,593 N/A N/A Prognostic Studies were N/A N/A 16 prognostic N/A Reports Identified N/A
(217) quality and literature titles indiex studies excluded if indices identified potential mortality
22235089 limitations of review of reviewer included if they prognostic index predicting sources of predictors for
prognostic prognostic validated and estimated overall mortality bias for each older adults
indices for indices for predicted intensive care (6 m-5 y) in diff measure need
mortality in mortality (6 absolute risk of unit, disease- pt groups/ additional
older adults m-5 y) in pts mortality in pts specific, or in- settings external
through age ≥60 y whose average hospital including validation but
systematic age ≥60 y mortality. community, may be useful
review. nursing home in comparing
and hospital. 2 efficacy of
were validated. treatment/inte
rvention
recommendat
ion (time to
benefit) vs.
life
expectancy in
older pts.
Fenning 2012 Compare Single site N=172 N/A N/A 172 Pts admitted N/A N/A GSF identified N/A GSF and GRACE Single-center study,
(218) utility of study of NSTE- consecutive, with ACS who 40 pts (23%) GRACE score 12-mo additional validation
22530044 palliative consecutive ACS pts, unselected pts died in hospital meeting criteria positive score mortality studies needed.
care pts admitted of these admitted for were excluded for approaching both prediction (C-
prognostic with NSTE- compared NSTE-ACS to from analysis. EoL (GSF+ independently statistic 0.75)
tool GSF ACS pts- n=40 pts urban hosp older, more associated + prev hosp
and GRACE compared identified over 8 wk comorb vs. with adm and
score, to 12-mo by GSF GSF-). 1-y increased stroke (C-
help identify outcome vs. with n=32 mortality: GSF+ number of statistic 0.88).
patients prog tool by vs. GSF- (20% comorbidities, GRACE
approaching estimate of GRACE vs. 7%, p=0.03). readmissions, (upper
EoL EoL care. score GRACE older age. tertile)+GSF
identified 32 Sens=78%,
(19%) pts with Spec=89%,
≥10% risk of NPV= 97%,
death within 6 PPV=44%

mo. GRACE
score at
discharge highly
predictive of 12-
mo mortality and
associated with
readmission
during subseq y.
Improved by
adding prev
hosp adm and
prev stroke hx.
Tinetti 2004 This is a very relevant expert/consensus opinion paper, but is not a study which can be put into a data supplement table.
(219)
15625341
Corsonello This reference is an extensive review and summary of major PD/PK changes with aging and their relevance to CV drugs. However, it is not amenable to list in data supplement format.
2010
(220)
20015034
Trifiro 2011 This reference is an extensive review and summary of major PD/PK changes with aging and their relevance to CV drugs. However, it is not amenable to list in data supplement format.
(221)
21495972
Alexander Investigation Retrospectiv N=30,136 N/A N/A NSTE-ACS pts Pts with missing N/A N/A 42% of NSTE- 15% of major Higher adjust Adjusted OR Dosing categories
2005 of e NSTE- in CRUSADE weight (n=826) ACS pts bleeding in mortality in for major based on weight and
(222) relationship exploratory ACS pts registry who or missing received ≥1 NSTE-ACS pts those bleeding with renal function dosing
16380591 between analysis of who had received creatinine initial dose of AT attributable to receiving excess (dependent on
UFH, LMWH CRUSADE received AT agents clearance agent outside excess AT excess vs. dosing (vs. no recorded data)
and GPI registry AT (n=1120) data rec range. dosing recomm dose excess studied population
excess agents excluded from Excess doses of GPI dosing): may vary from those
dosing and dosing per agent: (OR=1.50, UFH: OR: with missing data in
major calculations that UFH+32.8%, 95% CI 1.01- 1.08 (0.94- addition to limited
outcomes required these LMWH=13.8% 2.17). LOS 1.26) generalizability to
variables. Pt and GPI=26.8%. sig longer in LMWH: OR: general NSTE-ACS
who were Excess dose pts given 1.39 (1.11- pts in real world, esp
transferred or assoc with older excess vs. 1.74) older.
underwent age, female, low rec doses of GPI: OR:
CABG excluded body wt, DM UFH, LMWH 1.36 (1.10-
from bleeding and CHF. Pt and GPI. 1.68)
anal. who received
excess AT dose
had higher
bleeding rate,
mortality and
length of stay
vs. those given
rec dose.
Lincoff 2003 Determine RCT, N=6010 Bival+GPI- UFH+GPI=30 Pts ≥21 y PCI performed Bivalrudin UFH 65 U/kg Provisional GPI In Hosp major 30 d 30 d Included elective PCI
(223) efficacy of double-blind 2999 11 undergo PCI as reperfusion 0.75 mg/kg bolus+ GPI given to 7.2% bleeding rates death/MI/reva death/MI/reva – NSTE-ACS pts
12588269 bivalrudin trial in pt with approved therapy for AMI, bolus + 1.75 (abciximab or Bil pts. sig lower in sc: no diff in sc/in-hosp approx. 42% each
+GPI vs. undergoing device poorly controlled mg/kg/hr inf eptifibitide) Noninferiority Biv+GPI vs. MACE major arm + 30% positive
GPI+UFH urgent or Htn, unprotected during PCI Pts received statistically UFH+GPI BiV+GPI vs. bleeding:no stress test; 13% ≥75
for PCI on elective PCI- LM, PCI w/I past with ASA and achieved in 30 d (2.4% v 4.1%, UFH+GPI diff in MACE y
periproc prespecified mo., risk for provisional thienopyridine endpoint: p<0.001) (OR=0.90, in BiV+GPI v
ischemia for non- bleeding, serum GPI for ≥ 30 d MI/death/ p=0.4) UFH+GPI
and inferiority Cr >4 mg/dL, Pts received post PCI revasc/ in-hosp (OR=0.92,
bleeding prior heparin tx. ASA and major bleeding p=0.32).
thienopyridine between
for ≥ 30 d BiV+GPI vs.
post PCI UFH+GPI
Lopes RD, Evaluate Pre- Of 13,819 Of the pts in Of the pts in NSTE-ACS pts Pts excluded for Bivalrudin Bivalrudin+ Mortality and Major bleeding Older pts had Number N/A
2009 impact of specified ACUITY each age each age at moderate or any of following: alone GPI- composite increased in more comorb, needed to
(224) age on analysis of pts, 3,655 group (prev group (4th high risk for STEMI, recent All pts- ASA+ randomized ischemic each age were more treat with
19298914 antithrombot 30-d and 1-y (26.4%) column), 1/3 column), 1/3 adverse clinical bleeding, CrCl mtn (2×2 factorial) outcomes at 30 group often female, bivalirudin
ic strategy outcomes in were <55 were were outcomes at 30 <30 mg/mL, Clopidogrel to upstream d and 1 y were regardless. weighed less, alone to avoid
and 4 age y, 3,940 randomized randomized d. All pts thrombocytopeni post PCI × 1 or cath lab not statistically Major bleeding and had more 1 major
outcomes in groups, (28.5%) to receive to receive underwent cath a, shock, recent y GPI admin different in pts rates were hypertension, bleeding
moderate overall and were 55- bival alone Hep+GPI w/I 72 h of use of Clopidogrel Heparin +GPI randomized to higher in PCI prior cerebral event was
and high- among 64 y, admission abciximab, load per randomized bivalirudin alone pts in the age vascular lower in pts
risk NSTE- those 3,783 warfarin, invest (2×2 factorial) or randomized groups: 3.4%, disease, renal ≥75 y (23
ACS pts undergoing (27.4%) fondaparinux, to upstream to heparin with 5.1%, 5.5%, insufficiency overall and
PCI were 65- bival, LMWH, or cath lab GP IIb/IIIa and 11.8%, for (creatinine 16 for PCI-
74 y, and fibrinolytics GPI admin inhibitors across ages <55, 55- clearance treated pts)
2,441 All pts- ASA+ all age 64, 65-74, and ≤50 mL/min), than in any
(17.7%) mtn categories. ≥75 y, and prior other age
were ≥75 Clopidogrelpo respectively. CABG group.
y. st PCI × 1-y Rates were
Clopidogrel signif lower in
load per those treated w
invest Bivalrudin
alone in each
age group

Lemesle G,. Analyze Single N=2766 N=1,207 N=1,559 Consecutive pts None Bivalrudin UFH (dose Overall in- After In-hospital Bival vs. UFH Non-randomized
2009 impact of center (43.6%) (56.4%).recei ≥80 y at single (dose not not reported) hospital propensity major reduced 6-m observational study.
(225) replacing retrospectiv received ved UFH center who reported) at at operator’s bleeding and 6- score bleeding mortality Doses not reported.
19360860 heparin with e bivalrudin underwent operator’s discretion. mo mortality matching, bival assoc with 6- HR=0.6, 95% Differences in
bivalirudin in observation PCI/stent from discretion. GPI given at rates were 4.6% sign reduced mo mortality CI=0.4–0.9, baseline
octogenaria al analyses 2000-2007 GPI given at operator’s and 11.8%, periproc HR=2.5, p=0.01) In- characteristics-
ns of operator’s discretion. respectively. bleeding vs. 95%CI=1.6– hosp bleeding propensity analyses
undergoing consecutive discretion. ACT target Bival vs. UFH UFH 3.9, p<0.001) Bival vs. used.
PCI on post- pts ≥80 y ACT target >250 s reduced 6 mo (HR=0.38, UFH: HR=
procedure who >250 s All pts mort (8.8% vs. 95% CI=0.22– 0.41, (95%
hemorrhage underwent All pts received ASA 13.4%, 0.65, p=0.001). CI=0.23–
and 6-mo PCI received ASA 325 mg, p=0.003). Bival Bival vs. hep 0.73,
mortality. 325 mg, clopidogrel was assoc with reduced 6 mo p=0.003) by
clopidogrel ≥300 mg load sig less in-hosp MACE (10.1% MRL anal.
≥300 mg load then 75 mg bleeding rate vs. 20.2%, and by
then 75 mg qd mtn (2.2% vs. 6.8%, p<0.001) multivar COX
qd mtn advised for 1 p< 0.001).) (HR=0.6,
advised for 1 y 95% CI= 0.4–
y 0.9, p=0.01)
Summaria F, To Retrospectiv N=84 pts All pts were N/A Consecutive pt None Bivalrudin N/A Transradial N/A N/A N/A Pilot feasibility study
2012 explorefeasi e analyses (22 male; treated with >70 y with ACS bolus dose of approach in very elderly cohort.
(226) bility and of data from 52 pts bivalrudin and treated with EI 0.75 mg/kg successful in Single center, no
22476002 safety of consecutive >80 y) via tranradial strategy using immediately 100%, manual comparison group.
PCI via ACS pts >70 STEMI=5 approach tranradial followed by thrombus aspir
transradial y with Early 3, approach and continuous in 52% of
approach Invasive NSTEMI= bivalrudin as AT infusion of NSTEMI pts.
and strategy via 31 regimen. 1.75 mg/kg/h. Transfusions=0,
intraprocedu transradial All pts sign bleeding
ral approach received ASA events=1 (GI
bivalirudin in with 300 mg, bleed), in-pt
>70 y MI pts bivalrudin as clopidogrel mort=0,30 d
AT. 600 mg, UFH MACE=5 (6%, 1
bolus and death, 2 MI, 2
infusion in TLR)
emer dept –
stopped 6 h
prior to PCI
McKellar SH, To assess pt Systematic N=66 35 CABG 32 PCI Studies which Studies that CABG PCI with last 30-d mort CABG 3 y survival Greater Univariate Clinical trials
2008 characteristi review and studies studies studies included reported without enrollment vs. PCI (7.2% v CABG 78% number of analysis comparing PCI vs.
(227) cs, meta- (65,376 baseline combined CABG additional 1997 5.4%). 1-y (74%−82%) v reintervention showed that CABG enrolled
18825133 procedural analyses of pts, 56% characteristic and valve procedure survival: PCI 78% s post PCI vs. CABG, male younger pts of lower
success, 66 studies of male) and outcomes operations or (i.e. valve CABG=86% (68%−87%), 5 CABG. gender, risk with less
complication coronary in ≥80 y studies where replacement), (83%−88%) vs. y survival multivessel comorbidities, 65 of
s and revasc in undergoing baseline clinical last enrolled PCI 87% CABG 68% disease, and 66 studies
outcomes of ≥80 y revasculariztion data or 1996 (84%−91%) (62%−73%) v abnormal observational, Older
≥80 y who (subgroup (PCI vs. CABG) outcomes were PCI 62% LVEF studies w/o DES
undergo PCI anal by with 30-d not reported (46%−77%), predicted 30-
vs. CABG revasc type) survival separately were d mortality.
(English lang) excluded. Being treated
more
recently,
having
nonelective
status, and
having DM
were
protective.
The only
univariate
predictor of
decreased
survival at 1 y
was CABG
(p=0.005); a
more recent
date of
enrollment
(p=0.003)
and diabetes
(p<0.001)
were
protective
factors.
Kimura T, Assess Retrospecitv N=9,877 CABG=1,708 PCI=3,712 Consecutive pts Pts undergoing N/A N/A ≥75 y of age: 3- Stroke rate ≥75 y: Adj 75 y of age: Nonrandomized
2008 long-term e analyses enrolled, ≥75 y, (21%) ≥75 y (27%) undergoing 1st concomitant y survival higher in 4 y HR for death 3-y survival observational study.
(228) outcomes of 5420 ≥80 y (6%) ≥80 y (12%) PCI or CABG valvular, left adjusted for follow-up in PCI vs. adjusted for Meta-analyses
18824755 between multicenter (PCI: and excluding ventricular, or baseline char CABG vs PCI CABG baseline char performed in BMS
PCI vs. registry 3712, those pts with major vascular favored CABG prespecifieds favored era, non-urgent
CABG in (CREDO- CABG: AMI within wk operation were (HR for death ubgroups: CABG HR for cases only
younger and Kyoto) of 1708) had before index excluded from PCI vs. CABG DM HR= 1.85 death PCI vs.
older pts consecutive multivess procedure. the current HR=1.23 (0.99- (1.1–3.12) CABG
(≥75 y) pts el disease analysis. Pts 1.53, p=0.06), p=0.02 HR=1.23
undergoing without with disease of but not for All-cause [0.99-1.53,
1st PCI or left main the left main younger pts death cum p=0.06], but
CABG- involveme coronary artery (HR=1.09, incidence: not for

stratified by nt. and with single- p=0.55); 3VCAD 1 y: PCI 9% younger pts
age <75 vs. vessel disease Cox survival vs. CABG (HR=1.09,
≥75 y were excluded. favors CABG vs. 8.8% p=0.55)
PCI (p=0.004) 2 y: PC
15.4% vs.
CABG 12.2%
3 y: PCI
20.7% vs.
CAGB 13.3%
4y: PCI
22.7% vs.
15.5%
Dacey LJ, Compare Retrospectiv N=1693 ( CABG=991 PCI=702 Pts included Pts undergoing N/A BMS era In-hospital N/A CABG pts In-hospital Nonrandomized
2007 long-term e 57% 2V (2VCAD=443, (2VCAD=532, were 80-89 y emergent mortality: were more mortality: observational study.
(229) survival after observation CAD, 3VCAD=548) 3VCAD=170) with 2 or 3 procedure or PCI=3.0% vs. freq male, PCI=3.0% vs. Analyses performed
18036905 PCI vs. al analyses 42.3% 3V 80-84 y=83% 80-84 y=72% VCAD (>70% <24 h of MI, CABG= 5.9% had more CABG= 5.9% in BMS era. Regional
CABG in of regional CAD 85-89=17% 85-89=27% stenosis), those with left (p=0.005). 6-mo PVD and (p=0.005). 6- data. Limited data in
≥80 y (New without eligible for 1st main disease, or survival: CABG CHF and less mo to 8-y older half of cohort
England) LM PCI or CABG. sig valve vs. PCI renal failure survival- all and those with
registries of disease. (BARI criteria) disease. (HR,1.32; and prior MI. pts: CABG 3VCAD.Various
consecutive p=0.135). vs. PCI (HR, revasc indications.
80-89 y pts 6-mo to 8-y 0.72;
(1992-2001) survival- all pts: p=0.005)
who CABG vs. PCI
underwent (HR, 0.72;
PCI or p=0.005) and for
CABG but pts with 2VCAD
eligible for (HR, 0.68;
both p=0.016).
3VCAD
(HR=0.75,
p=0.17)
2º indicates secondary; 2VCAD, double-vessel coronary artery disease ; 3VCAD, triple-vessel coronary artery disease; ACC-NCDR indicates American College of Cardiology National Cardiovascular Data Registry; ACE, angiotensin-converting enzyme; ACS, acute
coronary syndromes; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; AMI, acute myocardial infarction; AP, antiplatelet; ASA, aspirin; AT, antithrombins; BARI, Bypass Angioplasty Revascularization Investigation; BEIR, Biological Effects of
Ionizing Radiation; BMS, bare metal stent; CHF, congestive heart failure; CABG, coronary artery bypass graft; CAD, coronary artery disease; CANRACE, Canadian Registry of Acute Coronary Events; cath, catheterization; CHF, congestive heart failure; CR, creatinine;
CrCl, creatinine clearance; CREDO-Kyoto, Coronary Revascularization Demonstrating Outcome Study in Kyoto; CRUSADE, Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of
Cardiology/American Heart Association Guidelines; CT, computed tomography; CTCA, Cancer Treatment Centers of America; DES, drug-eluting stent; DM, diabetes mellitus; EoL, end of life; EPR, electronic patient record; EPS, electrophisiology study; ETT, Exercise
tolerance testing; FRISC, Framingham and Fast Revascularization During Instability in Coronary Artery Disease; GDMT, guideline-directed medical therapy; GI, gastrointestinal; GP, glycoprotein; GPI, glycoprotein IIb/IIIa inhibitors; GRACE; Global Registry of Acute
Coronary Events; GSF, Gold Standards Framework; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HF, heart failure; HTN, hypertension; Hx, history; ICTUS, Invasive versus Conservative Treatment in
Unstable Coronary Syndromes; LAR, life attributable risk; LBBB, left bundle branch block; LOS; length of stay; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac event; MI, myocardial infarction; MINAP, Myocardial Ischaemia National Audit Project;
MPI, myocardial perfusion imaging; MUGA, Multigated Wall Motion Study; N/A, not applicable; NPV, negative predictive value; NS, not significant; NRMI, National Registry of Myocardial Infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome; NSTEMI, non-
ST-elevation myocardial infarction; OA, osteoarthritis; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; PET, positron emission tomography; PPV, positive predictive value; pts, patients; PVD, peripheral vascular disease; RITA, Randomized Trial
of a Conservative Treatment Strategy Versus an Interventional Treatment Strategy in Patients with Unstable Angina; RBC, red blood count; revasc, revascularization; RR, relative risk; Rx, prescription; SCr, serum creatinine; Sx, symptom(s); TACTICS, Treat Angina
With Tirofiban and Determine Cost of Therapy With an Invasive or Conservative Strategy; TIA, transient ischemic attack, TIMI, Thrombolysis In Myocardial Infarction; UFH, unfractionated heparin; U.S., United States; and VIGOUR, Virtual Coordinating Center for Global
Collaborative Cardiovascular Research.
Data Supplement 25. Heart Failure (Section 7.2)

Study Name, Aim of study Study Study Study Study Patient Population Study Study Endpoints P Values, Study Limitations
Author, Year Type Size (n) Intervention Comparator Interventi Comparat OR: HR: RR & & Adverse Events
Group (n) Group (n) on or 95% CI:
Inclusion Exclusion Primary Endpoint Safety Secondary
Criteria Criteria (efficacy) Endpoint Endpoint
and Results and and Results
Results
Boersma 2000 Develop a Retrospecti N/A Pts enrolled Pts not N/A 1º outcome: 30- N/A N/A There were 7 factors N/A Regression Develop a model Retrospective
(2) model for ve analysis in PURSUIT enrolled in d death; 2º most predictive of model for predicting 30-d analysis of pts with
10840005 predicting 30- of pts with trial PURSUIT outcome: death: age (adjusted developed in pts death and NSTE-ACS enrolled
d death and NSTE-ACS trial; pts with composite of 30- [Χ]2=95), heart rate with diagnosed myocardial in PURSUIT trial
myocardial enrolled in STE on initial d death and ([Χ]2=32), SBP ACS and not (re)infarction in (n=9,461; 3.6% with
(re)infarction PURSUIT ECG myocardial ([Χ]2=20), ST- designed to be pts without STE- 1º outcome)
in pts without trial (re)infarction; segment depression applied ACS
STE-ACS (n=9,461; More than 20 ([Χ]2=20), signs of indiscriminately
3.6% with variables were HF ([Χ]2=18), and to
1º found to be cardiac markers undifferentiated
outcome) predictive of 1º ([Χ]2=15); The C- chest pain pts;
and 2º index for the difficult to
outcomes mortality model was calculate;
0.814 original model
requires
preexisting
programmed
calculator;
simplified
version requires
print-out of
scoring system
for each variable
with
corresponding
figure to
interpret data
Granger 2003 Develop a Retrospecti N/A Inclusion in Not included N/A Adverse event N/A N/A The discrimination N/A Regression Develop a Retrospective
(3) regression ve GRACE or in these trials defined as inability of the model regression model observational study
14581255 model in pts observation GUSTO-IIb hospital simplified model was developed in in pts with utilizing pts from
with al study trial mortality; excellent with C- patients with diagnosed ACS GRACE (n=11,389;
diagnosed utilizing pts Regression statistics of 0.83 in diagnosed ACS (including pts with 509 deaths);
ACS from model identified the derived (including STEMI) for in- validation set
(including pts GRACE the following 8 database, 0.84 in the STEMI pts) and hospital mortality included a
with STEMI) (n=11,389; independent risk confirmation GRACE was not subsequent cohort
for in-hospital 509 factors:accounte data set, and 0.79 in designed to be of 3,972 pts enrolled
mortality deaths); d age, Killip the GUSTO-IIb applied in GRACES and
validation class, SBP, ST- database; OR for the indiscriminately 12,142 pts enrolled
set segment 8 independent risk to in GUSTO-IIb trial
included a deviation, factors were: age ( undifferentiated
subsequent cardiac arrest OR: 1.7 per 10 y), chest pain pts;
cohort of during Killip class (OR: 2.0 difficult to
3,972 pts presentation, per class), SBP (OR: calculate;
enrolled in serum creatinine 1.4 per 20 mmHg original model
GRACES level, positive decrease), ST- requires pre-
and 12,142 initial cardiac segment deviation existing
pts enrolled enzyme (OR: 2.4), cardiac programmed
in GUSTO- findings, and arrest during calculator;
IIb trial heart rate presentation (OR: simplified
4.3), serum version requires
creatinine level (OR: print-out of
1.2 per 1 mg/dL scoring system
[88.4 μmol/L] for each variable
increase), positive with
initial cardiac corresponding
enzyme findings nomogram
(OR: 1.6), and heart
rate (OR: 1.3 per 30
beat/min increase)
Pollack 2006 Validation in Convenien N/A Chest Sx and New STE N/A Death/MI/revasc N/A In-hospital Graded relationship N/A Used parts of Validation in an Convenience
(13) an ED ce sample ECG over 30 d and 14-d between score and score to define ED population sample N=3,326
16365321 population N=3,326 obtained events events management with chest pain without new STE
with chest without
pain new STE
Go 2011 Attempt to Single N/A Ischemic Sx STEMI N/A CV death, MI, N/A N/A Renal dysfunction N/A Small and only Attempt to add Single center N=798
(14) add creatinine center within 48 h urgent revasc or increased risk but 9% with eGFR, creatinine to TIMI
21691204 to TIMI risk N=798 Sx and elevated not enough to add 30 risk score
score biomarkers variable to system
Huynh 2009 Across all Multicenter N/A NSTE, ACS N/A N/A 6-mo death and N/A N/A 2 mm ST deviation N/A All high-risk pts Across all ACS Multicenter RCT with
(15) ACS RCT with and STEMI MI increased risk and spectrum N=1,491 from
19960136 spectrum N=1,491 risk was less angiographic arm
from regardless of score

angiographi with less
c arm
Eagle 2004 Original Registry N/A All ACS N/A N/A 6-mo all-cause N/A N/A p<0.25 into N/A Registry data, Original GRACE Registry N=17,141
(16) GRACE N=17,141 mortality multivariate model 200 pts without validation
15187054 validation 6 mo follow-up
Eggers 2010 Incremental Single NT- Possible ACS N/A Biomarkers All-cause N/A NT-proBNP ROC analysis N/A Small but 92 Incremental Single center trial of
(17) prognostic center trial proBNP, at mortality at 6 mo not deaths. prognostic value 453 chest pain pts
20598977 value of of 453 cystatin presentation additive, of multiple
multiple chest pain GDF-15 cystatin biomarkers in
biomarkers in pts minimally NSTE-ACS
NSTE-ACS and GDF-
15 helpful
Cannon 2001 To compare Prospective Interventi Pts ≥18 y if Persistent Pts assigned Pts assigned to Combined Bleeding Death, death or MI, At 6 mo, Study excluded To compare an Prospective,
(186) an early , on: 1,114 they had STE, 2º to early early incidence fatal or nonfatal MI, the rate of pts with severe early invasive randomized,
11419424 invasive randomized vs. episode of angina, Hx of invasive conservative of death, rehospitalization for the 1º comorbid strategy to a more multicenter trial
strategy to a , Compara angina (with PCI or CAB strategy were strategy were nonfatal MI endpoint conditions or conservative 2,220
more multicenter tor: accelerating grafting within to undergo treated MI, and was 15.9% other serious approach
conservative trial 2,220 1,106 pattern or preceding 6 coronary medically and, if rehospitali with use of systemic illness
approach prolonged mo, factors angiography their condition zation for the early
[>20 min] or associated between 4 h was stable, an ACS at invasive
recurrent with increased and 48 h underwent an 6 mo strategy
episodes at risk of after exercise- and 19.4%
rest or with bleeding, randomizatio tolerance test with use of
minimal LBBB or n and revasc (83% of such the
effort) within paced rhythm, when tests included conservativ
preceding 24 severe CHF appropriate nuclear e strategy
h, candidates or cardiogenic on the basis perfusion (OR: 0.78;
for coronary shock, serious of coronary imaging or 95% CI:
revasc, and systemic anatomical echocardiograp 0.62-0.97;
at least 1 of disease, a findings hy performed p=0.025).
the following: serum according to the
new finding of creatinine protocol of the
ST-segment level of <2.5 institution)
depression of mg/dL (221 before being
at least 0.05 μmol/L), or discharged
mV, transient current
(<20 min) participation in
STE of at another study
least 0.1 mV, of an
or T-wave investigational
inversion of drug or device
at least 0.3
mV in at least
2 leads;
elevated
levels of
cardiac
markers; or
coronary
disease, as
documented
by Hx of cath,
revasc, or M
de Winter 2005 To compare RCT 1,200 Interventi Eligible pts Exclusion Pts assigned Pts assigned to 1º Bleeding Percentage of pts Estimated Revasc rates To compare an RCT 1,200
(188) an early on: 604 have all 3 of criteria were to early the selectively endpoint free from anginal Sx cumulative were high in the early invasive
16162880 invasive vs. the following: an age >18 y invasive invasive was rate of 1º 2 groups in our strategy to a
strategy to a Compara Sx of or <80 y, strategy were strategy were composite endpoint study (76% in selectively
selectively tor: 596 ischemia that STEMI in past scheduled to treated of death, was 22.7% the early- invasive strategy
invasive were 48 h, undergo medically. Pts RMI, or in the invasive- for pts who have
strategy for increasing or indication for angiography were scheduled rehospitali group strategy group ACS without STE
pts who have occurred at 1º PCI or within 24-48 to undergo zation for assigned and 40% in the and with an
ACS without rest, with the fibrinolytic h after angiography angina to early selectively- elevated cTnT
STE and with last episode therapy, randomizatio and subsequent within 1 y invasive invasive- level
an elevated occurring no hemodynamic n and PCI revasc only if after manageme strategy group
cTnT level more than 24 instability or when they had randomizat nt and during the initial
h before overt CHF, appropriate refractory ion 21.2% in hospitalization,
randomizatio the use of oral on the basis angina despite the group and 79% and
n; elevated anticoagulant of the optimal medical assigned 54%,
cTnT level drugs in past coronary treatment, to respectively,
(≥0.03 μg/L); 7 d, fibrinolytic anatomy hemodynamic or selectively within 1 y after
and either treatment rhythmic invasive randomization
ischemic within past 96 instability, or manageme
changes as h, PCI within clinically nt (RR:
assessed by the past 14 d, significant 1.07; [0.87-
ECG (defined contraindicatio ischemia on the 1.33];
as ST- n to treatment predischarge p=0.33).
segment with PCI or exercise test.
depression or GP IIb/IIIa
transient STE inhibitors,
exceeding recent trauma
0.05 mV, or or risk of
T-wave bleeding,
inversion of hypertension
≥0.2 mV in 2 despite
contiguous treatment (i.e.,
leads) or systolic
documented pressure >180
Hx of CAD as mmHg or
evidenced by diastolic
previous MI, pressure >100
findings on mmHg),
previous weight <120
coronary kg, or inability
angiography, to give
or a positive informed
exercise test consent
Fox KA 2002. To compare RCT 1,810 Interventi Pts eligible All those with Pts assigned Pts assigned to Coprimary Bleeding Death, MI, refractory At 4 mo, 1º endpoint To compare RCT 1,810
(187) interventional on: 895 for inclusion if probable to the conservative endpoints angina as individual 86 (9.6%) driven by interventional
12241831 strategy and vs. they had evolving MI, interventional strategy were were: a endpoints of 895 pts reduction of strategy and
conservative Compara suspected including treatment managed with combined in refractory conservative
strategy in pts tor: 915 cardiac chest those for strategy were antianginal and rate of interventio angina with no strategy in pts
with unstable pain at rest whom managed antithrombotic death, n group difference in with unstable
CAD and had reperfusion with optimum medication nonfatal had died or hard clinical CAD
documented therapy was antianginal MI, or had a MI or endpoints
evidence of indicated, and refractory refractory
CAD with at were antiplatelet angina at 4 angina,
least 1 of the ineligible. treatment (as mo; and a compared
following: Those in for the combined with 133
evidence of whom new conservative rate of (14.5%) of
ischaemia on pathological Q group), and death or 915 pts in
ECG (ST- waves enoxaparin 1 nonfatal MI the
segment developed, or mg/kg at 1 y conservativ
depression, those with CK subcutaneou e group
transient or CK-MB sly 2× for 2-8 (RR: 0.66,
STE, LBBB concentration d. Protocol [0.51-0.85],
[documented s 2× the ULN specified that p=0.001).
previously], before coronary
or T-wave randomization arteriography
inversion); , were should be
pathological excluded. done as soon
Q waves Also excluded as possible
suggesting were those after
previous MI; with MI within randomizatio
or the previous n and ideally
arteriographic mo, PCI in the within 72 h
ally proven preceding 12

CAD on a mo, or CABG
previous at any time.
arteriogram
Spacek 2002 To compare RCT 131 Interventi Rest Unstable post- 1-d Conservative Composite None Length of the initial 1º endpoint Small sample To compare 1-d RCT 131
(120) 1-d on: 64 ischaemic infarction angiography treatment of death or hospitalization and (death/ size, angiography/
11792138 angiography vs. chest pain, angina /angioplasty strategy nonfatal the number of reinfarction interventions angioplasty vs.
/angioplasty Compara lasting <20 pectoris treatment guidelines were RMI 6 mo subsequent ) at 6 mo were done in early conservative
vs. early tor: 67 min, within resistant to strategy characterized by after the hospitalizations for occurred in only one high therapy of
conservative last 24 h maximal guidelines initial medical randomizat UAP 6.2% vs. volume tertiary evolving MI
therapy of before pharmacother characterized treatment with ion 22.3% center without persistent
evolving MI randomizatio apy; by coronary coronary (p<0.001). STE
without n; ECG cardiogenic angiogram angiography 6-mo
persistent evidence of shock; acute as soon as and subsequent mortality in
STE AMI without LBBB or possible after revasc only in 1-d
STE (ST- RBBB or STE randomizatio the presence of angiograph
segment 2 mm in 2 n followed by recurrent y/
depressions leads; QMI or immediate myocardial angioplasty
minimally 0.1 IV coronary ischaemia group was
mm in at thrombolysis angioplasty 3.1% vs.
least 2 >1 mo; of the culprit 13.4% in
contiguous coronary coronary the
leads and/or angioplasty or lesion + stent conservativ
negative T bypass implantation e group
waves or surgery >6 whenever (p<0.03).
documented mo; any suitable
old LBBB/ concomitant
RBBB; CK- disease which
MB higher may have
than 1.5× X possible
ULN and/or influence on 1
positive TnI y Px; lack of
assay pt cooperation
Hochman 1999 Evaluate early Multicenter 302 pts 152 pts 150 pt-initial STEMI, new N/A N/A N/A Mortality from all N/A 6-mo survival N/A Emergency revasc
(230) revascularizat RCT randomized medical LBBB, causes at 30 d 6-mo mortality did not significantly
10460813 ion in pts with to emergency stabilization posterior At 30-d mortality p=0.027 reduce overall
cardiogenic revasc infarction p=0.11 Revasc 50.3% mortality at 30 d.
shock with anterior Revasc 46.7% Medical therapy However, at 6 mo
ST segment Medical therapy 63.1% significant survival
depression 56.0% benefit
and
cardiogenic
shock 2º to
LV
dysfunction
Bhatt 2004 Determine Registry- 17,926 8,037 (44%) N/A NSTEMI pts N/A N/A N/A Use of early invasive N/A N/A N/A Predictors of early
(231) use and observation with underwent presenting to management within invasive
15523070 predictors of al study NSTEMI early cardiac 248 US 48 h of presentation management: lower-
early invasive trial 8,037 cath <48 h hospitals with Predictors of early risk pts with lack of
management (44.8%) cardiac cath invasive prior or current CHF,
strategies in underwe facilities and management renal insufficiency,
high-risk pts nt early PCI or CABG In-hospital mortality positive biomarkers
with NSTEMI cardiac availability Pts treated with
cath <48 early invasive
h strategy had lower
in-hospital mortality
2.5% vs 3.7%,
p<0.001
1º indicates primary; 2º indicates primary; ACS, acute coronary syndromes; AMI, acute myocardial infarction; BNP, B-type natriuretic peptide; CHF, congestive heart failure; CAB, coronary artery bypass; CABG, coronary artery bypass graft; CAD, coronary artery
disease; CI, confidence interval; CK-MB, creatine kinase MB; cTnT, cardiac troponin T; CV, cardiovascular; ECG, electrocardiography; ED, emergency department; eGFR, estimated glomerular filtration rate; GDF, growth differentiation factor; GP, glycoprotein; GRACE;
Global Registry of Acute Coronary Events; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial; HF, heart failure; Hx, history; LBBB, left bundle-branch block; MI, myocardial infarction; NSTE-ACS, non–ST-
elevation acute coronary syndrome; NSTE, non–ST-elevation; NSTEMI, non–ST-elevation myocardial infarction; NT-pro, N-terminal pro; PCI, percutaneous coronary intervention; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using
Integrilin Therapy; Pt, patient; Px, prognosis; QMI, q-wave myocardial infarction; RBBB, right bundle-branch block; RCT, randomized clinical trial; RMI, recognized myocardial infarction; ROC, receiver operating characteristic; RR, relative risk; SBP, systolic blood
pressure; STEMI, ST-elevation myocardial infarction; Sx, symptom; TIMI, Thrombolysis In Myocardial Infarction trial; TnI, troponin I; ULN, upper limit normal; US, United States.
Data Supplement 26. Cardiogenic Shock (Section 7.2.2)

Study Aim of study Study Study Size Study Study Patient Population Study group Comparator Endpoints Conclusions Study Limitations &
Name, Type (N) Interventio Comparator group Adverse Events
Author, n Group Group (n)
Year (n)
Inclusion Exclusion Major Study Additional Findings
Criteria Criteria Findings
Jacobs A. et Determine the Registry 881 152 pts with 729 pts with Cardiogen Excluded pts NSTEMI + STEMI + In-hospital Compared with shock pts who Pts with cardiogenic No hemodynamic or LV
al, 2000 outcomes of Sub- NSTEMI STEMI and ic shock with missing cardiogenic cardiogenic mortality similar in had STEMI, pts with NSTEMI shock and NSTEMI function data
(232) pts with study of and cardiogenic due to LV ECG + shock shock the 2 groups were older and more likely to have a higher-risk Registry data – subject to
10985710 cardiogenic the cardiogenic shock failure cardiogenic (62.5% for have comorbid disease, prior profile than shock confounding
shock SHOCK shock shock due to NSTEMI vs. infarctions and MVD pts with ST-segment
complicating trial mechanical 60.4% STEMI). Left circumflex artery was the elevation, but similar
NSTEMI complications, After adjustment, culprit vessel in 34.6% of non- in-hospital mortality.
tamponade, STEMI did not ST-elevation vs. 13.4% of ST-
cardiac independently elevation MI pts (p<5 0.001)
catheter predict in-hospital Similar LVEF in-hospital, and
laboratory mortality (OR: similar revascularization
complication, 1.30; 95% CI:
isolated RV 0.83-2.02;
dysfunction, p=0.252)
severe valvular
heart disease
Holmes DR Assess the Pre- 12, 084 (of 200 pts 173 pts Pts who Pts who had NSTEMI STEMI Lower OR of Pts without ST-segment Pts without STE GUSTO-IIb is a
et al., 1999 incidence and specified those 4,092 developed developed developed shock on (incidence/ (incidence/ developing elevation were older, more developed shock thrombolytic trial
(233) outcomes of sub-study or 34% had cardiogenic cardiogenic shock presentation outcome of outcome of cardiogenic shock frequently had DM and 3- much later than (excluded pts ineligible for
10562262 cardiogenic from the NSTEMI) shock (out shock (out of after (n=58) + 11 pts cardiogenic cardiogenic in NSTEMI vessel disease, but had less those with STEMI thrombolytics)
shock GUSTO- of 7,986 4,087 STEMI enrollment with missing shock) shock) compared with TIMI grade 0 flow at suggesting a Subgroup analysis
developing IIb trial NSTEMI pts) in GUSTO data STEMI angiography window of Different baseline risk
among pts with pts) 4.2% GUSTO Also excluded Incidence: 4.2% Shock developed significantly opportunity to
and without 2.5% eligibility pts with STEMI vs. 2.5% (OR: later among pts without ST- prevent shock
ST-segment criteria: who were not 0.58; 95% CI: segment elevation Shock pts without
elevation chest pain candidates for 0.47-0.72; No STE was significant STE had more high-
of thrombolytic p<0.001) predictor of 30-d mortality risk clinical
myocardia therapy High 30-d (p=0.048) characteristics, more
l ischemia mortality in both: extensive CAD, and
within 12 h 63% among pts more frequent
+ STE or with STEMI with recurrent ischemia
ST- shock vs. 73% in and MI before the
depressio NSTEMI with development of
n, or shock (p NS) shock
persistent Regardless of the
T-wave initial ECG findings,
inversion Shock was
associated with a
marked increase in
mortality.
1º indicates primary; CAD, coronary artery disease; DM, diabetes mellitus; ECG, electrocardiogram; GUSTO, Global Use of Strategies To Open Occluded Coronary Arteries; LV, left ventricular; LVEF; left ventricular ejection fraction; MVD, multi-vessel disease; NS,
nonsignificant; NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; Pts, patients; RV, right ventricular; SHOCK, Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock; STE, ST-elevation; STEMI, ST-elevation myocardial
infarction; and TIMI, Thrombolysis In Myocardial Infarction.
Data Supplement 27. Diabetes Mellitus (Section 7.3)

Study Aim of study Study Study Study Intervention Study Patient Population Study Study Endpoints P Values, Study
Name, Type Size Group (n) Comparator Interventio Comparat OR: HR: RR & Limitations &
Author, (N) Group (n) n or 95% CI: Adverse Events
Year
and Results
Cannon To compare Prospecti Interve Pts ≥18 y if they had Persistent STE, Pts assigned Pts assigned to Combined Bleeding Death, death or At 6 mo, the rate Study To compare an Prospective,
2001 an early ve, ntion: had an episode of 2º angina, a Hx to the early the early incidence of MI, fatal or of the 1º excluded pts early invasive randomized,
(186) invasive randomiz 1,114 angina (with an of PCI or CABG invasive conservative death, nonfatal MI, endpoint was with severe strategy to a multicenter trial
11419424 strategy to a ed, vs. accelerating pattern or within the strategy were strategy were nonfatal MI, reshospitaliztion 15.9% with use comorbid more 2,220
more multicente Compa prolonged [>20 min] preceding 6 mo, to undergo treated and for MI of the early conditions or conservative
conservative r trial rator: or recurrent episodes factors coronary medically and, if rehospitaliz invasive strategy other serious approach
approach 2,220 1,106 at rest or with minimal associated with angiography their condition ation for an and 19.4% with systemic
effort) within the an increased risk between 4 h was stable, ACS at 6 use of the illness
preceding 24 h, were of bleeding, and 48 h underwent an mo conservative
candidates for LBBB or paced after exercise- strategy (OR:
coronary revasc, and rhythm, severe randomizatio tolerance test 0.78; 95% CI:
had at least 1 of the CHF or n and revasc (83% of such 0.62-0.97;
following: a new cardiogenic when tests included p=0.025).
finding of ST-segment shock, serious appropriate nuclear
depression of at least systemic on the basis perfusion
0.05 mV, transient disease, a serum of coronary imaging or echo
(<20 min) STE of at creatinine level of anatomical performed
least 0.1 mV, or T- <2.5 mg/dL (221 findings according to the
wave inversion of at μmol/L), or protocol of the
least 0.3 mV in at current institution)
least 2 leads; elevated participation in before being
levels of cardiac another study of discharged
markers; or coronary an investigational
disease, as drug or device
documented by a Hx
of catheterization,
revasc, or M
FRISC II Compare Multicente 2,457 Early invasive Study Inclusion: N/A N/A N/A 6-mo composite N/A Angina at 6 N/A Early invasive
(185) early invasive r RCT of pts, strategy N=1,222 comparator UA, NSTEMI of death or MI mo strategy
10475181 with a 2,457 pts 21.4% group: Pts with DM– 9.4% in invasive In pts with preferred in most
noninvasive diabeti noninvasive 21.4% of vs. 12.1% in DM invasive pts with unstable
treatment c strategy n=1,235 total but not noninvasive strategy CAD who have
strategy in analyzed group (RR: 0.78, improved signs of
unstable CAD separately 95% CI: 0.62– anginal Sx – ischemia or have
0.98, p=0.031) 24% for NSTEMI
Decrease in MI invasive vs. Benefit is
alone 7.8% in 41% for greatest in pts at
invasive vs. noninvasive higher risk at
10.1% in RR: 0.59 entry
conservative (0.41–0.84)
group (RR: 0.77
95% CI: 0.60–
0.99; p=0.045)
Nonsignificant
decrease in death
1.9% vs. 2.5%
(HR: 0.65, 95%
CI: 0.39–1.09;
p=0.10)
Norhammar Evaluate Randomiz 299 pts 299 pts with DM 2,158 patients UA, NSTEMI N/A N/A N/A 1º composite of N/A N/A N/A An invasive
2004 influence of ed clinical with without DM Pts with DM death or MI. strategy
(234) DM in trial diabete defined as ITT. improved
14975468 outcome of s treated with DM remained a outcomes for
unstable CAD mellitus diet, oral strong both patients
and agents, or independent with and without
2,158 insulin predictor of death DM with
without Pts with DM and MI in unstable CAD
Rando were at multivariable DM is an
mizatio higher analyses independent risk
n to baseline risk Invasive strategy factor for dearth
early – more prior reduced and MI in both
invasiv MI, CHF, composite of invasive and
e or a PAD, HBP, death or MI in pts noninvasive
noninv more 3VD with DM from groups
asive 29.9% to 20.6%
strateg (OR 0.61; CI
y 0.36–1.04,
p=0.066)
Invasive strategy
reduced
composite of
death or MI in
nondiabpatients
without DM from
12.0% to 8.9%
(OR 0.72; CI
0.54–0.95
p=0.019)
Farkouh Compare Multicente 1,900 Aggressive medical CABG, n=947 Pts with DM LMCA lesions N/A N/A Composite of N/A MACE at 30 N/A For pts with DM
2012 strategy of r pts therapy plus DES, with excluded death from any d and 12 mo and severe CAD
(235) aggressive randomiz n=953 angiographic Minimum follow- cause, nonfatal undergoing
23121323 medical ed clinical ally up 2 y MI or nonfatal revascularization
therapy and trial confirmed stroke , CABG was
DES vs. MVD of ≥2 Composite 5-y associated with
CABG for pts major rate 26.6% in PCI significant
with DM and epicardial vs. 18.7% in reduction in
multivessel vessels CABG; p=0.005 death and MI,
CAD 5-y rate death but with a
from any cause significant
16.3% vs. 10.9%; increase in
p=0.049 PCI vs. stroke compared
CABG with PCI
5-y rate MI 13.0 Limitations:
vs. 6.0%;p<0.001 Trial not blinded
PCI vs. CABG Some
Rate stroke prespecified
increased with subgroups had
CABG 5.2% - very low
CABG vs. 2.4% prevalence
PCI; p=0.03
No subgroup
analysis of pts
with ACS
1º indicates primary; 2º, secondary; 3VD, three-vessel disease; ACS indicates acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; DES, drug-eluting stents; DM, diabetes mellitus; HBP, high
blood pressure; Hx, history; ITT, intention to treat; LBBB, left bundle-branch block; LMCA, left main coronary artery disease; MACE, major adverse cardiac events; MI, myocardial infarction; MVD, multi-vessel disease; N/A, not applicable; NSTEMI, non-ST-elevation
myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; Pts, patients; RCT, randomized controlled trial; RR, relative risk; Sx, symptom(s); UA, unstable angina.
Data Supplement 28. Post-CABG (Section 7.4)

Study Name, Aim of study Study Study Size Study Study Patient Population Study Study Endpoints P Values, Study Limitations
Author, Year Type (N) Intervention Comparator Intervention Comparator OR: HR: RR & & Adverse Events
Group (n) Group (n) 95% CI:
(efficacy) and and Results
and Results Results
Kavsak 2006 Impact of new Retrospecti TrI vs. CK- 2 SPSS CK- N/A 2 specimens AMI N/A TrI vs. CK- cTnI N/A Exclusion of Impact of new Retrospective
16824840 (23) classification of ve analysis MB Dx MB, TrI CK-MB, TrI prevalence” MB p<0.001 35.7% (30.1- nonischemic classification of analysis using CK-
MI using CK- based on ≥20% drawn at MONICA CK- for increase 41.7) diseases MI MB vs. TrI analysis
MB vs. TrI MONICA or change using least 6 h MB 19.4% MI def using Relative inc causing Tr for MI def. 258 pts
analysis for AHA def of 99% TrT apart AHA 19.8%. TnI 84% elevation with ACS
MI def. 258 MI cutoff TnI increase.
pts with to 35.7%
ACS
Goodman 2006 Diagnostic and Multicenter Use of CK >18 y with NS CK Tn+ levels N/A In entire Hospital fatality N/A 34% in GRACE Diagnostic and Multicenter
16504627 (25) prognostic observation and -Tn possible ACS comorbity, CK-MB demonstrated population, rates higher registry prognostic impact observational
impact of new al 16,797 vs. with ECG trauma, Tn higher in Tn+ status with Tn+ vs. excluded of new UDMI prospective
UDMI prospective CK-MB and abnormal or surgery, lack Follow-up for hospital and 6- vs. CK CK+: 2.2 (1.6- because of use Registry (GRACE)
Registry Tn CAD history. of 1 6 mo mo mortality status 6-mo 2.9) with of 1 biomarker 26,267 ACS pts
(GRACE) 10,719 for CK, CK-MB. biomarker rates than mortality:1.6 Tn+/CK-MB-: only
26,267 hospital. Tn higher CK (1.4-1.9) 2.1 (1.4-3.2)
ACS pts fatality, levels
14,063 vs.
8,785 for 6-
mo mortality
Eggers 2011 Clinical Retrospecti UDMI with N/A cTnI <99th cTnI levels Peak cTnl N/A N/A All 160 had NA Analysis of Clinical Retrospective
20869357 (26) implications of ve study of presp cTnI percentile level ≥99th significant assay could implications of study of 454 ACS
relative change 454 ACS changes percentile + raised mortality not be relative change in pts within 24 h of
in cTnI levels pts within from ≥20%, change ≥20% HR: 2.5 (1.7- validated by hs cTnI levels with admission with 5.8
with chest pain 24 h of 50%, 100% in 160. 25 had 3.8) Higher TnI Tr assay. chest pain y follow-up
admission no AMI by deltas were not No review of
with 5.8 y ESC/ACC associated with pts records for
follow-up criteria higher type I or 2 AMI
mortalities No long-term
risk
assessment
Giannitsis 2010 Dx, perf. of hs- Retrospecti Baseline vs. UA or Immed PCI Hs-cTnT Hs –cTnt Dx N/A Doubling of Delta changes N/A Admission to Dx, perf. of hs- Retrospective
(33) cTnT for ve cohort and serial NSTEMI with or kidney baseline,3,6 61% at hs-Tnt with and ROC opt. chest pain unit cTnT for cohort analysis
20167697 detection. of analysis conc. at 3 h initial -cTnT dysfunction h baseline to initial 99% + values spec more selective detection. of 57 with UA and
NSTEMI in ACS 57 with UA and 6 h delta change 100% at 6 h. pos 100% with than typical ED NSTEMI in ACS evolving NSTEMI
and >20%,or Dx inc by 34% predicted sens 69% and admissions

evolving ROC above std value 100% 76%
NSTEMI optimized cTnT neg
value >117% predicted
3 h, or 246% value 88%
6h
Ie 2004 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
(236)
15528943
Lindahl 2010 Hs-cTnT Prospective Effect of ACS pts No coronary Both cTnT +hs-TnT same N/A For death or +hs-TnT 1-y N/A Pts with higher Hs-cTnT Prospective cohort
(32) comparison with cohort pos. by both angiography collected 48 1-y mortality. AMI at 30 d mortality 9,2% pretest risk comparison with 1,452
20691825 std cTnT for risk 1,452 assays vs. within 12 h h after Whether + or – + only for hs- vs. 1.6% than typical std cTnT for risk
assessment only 1 assay randomizatio with st-TnT TnT had p=0.001 chest pain pts assessment
n interim risk For – by both in ED
assays
Cannon 2001 To compare an Prospective Intervention: Pts ≥18 y if Persistent Pts assigned Pts assigned Combined Bleeding Death, death or At 6 mo, Study excluded To compare an Prospective,
(186) early invasive , 1,114 vs. they had had STE, 2º to the early to the early incidence of MI, fatal or the rate of pts with severe early invasive randomized,
11419424 strategy to a randomized Comparator: an episode of angina, a Hx invasive conservative death, nonfatal nonfatal MI, the 1º comorbid strategy to a multicenter trial
more , 1,106 angina (with of PCI or strategy were strategy were MI, and rehospitalizatio endpoint conditions or more 2,220
conservative multicenter an CABG within to undergo treated rehospitalizatio n for MI was other serious conservative
approach trial accelerating the coronary medically and, n for ACS at 6 15.9% systemic approach
2,220 pattern or preceding 6 angiography if their mo with use illness
prolonged mo, factors between 4 h condition was of the
[>20 min] or associated and 48 h stable, early
recurrent with an after underwent an invasive
episodes at increased randomizatio exercise- strategy
rest or with risk of n and revasc tolerance test and
minimal bleeding, when (83% of such 19.4%
effort) within LBBB or appropriate tests included with use
the preceding paced on the basis nuclear of the
24 h, were rhythm, of coronary perfusion conservati
candidates severe CHF anatomical imaging or ve
for coronary or findings echocardiogra strategy
revasc, and cardiogenic phy performed (OR: 0.78;
had at least 1 shock, according to 95% CI:
of the serious the protocol of 0.62-0.97;
following: a systemic the institution) p=0.025).
new finding disease, a before being
of ST- serum discharged
segment creatinine
depression of level of <2.5
at least 0.05 mg/dL (221
mV, transient μmol/L), or

(<20 min) current
STE of at participation
least 0.1 mV, in another
or T-wave study of an
inversion of investigation
at least 0.3 al drug or
mV in at least device
2 leads;
elevated
levels of
cardiac
markers; or
coronary
disease, as
documented
by a Hx of
catheterizatio
n, revasc, or
M
Fox 2002 To compare RCT 1,810 Intervention: Pts were All those with Pts assigned Pts assigned The coprimary Bleeding Death, MI, At 4 mo, 1º endpoint To compare RCT 1,810
(187) interventional 895 vs. eligible for probable to the to the trial endpoints refractory 86 (9.6%) driven by interventional
12241831 strategy and Comparator: inclusion if evolving MI, interventional conservative were: a angina as of 895 pts reduction of strategy and
conservative 915 they had including treatment strategy were combined rate individual in the refractory conservative
strategy in pts suspected those for strategy were managed with of death, endpoints interventio angina with no strategy in pts
with unstable cardiac chest whom managed antianginal nonfatal MI, or n group difference in with unstable
CAD pain at rest reperfusion with optimum and refractory had died hard clinical CAD
and had therapy was antianginal antithrombotic angina at 4 mo; or had a endpoints
documented indicated, and medication and a MI or
evidence of were antiplatelet combined rate refractory
CAD with at ineligible. treatment (as of death or angina,
least 1 of the Those in for the nonfatal MI at 1 compared
following: whom new conservative y with 133
evidence of pathological group), and (14.5%) of
ischaemia on Q waves enoxaparin 1 915 pts in
ECG (ST- developed, mg/kg the
segment or those with subcutaneou conservati
depression, CK or CK- sly 2× for 2-8 ve group
transient MB d. The (RR: 0.66,
STE, LBBB concentration protocol [0.51-
[documented s 2× the ULN specified that 0.85],
previously], before coronary p=0.001).
or T-wave randomizatio arteriography

inversion); n, were should be
pathological excluded. done as soon
Q waves Also as possible
suggesting excluded after
previous MI; were those randomizatio
or with MI within n and ideally
arteriographi the previous within 72 h
cally proven mo, PCI in
CAD on a the
previous preceding 12
arteriogram mo, or CABG
at any time.
Spacek 2002 To compare 1st RCT 131 Intervention: Rest Unstable 1st d Conservative Composite of None Length of the 1º Small sample To compare 1st d RCT 131
(120) d angiography/ 64 vs. ischaemic post- angiography/ treatment death or initial endpoint size, angiography/
11792138 angioplasty vs. Comparator: chest pain, infarction angioplasty strategy nonfatal RMI 6 hospitalization (death/ interventions angioplasty vs.
early 67 lasting <20 angina treatment guidelines mo after the and the reinfarctio were done in early
conservative min, within pectoris strategy were randomization number of n) at 6 mo only one high conservative
therapy of the last 24 h resistant to guidelines characterized subsequent occurred volume tertiary therapy of
evolving MI before maximal were by initial hospitalizations in 6.2% center evolving MI
without randomizatio pharmacothe characterized medical for UAP vs. 22.3% without persistent
persistent STE n; ECG rapy; by a treatment with (p<0.001). STE
evidence of cardiogenic coronary coronary 6 mo
AMI without shock; acute angiogram angiography mortality
STE (ST- LBBB or as soon as and in the 1st d
segment RBBB or possible after subsequent angiograp
depressions STE 2 mm in randomizatio revasc only in hy/
minimally 0.1 2 leads; QMI n followed by the presence angioplast
mm in at or IV immediate of recurrent y group
least 2 thrombolysis coronary myocardial was 3.1%
contiguous >1 mo; angioplasty ischaemia vs. 13.4%
leads and/or coronary of the culprit in the
negative T angioplasty coronary conservati
waves or or bypass lesion + stent ve group
documented surgery >6 implantation (p<0·03).
old LBBB/ mo; any whenever
RBBB; CK- concomitant suitable
MB higher disease
than 1.5 × X which may
ULN and/or have
positive TnI possible
assay influence on
1-y Px; lack

of pt
cooperation
1º indicates primary; 2º, secondary; 3VD, three-vessel disease; ACS indicates acute coronary syndrome; AMI acute myocadial infarction; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; CK, creatine kinase;; CK-MB,
creatine kinase MB; Dx, diagnosis; ECG, electrocardiograph; ESC, European Society of Cardiology; GRACE, Global Registry of Acute Coronary Events; HBP, high blood pressure; Hs-cTnT, high-sensitivity cardiac troponin I; Hx, history; IV, intravenous; LBBB, left
bundle-branch block; MI, myocardial infarction; MONICA, Multinational MONItoring of trends and determinants in CArdiovascular disease; NS, no(n) significance; PCI, percutaneous coronary intervention; Pt, patient; Px, prognosis; QMI, Q-wave myocardial infarction;
RBBB, right bundle-branch block; RCT, randomized controlled trials; revasc, revascularization; ROC, receiver operating characteristic;RMI; RR, relative risk; cTnT, cardiac troponin T; SSPS; STE, ST-elevation; Tn, troponin; TnI, troponin I; UAP; UDMI, Universal
Definition of Myocardial Infarction; and ULN, upper limit of normal.
Data Supplement 29. Chronic Kidney Disease (Section 7.6)

Study Name, Aim of study Study Type Study Size (N) Study Study Patient Population Endpoints P Values, Study Limitations &
Author, Year Intervention Comparator OR: HR: Adverse Events
Group (n) Group (n) RR &
95% CI:
Inclusion Criteria Exclusion Criteria Primary Endpoint Safety Secondary
(efficacy) Endpoint Endpoint
and Results and Results and Results
Wright 2002 Compare Retrospectiv 4,426 n=3,106 with: n=1,320 with Consecutive pts N/A Short- and long-term Pts with renal N/A N/A Retrospective Analysis
12353943 outcomes after e cohort endstage renal normal renal with acute infarction survival compared after failure received Potential referral bias
(237) AMI in pts with study disease, severe function between 1988 and pts were stratified by reperfusion Single center study
varying degrees renal 2000. Renal CrCl. therapy less
of renal function insufficiency function estimated In-hospital mortality : frequently than
CrCl <35 according to the 2% in pts with normal pts with normal
mL/min, Cockcroft-Gault. renal function, 6% in pts renal function;
moderate renal with mild renal failure, p<0.001. Post-
insufficiency 14% in pts with discharge death
CrCl ≥35, ≤50 moderate renal failure, less likely in pts
mL/min, mild 21% in pts with severe who received
renal renal failure, and 30% acute reperfusion
insufficiency in pts with endstage therapy. OR: 0.7
CrCl > 50 renal disease; p<0.001 (CI: 0.6–0.9)
mL/min Post-discharge mortality ASA OR: 0.7 (CI:
in abnormal renal 0.5–0.8)
function vs. normal BB OR: 0.7 (CI:
renal function 0.6–0.9)
Mild renal failure HR:
2.4 (CI 1.7–3.3;
p<0.001)
Moderate renal failure
HR: 2.2 (CI: 1.5–3.3;
p<0.001)
Severe renal failure HR:

1.9 (CI: 1.2–3.0;
p=0.006)
End-stage renal
disease HR: 5.4 (CI:
3.0–9.7; p<0.001)
Shlipak 2002 Determine how All 130,099 older Mild renal No renal All older (age ≥65 y) 6,790 pts with Primary: pts with N/A 1 y-mortality N/A No measurement of true
12353942 pts with renal nongovernm pts with MI insufficiency: Cr: insufficiency: Cr Medicare severe renal moderate renal 24% with no GFR
(238) insufficiency are ental U.S. 1994-1995 1.5-2.4 mg/dL <1.5 mg/dL beneficiaries with insuffieciency Cr insufficiency less likely renal Size of data collected from
treated during hospitals n=36,756 n=82,455 AMI 1994-1995 ≥4.0 mgm/dL to receive aspirin, BB, insufficiency 1994-1995
MI cohort study Moderate renal 10,570 pts with no thrombolytic therapy, 46% with mild Focus on patients ≥65 y
Determine insufficency: Cr: information on angiography or PCI renal
association of 2.5-3.9 mg/dL estimating CrCl insufficiency
renal n=10,888 66% with
insufficiency on moderate
survival after MI renal
insuffieciency
Secondary:
after
adjustment for
pt and
treatment
characteristic
s, renal
insufficiency
was
associated
with elevated
risk of death
after MI
Mild renal
insufficiency:
HR: 1.68
(95% CI:
1.68–1.73)
Moderate
renal
insufficiency:
HR: 2.35
(95% CI:
2.26–2.45)
Solomon 1994 Evaluate effect RCT 78 n=28, 45% n=25 78 pts with chronic N/A An increase in baseline N/A N/A N/A Hydration with 0.45% saline
7969280 (239) of saline, saline alone for 1) 45% saline renal insufficiency serum Cr of ≥0.5 provides better protection
mannitol on 12 h before and plus mannitol undergoing mgm/dL within 48 h of against CIN than hydration
renal function in 12 h after n=25 coronary angiography plus either mannitol or
pts undergoing 2) 45% saline angiography 11% with saline furosemide
coronary plus furosemide Serum Cr measure 28% with saline + Limitations:
angiography prior to and 48 h mannitol Small sample size
after angiography 40% with saline +
furosemide
p=0.05
Charytan Evaluate Collaborative 5 randomized Early invasive Conservative Total 1,453 pts with N/A 1-y mortality N/A In-hospital N/A Routine coronary
2009 effectiveness of meta- studies of strategy of strategy of CKD in 5 RCT Invasive strategy death, MI, angiography should be
19423566 an early analysis of 1,453 pts with routine coronary selective stages 3a, 3b, and associated with: death/MI, 1-y considered for pts with CKD
(240) invasive RCT CKD angiography coronary 4-5 Nonsignificant reduction MI, who are admitted with
strategy or angiography GFR calculated in all-cause mortality rehospitalizati NSTEMI
conservative using modification RR: 0.76; 95% CI: on, combined Limitations:
strategy in pts of diet in renal 0.49–1.17; p=0.21 death/MI Publication bias
with CKD disease Nonfatal MI RR: 0.78; Small number trials
admitted with Serum Cr measure 95% CI: 0.52–1.16; Small number of stage 4-5
UA/NSTEMI prior to and 48 h p=0.22 CKD
after angiography Death or nonfatal MI
RR: 0.79; 95% CI:
0.53–1.18; p=0.24
Significant reduction in
rehospitalization RR:
0.76; 95% CI: 0.66–
0.87; p<0.0001
Szummer Evaluate Nationwide 23,262 Pts Patients not 23,262 consecutive N/A After adjustment overall N/A N/A N/A Early invasive therapy is
2009 influence of registry consecutive revascularized revascularized pts ≤80 y with 1-y mortality was 36% associated with greater 1-y
19704097 renal function NSTEMI pts within 14 d of within 14 d of NSTEMI lower (HR: 0.64; 95% survival in pts with NSTEMI
(241) on effects of ≤80 y old admission, admission, Subdivision in 5 CI: 0.56–0.73; p<0.001) and mild-moderate renal
early treated from N=12,030 n=11,232 groups with invasive strategy insufficiency. Benefit
revascularizatio 2003-2006 eGFR ≥90 Magnitude of survival declines with lower renal
n in NSTEMI n=6,064 difference similar in function.
eGFR 60-89 normal to moderate Limitations:
n=11,509 renal function groups Registry study
eGFR 30-59 Lower mortality Selection bias
n=4,839 observed with invasive Arbitrary cut point 14 d
eGFR 15-29 therapy declined with Pts ≤80 y
n=572 lower renal function
eGFR <15/dialysis No difference in
N=278 mortality in pts with
Cox regression kidney failure or in

model with those dialysis p=0.15,
adjustment for HR: 1.61; 95% CI:
propensity score 0.84–3.09
and discharge
medication to
assess association
between early
revascularization
and 1-y mortality
AMI indicates acute myocardial infarction; BB, beta blocker; CKD, chronic kidney disease; CIN, contrast induced nephropathy; Cr, creatinine; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; MI, myocardial infarction;
N/A, nonapplicable; NSTEMI, Non–ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; pts, patients; RCT, randomized controlled trial; RR, relative risk; UA, unstable angina; and U.S., United States.
Data Supplement 30. Women (Section 7.7)

Study Name, Aim of study Study Study Size Study Study Patient Population Study Study Endpoints P Values, Study Limitations
Author, Year Type (N) Intervention Comparator Intervention Comparato OR: HR: RR & & Adverse Events
Group (n) Group (n) r 95% CI:
(efficacy) and and
and Results Results Results
Hutchinson- Characterize Retrospecti N=13,556 None None Pts with NSTE- Pts with NSTE- N/A N/A Pts enrolled in N/A N/A Results too N/A
Jaffe AB, differences in ve case- pts with ACS in 4 large ACS with ACS clinical trials were numerous to list
Goodman SG, clinical control of NSTE-ACS prospectively precipitated or younger, more
Yan RT, et al. characteristics several (8.3% in collected accompanied likely to be men,
Comparison of and clinical large clinical registries: by a serious and had fewer
baseline management NSTE-ACS trials) Canadian ACS I concurrent comorbidities.
characteristics between pts registries (1999 to 2001), illness, such as Clinical trial pts
, management with NSTE- ACS II (2002- trauma or GI were more likely
and outcome ACS in clinical 2003), GRACE bleeding to be on several
of patients trials and not in (2004-2007), GDMT, undergo
with non-ST- clinical trials and CANRACE invasive
segment (2008) over 10 procedures (all
elevation y, ≥18 y age, p<0.001).
acute within 24 h of Unadjusted in-
coronary NSTE-ACS hospital mortality
syndrome in presentation nonclinical vs.
versus not in clinical trials
clinical trials. (2.1% vs. 0.7%,
Am J Cardiol. p<0.001) and 1-y
2010;106:138 (8.9% vs. 6.3%,
9-96. p=0.037) In
multivariable
21059426 analysis, pts who
(242) were older,
women, had Hx of
CHF failure, and
increased CrCr
levels on
presentation were
less likely to be
enrolled in clinical
trials.
Akhter N, To assess Retrospecti N=199,690 All pts None Men and women Not fitting N/A N/A Women presented N/A Too Too numerous to Limited extrapolation
Milford-Beland clinical and ve case- pts, 55,691 underwent with NSTE-ACS predefined more often with numerous list – all subjects are
S, Roe MT, et angiographic control of women PCI (index) who underwent NSTE-ACS NSTE-ACS than to list registry NSTE-ACS
al. Gender characteristics, registry presented PCI in ACC- definition or not men (82% vs. pts
differences procedural and data with NSTE- NCDR Registry undergoing PCI 77% of men,
among treatment UA vs. 1/104-3/30/06; <0.0001). Women
patients with patterns, and 101,961 index PCI only with NSTE-ACS
acute in-hospital men had more
coronary outcomes comorbidities, but
syndromes between men fewer high-risk
undergoing and women angiographic
percutaneous features than
coronary men. Women
intervention in were less likely to
the American receive ASA, GPI,
College of and less often
Cardiology- discharged on
National ASA or statin. In-
Cardiovascula hospital mortality,
r Data was similar for
Registry women and men
(ACC-NCDR). (OR: 0.97, p=0.5).
Am Heart J. Women had
2009;157:141- higher rates of
8. cardiogenic
19081410 shock, CHF, any
(243) bleeding (7.6 vs.
3.6%, p<0.01),
and any vascular
complications, but
subacute stent
thrombosis rates
were less in
women compared
to men (0.43% vs.
0.57%, p=0003).
Blomkalns AL, To examine Retrospecti N=35,875 None None 35,875 pts with Pts excluded N/A N/a Women were N/A Too Too numerous to Limited
Chen AY, differences of ve case- pts (41% NSTE-ACS from this older (median age numerous list generalizability from
Hochman JS, gender in control of women) (14,552 women) analysis 73 vs. 65 y) and to list registry data
et al. Gender treatment and registry at 391 U.S. included those more often had
disparities in outcomes data hospitals who were DM and HTN.
the Dx and among pts with participating in transferred to Women were less
treatment of NSTE ACS the CRUSADE another likely to receive
non-ST- initiative hospital, (3,210 acute heparin,
segment between March men and 1,827 ACE-I, and GPI
elevation 31, 2000, and women), and and ASA, ACE-I,
acute December 31, pts with and statins at
coronary 2002 missing gender discharge. Men
syndromes: status (n=66) underwent more
large-scale angiography/
observations revere then
from the women, but
CRUSADE among pts with
National significant CAD,
Quality PCI was
Improvement performed
Initiative. J Am similarly in men
Coll Cardiol. and women. NS
2005;45:832- gender difference
7. was seen in
adjusted rates of
15766815 in-hospital death,
(244) reinfarction, HF,
and stroke. RBC
transfusion rates
were higher in
women (OR: 1.17;
CI: 1.09-1.25)
Lansky AJ, To examine Retrospecti 4,157 Overall Overall men Men and women Missing AT Strategy: 1) Men vs. No gender In women: Same as 1º 30-d composite Although
Mehran R, gender impact ve analysis women with women =4, =9,662 enrolled in data/follow-up GPI + women ± difference in 30 d bivalirudin endpoint ischemia: prespecificed gender
Cristea E, et on of ACUITY NSTE-ACS 157 GPI + ACUITY trial, heparin PCI – composite alone findings at women=7%, analysis, study was
al. Impact of antithrombotic trial (31% of GPI + heparin randomized to Bivalirudin + bleeding, ischemia; women significantly 1 y and ± men=8% p=NS; underpowered to
gender and therapy for (prespecifie total heparin (UFH or open-label AT GPI net significantly less PCI 30-d bleeding: detect difference so
antithrombin ischemia vs. d but not enrolled) (UFH or enoxaparin) treatment Bivalirudin ischemia, higher 30-d bleeding women=8% vs. regression analysis
strategy on bleeding in pts powered) enoxaparin) vs. Intervention: and overall bleeding; net than GPI + men=3%; performed to
early and late with NSTE- n=1,354 bivalirudin + PCI clinical clinical outcome heparin p<0.0001; 30-d net account for baseline
clinical ACS in women vs. GPI vs. Non-PCI benefit at 30 d worse in (5% vs. clinical outcome difference
outcomes in ACUITY trial bivalirudin + bivalirudin 30-d women due to 10%, women=13% vs.
patients with GPI=1,386 2) AT bleeding p<0.0001) men=10%;
non-ST- women vs. PCI=3,838 strategy on with no p<0.0001
elevation bivalirudin men outcome in difference
acute =1,417 No women ± in
coronary women PCI=5,824 PCI at 30 d composite
syndromes PCI=1,190 men ischemia
(from the women (7% vs.
ACUITY trial). No PCI 6%); no
Am J Cardiol. =2,967 difference
2009;103:119 women in
6-203. bivalirudin
+ GPI and
19406258 GPI +
(245) herparin
Alexander KP, To examine Retrospecti N=32,601 Use of GPI- Rate of All enrolled Contraindicated Those Those For GPI Rx: Rate Despite NS Excess GPI N/A N/A
Chen AY, gender impact ve analysis total; GPI dose was dosing, CRUSADE pts to GPI; those treated with treated with of bleeding difference dose
Newby LK, et on GPI use, of Rx=18,436 evaluated excessive Jan.-Dec. 2004 without GPI vs. not; GPI vs. not; significantly in serum associated
al. Sex dose, bleeding CRUSADE (6,084 based on dosing, complete data women vs. women vs. higher in women Cr, women with
differences in in pts with registry women, pts’ CrCl bleeding and including GPI men men vs. men (15.7% had mean increased
major bleeding NSTE-ACS in 12,352 outcome dose, CrCl, vs. 7.3%; CrCl bleeding.
with CRUSADE men) were follow-up p<0.0001); significantly Women
glycoprotein compared by For those NOT lower (20 (OR: 1.72;
IIb/IIIa gender GPI Rx’d: women mg/min) vs. 95% CI:
inhibitors: had significantly men; 1.30-2.28)
results from higher bleeding excess GPI Men (OR:
the CRUSADE rates than men dose given 1.27; 95%
initiative. (8.5 vs. 5.4%; to women CI: 0.97-
Circulation. p<0.0001) significantly 1.66)
2006;114:138 more than GPI
0-7. men (46.4 bleeding
vs. 17.2%; attributed
16982940 p<0.0001) risk=25%
(246) women,
4.4% men;
Excess GPI
dose for
women vs.
men=3.81
(95% CI:
3.39-
4.27)
Bhatt DL, Roe Determine use Registry- 17,926 with 8,037 (44%) N/A Pts with N/A N/A N/A Use of early N/A Female sex Registry data Predictors of early
MT, Peterson and predictors observation NSTEMI in underwent NSTEMI invasive as predictor estimating “real invasive
ED, et al. of early al study trial CRUSADE early cardiac presenting to management of early world” practice’ management: lower-
Utilization of invasive (women cath <48 h 248 UShospitals within 48 h of invasive with usual risk pts with lack of
early invasive management =7,353) with cardiac cath presentation; OR: 0.86 limitations of prior or current CHF,
management strategies in facilities and PCI predictors of early (95% CI: generalizability renal insufficiency,
strategies for high-risk pts 8,037 or CABG invasive 0.80-0.92); positive biomarkers
high-risk with NSTEMI (44.8%) availability management; in-
patients with underwent hospital mortality Pts treated with early
non-ST- early Propensity invasive strategy
segment cardiac matched analyses had lower in-hospital
elevation cath <48 h revealed OR: 0.8 mortality 2.5% vs.
acute (women significantly favors 3.7%; p<0.001
coronary =2,842) early invasive
syndromes: over selective
results from invasive in women
the CRUSADE
Quality
Improvement
Initiative.
JAMA.
2004;292:209
6-104.
15523070
(231)
O'Donoghue To compare Meta- Data Women: Men: Pts with NSTE- Pts with N/A N/A Women had lower N/A In men: MACE early Results persisted for
M, Boden WE, the effects of analysis of combined Early Early ACS in 8 RCTs missing MACE with early early invasive vs. initial 12-m follow-up.
Braunwald E, an invasive vs. RCTs from8 trials invasive invasive: evaluate early biomarker data invasive vs. initial invasive vs. conservative: Heterogeneity
et al. Early conservative (1970- (3,075 =1,571 3,641 invasive vs. excluded from conservative as initial Women: OR: 0.81 between trials; trials
invasive vs strategy in 4/2008) women and selective high-risk did men without conservativ (95% CI: 0.65- not individually
conservative women and with 7,075 men). Initial Initial invasive (if analyses significant gender e for 1.01) powered for sex-
treatment men with NSTE gender- conservative conservative recurrent Sx) or interaction. MACE. Men: OR: 0.73 specific analyses
strategies in ACS specific =1,581 : 3,619 positive stress Biomarker- Biomarker (95% CI: 0.550.98)
women and analyses test after initial positive women. positive:
men with pharmacological Early invasive vs. OR: 0.56)
unstable test initial conservative (95% CI:
angina and for death/MI/ACS 0.46-0.67)
non-ST- (OR: 0.67; 95% Biomarker
segment CI: 0.50-0.88), but Negative

elevation not in biomarker OR: 0.72
myocardial negative women (95% CI:
infarction: a and 35% higher 0.51-1.01)
meta-analysis. risk of death/MI
JAMA. (OR: 1.35; 95%
2008;300:71- CI: 0.78-2.35)
80.
18594042
(247)
Dolor RJ, To determine Meta- 7 studies Analyses run N/A Pts with NSTE- Those with Early N/A Women showed Increased Early N/A N/A
Melloni C, efficacy and analyses of early separately ACS in RCT of missing data invasive vs. trend toward bleeding in invasive
Chatterjee R, safety of early RCTs and invasive vs. for different early invasive initial benefit from early women vs. showed
et al. invasive vs. systematic initial time points vs. initial conservative invasive vs. initial men in benefit
Treatment initial reviews of conservativ (6 mg, 1 y, 5 conservative conservative at 6 NSTE-ACS (death/MI)
Strategies for conservative observation e for y); n=4,030 studies including mo and 1 y pts over initial
Women With strategy in al studies women with (36% FRISC-II, (death/MI) OR: undergoing conservativ
Coronary women with NSTE- women) for TACTICS-TIM- 0.78; OR: 0.77, PCI e in men at
Artery Disease NSTE-ACS ACSMI risk modifier 18, GUSTO-IV- respectively), but (adjusted 6 m (OR:
[Internet].2012 N=17,930 studies; ACS, ICTUS, at 5 y the trend OR: 3.6; 0.65; CI:
pts, of n=2,220 RITA-3, TIMI- favored initial 95% CI: 0.52-0.82;
23016160 which 6,084 (34% IIIB conservative 1.6-8.3) p=0.0002).
(248) (34%) were women) for (1.05; CI: 0.81- Results for
women safety 1.35); Troponin- these at 1y
studies positive women (OR: 0.88;
benefit from early CI: 0.64-
invasive vs. initial 1.20); 5 y
conservative (OR: (OR: 0.91;
0.56; CI: 0.32- CI: 0.53-
0.97) 1.56)
Glaser R, To determine Analyses of N=2,220 Early Initial Pts with NSTE- Missing data, Early Initial Women were Women For women Early invasive vs. This subanalysis
Herrmann HC, sex differences data from (women invasive conservative ACS without lack of follow- invasive conservativ older, had more who with NSTE- initial conservative may not be
Murphy SA, et in baseline TACTIC =757) =1,114 – =1,106 – contraindications up (6 mo and 1 =angiograph e =medical HTN, less Hx underwent ACS for MACE adequately powered
al. characteristics TIMI-18 by Angiography medical to angiography; y) y 4-48 h therapy – CAD, and less PCI had troponin Women: OR: 0.45 to detect differenced
Benefit of an and outcome in gender 4-48 h after therapy – pt received ASA after angiograph positive higher negative (95% CI: 0.24- among women.
early invasive ACS and if (multivariab randomizatio angiography/ (325 mg), UFH, randomizatio y/PCI if biomarkers, no bleeding OR: 1.46 0.88) adjusted for
management women benefit le logistic n with PCI if tirofiban n with recurrent difference in TIMI rate vs. (CI: 0.78, baseline difference
strategy in from early regression PCI/revasc recurrent Sx PCI/revasc Sx or risk score. men (8.3% 2.72); TIMI Men: OR: 0.6 (95%
women with invasive of sex as as indicated or positive as indicated positive Women had less vs. 2.9%, Risk 0-2 CI: 0.47- 0.88)
acute strategy predictor of stress test stress test severe CAD. OR: 3.6, OR: 1.59 (p=0.6 for gender
coronary outcome– Women benefit 1.6-8.3). (CI: 0.69- interaction)
syndromes. prospective from early Rates of 3.67), no
JAMA. RCT of invasive vs. initial bleeding ST

2002;288(24): early conservative in and stroke segment
3124-9. invasive vs. MACE (OR: 0.72; showed in changes
initial 95% CI: 0.47- women OR: 1.00
12495392 conservativ 1.11) overall but undergoing (CI: 0.61-
(249) e strategy) OR: 0.47 (95% CI: CABG no 1.65)
0.26-0.83) for different
elevated troponin from men
Chen J, To determine Retrospecti N=952,420 Determine 3 categories Insured adults N/A N/A N/A 9.5% underwent Myocardial Radiation N/A Radiation estimates,
Einstein AJ, the cumulative ve, enrollees, cumulative were 3 (18-65) with 3 y having ≥1 cardiac imaging levels for insured younger
Fazel R, et al. dose of ionizing observation n=90,121 dose- mSv/y data – member imaging studies comparable adult population
Cumulative radiation al. ≥1 cardiac cardiac background 1 of 5 health procedure within 3 account for procedure studied, not specific
exposure to exposure of Administrati imaging procedure= level of care markets y. Mean most of higher in to those with NSTE-
ionizing cardiac ve claims procedure myocardial naturally having ≥1 cumulative radiation- doctors’ ACS
radiation from imaging over 3 used to perfusion absorbed cardiac imaging dose=23.1 mSv identifies office vs.
diagnostic and y identify imaging (CT radiation in procedure (range 1.5 mSv- potential to hospital.
therapeutic insured or PET), the U.S; 3- 544 mSv). MPI reduce Higher in
cardiac adults cardiac CT, 20 mSv/y, accounted for radiation men and
imaging undergoing diagnostic and 20 74%; 80/100 rec with increasing
procedures: a cardiac cath/PCI, mSv/y >3-20 mSv; alternate exposure
population- imaging cardiac PET, (upper 3.3/1,000 rec >20 imaging with age.
based MUGA, EPS/ annual limit mSv
analysis. J Am ablation for
Coll Cardiol. 2005-7 vs. occupational
2010;56:702- background exposure for
11. radiation at-risk
20619569 level workers/ 5 y)
(250)
Einstein AJ, To characterize Retrospecti N=1,097 MPI N/A Consecutive Radiotherapy N/A N/A Median N/A Women Multiple outcomes- Likely
Weiner SD, procedure ve cohort pts with inpts and outpts procedures procedures=15 underwent doses/types of underestimation of
Bernheim A, counts, study of index exam in single center excluded (IQR 6-32), 4 more testing. Multiple longitudinal radiation
et al. Multiple cumulative consecutive in 2006; undergoing were high-dose ionizing MPI performed on exposure if scans
testing, estimated pts (51.5% single-photon ionizing radiation; radiation individual pats with could not be assess
cumulative effective undergoing women) emission CT 31% received procedures highest radiation (other institutions,
radiation dose, radiation MPI –single MPI (index cumulative dose than men, dose associated not known); changes
and clinical doses, and center- procedure) in >100 mSv. even in technology over
indications in clinical index exam 2006- EPR Multiple MPIs excluding time, some date
patients indications for linked to all linked records performed on mammogra imputed, single
undergoing pts undergoing radiation 1988-2008 39% pts, MPI m, but center experience.
myocardial MPI studies pre accounted for cumulative
perfusion (18 y)/post majority of effective-
imaging. (2 y) follow- radiation dose higher
JAMA. up exposure. in men.

2010;304:213 More
7-44. procedure/d
21078807 ose in
(251) White>Blac
ks and
Hispanics
Einstein AJ, To determine Monte N/A N/A N/A N/A N/A N/A N/A Doses of 8 CTCA N/A N/A RR of attributable Models for single
Henzlova MJ, the LAR of Carlo protocols given for cancer vs. 80 y CTCA scans without
Rajagopalan cancer simulation organs; younger shielding
S. Estimating incidence estimation women had a Male: 20 y
risk of cancer associated with of organ significantly
associated 64-slice CTCA doses from higher LAR of Female RR: 23, 40
with radiation radiation 64 slice cancer, especially y
exposure from exposure and CTCA- age breast and lung,
64-slice determine and sex- from single CTCA Female OR: 11.5,
computed influence of specific 60 y
tomography age, sex, and LAR of Female OR: 7.0 for
coronary scan protocol cancer heart scan (slightly
angiography. using BEIR higher for
JAMA. 2007 VII heart/aorta scan)
Jul
18;298(3):317-
23.
17635892
(252)
ACC-NCDR indicates American College of Cardiology National Cardiovascular Data Registry; ACE, angiotensin-converting enzyme; ACS, acute coronary syndromes; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy trial; ASA, aspirin; AT,
antithrombins; BEIR, Biological Effects of Ionizing Radiation VII; CHF, congestive heart failure; CABG, coronary artery bypass graft; CAD, coronary artery disease; CANRACE, Canadian Registry of Acute Coronary Events; cath, catheterization; Cr, creatinine; CrCl,
creatinine clearance; CRUSADE, Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines; CT, computed tomography; CTCA,
Cancer Treatment Centers of America; DM, diabetes mellitus; EPR, electronic patient record; EPS, electrophisiology study; FRISC, Framingham and Fast Revascularization During Instability in Coronary Artery Disease trial; GDMT, guideline-directed medical therapy;
GI, gastrointestinal; GPI, glycoprotein IIb/IIIa inhibitors; GRACE; Global Registry of Acute Coronary Events; GUSTO-IV-ACS, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries –IV-acute coronary syndrome trial; HF,
heart failure; HTN, hypertension; Hx, history; ICTUS, Invasive Versus Conservative Treatment in Unstable Coronary Syndromes trial ; IQR, interquartile range; LAR, life attributable risk; MACE, major adverse cardiac event; MI, myocardial infarction; MPI, myocardial
perfusion imagin; MUGA, Multigated Wall Motion Study; N/A, not applicable; NS, not significant; NSTE-ACS, non–ST-elevation acute coronary syndrome; NSTEMI, non–ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PET, positron
emission tomography; pts, patients; RCTs, randomized controlled trials; RITA, Randomized Trial of a Conservative Treatment Strategy Versus an Interventional Treatment Strategy in Patients with Unstable Angina-3 trial; RBC, red blood count; revasc,
revascularization; RR, relative risk; Rx, prescription; Sx, symptom(s); TACTICS, Treat Angina With Tirofiban and Determine Cost of Therapy With an Invasive or Conservative Strategy; TIMI, Thrombolysis In Myocardial Infarction; UFH, unfractionated heparin; and U.S.,
United States.
Data Supplement 31. Anemia, Bleeding, and Transfusion-Relationship Between Transfusion and Mortality (Section 7.8)
Study Aim of Study Type of Study Study Size Patient Population Primary Endpoint Outcome Comments
Alexander KP 2008 To describe the association between Post hoc registry analysis 44,242 CRUSADE registry of Numerous endpoints. Most Adjusted OR: Transfusion only beneficial at HCT
18513518 (253) transfusion nadir HCT and outcome NSTE-ACS pts relevant: adjusted OR for HCT ≤24%: 0.67 (0.45-1.02) ≤24%
mortality with transfusion for HCT 24.1%-27%: 1.01 (0.79-1.30)
HCT range HCT 27.1%-30%: 1.18 (0.92-1.50)

HCT >30%: 3.47 (2.30-5.23)
Yang 2007 To assess transfusion patterns and Post hoc registry analysis 74,271 CRUSADE registry of Relevant endpoints: Adjusted OR: N/A
17711710 (254) in-hospital outcomes in pts receiving NSTE-ACS pts Death and death or MI Death: 1.67 (1.48-1.88)
transfusions Death or MI: 1.44 (1.30-1.60)
Rao 2004 To determine the association Post hoc analysis of data 24,112 GUSTO-IIb, PURSUIT, 30-d mortality rates in Adjusted HR: Transfusion associated with
15467057 (255) between blood transfusion and from 3 randomized trials and PARAGON pts with transfused and nontransfused 3.94 (3.26- 4.75) increased mortality for Hct >25%
mortality in pts with ACS ACS pts
Carson 2012 Clinical guideline from the AABB on Analysis of all randomized 19 trials; 30-d mortality
Published randomized Numerous endpoints Restrictive transfusion strategy: 6.9% N/A
22751760 (256) RBC transfusion trials of restrictive vs. liberal available in 11 trials trials; various pt assessed. Most relevant: 30-d Liberal transfusion strategy: 8.0%
transfusion strategies populations mortality RR: 0.85 (0.7- 1.03)
Carson 2012 Cochrane Database Systematic Analysis of randomized 19 trials Various trials in context of Numerous endpoints Hospital mortality OR: 0.77 (0.62- 0.95) N/A
22513904 (257) Review trials of restrictive vs. liberal surgery, acute blood assessed. Restrictive 30-d mortality OR: 0.85 (0.70- 1.03)
transfusion strategies loss/trauma, coronary care transfusion strategy MI OR: 0.88 (0.38-2.04)
unit pts, or leukemia pts compared to liberal
transfusion strategy
AABB indicates American Association of Blood Banks; ACS, coronary artery syndrome; CRUSADE, Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines Registry; GUSTO IIb,
GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial; HCT, hematocrit; MI, myocardial infarction; N/A, nonapplicaple; NSTE-ACS, non-ST-elevation-acute coronary syndrome; PARAGON, Platelet IIb/IIIa
Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial; Pts, patients; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; and RBC, red blood cell.
Data Supplement 32. Anemia, Bleeding, and Transfusion Studies for Weight-Based and Renally-Adjusted Dosing of Anticoagulants (Section 7.8)
Study Aim of Study Type of Study Study Size Patient Population Primary Endpoint Outcome
Alexander 2005 Investigation of relationship between Exploratory registry 3,354 NSTE-ACS pts in Major clinical outcomes and Adjusted OR for major bleeding with excess dosing (vs. no excess
16380591 (258) UFH, LMWH and GPI excess dosing and analysis CRUSADE registry bleeding dosing):
major outcomes UFH: OR: 1.08 (0.94 — 1.26)
LMWH: OR: 1.39 (1.11 — 1.74)
GPI: OR: 1.36 (1.10 — 1.68)
Melloni 2008 Exploratory analysis of CRUSADE Post hoc analysis of 31,445 NSTE-ACS pts in Excess dosing percent; Dosing of UFH above recommended weight-based dosing
18657648 (259) registry examining relation between UFH registry CRUSADE registry factors associated with associated with increased major bleeding
dosing and bleeding excess dosing; major bleeding Excess bolus OR: 1.03 (1.00 — 1.06)
Excess infusion dosing OR: 1.16 (1.05 — 1.28)
LaPointe 2007 Exploratory analysis of CRUSADE Post hoc analysis of 10,687 NSTE-ACS pts in Inappropriate dosing percent; Excess dosing associated significantly associated with increased
17646609 (260) registry examining relation between registry CRUSADE registry major bleeding and death risk of major bleeding (adjusted OR: 1.43; CI: 1.18 — 1.75)
enoxaparin dosing and bleeding
Taylor LA 2012 Chart review assessing incidence of Chart review 199 Pts undergoing PCI Incidence and extent of Eptifibatide:
22170973 (261) bleeding in CKD pts with incorrectly bleeding (TIMI or GUSTO) Incorrectly dosed in 64%
dosed bivalirudin or GPI Incorrectly dosed pts experienced more overall bleeding (64% vs.
35%; p=0.04), numerically more TIMI major bleeding (19% vs. 5%;
no p value given), and a greater extent of bleeding (p=0.03 for TIMI
bleeding and p=0.009 for GUSTO bleeding)
Bivalirudin:
Incorrectly dosed in 28%
Bleeding rates (incorrect vs. correct) 37% vs. 21% (p=0.055)
Extent of bleeding greater with incorrect bleeding (p=0.013 for
GUSTO bleeding; p=0.058 for TIMI bleeding)
Becker 2002 Pharmacokinetic/dynamic study of Pharmacokinetic/pharm TIMI 11A study of ACS pts Relationship of pt factors and Pts with creatinine clearance <40 mL/min had sig higher trough and
12040334 (262) enoxaparin and anti-Xa activity and acodynamic substudy anti-Xa levels peak anti-Xa levels (numerous statistically significant p values for
factors that affect anti-Xa levels multiple comparisons)
ACS indicates acute coronary syndrome; CKD, chronic kidney disease; CRUSADE, Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines Registry; GPI, glycoprotein; GUSTO,
Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; LMWH, low molecular weight heparin; N/A, not applicable; NSTE-ACS, non-ST-elevation-acute coronary syndrome; PCI, percutaneous coronary intervention; Pts,
patients; TIMI, Thrombolysis In Myocardial Infarction; and UFH, unfractionated heparin.
Data Supplement 33. Cocaine and Methamphetamine Users (Section 7.10)

Study Name, Study Aim Study Type/ Intervention Patient Population Study Intervention Endpoints P Values, Adverse Study Limitations
Author, Year Size (N) vs. OR: HR: RR: & 95 Events
Comparator CI:
(n)
Inclusion Exclusion Primary Endpoint & Safety Secondary Endpoint
Criteria Criteria Results Endpoint & Results
& Results
Potentiation of To determine Prospective; Intracoronary Pts referred HTN, recent Quantitative Heart rate, arterial N/A None Decrease in N/A Small n; not
cocaine-induced whether beta- N=30 propranolol for coronary MI angiography BP, coronary sinus coronary blood flow randomized; intranasal
vasoconstriction by blockade (n=15) arteriogram performed before blood flow, epicardial (p<0.05); increase cocaine during
beta-blockade augments vs. saline for chest pain and 15 min after left coronary arterial in coronary vascular catheterization does
Lange RA et al. cocaine-induced (n=15) intranasal saline or dimensions; resistance (p<0.05) not apply to real world
1990 coronary cocaine; repeat Intracoronary pts presenting with
1971166 (263) vasoconstriction measurements propranolol caused cocaine induced chest
obtained following no change in BP or pain; intracoronary
intracoronary heart rate, but propranolol does not
propranolol decreased coronary pertain to intravenous
sinus blood flow and BB
increased coronary
vascular resistance
BB associated with Determine if rates Retrospective BB treatment Admitted pts Cardiac N/A In-hospital MI after N/A In-hospital mortality; Incidence MI in BB N/A Included pts without
reduced risk of MI of MI increased N=348 (60 vs. no BB with positive markers not BB use; lower trend for lower vs. no BB 6.1% vs. ACS Sx (56% with
after cocaine use with BB treatment with recent treatment urine drug obtained; pt incidence of MI after mortality in pts 26.0% (95% CI: chest pain);
Dattilo PB et al. after recent cocaine use) screen for on oral BB administration of BB receiving BB 10.3% — 30.0%); retrospective; did not
2008 cocaine use cocaine who Mortality 1.7% take into consideration
17583376 (264) received BB vs.4.5% (95% CI: - time of cocaine use;
during current 1.2% — 6.7% did not check serum

hospitalization cocaine levels; urine
drug screen only
detects pts with
cocaine use within 48-
72 h. Selection bias as
pts receiving BB were
older, more frequent
Hx of HBP and CHF,
higher SBP, and higher
glucose levels;
mortality mainly due to
non-ACS causes
BB for chest pain Determine if rates Retrospective BB treatment Chest pain No chest N/A Death on long-term N/A ED BP; Peak Tn BB use associated N/A Retrospective;
associated with of adverse vs. no BB pts with urine pain; urine follow-up of National levels, ventricular with 70% reduction unknown how recent
recent cocaine use advents 331 (151 treatment drug screen drug screen Death Registry fibrillation/tachycardia, in risk of CV death was time of cocaine
Rangel C et al associated with received BB) positive for not (median 972 d) intubation, or (HR: 0.29; 95% CI: use; patients treated
2010 BB treatment in cocaine performed vasopressor agents 0.09 — 0.98) with BB more likely to
20498415 (265) chest pain pts with or urine drug be given nitrates in ED
recent cocaine screen Pts receiving BB had which may have
use negative for larger decrease in ameliorated any
cocaine SBP in ED even after cocaine induces
adjusting for other spasm; unknown what
anti-HTN agents factors may have
administered; there influenced clinican to
were no differences in treat or not treat with
any of the secondary BB (note: clinicians
outcome measures most commonly were
treating pt without
knowledge of cocaine
use as results of drug
screen pending)
Benzodiazepines and To compare the Prospective, NTG (n=15) Chest pain Age >45 y, NTG vs. NTG + Chest pain relief as N/A N/A Kruskal-Wallis None Small n; none of the
Nitroglycerine in use of lorazepam randomized, vs. NTG + and self- chest pain lorazepam assessed on a 0- 10 testing showed a pts diagnosed with MI;
treatment of cocaine and nitroglycerine single- lorazepam reported duration >72 ordinal scale was sig difference in lorazepam only
chest pain in treatment of blinded (n=12) cocaine use h, greatest in the pts pain relief between subgroup not
Honderick T et al cocaine chest pain controlled in the documented treated with the the 2 study groups investigated
2003 trial; N=27 preceding 72 CAD, combination of NTG (p=0.003) with
12563578 (266) h pretreatment and lorazepam. greater pain relief
with NTG noted at 5 and 10
min in the NTG +
lorazepam group
(p=0.02 and 0.005

respectively)
Diazepam, To compare Randomized Diazepam Chest pain <18 y age; Diazepam vs. NTG Chest pain resolution Chest Changes in BP, pulse Hemodynamic None Small n; only 3 pts had
Nitroglycerin, or both diazepam, double- (n=12) vs. and cocaine >60 y age vs. both as measured by a pain rate, cardiac output, parameters MI and 5 pts Dx of UA
for treatment of nitroglycerin, or blinded trial; NTG (n=13) use within the visual analog scale resolution cardiac index, stroke equivalent in all
cocaine ACS both in treatment N=40. vs. both preceding 24 equivalent volume, and stroke subgroups.
Baumann BM et al of pts with (n=15) h in all 3 index Outcomes: though
2010 potential cocaine- groups not statistically sig,
10958127 (267) associated ACS changes in mean
arterial pressure for
diazepam,
diazepam + NTG,
and NTG
respectively were
2.1, -12.1, and -8.4
mm Hg respectively
(p=0.08)
ACS in chest pain pts Determine Retrospective N/A Nontraumatic Not admitted N/A ACS defined as MI, N/A Cardiac arrhythmias ACS diagnosed in 9 N/A Retrospective; small n;
after amphetamine frequency of ACS chest pain, for MI rule ischemia on cardiac (V-tach, V-fib, SVT) pt visits (25%; 95% only investigated
use in pts presenting N=36 visits in positive out; stress testing, or CI: 11%- 48%) results in admitted pts
2003 with 33 pts (3 with amphetamine abnormal ≥70% stenosis on and thus ACS rate
Turnipseed SD et al. methamphetamine CV events) on urine drug CXR cardiac cath 3 pt visits with over-estimated; urine
12745036 (268) induced chest screen arrhythmias (8%; drug testing in
pain 95% CI: 2%- 24%) admitted pts not done
routinely
ACS indicates acute coronary syndrome; BB, beta blocker(s); BP, blood pressure; CAD, coronary artery disease; CHF, congestive heart failure; CV, cardiovascular; CXR, chest x-ray; Dx, diagnosis; ED, emergency department; HBP, high blood pressure; HTN,
hypertension; Hx, history; MI, myocardial infarction; N/A, not applicable; NTG, nitroglycerin; pt(s), patient(s); SBP, systolic blood pressure; SVT, supraventricular tachycardia; Sx, symptoms; Tn, troponin; UA, unstable angina; V-fib, ventricular fibrillation;and V-tach,
ventricular tachycardia.
Additional Data Supplement Tables

(These tables were created during the evidence review process but do not support a specific section of recommendations in the guideline. They are provided for transparency and completeness.)
Data Supplement A. Other (Newer) Biomarkers

Inclusion Criteria Exclusion Criteria Primary Endpoint & Secondary
Results Endpoint &
Results
FRISC-II Effect of PGF-15 on Multicenter PGF-15 in ACS with criteria for Previous heart PGF-15 with PCI or 2-y MACE. Occurrence of 2-y MACE prediction PGF-15 not
Wollert 2007 ACS outcomes in prospective study intervention vs. PCI or conservative surgery, PCI within 6 conservative strategy PGF independently MACE reduced with PGF-15 levels independently related
(269) invasive vs. (FRISC –II) conservative strategy with PGF- mo, bleeding predicted outcomes in with PCI with p=0.016 to ST depression or Tn
17848615 conservative 2,079 treatment 15 levels tendency, high conservative strategy only highest levels
strategy outcomes creatinine PGF-15 levels:
0.49 (0.33-0.73)
p=0.001
C-NET Px value of H-FABP Prospective H-FABP vs. Tn Chest pain Non-cardiac H-FABP/Tn Death/MI Among Tr- HR:2.62 (1.30- 5.28) Only 53% of eligible
Viswanathan 2010 in low-int. risk ACS observational Chest pain. Age <18 12-24 h from Sx onset 12 mo H-FABP predicted pts, (79% of p=0.0007 pts enrolled because
(270) pts cohort y outcome after multivariate cohort) H-FABP for adverse of timing.
20513600 955 adjustment high FH-FA bp events Statistical modeling/
identify pts at high ROC 0.79 (0.74- 0.84) adjustment
risk ROC TnI
0.77 (0.72- 0.82)
Charpentier 2010 Detection of AMI by Prospective. H-FABP vs. IMA Chest pain and Age <18 y H-FABP and IMA on Dx NSTEMI H-FABP did not IMA OR Relatively low
(271) H-FABP and IMA observational suspected NSTEMI Skeletal muscle admission IMA not predictor of ACS add info to std 1.23 (0.87-1.81) enrollment.
20078436 cohort injury, trauma, renal Dx H-FABP predictor predicted model H-GFABP OR Some lack of
677 impairment. 4.65 (2.39-9.04) agreement on Dx by 2
Sens 96.8% physicians.
Spec 98.1% Possible
misclassification of UA
pts.
No serial testing.
Haaf 2011 BNP in Dx and risk Prospective BNP vs. TnT Possible ACS ESRD with dialysis BNP and TnT at Dx accuracy of BNP for MI BNP predicted 24 BnP Dx: AUC: Clinical benefit of risk
(272) in chest pain pts multicenter admission and 1 h, 2 h, lower than Tn mo outcome 0.74 (0.70-0.78) stratification
21531234 1,075 3 h, 6 h more accurate TnT: BNP levels linked to
than TnT 0.88 (0.84-0.92) factors related to
AUC 0.81 vs. 0.76 p<0.001 outcome confusing.
p<0.001
Keller 2010 Copeptin in Dx of Prospective Copeptin vs. TnI Possible ACS Trauma, major Copeptin and TnT on TnT vs. combined C- C-statistic within 3 Combination of Using Tn for Dx might
(273) AMI multicenter surgery, IV drug admission statistic vs. TnT alone: h chest pain copeptin and TnT favor tested Tr
20447532 1,386 abuse, anemia 0.93 vs.0.84 combined 0.90 T superior to all single or compared with
alone 0.77 other marker detm. copeptin
p<0.001 (myocardial, CK-MB,

BNP)
Peacock 2011 MPO for Dx of AMI Prospective MPO vs. TnI Possible ACS <8 h <18-y non-cardiac MPO and TnT on Using 90% spec. cutpoint MPO C-statistic: MPO sens Spectrum bias
(274) multicenter Sx chest pain admission MPO had insufficient ACS vs. NCCP 18% -PV 69%, Physician Dx bias
22093206 1,018 accuracy 0.623 +PV 0.47 to diff ACS Differing local
AMI vs. NCCP from non-cardiac chest Tn platforms
0.666 pain.
Iversen 2009 PAPP-A as risk Prospective PAPP-A vs. std Dx Possible ACS STE-ACS (evaluated PAPP-A on admission Risk for MI and death 2.66 N/A PAPP-A risk Long time between
(275) marker in ACS cohort (TnT) NSTE separately) and every 6 h to 8 h y to 3.47 y MI p =0.02 sample collection (6 h
19932776 123 NSTEMI PAPP-A related to risk for Death p=0.03 to 8 h)
both in NSTEMI Multivariable:
combined risk
2.65 (1.40-5.03)
in NSTEMI
RISCA CRP in pred 1-y Prospective CRP Dx of UA or AMI Transfer from other CRP on admission MACE at 1-y multivariate NS pred of UA, Adjusted OR for Not stated
Bogaty 2008 outcome in ACS cohort No comparator hospital discharge and 1 mo analysis: NS predictability MI, or death MACE admission:1.04
(276) 1,210 later individually (0.91-1.14)
18549920 Discharge: 0.90 (0.77-
1.06)
1 m. 1.12 (0.93-1.34)
Kuch 2008 CRP and TnT in Prospective CRP vs. Tn in 28-d Dx of NSTEMI STEMI separately CRP and TnT on Multivariate analysis In NSTEMI Tr+ Possible CRP
(277) short term Px in cohort 697 mortality event evaluated admission Both CRP+ and TnT+ CRP+ but not Tr+ OR 1.99 (1.15-3.44) influenced by larger
18940277 NSTEMI NSTEMI (612 showed pred of 28 d pred mortality: CRP+ myocardial necrosis or
MONICA/KORA with STEMI) mortality 4.59 (1.68 — OR 2.05 (1.09-3.84) longer prehospital
12.5) vs. For 28-d mortality delay
1.75 (0.55 — prediction
5.54)
Schaub 2012 GDF-15 in early Dx Prospective GDF-15 vs. TnT ACS Sx ESRD Assays on admission ROC for MIAUC GDF-15 pred 26- 26-mo mortality AUC Clinical benefit of imp.
(278) and risk in AMI multicenter and BNP to ED GDF-15 0.69 mo mortality >TnT GDF-15: 0.85 risk strategy
22205695 646 Hs-TnT 0.96 and BNP TnT: 0.77 p=0.002
BNP 0.74 BNP: 0.75 p=0.007
Mega 2008 Px of TpP in ACS Prospective TpP+ vs. TpP– in NSTEMI STEMI evaluated Assay at median 40 h 10-mo MACE Weak correlation HR for MACE: TpP not measured at
(279) multicenter predicted. UA separately from presentation TpP significant pred risk of TpP with TnI, 1.45 (1.20- presentation
18565400 2,349 with ACS Compared with Tn for comparative events as BNP, and Hs-CRP 1.95)<0.001 Possible that study
well as death or MI R<0.15 for each adjusted for Cl. median inflated TpP
characteristic and levels
other biomarkers:
1.51 (1.19-1.91)
<0.001
Saraf 2010 Px significant of Prospective Use of GTT ACS Sepsis, malignancy Assay time not stated 12-mo death, MI, or stroke No correlation LT predicted MACE: Antiplatelet effects of
(280) ETA in ACS cohort 300 with blood, Dyscrasia, Evaluation OT and LT by LT pred MACE between OT and 2.52 (1.34- ASA and Clopidogrel.
20447533 ACS on dual anticoagulant and CV death MACE 4.71)=0.004 Heparin effects.
antiplatelet CV Death: Diurnal variation of

therapy 4.2 (1.13- TpP
15.62)=0.033
Body 2010 Effect of P-selectin Prospective P-selectin vs. TnT Suspected ACS Chest trauma, Assay time at present. Only P-selectin and PAPP- 30-d MACE C-statistic for MI No serial evaluation
(281) on Dx of AMI and cohort with 5 other novel ESRD, pregnancy, for P-selectin A Dx AMI prediction: only P- P-selectin: 0.68 (0.63-
21167826 risk 713 biomarkers prisoners selectin 0.73)
1.84 (1.1-3.1) PAPP: 0.57 (0.51-
<0.001 0.63)
Wang 2007 Presence of PMAs Prospective PMAs and other ACS SAP Renal, hepatic, Assay at presentation Pts with ACS have higher PMA, CRP, IL-6 Regression analysis Small observational
(282) and other novel cohort novel biomarkers hematologic, included IL-6, IL-8, levels of PMAs compared Each confer risk ACS and biomarkers study
16887214 biomarkers in ACS 132 immunologic MCP-1, sCD40L with SA for ACS PMA 1.33 (1.05-1.68)
74 ACS disorders CRP 2.64 (1.01-6.89)
58 SAP IL-6 1.03 (1.001- 1.06)
ACS indicates acute coronary syndrome; ACS NSTE, acute coronary syndrome non-ST elevation; AMI, acute myocardial infarction; ASA, aspirin; AUC, area under the curve; BNP, B-type natriuretic peptide; BP, blood pressure: CK-MB, creatine kinase- MB; CRP, C-
reactive protein; CV, cardiovascular; Dx, diagnosis; ED, emergency department; ESRD, end stage renal disease; ETA, End Thrombosis Act; FRISC, Fragmin During Instability in Coronary Artery Disease; GDF- 15, growth differentiation factor- 15; GTT, global
thrombosis test; H-FABP, heart fatty acid- binding protein; hs-CRP, high sensitivity C-reactive protein; hs-TnT, high-sensitivity troponin T; IL, interleukin; IMA, ischemia-modified albumin; IV, intravenous; LT, lysis time; MACE, major adverse cardiac events; MCP,
monocyte chemaatractive protein; MI, myocardial infarction; MPO, myeloperoxidase; N/A, not applicable; NS, not significant; NSTEMI, non-ST elevation MI; NCCP, non-cardiac chest pain; OT, occluded time; PAPP-A, pregnancy-associated plasma protein A; PCI,
percutaneous coronary intervention; PMA, platelet-monocyte aggregates; Pts, patients; Px, prognosis; ROC, receiver operator curve; SA, stable angina; SAP, stable agina pectoris; sCD40L, soluble CD40 ligand; Sens, sensitivities; Spec, specificities; Std, standard;
STE-ACS, ST-elevation acute coronary syndrome; Sx, symptoms; Tn, troponin; TnI, troponin I; TnT, troponin T; TpP, thrombus precursor protein; and UA, unstable angina.
Data Supplement B. Other Anticoagulants

Study Name, Aim of study Study Type Study Study Study Patient Population Study Study Endpoints P Values, Study Limitations
Author, Year Size (N) Intervention Comparato Intervention Comparator OR: HR: RR & & Adverse Events
Group (n) r Group (n) 95% CI:
and Results
Oldgren 2011 Safety and Multictr 1,861 on Dabigatran PC AMI <14 d Severe stroke 4 doses of PC 6-mo bleeding 3.8% PC pts Dabigatran Bleeding Dose-dependent
(283) efficacy of Prosp. dual bid. 371 Dual Bleeding dabigatran Dose dependent had stroke, reduced D- Dabigatran vs. increase in bleeding
21551462 dabigatr in Dose platelet 50 mg 369 Both groups antiplatelet diathesis for 6 mo Increase with MI, or death dimer in all Warfarin significant at 110
RE-DEEM ACS Escalation therapy 75 368 ASA and therapy at Recent GI ulcer Dabigatran vs., 3.0%- dose groups Significant: and 150 mg qd
trial 110 406 clopidogrel least 1 risk Uncontrolled Sig with 110 mg 4.9% Dabigatran 110 Dabigatran.
150 347 factor for CV HTN and 150 mg dose Dabigatran m:
complication Anemia (not dose 3.92 (1.71,8.95)
s Recent related) Dabigatran 150
fibrinolytic mg
agents 4.27 (1.86,9.81)
Uchino 2012 AMI risk with Meta-analysis 30,514 Dabigatran Warfarin RCTs Not stated Dabigatran Warfarin, Risk of ACS with Not Dabigatran Dabigatran risk : Dominant effect of
(178) dabigatrn of 7 trials 20,001 7,357 including 6-10 d enoxaparin,o Dabigatran higher analyzed risk with 1.33 (1.03,1.71) RE-LY
22231617 Enoxaparin stroke, AFIB, 28- 35 d r PC than control exclusion of p=0.03 trial on results of
2,851 Or PC ACS, DVT, 12 wk group. short-term meta-analysis. MI

371 acute 6 mo Risk similar when trials: events few and
embolus eliminating short- 1.33 (1.03 — infrequent in other
term trials. 1.72) studies.
p=0.03
APPRAISE Safety and Multcenter 1,715 Apixaban PC MI within 7 d Planned PCI 1 of 4 doses PC Clinically relevant Similar liver Apixaban Bleeding with 10 One intracranial
2009 efficacy of prospective 2.5 bid 317 611 with at least ASA allergy of apixaban bleeding: enzyme 2.5 mg bid mg hemorrhage with
(284) apixaban in trial 10 qd 318 1 additional Significant. HTN 26-wk follow- On ASA Apixaban elevations and 10 2.45 (1.31 — apixaban. 2 higher-
19470889 ACS 10 bid248 risk factor for Bleeding up on ASA increased Apixaban and mg qd trend 4.61) dose Apixaban arms
20 qd 221 recurrent diathesis bleeding at 10 mg PC toward p=0.005 discontinued
(611 total) events Recent stroke qd decreased Reduced because of excess
Pericardial ischemic ischemia bleeding.
effusion events 0.61 (0.35 —
1.04)
p=0.07
Alexander Risk of Multicenter 7,392 Apixaban PC Median 6 d Planned PCI, Apixaban PC MACE: Trial stopped Bleeding MACE: Only high-risk pts.
2011 events with prospective 3705 3687 after ACS ASA allergy, 5 mg bid ASA NS difference because of Apixaban vs. Apixaban vs. PC. No pts undergoing
(179) Apixaban in trial with Significant HTN Median between apixaban major PC 0.95 (0.80- 1.11) revascularization.
21780946 ACS significant Bleeding follow-up and PC bleeding with 1.3% vs. p=0.051
risk factors: diathesis 241 d ASA apixaban 0.5%
prior MI, DM, Recent stroke 2.59
HF Pericardial (1.5,4.46)
effusion p=0.001
RUBY-1 Safety and Multicenter 1,258 Darexaban PC ACS <7 d Bleeding One of 6 PC Bleeding Safety was Sl Increase Pooled bleeding Limited power for
Steg 2011 tolerability of prospective Multiregimen 319 from event diathesis regimens 26 wk numerically higher primary in efficacy rate for efficacy.
(285) darexaban trial 939 Planned PCI Darexaban in all darexaban outcome outcomes darexaban: Only relevant with
21878434 5 mg bid Recent stroke 26-wk follow- arms than PC. Darexaban 2.275 (1.13- 4.60) dual platelet
10 mg qd Renal or hepatic up Dose response 5.6% p=0.022 treatment
15 mg bid Insufficiency effect PC Dose response:
30 mg qd Allergy to study 4.4% 6.2,6.2,9.3%
30 mg bid drug Sig for 30 bid
60 mg qd p=0.002
ATLAS CV outcomes Multicenter 15,526 Rivaroxaban PC ACS <7 d Low platelet 1 of 2 PC MACE Increased Decreased Primary endpoint Increased major
ACS-2 with prospective 2.5 mg bid (5,176) from event count rivaroxaban Mean 13mo Rivaroxaban major total 8.9% vs. 10.7% bleeding unrelated
TIMI-51Mega Rivaroxaban trial (5,174) Low hematocrit regimens follow-up lower than PC bleeding mortality 0.84 (0.74, 0.96) to CABG
2012 in ACS Rivaroxaban Renal Mean 13 mo 2.1% vs, 0.6% 9.2% vs. 9=0.008 Large missing data
(180) 5 mg bid dysfunction follow-up p<0.01 11.0% 2.5 mg dose
(5,176) Recent GI bleed HR:0.84 CV death
22077192 Hx of (0.74- 2.7% vs. 4.1%
intracranial 0.95)p=0.00 p=0.002
bleed 6 Total mortality:
Stroke/TIA with Reduced 2.9% vs. 4.5%

antiplatelets stent-throm p=0.002
0.69 (0.51,
0.93) p-
0.002
Meta-analysis Bleeding, Meta-anlysis 31,286 Apixaban PC or ACS Trials of OAC with Antiplatelet Increase major Major Net clinical Mixed clinical
2012 (7) outcomes in Dabigatran warfarin (4-71%) parental AC, antiplatelet with PC or bleeding: Bleeding benefit conditions
ACS Darexaban <6 to <14 d VKA 6-31 mo warfarin 3.03 (2.20- 0.98 (0.90- Only 58% (avg)
Rivaroxaban from event Decrease stent 4.16) <0.01 1.06) ACS
Ximelagatran thrombosis, Ischemic <pst;y PC but
ischemic events, events also warafarin
no difference in 0.73 (0.63- control
overall death, net 0.84)<0.001 Ximelagatran no
clinical benefit Mortality longer active
0.90 (0.76- Newer antiplatelet
1.06) drugs not
Stent adjuncts
thrombosis
0.73 (0.54-
0.98)
ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; ASA, aspirin; AFIB, atrial fibrillation; bid, twice daily; CABG, coronary artery bypass graft; CV, cardiovascular; DM, diabetes mellitus; DVT, deep vein thrombosis; GI, gastrointestinal; HF, heart
failure; HTN, hypertension; Hx, history; MACE, major adverse cardiovascular events; MI, myocardial infarction; NS, nonsignificant; OAC, oral anticoagulant; PC, placebo; PCI, percutaneous coronary intervention; Pts, patients; qd, daily; RE-LY, Randomized Evaluation
of Long-Term Anticoagulant Therapy; RCT, randomized controlled trial; TIA, transient ischemic attack; and VKA, vitamin K antagonist.
Data Supplement C. Lipid Management

Study Name, Aim of Study Study Study Study Patient Population Study Study Endpoints P Values, Study Limitations &
Author, Year study Type Size Intervention Comparator Intervention Comparator OR: HR: RR & Adverse Events
(N) Group (n) Group (n) 95% CI:
and Results
Cannon 2006 Efficac Meta- 27,548 High-dose Standard- Stable CAD Not stated High-dose Standard- High dose High-dose: Trend Coronary death Underpowered for CV
(286) y of analysi statin dose statin or ACS statin dose statin produced a Rhabdomyoly toward or MI death and total death.
15687136 high s 13,798 13,750 Intensive vs. significant 16% sis decreased 0.84 (0.77- 0.91) Different duration and
dose 4 trials standard reduction in 0.13% A to Z CV mortality p<0.00001 treatments. No individual pt
vs. statin >1000 coronary death or trial with high Coronary death data. No evaluation of
standar pts each MI CK>10× ULN dose or CV events benefit from statin or LDL–
d 0.15% p=0.054 0.84 (0.80- 0.89) C level.
dosing Significant 16% PROVE-IT p<0.0000001
for CV reduction in AST or ALT
outcom coronary death or 3×

e any CV event ULN:
3.3% PROVE-
IT
Spencer 2007 Use of Registr 8,492 Statin use No statin at ACS ACS not Statin use Control LDL levels <100 N/A Statin at Statin at time of 6-mo statin use by pt self-
(287) statin y with LDL-C discharge precipitated by with LDL- 55% receiving time of discharge report
17826369 at Retros <100 mg/dL 2,782 non-CV C<100 or statin at discharge associated with 6-
GRACE hospita pective or ≥100 comorbidities ≥100 mg/dL discharge associated mo total mortality No info on statin types or
l analysi mg/dL at LDL levels >100 with MACE 0.66 (0.51- 0.85) dosages
dischar s discharge 72% receiving reduction
ge with 5,710 statin at 0.76
ACS discharge (0.63,0.93)
Robinson 2009 Non- Meta- 11,254 Non-HDL–C Change in risk Randomized <2-y trial Change in Change in Statins: each 1% N/A Fibrate and Fibrate trials vs. Lack of access to pt data
(288) HDL–C analysi 1 change PC or active No serious non- lipid level risk Decrease in non- niacin statin trials no
19161879 reducti s 30 14 statin control trials CV disease HDL-C decreased models also different results Unknown method of
on and trials 100,827 4.5-y RR by 1% had a 1:1 Bayes factor endpoint adjudication. No
CV risk 7 fibrate (0.98-1.00) relation K=0.49 info on fibrates=statins.
21,667 between Moderate
6 niacin non-HDL–C different effect on
4,445 reduction non-HDL–C
3 others and risk niacin vs. statin
5,102 reduction Bayes factor
K=7.43
Hulten 2008 Effect Meta- 17,963 Early statin in No statin, PC Statin<14 d Standard attain Intensive PC or 2-y rate of death Comparable Pooled 2-y Rate of death and Sig. statistical
(289) of analysi ACS or usual care of dose statin standard and CV events tolerability for HR CV events heterogeneity.
17000936 statin s hospitalizatio statin reduced with intensive For intensive reduction: Limited trials available.
therapy 13 Approximatel Approximately n for ACS intensive statin statins and statin 0.81 (0.77 — Not a pooled analysis.
in ACS trials y 50% 50% therapy control. Only therapy MI 0.87) Adverse effects under
3 cases of 0.89 p<0.001 safety box.
rhabdomyolys (0.60,1.33)
is. Ischemia
PROVE-IT: 0.68 (0.50-
3.3% hepatitis 0.92)
in high-dose CV death
GP. 0.76
(0.66=0.87)
Sattar 2007 Risk of Meta- 4,278 Statin use No statin Statin Mean follow-up Statin No statin Statin therapy Aside from Lipophilic DM risk: Varied methods of dx of
(290) DM analysi 2,226 2,052 Trials with ≤1 y was associated DM risk, not Statins risk: 1.09 (1.02 — DM. HRs not available in
20167359 with s >1 y follow- with a 9% available 1.10 1.17) all trials.In 2 trials Dx
statins 13 up in both increased risk of (0.99=1.22) PC controlled based on physician
statin treatment incident DM with Hydrophilic trials: reporting rather than
trials groups little Statins risk: 1.10 (1.01 — biochemical analysis.
heterogeneity 1.08 (0.98- 1.20) Nonstandard criteria for Dx

(11%) between 1.20) of DM in some studies.
trials
Javed 2010 Dischar Retros 65,396 Intensive LLT Less intensive ACS related Left against Intensive Less Mostly AMI pts at N/A Factors Factors Discharge LLT dosing data
(291) ge pective regimen LLT regimen hospitalizatio medical advice LLT regimen intensive discharge 38% associated associated with not available on 50% of
21146668 intensiv data likely to 40,360 n with LLT discontinued LLT regimen received intensive with lack of intensive LLT: pts. Performance feedback
GWTG e LLT base cause >50% care LLT and 62% less LLT LLT prior to in GWTH hospitals may
in ACS analysi LDL Discharged to intensive LLT Female sex admission influence pt care giving
s reduction nonparticipating Increased PCI with stent higher rates of LLT than
25,036 facility age Known CAD on general hospitals. Change
Dialysis admission in LLT dosing after not
(Multivariate PVD available.
95% Prior MI
CI<1.00) (Mltivariate 95%
CI>1.00)
Baigent 2010 Efficac Meta- 165,13 More Less intensive Main effect of Lack of trial Intensive Less MACE reduction No further Reduction in MACE reduction Nonsignificant excess of
(292) y and analysi 8 intensive 19,783 trial to lower eligibility criteria LLT regimen intensive in 4.8 y by adverse revasc by intensive LLT hemorrhagic stroke with
21067804 safety s 26 19,829 LDL–C LLT regimen intensive LLT effects from 19% (15-24) 15% (11-18) lowering cholesterol p=0.2
CTT of trials 5 trials Control 1000+ pts >2 15% lowering p<0.0001 <0.0001
intensiv 64,782 y follow-up cholesterol Ischemic Major vascular
e LDL– Statin treatment including stroke events
C 64,744 cancer risk 16% (5-26] 13% 97-19)
decrea 21 trials p=0.005 <0.0001
se Total mortality
10%/1 mmol/L
LDL–C
Reduction
0.90 (0.87 —
0.93)
Boekholdt 2012 RRs of Meta- 38,153 Statin Risk with 1 Trials with Lack of trial LDL–C RRs for Adjusted HR for N/A HRs higher Adjusted HR per Fatal CV events occurring
(293) lipid analysi therapy SD increase serial eligibility criteria HDL–C values major CV events for non- I-SD increase in the 1st y of therapy not
22453571 values s in LDL–C evaluation of Apo B during Per 1-SD HDL–C than non-HDL–C :1.16 accounted for. Participating
in 8 trials non--HDL–C TC, LDL–C, statin Rx increase LDL–C (1.12,1.19) trials had different inclusion
statin apoB HDL–C, TG 1.16 non-HDL–C p=0.002 and apo B 1.14 (1.11 criteria.
treatme >2 y followup 1.14 apoB apo B — 1.18)
nt 1000+ 1.13 LDL–C p=0.02 LDL–C 1.13 (1.10
participants — 1.17)
Mora 2012 CV risk Retros 9251 High-dose Low-dose CAD TG>600 mg/dL High-dose Low-dose Multivariable Decreased Known Residual Excluded patients >130
(294) in pective statin statin Unstable CAD atorvastatin atorvastatin detection of residual risk: baseline increased risk: mg/dL on Atorvastatin 10
22461416 statin evaluat 80 mg 10 mg increased High-dose variables HTN 1.38 mg, study was
treated ion of a Atorvastatin Atorvastatin residual risk statin performed (1.17,1.63) observational, novel risk
pts multice Approximatel Approximately Older age Aspirin use moderately DM 1.33 factor data not available for
nter y 50% 50% Increased BMI Apo A1 well in (1.11,1.60) the entire study group
trial Male sex discriminatin Male 1.33
HTN g future (1.07,1.65)
DM cases Age 1.13
Apo B Harrell c (1.04,1.23)
BUN index=0.679 Apo B 1.19
(1.11,1.28)
BUN 1.10
(1.03,1.17)
BMI 1.09
(1.02,1.17)
A to Z indicates Aggrastat to Zocor; ACS, acute coronary syndrome; ALT, alanine aminotransferase; AMI, acute myocardial infarction; Apo A, Apolipoprotein A; Apo B, Apolipoprotein B; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea
nitrogen test; CAD, coronary artery disease; CV, cardiovascular; DM, diabetes mellitus; Dx, diagnosis; GP, glycoprotein; GWTG, Get With the Guidelines; HDL–C, high density lipoprotein cholesterol; HR, hazard ratio; HTN, hypertension; LDL–C, low-density lipoprotein
cholesterol; LLT, lipid lowering therapy; MACE, major adverse cardiovascular events; N/A, not available; PC, placebo; PCI, percutaneous coronary intervention; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; Pts, patients; PVD, peripheral
vascular disease; Revasc, revascularization; Rx, prescription; Sig, significant; TC, total cholesterol; TG, triglyceride; and ULN, upper limit of normal.
Data Supplement D. Blood Pressure Control

Author, Year study Type Size Intervention Comparator Intervention Comparat OR: HR: RR & Adverse Events
(N) Group (n) Group (n) or 95% CI:
and Results
Nissen 2004 Antihypert Multicente 1991 Amlodipine PC Angiog.Doc. Left main CAD Amlodipine PC CV events in 24 BP baseline Individual CV events: Amlodipine D/ced for
(295) ensive r 274 663 655 CAD LVEF<40% 10 mg or mo/CV events in 129/78 components of Amlodipine: edema in 5.0%.
15536108 agents on prospectiv IVUS Enalapril IVUS substdy: Age 30- 79 Moderate or Enalapril 20 fewer Amlodipine Decreased by primary and 2º 16.6% Enalapril D/C for cough
CAMELOT CV events e study 673 95 DBP<100 severe CHF mg vs. PC 4.8/2.5 mm in endpoints 0.69 (0.54 — in 3.9% HTN in 3.2%
in CAD IVUS BB, a1 >79 y + IVUS Substdy: No Amlodipine, showed trend 0.88)=.003 PC, 2.2% amlodipine,
and substudy: blockers, Substudy athero. 4.9’2.4 in toward fewer Enalapril:20.2% 9.5% enalapril.
normal BP Amlodipine Diuretics 24-mo Px in amlodipine Enalapril events with 0.85 (0.67 — Limitations: extended
91 permitted follow-up Trend toward Px increased in enalapril 1.07)=.16 composite endpoint,
Enalapril in Enalapril, PC NS diff between modest sample size,
86 progression in PC p<0.001 vs. Enalapril and CIs around point
p<0.001 Amlodipine Amlodipine 0.81 estimates relatively
and Enalapril (0.63 — large.
1.04)=.10
Messerli 2006 Low Multictr 22576 BP reduction Outcome Stable pts MI within 3 mo Verapamil Atenolol All-cause death Lowest DBP Primary outcome 2º analysis, limited to
(296) BP with Ad hoc Sustained with CAD and Class IV or Purpose was and total MI outcome Nadir for 18% vs. 9% hypertensive pts with
16785477 adverse analysis Rel. and V CHF to evaluate 2.7 y/pts 120-140 MI: 70-90 SBP 110 vs. 120- stable CAD.
events in verapamil or hypertension BP with J-shaped curve systolic mmHg 130
CAD atenolol outcomes, Nadir at 119/84 70-90 Nadir for stroke 32% vs. 8%
not compare diastolic 70-90 mmHg DBP 60 vs. 80-90
agents No p values
provided
PROVE-IT TIMI BP control Multicente 4162 BP level Outcome ACS within Not stated Pravastatin Atorvastati Composite MACE Significant CAD Risk for 1º Ad hoc analysis limited
22 and r reached MACE 10 d 40 mg n SBP followed a J- increased risk death,nonfatal outcome to pts studies for lipid
Bangalore 2010 adverse prospectiv Randomly Purpose was 80 mg or U-shaped for outcomes MI or revasc increased 4.9 fold evaluation. Not
(297) events in e study assigned to to evaluate curve As SBP Similar J- or U- with SBP<100 vs. adjusted for many
21060068 ACS Ad hoc Pravastatin BP with Risk Nadir: decrease shaped curve. 130-140 mmHg confounders nor
analysis or outcome, not 136 mmHg below 110 For SBP/DBP 136 mmHg had dosages of
atorvastatin to compare systolic systol. X2=37,<0.0001 lowest event rate antihypertensive
agents 85 mmHg or 70 diastolic X2=47,<0.0001 by Cox model on agents received.
diastolic respectively a continuous Cannot determine
HR 49% vs. 13% scale whether SBP, DBP, or
SBP<100 vs. 130- X2 =49, p<0.0001 mean BP is main risk
140
HR 46% vs. 15%
DBP<60 vs. 80-
90
Cooper-DeHoff Effect of Observati 6400 Tight BP Usual BP Stable CAD Not stated Tight BP Usual BP Composite MACE Extended Mortality: Tight vs. usual Post hoc analysis. No
2010 tight BP onal control control and control control Usual control analysis 11.0% vs. control randomization for
(298) control in substudy BP 130/85 hypertension Verapami/tra vs. uncontrolled follow-up 10.2% MACE different BP groups.
20606150 CAD and of with diabetes ndolapril 12.8% vs. 19.8% indicated Tight vs. Usual Usual control: Data only applied to
INVEST diabetes multicente 16,893 Tight vs. usual increased risk 1.20 (0.99-1.45) 1.11(0.93-1.32)= CAD pts with diabetes.
r clinical patient/y of Control : with tight BP p=0.06 24
trial follow-up NS diff. control Extended
12.6% vs. 12.7% follow-up
1.15 (1.01-1.32)
p=0.04
1º indicated primary; 2º, secondary; ACS, acute coronary syndrome; BP, blood pressure; CAD, coronary artery disease; CHF, congestive heart failure; CV, cardiovascular; DBP, diastolic blood pressure; IVUS, intravascular ultrasound; LVEF, left ventricular ejection
fraction; MACE, major adverse cardiovascular events; PC, placebo; Pts, patients; Px, prognosis; and SBP, systolic blood pressure.
Data Supplement E. Diabetes Mellitus


(efficacy) and and Results and Results
Results
DIGAMI Glyco- Multice 620 Intensive 314 DM with AMI Not stated Intensive Regular DM Mortality Admission Admission Long-term No indication whether
Malmberg 1999 metabo nter Insulin Routine <24 h insulin- coverage 33% died in body weight, blood mortality increased use of insulin or
(299) lic state prospe 306 diabetic glucose intensive group, HbA1c, glucose reduction decreased use of
10338454 in DM ctive therapy infusion, 44% in regular pulmonary HbA1c were Intensive vs. sulfonylureas decreased
in ACS study then sc group rates, heart independent regular 28% (8- risk.
and insulin 3.4-y rate were all predictors of 45%)p=0.011
mortalit follow-up independently mortality No prior insulin
y risk linked to and low CV risk:
hyperglycemi reduction
a 51%(19-
p<0.001 0.00 70)=0.004
01
Diabetes Prevention Effects Multice 3234 Metformin PC 25 y or older Glucose Metformin PC or lack of Incidence of DM Hospitalizatio Average Reduced GI Sx highest in metformin
Program Research of nter 1,073 1,082 BMI ≥24 tolerance affects 850 mg bid lifestyle 2.8-y follow-up ns and deaths weight loss incidence vs. PC group and musculoskeletal
Group Knowler 2002 treating prospe Or lifestyle FBS 95-125 medications Or lifestyle intervention Cases/100 pat-y NS different PC 0.1 kg Lifestyle: 58% (48 highest in lifestyle GP
(300) elevate ctive modification Or 140-199 Short life Int. to reduce PC 11.0 among groups Metformin — 66) Incidence of DM in PC
11832527 d study 1,079 2-h global expentancy weight and Metformin 7.8 GI sx 2.1 kg Metformin 31 (17 group higher than
glucos thrombosis inc exercise Lifestyle 4.8 p<0.0167 Life 5.6 kg — 43) anticipated
e on test metformin vs. p<0.001 v. Lifestyle vs.
develo PC Metformin metformin
pment and PC 39%[24-51%]
of DM
Suleiman 2005 Fasting Prospe 735 Fasting Admission Non-DM AMI >24 h from Sx Fasting Admission 30-d mortality 30-d death 30 d- 30-d mortality by Did not attempt to evaluate
(301) glucos ctive glucose glucose <24 h onset, blood blood compared with and heart mortality co tertile vs. normal for undiagnosed DM
15699267 e and cohort inflammatory glucose glucose FBG failure vs. mpared with FBS Significant overlap in
30-d observ disease, surgery <110, adjusted 30 normal FBG: normal AG 1st: 4.6 (1.7 — HbA1c levels in AMI in
mortalit ational or trauma d-mortality Impaired FBS: and FG 12.7) known or newly diagnosed
y in study preceding mo increased with 2.6 (1.3- Elevated FG P=0.003 DM and no DM
AMI increasing tertile 5.0)=0.004 and AG: 9.6 2nd: 6.4 (2.5 —
of FBG FBS ≥126: Elevated AG 16.6)
5.8 (2.2 — and Normal P<0.0001
10.3) FG 3.4 3rd: 11.5 (4.7 —
<0.0001 20.0)
P<0.0001
Sinnaeve 2009 Elevate Multice 13,526 Range of In-hospital ACS Noncardiac Admission Mortality in- Higher FBS Major 6-mo death: 6 mo-mortality: Retrospective analysis,
(302) d FBS nter FBS and 6-mo chest pain and FBS 6- hospital 6 associated with bleeding FBS <100 FBS 126 — 199 unmeasured variables not
19237725 in ACS retrosp mortality mo follow-up mo graded in-hospital complications vs. mg/dL accounted for, hospital
GRACE and ective and 6-mo increased with 100- 125 1.71 (1.25 — glucose levels may not
mortalit study mortality. higher FBS. NSTEMI: 2.34) reflect “true” glucose
y 6 mo sig higher Stroke level 4.66 vs. FBS≥300: levels. Because of glucose
with FBS above unrelated to 7.14I% 2.93 (1.33 — infusions, some FBS levels
125 glucose level. UA: 6.33) might not have been truly
mg/dL vs. <100 2.56 vs.2.28 But not 200 — fasting levels.
mg/sL 299:
1.08 (0.60 —
1.95)
ACS indicates acute coronary syndrome; AG, admission glucose; AMI, acute myocardial infarction; bid, twice daily; CV, cardiovascular; DM, diabetes mellitus; FBG, fasting blood glucose; FBS, fasting blood sugar; FG, fasting glucose; GI, gastrointestinal; GP,
glycoprotein; HbA1c, Hemoglobin A1c; NS, nonsignificant; NSTEMI, non-ST-elevation myocardial infarction; PC, placebo; Sig, significant; Sx, symptom; and UA, unstable angina.
Data Supplement F. Smoking Cessation

Criteria Criteria Endpoint Endpoint and Endpoint
Results
Daly 1983 Persistence Prospe 498 Smoking Continued Survived 1st Nonsmokers at Follow up by Continued Mortality 13-y life Vascular Mortality of Mortality 2-15 y Average annual mortality:
(303) of smoking ctive cessation smoking attack of entry who life tables for smoking tables beyond 1st causes of previous beyond ACS: stopped vs. continued
6409291 cessation cohort 217 157 ACS by at started to 13 y beyond 2 y from ACS death: 68% nonsmoker stopped vs. smoking
after ACS study Nonsmokers least 28 d smoke died 2 y survival Stopped smoking 24% MI 62.1% continued Initial ACS St Cont
at entry and within 2 y of stopped vs. continued 35% sudden n=124 36.9% vs. 82.1% RR
follow-up entry. smoking smoking was 2.8× death Average p<0.01 UA 1.9 10.0 5.4; p<0.01
147 lower NS diff among annual RR MI uncomp 3.9 8.6 2.2
3 groups of death: p<0.05
2.4× for MI comp 4.7 12.4 2.7
smokers vs. p<0.01
stopped
p<0.01
Jorenby 2006 Efficacy and Multice 1,027 Varencline PC 18-75 y. Previous use of Varencline 1 PC+brief Continuous >10% side Wk 9-52 Abstinence 9-12 Volunteers. Minimal
(304) safety of nter 344 341 10+ bupropion. mg bid smoking abstinence: wk 9- effects: Abstinence vs. PC counseling may confound
16820547 varencline Prospe Bupropion cigarettes/d Contraindication Bupropion cessation 12 Bupropion Varecline vs. 3.85 (2.69,5.50) results. Exclusion of
ctive 342 during s to SR counseling Varecline vs. PC: Insomnia 21% PC p<0.001 depression.
Study previous y medications. 150 mg bid 43.9% vs. 17.6% Varencline 23% vs. 9-12 Bupropion 35% did not complete
No Sig CV disease; 12 wk + brief Bupropion vs. PC: Nausea 29% 10.3% vs. PC: follow-up period.
abstinence HTN; pulmonary counseling 29.8% vs. 17.6% Abnormal 2.66 1.90 (1.38- 2.62) Dropout rate for adverse
longer than 3 disease; 12 wk with dreams (1.72,4.11) p<0.001 events higher in PC group.
mo depression 40-wk follow- 13.1% p<0.001
up Headache Bupropion
12.8% vs. PC
1.77
(1.19,2.63)
p=0.004
Tonstad 2006 Effect of Multice 1,210 Varencline PC 18-75 y. Unstable 12-wk open PC Continued Major adverse N/A Abstinence vs. Generally healthy group.
(305) varenicline nter 603 607 10 cigarettes/ disease, label vs. if abstinence Effects: PC No depression. CO may
16820548 on smoking Prospe d + smoking depression, stopped Wk 13-24 Varenclin Wk 13-24 not evaluate complete
cessation ctive cessation COPD, CV smoking Varenicline vs. Nasopharyngi 2.48 (1.95- check on self-report of
Study Ation after 12 disease within 6 Randomized PC tis 3.16)<0.001 nonsmoking. Those lost to
wk of mo, for 40 wk 70.5% vs. 49.6% 4.8% Wk 13-52 follow-up differed between
varenicline uncontrolled Wk 13- 52 Headache 1.34 groups.
HTN, smoking 43.6% vs. 36.9% 2.8% (1.06,1.69)=0.02
cessation aid Psych
disorders
6.4%
Rigoitti 2006 Bupropion in Multice 248 Bupropion PC Smoked >1 Not willing to Smoking Same Abstinence and Noncardiac CV mortality Abstinence vs. 1/3 lost at 1 y. Study not
(306) smokers with nter 124 124 Cigarette in stop counseling smoking CV events 3 m serious 1y PC powered to detect less
17145253 ACS Prospe previous mo Smoking. Risk to 12-wk counseling and 1 y adverse Bupropion 3 mo: 37.1% vs. than a 1.8-fold increase in
ctive CAD of seizure, sig. postdischarg PC Borderline Sig events: NS vs. PC 26.8% cessation rates with
Study admissions HTN, heavy e Bupropion abstinence at 3 3 mo: 1.31 0% vs. 2% 1.61 bupropion.
alcohol use, SR mo only. (0.62,2.77) CV events 1 (0.94,2.76)=0.08 Many eligible declined to
depression, liver 1-y follow-up NS diff in 1 y: 1.34 y: 1 y: 25.0% vs. enroll.
or renal outcome (0.64,2.84) 26% vs. 21.3% Reluctance to be
disease, illegal events 18% 1.23 (0.68,2.23) randomized to PC.
drug use 1.56 NS
(0.91,2.69)
NS
PREMIER Predictors of Retros 639 342 smokers 297 AMI Transfer to Smoking Same but 6-mo post MI: Not evaluated Hospital Smoking Limited insights on
Registry smoking pective at 6 m Nonsmokers Smoker >18 hospital >24 h behavior by stopped 46% had stopped smoking cessation with smoking cessation
Dawood 2008 cessation from at 6 mo y age from AMI self-report smoking at 6 Odds greater for cessation rehab: programs available at
(307) after AMI registry Did not speak During mo those receiving counseling 1.80 (1.17-2.75) different hospitals.
18852396 English or hospital and discharge did not Treated at Loss to follow-up.
Spanish. Could 6 mo in pt recommendations predict smoking Self-reporting assessment
not consent smoking for cardiac rehab cessation: cessation facility: without biochemical
cessation or smoking 0.80 1.71 (1.03=2,83) evaluation.
program cessation facility (0.51,1.25) Unmeasured confounding.
Continued Depressive
smoking pts during MI
less likely to
quit:
0.57 (0.36-
0.90)
p<0.05
Mohuiddin Intensive Prospe 209 Intensive Usual care 30-75 y Alcohol or illicit 30-min Same At each follow-up Over 2-y 2-y all-cause 2-y abstinence: Small sample size-lacking
2007 smoking ctive intervention 100 Daily drug use counseling counseling interval, point period more in mortality: 33% intensive vs. multivariate analysis to
(308) cessation random 109 smokers Unfamiliar with before before prevalence and UC group 2.8% 9% UC adjust for other factors on
17296646 intervention ized 2 y follow-up 2-y follow-up >5 y in CCU English discharge. discharge continued Hospitalized intensive vs. p<0.0001 outcome.
in acute CV cohort with AMI or Intensive only. abstinence RR 12.0% UC Pharmacotherapy at no
disease heart failure counseling greater in the reduction:44% RR cost.
for 3 mo + intensive (16,63)=0.007 reduction: Question of whether
pharmacothe treatment group 77% (27, results would have been
rapy in 75% 93%) achieved if smokers
p=0.014 purchased their own
medications.
Smith 2009 Hospital Multi- 275 Intensive Minimal 18 or older Pregnant Minimal Minimal 1-y abstinence Not evaluated Abstinence 1-y abstinence Pharmacotherapy used by
(309) smoking institut smoking intervention Smoked in Medically intervention intervention self-reported lower in self-reported: 34% of pts in both groups.
19546455 cessation in e cessation 139 previous mo unstable + 45-60 min 2 pamphlets 62% intensive GP those using 2.0 (95% CI: 1.2- Slightly less than ½
CAD with Prospe intervention AMI or Lived in an bedside No smoking vs. 46% minimal pharmacoth 3.1) smokers did not want to
long-term ctive 136 CABG institution counseling message by GP erapy Confirmed: quit or refused to
effects Study admission No English 7 telephone physician Confirmed: 54% p<0.01 2.0 (CI: 1.3-3.6) participate.
Psychiatric counseling intensive GP vs. Abstinence Exclusion of pts with
disorder sessions 35% minimal higher in substance abuse or
Substance after group CABG vs. MI psychiatric comorbidities,
abuse discharge pts many of whom are
p<0.05 smokers, limits
generalizability of results.
Rigotti 2008 Hospital Meta- 6,252 Intensive Usual care or Hospitalized Trials not Intensive Usual care Smoking Not evaluated Adding NRT Smoking Benefit of adding
(310) smoking analysi (using intervention control and current recruiting on intervention with minimal cessation rates 6- produced a cessation 6-12 bupropion limited to 1
18852395 cessation s of 33 number counseling counseling smokers basis of with or smoking 12 mo decreased trend toward mo with study. Counseling
intervention trials s 2,673 2,935 smoking, Hx, without counseling with smoking efficacy vs. counseling: intervention not delivered
with 6-mo in Hospitalization pharmacothe counseling. counseling 1.65 (CI: 1.44- by staff responsible for
follow-up Figure Pharmacothe No with psychiatric rapy No benefit with alone: 1.90) patient care. Only
1 and rapy pharmacother disorder, or less 1.47 (CI: 1/2studies used sustained
2) 332 apy substance postdischarge 0.92- 2.35) abstinence to assess
312 abuse contact. outcome, the rest point
prevalence
Colivicchi Smoking Prospe 813 12-mo Predictors of Previous Major Several in- Predictors of Age and female Resumption Age and Cardiac rehab Sig diff in age and CV risk
2011 relapse rate ctive relapse relapse smokers who concurrent hospital relapse sex were of smoking resumption: and abstinence: factors in cohort.
(311) after quitting cohort 813 stopped after illness, counseling predictors of predicted 1-y 1.034 0.74 (CI: 0.51- Questions about sens of
21741609 following study (of 1,294 not ACS depression, sessions. relapse. mortality: (1.03,1.04) 0.91)=0.02 troponin assay for Dx of
ACS relapsing) following alcohol and 12-mo Pts in cardiac 3.1 (CI: 1.3- p=0.001 DM and AMI
hospital drug abuse, follow-up rehab and pts 5.7) p=0.004 Female: abstinence:
discharge renal, lung, liver with DM more 1.23 0.79 (CI: 0.68-
disease, stroke, likely to remain (1.09,1.42) 0.94)=0.03
malignancy abstinent
Planer 2011 Efficacy of 2 149 Bupropion PC Smokers Prior use of Bupropion PC Same Abstinence rates Bupropion Adverse 3-mo abstinence: Recruitment stopped early
(303) bupropion in center 74 75 hospitalized bupropion in 150 mg bid abstinence at 3 mo, 6 mo and safe. NS diff effects Bupropion vs. after interim analysis
21403011 smoking prospe for ACS past y or NRT in for 2 mo evaluation 1 y were not vs. PC in: attributed to PC: limiting sample size.
cessation ctive Smoking >10 past 6 mo 1-y increased by death, any treatment 45% b 44% Self-reports of quitting, no
after AMI study cigarettes/d Prior head abstinence bupropion hospitalization
was a p=0.99 biochemical confirmation.
Intention to trauma, evaluation s, MI, ACS, negative 6 mo. Abstinence: High self-reports of quitting
quit smoking depression, Chest pain predictor of Bupopion vs. PC: in PC group.
bulimia liver or smoking 37% vs. 42% Dizziness more common
kidney disease, cessation: p=0.61 than PC 14% vs. 1.4%
pregnancy 0.23 (95% 1-y abstinence: p=0.005
CI: 0.07- 31% vs. 33%
0.78) p=0.86
ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; bid, twice daily; CAD, coronary artery disease; CABG, coronary artery bypass graft; CCU, coronary care unit; CO, COPD, chronic obstructive pulmonary disease; CV, cardiovascular; Diff,
difference(s); DM, diabetes mellitus; GP, glycoprotein; HTN, hypertension; Hx, history; MI, myocardial infarction; N/A, not available; NRT, nicotine replacement therapy; NS, nonsignificant; PC, placebo; Pt, patient; RR, relative risk; Sens, sensitivity; Sig, significance;
SR, sustained release; UA, unstable angina; and UC, usual care.
Data Supplement G. Weight Management

and Results
Nordmann 2006 Low- Meta- 447 Low carb Low fat Randomized Trials with Low-carb Low fat Weight loss to 6 Trend toward In diabetics, Weighted mean Substantial losses to
(312) carb analysi 5 trials 222 225 controlled cross-over or weight loss same and 12 mo. lower BP in HbA1cdec. difference 6 mo follow-up.
16476868 vs. low- s low carb vs. sequential at 6 and 12 6 mo: low low carb In low carb Low carb vs. low No blinded outcome
fat low fat, design mo carb>weight loss. group at 6 mo gp. vs. low fat assessment.
diets BMI≥25, 12 mo: NS only. fat: 12 mo -3.3 kg (-5.3,-1,4) Had to use ITT analysis
on Follow-up 6 difference TG and HDL -0.7% vs.- 12 mo. because of dropouts.
weight mo + Age changed more 0.1% -1.0 kg (-3.5,1.5) Heterogeneity concerning
loss 16+ favorably in p=0.02 main outcome.
and CV high-carb
risk diets, LDL-C
in low-fat diets
Chow 2010 Adhere Multice 18,809 Adherence to Nonadeheren UA, NSTEMI Contraindication Survey at 30, No diet, CV events at 6 Side effects Decreased Risk of CV events No active study
(313) nce to nter diet, ce to Age 60+ y to LMW heparib, 90, 180 d on exercise, mo decreased not addressed independent Exercise vs. no intervention program. Self-
20124123 behavi Observ exercise, individual recent 3 lifestyle No smoking with exercise risk of 0.69 report of outcomes.
oral ational smoking components hemorrhagic values cessation onlyand diet + stroke/MI/de (0.54,0.89)]=.003 No details of actual diet
recom substu cessation stroke adherence exercise and ex- ath 7 and exercise quantification.
mendat dy AC for other smoker vs. All 3 with Exercise/diet vs. Adherers/nonadherers
ion in than ACS, high persistent smoker diet/exercise no categorized only at 30-d
CV risk creatinine Death with 0.46 (0.38- 0.57) follow-up.
ex-smoker <0001
vs. Ex-smoker vs.
continued smoker
smoker 0.68 (0.51-
.90).0067
Gadde 2011 Efficac Multice 2,448 Phenteramin PC Age: 18-70 BP >160/100 Phenteramin PC for same Proportion of pts Adverse >10% weight 5% weight loss: Endpoint assessment not
(314) y and nter e/Topiramate 979 BMI: 27-45 FBS >13.32 e/ period achieving at least effects vs. PC loss Low-dose Qnexa available for 31% of
21481449 safety prospe 7.5mg/46mg Or diabetes mmol/L Topiramate 5% weight loss: 10% or more Low-dose OR: 6.3 (4.9-8.0) sample.
of ctive 488 2 or more CV TG >4.52 1 of 2 Low-dose Qnexa: with sig dif: Qnexa p<0.0001 Restriction of upper limit to
Qnexa trial P/T 15/92mg risk factors mmol/L dosages for 62% Dry mouth 37% High-dose Qnexa BMI: 45. Lack of ethnic
Phase 981 Type 1 diabetes 56 wk High-dose 21% p<0.0001 OR: 9.0 (7.3- diversity (86% white), few
3 or Type 2 Qnexa:70% Paresthesia High-dose 11.1) men (30%). No active
managed with PC: 21% 21% Qnexa p<0.0001 comparator group such as
antidiabetic Constipation 48% orlistat or lorcaserin
drugs except for 17% p<0.0001
metformin Dysgeusia PC
10% 7%
Headache
10%
Cognitive (sig
Attention dist
4%
Garvey 2012 Long- Multice 676 Phenteramin PC See above See above See above PC for same Percentages Change in Percentage >5% weight loss Discontinuation rates
(315) term nter Out of e/Topiramate 227 agreed to 52-wk period achieving >5%, percentages changes in Low dose: 79.3% similar to 1st 56-wk period
22158731 efficacy prospe original 7.5mg/46mg extension extension >10%, >15% and Adverse BP, lipid, DM High dose: 75.2% above. Higher rate lost to
and ctive 2,448 173 >20% weight loss effects were meds: PC: 30.0% follow-up in the 15/92 arm.
safety trial P/T15/92mg in 108-wk period, 0-56 vs. 56- p<0.0001 Impact of Rx of
of Extensi 295 in all 4 categories, 108 High-dose Q >10% weight loss dyslipidemia and HTN on
Qnexa on of Qnexa low and High-dose Q BP: -9.8% Low dose: 53.9 secondary cardiometabolic
previou high dose >PC constipation Lipid: +4.7% High dose: 50.3% variables. Type of adverse
s trial 21% to 4% DM: 0% PC: 11.5% events similar to 1st 56-wk
(4) Paresthesia p<0.0001 period but incidence rates
21% to 2.4% Low-dose Q >15% weight loss lower.
Dry mouth BP: -3.9% Low dose: 31.9%
20% to 1.4% Lipid:+5.2% High dose: 24.2%

upper DM: +1.9% PC: 6.6%
respitory p<0.0001
infection PC >20% weight loss
18.6% to BP: +3.5% Low dose 9.2%
15.3% Lipid:+17.2% High dose: 15.3%
Nasopharyngi DM: +7.1% PC: 2.2%
tis p=.0072 for low
13.2% to dose <0.0001 for
8.8% high dose.
Depression
NS
From PC
AC indicates anticoagulant; ACS, acute coronary syndrome; BMI, body mass index; BP, blood pressure; CV, cardiovascular; DM, diabetes mellitus; FBS, fasting blood sugar (glucose); HbA1c, Hemoglobin A1C; HDL–C, high-density lipoprotein cholesterol; HF, heart
failure; HTN, hypertension; ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol; LMW, low molecular weight; MI, myocardial infarction; NS, no(n) significance; NSTEMI, non-ST-elevation myocardial infarction; PC, placebo; Pt, patient; Rx, prescription; TG,
triglycerides; and UA, unstable agina.
Data Supplement H. Cardiac Rehabilitation

Study Name, Study Aim Study Type/ Intervention vs. Patient Population Study Endpoints P Values, Adverse Events Study Limitations
Author, Year Size (N) Comparator (n) Intervention OR: HR: RR: &
95 CI:
Criteria Criteria Endpoint & Endpoint & Endpoint &
Goel, K et al Assess CR 2,395 CR (1431) vs. non- PCI No prior pt At least 1 CR All-cause Subsequent MI, Death, PCI, MI, HR 0.54 (0.41- Events in CR=83; in Observational,
Circulation. 2011; participation CR (964) registry, authorization outpatient mortality HR PCI-NS CABG p=0.28 0.71) non-CR=139 Cohort
123: 2344-2352 and impact on participants Olmstead session p<0.001
(316) mortality County
21576654
Hammil, Characterize 30,161 (6,181 Internal: Medicare None identified At least 1 CR Death Subsequent MI Death HR 0.86 Subsequent Observational,
Circulation. dose-response with AMI as cumulative 5% sample outpatient hospitalization (0.76-0.97) for hospitalization sample of Medicare
2010;121:63-70 for # CR qualifying comparison with # 2001-2005 session billed to those attending claims
(317) sessions reason for CR) of CR sessions Medicare >6 sessions
20026778 (“dose”)
AMI indicates acute myocardial infarction; CABG, coronary artery bypass graft; CR, cardiac rehabilitation; HR, hazard ratio; MI, myocardial infarction; NS, not significant; PCI, percutaneous coronary intervention; Pt, patient; and RR, relative risk.
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2014 AHA NSTEMI Management

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AHA/ACC Guideline

2014 AHA/ACC Guideline for the Management

ACC/AHA TASK FORCE MEMBERS

Table of Contents 5. Myocardial Revascularization:

1.1. Methodology and Evidence Review . . . . . . . . . 2357 Antiplatelet Agents . . . . . . . . . . . . . . . . . 2369

Table 1. Applying Classification of Recommendations and Level of Evidence

taking associated conditions and comorbidities into consid- 1. Introduction

Table 2. Associated CPGs and Statements

Coronary artery bypass graft surgery ACC/AHA 201124

3.4.1. Biomarkers: Diagnosis

Table 4. Summary of Recommendations for Prognosis: Early Risk Stratification

Table 6. Summary of Recommendations for Early Hospital Care

Obtain a fasting lipid profile, preferably within 24 h IIa C N/A

ischemia, heart failure (HF), or hypertension.106–111 tolerated anti-ischemic medications.115,116 (Level of

Class III: Harm Class III: Harm

shock, or 4) other contraindications to beta block- 4.1.6. Cholesterol Management

1. It is reasonable to continue beta-blocker therapy in 1. Angiotensin-converting enzyme (ACE) inhibitors should

Class III: Harm Class I‡

continued for at least 12 mo in post–PCI patients treated with

Class III: No Benefit revascularization and comorbid conditions are

Table 8. Factors Associated With Appropriate Selection 5. Myocardial Revascularization:

Temporal change in Tn (Section 3.4) before PCI.27,190–192 (Level of Evidence: B)

1. Continuation of DAPT beyond 12 months may be

Class I 1. Performance of PCI with enoxaparin may be reason-

Table 9. Dosing of Parenteral Anticoagulants During PCI

• No IV GPI planned: additional UFH as needed (eg, 2000–5000 U) to •N

Evidence: B) aged with aspirin and a P2Y12 inhibitor. (Level of

Class III: No Benefit 1. Older patients** with NSTE-ACS should be

3. Management decisions for older patients** with

Table 10. Summary of Recommendations for Special Patient Groups

Table 10. Continued

It is reasonable to use benzodiazepines alone or in combination with NTG IIa C 326–329

It is reasonable to administer catecholamines for symptomatic hypotension in the IIa C N/A

7.3. Diabetes Mellitus early invasive strategy because of their increased

glycerin are reasonable for management of hyperten-

Elliott Antman, MD, FAHA, President 2014;130:e199-267.

99th percentile cut-off and clinical utility of myoglobin measurement in 2002;40:1044–50.

Rosemary F. University of None None None None None None None

Imaging Section Cardiologist

Sabatine, Richard W. Smalling and Susan J. Zieman

Circulation. 2014;130:2354-2394; originally published online September 23, 2014;

Data Supplement (unedited) at:

Reprints: Information about reprints can be found online at:

Subscriptions: Information about subscribing to Circulation is online at:

The fourth row originally read,

The corrected row now reads,

Division of  Bristol-Myers  Bristol-Myers Squibb*  Daiichi-Sankyo*

© American Heart Association, Inc and American College of Cardiology Foundation 1

Data Supplement B. Other Anticoagulants .............................................................................................................................................................................................................................................................. 127

© American Heart Association, Inc and American College of Cardiology Foundation 2

Data Supplement 1. Clinical Assessment and Initial Evaluation (Section 3.1)

level > 99th

Data Supplement 2. Risk Stratification (Section 3.3)

Inclusion Criteria Exclusion Primary Endpoint & Secondary

© American Heart Association, Inc and American College of Cardiology Foundation 7

© American Heart Association, Inc and American College of Cardiology Foundation 8

Data Supplement 4. Cardiac Troponins (Section 3.4.3)

Tr+ and MBCK -

Data Supplement 6. Bedside Testing for Cardiac Biomarkers (Section 3.4.4)

Inclusion Exclusion Primary Safety Secondary

Data Supplement 7. Summary Comparison of Injury Markers (Section 3.4.4)

Data Supplement 8. Discharge from ED or Chest Pain Unit (Section 3.5.1)

Data Supplement 9. Nitrates (Section 4.1.2.1)

Data Supplement 10. Analgesic Therapy (Section 4.1.2.2)

Table of Contents 5. Myocardial Revascularization:

• No IV GPI planned: additional UFH as needed (eg, 2000–5000 U) to •N