AHA/ACC Guideline 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.0000000000000134 The writing committee gratefully acknowledges the memory of Dr. Francis M. Fesmire (representative of theAmerican 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. This document was approved by theAmerican HeartAssociation ScienceAdvisory and Coordinating Committee and theAmerican 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.0000000000000134/-/DC1. The online-only Data Supplement files are available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/ CIR.0000000000000134/-/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 ACC/AHA guideline for the management of patients with non ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344 e426. This article is copublished in the Journal of the American College of Cardiology. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org) and the American College of Cardiology (www.cardiosource.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/ Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2014 AHA/ACC Guideline for the Management of Patients With Non ST-Elevation Acute Coronary Syndromes 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 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 ; 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 Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e345 Table of Contents Preamble e346 1. Introduction e347 1.1. Methodology and Evidence Review e347 1.2. Organization of the GWC e348 1.3. Document Review and Approval e349 1.4. Scope of the CPG e349 2. Overview of Acs e349 2.1. Definition of Terms e349 2.2. Epidemiology and Pathogenesis e349 2.2.1. Epidemiology e349 2.2.2. Pathogenesis e350 3. Initial Evaluation and Management e350 Clinical Assessment and Initial Evaluation: Recommendation e350 ED or Outpatient Facility Presentation: Recommendations e352 3.2. Diagnosis of NSTE-ACS e352 3.2.1. History e352 3.2.2. Physical Examination e352 3.2.3. Electrocardiogram e353 Biomarkers of Myocardial Necrosis e353 3.2.5. Imaging e353 Prognosis Early Risk Stratification: Recommendations e353 Rationale for Risk Stratification and Spectrum of Risk: High, Intermediate, and Low e354 3.3.2. Estimation of Level of Risk e354 3.3.2.1. History: Angina Symptoms and Angina Equivalents e354 Demographics and History in Diagnosis and Risk Stratification e354 Early Estimation of Risk e355 3.3.2.4. Electrocardiogram e355 3.3.2.5. Physical Examination e357 Cardiac Biomarkers and the Universal Definition of MI: Recommendations e357 3.4.1. Biomarkers: Diagnosis e357 3.4.2. Biomarkers: Prognosis e357 3.4.3. Cardiac Troponins e357 3.4.3.1. Prognosis e358 CK-MB and Myoglobin Compared With Troponin e359 3.5. Immediate Management e359 Discharge From the ED or Chest Pain Unit: Recommendations e359 4. Early Hospital Care e359 4.1. Standard Medical Therapies e360 4.1.1. Oxygen: Recommendation e360 4.1.2. Anti-Ischemic and Analgesic Medications e360 4.1.2.1. Nitrates: Recommendations e360 4.1.2.2. Analgesic Therapy: Recommendations e361 4.1.2.3. Beta-Adrenergic Blockers: Recommendations e362 Calcium Channel Blockers: Recommendations e362 4.1.2.5. Other Anti-Ischemic Interventions e363 4.1.2.6. Cholesterol Management e363 Inhibitors of the Renin-Angiotensin-Aldosterone System: Recommendations e363 4.3. Initial Antiplatelet/Anticoagulant Therapy in Patients With Definite or Likely NSTE-ACS e364 Initial Oral and Intravenous Antiplatelet Therapy in Patients With Definite or Likely NSTE-ACS Treated With an Initial Invasive or Ischemia-Guided Strategy: Recommendations e364 4.3.1.1. Aspirin e365 Receptor Inhibitors e365 4.3.2. Initial Parenteral Anticoagulant Therapy in Patients With Definite NSTE-ACS: Recommendations e367 Heparin e367 4.3.2.2. Bivalirudin e367 4.3.2.3. Fondaparinux e367 4.3.2.4. Unfractionated Heparin e367 4.3.2.5. Argatroban e368 Fibrinolytic Therapy in Patients With Definite NSTE-ACS: Recommendation . e368 Ischemia-Guided Strategy Versus Early Invasive Strategies e368 4.4.1. General Principles e368 Rationale and Timing for Early Invasive Strategy e368 Routine Invasive Strategy Timing e368 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 Rationale for Ischemia-Guided Strategy e368 Early Invasive and Ischemia-Guided Strategies: Recommendations e368 Comparison of Early Versus Delayed Angiography e370 Subgroups: Early Invasive Strategy Versus Ischemia-Guided Strategy e371 4.4.6. Care Objectives e371 Risk Stratification Before Discharge for Patients With an Ischemia-Guided Strategy of NSTE-ACS: Recommendations e371 4.5.1. Noninvasive Test Selection e371 4.5.2. Selection for Coronary Angiography e372 5. Myocardial Revascularization e372 5.1. Percutaneous Coronary Intervention e372 5.1.1. PCI General Considerations: Recommendation e372 5.1.2. PCI Antiplatelet and Anticoagulant Therapy e372 Oral and Intravenous Antiplatelet Agents: Recommendations e372 GP IIb/IIIa Inhibitors: Recommendations e373 5.1.2.3. Anticoagulant Therapy in Patients Undergoing PCI: Recommendations e374 Timing of Urgent CABG in Patients With NSTE-ACS in Relation to Use of Antiplatelet Agents: Recommendations e375 Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care e376 General Principles (Cardioprotective Therapy and Symptom Management) e376 Medical Regimen and Use of Medications at Discharge: Recommendations e376 Late Hospital and Posthospital Oral Antiplatelet Therapy: Recommendations e376 6.2.2. Combined Oral Anticoagulant Therapy and Antiplatelet Therapy in Patients With NSTE-ACS e378 Platelet Function and Genetic Phenotype Testing e379 Risk Reduction Strategies for Secondary Prevention e379 Cardiac Rehabilitation and Physical Activity: Recommendation e379 6.3.2. Patient Education: Recommendations e380 6.3.3. Pneumococcal Pneumonia: Recommendation e380 6.3.4. NSAIDs: Recommendations e380 6.3.5. Hormone Therapy: Recommendation e380 Antioxidant Vitamins and Folic Acid: Recommendations e381 Plan of Care for Patients With NSTE-ACS: Recommendations e381 Systems to Promote Care Coordination e382 7. Special Patient Groups e382 NSTE-ACS in Older Patients: Recommendations e382 7.2. HF: Recommendations e383 7.2.1. Arrhythmias e383 7.2.2. Cardiogenic Shock: Recommendation e386 7.3. Diabetes Mellitus: Recommendation e386 7.3.1. Adjunctive Therapy e387 7.4. Post CABG: Recommendation e387 Perioperative NSTE-ACS Related to Noncardiac Surgery: Recommendations e387 7.6. CKD: Recommendations e388 7.6.1. Antiplatelet Therapy e388 7.7. Women: Recommendations e389 Anemia, Bleeding, and Transfusion: Recommendations e389 7.9. Thrombocytopenia e390 Cocaine and Methamphetamine Users: Recommendations e390 7.11. Vasospastic (Prinzmetal) Angina: Recommendations e391 7.12. ACS With Angiographically Normal Coronary Arteries: Recommendation e392 Stress (Takotsubo) Cardiomyopathy: Recommendations e392 7.14. Obesity e393 7.15. Patients Taking Antineoplastic/ Immunosuppressive Therapy e393 Quality of Care and Outcomes for ACS Use of Performance Measures and Registries e393 Use of Performance Measures and Registries: Recommendation e393 Summary and Evidence Gaps e393 References e394 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) e414 Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) e417 Appendix 3. Abbreviations e422 Appendix 4. Additional Tables e423 Preamble TheAmerican College of Cardiology (ACC) and theAmerican Heart Association (AHA) are committed to the prevention and management of cardiovascular diseases through professional education and research for clinicians, providers, and patients. Since 1980, the ACC and AHA have shared a responsibility to translate scientific evidence into clinical practice guidelines (CPGs) with recommendations to standardize and improve cardiovascular health. These CPGs, based on systematic methods to evaluate and classify evidence, provide a corner- stone of quality cardiovascular care. In response to published reports from the Institute of and the ACC/AHA s mandate to evaluate new knowledge and maintain relevance at the point of care, the ACC/AHA Task Force on Practice Guidelines (Task Force) began modifying its methodology. This modernization effort is published in the 2012 Methodology Summit Report3 and The latter recounts the history of the collaboration, changes over time, current policies, and Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e347 planned initiatives to meet the needs of an evolving health- care environment. Recommendations on value in proportion to resource utilization will be incorporated as high-quality comparative-effectiveness data become available.5 The rela- tionships between CPGs and data standards, appropriate use criteria, and performance measures are addressed elsewhere.4 Intended Use CPGs provide recommendations applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but CPGs developed in collaboration with other organizations may have a broader target.Although CPGs may be used to inform regula- tory or payer decisions, the intent is to improve the quality of care and be aligned with the patient s best interest. Evidence Review Guideline writing committee (GWC) members are charged with reviewing the literature; weighing the strength and quality of evidence for or against particular tests, treatments, or procedures; and estimating expected health outcomes when data exist. In analyzing the data and develop- ing CPGs, the GWC uses evidence-based methodologies devel- oped by the Task Force.6 A key component of the ACC/AHA CPG methodology is the development of recommendations on the basis of all available evidence. Literature searches focus on randomized controlled trials (RCTs) but also include regis- tries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only selected references are cited in the CPG. To ensure that CPGs remain current, new data are reviewed biannually by the GWCs and the Task Force to determine if recommendations should be updated or modified. In general, a target cycle of 5 years is planned for full revisions.1 Guideline-Directed Medical Therapy Recognizing advances in medical therapy across the spectrum of cardiovas- cular diseases, the Task Force designated the term guideline- directed medical therapy (GDMT) to represent recommended medical therapy as defined mainly by Class I measures, gen- erally a combination of lifestyle modification and drug- and device-based therapeutics. As medical science advances, GDMT evolves, and hence GDMT is preferred to optimal medical therapy. For GDMT and all other recommended drug treatment regimens, the reader should confirm the dosage with product insert material and carefully evaluate for contraindi- cations and possible drug interactions. Recommendations are limited to treatments, drugs, and devices approved for clinical use in the United States. Class of Recommendation and Level of Evidence Once recommendations are written, the Class of Recommendation (COR; ie, the strength the GWC assigns to the recommen- dation, which encompasses the anticipated magnitude and judged certainty of benefit in proportion to risk) is assigned by the GWC. Concurrently, the Level of Evidence (LOE) rates the scientific evidence supporting the effect of the intervention on the basis on the type, quality, quantity, and consistency of data from clinical trials and other reports Unless otherwise stated, recommendations are presented in order by the COR and then the LOE. Where comparative data exist, preferred strategies take precedence. When more than 1 drug, strategy, or therapy exists within the same COR and LOE and there are no comparative data, options are listed alphabetically. Relationships With Industry and Other Entities The ACC and AHA exclusively sponsor the work of GWCs with- out commercial support, and members volunteer their time for this activity. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All GWC members and reviewers are required to fully dis- close current industry relationships or personal interests from 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced GWC and requires that both the chair and a majority of GWC members have no rel- evant RWI (see Appendix 1 for the definition of relevance). GWC members are restricted with regard to writing or voting on sections to which their RWI apply. In addition, for trans- parency, GWC members comprehensive disclosure informa- tion is available as an online supplement. Comprehensive disclosure information for the Task Force is available as an additional supplement. The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds repre- senting different geographic regions, sexes, ethnicities, races, intellectual perspectives/biases, and scopes of clinical prac- tice. Selected organizations and professional societies with related interests and expertise are invited to participate as partners or collaborators. Individualizing Care in Patients With Associated Conditions and Comorbidities The ACC and AHA recog- nize the complexity of managing patients with multiple condi- tions, compared with managing patients with a single disease, and the challenge is compounded when CPGs for evaluation or treatment of several coexisting illnesses are discordant or CPGs attempt to define practices that meet the needs of patients in most, but not all, circumstances and do not replace clinical judgment. Clinical Implementation Management in accordance with CPG recommendations is effective only when followed; there- fore, to enhance their commitment to treatment and compliance with lifestyle adjustment, clinicians should engage the patient to participate in selecting interventions on the basis of the patient s individual values and preferences, taking associated conditions and comorbidities into consideration (eg, shared decision making). Consequently, there are circumstances in which deviations from these guidelines are appropriate. The recommendations in this CPG are the official policy of the ACC and AHA until they are superseded by a published addendum, focused update, or revised full-text CPG. Jeffrey L. Anderson, MD, FACC, FAHA Chair, ACC/AHA Task Force on Practice Guidelines 1.1. Methodology and Evidence Review The recommendations listed in this CPG are, whenever pos- sible, evidence based. An extensive evidence review was conducted through October 2012, and other selected refer- ences published through April 2014 were reviewed by the GWC. Literature included was derived from research involv- ing human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality Reports, and other selected databases relevant to this CPG. The rel- evant data are included in evidence tables in the Online Data Supplement. Key search words included but were not limited to the following: acute coronary syndrome, anticoagulant therapy, antihypertensives, anti-ischemic therapy, antiplatelet therapy, antithrombotic therapy, beta blockers, biomarkers, calcium channel blockers, cardiac rehabilitation, conserva- tive management, diabetes mellitus, glycoprotein IIb/IIIa inhibitors, heart failure, invasive strategy, lifestyle modifica- tion, myocardial infarction, nitrates, non-ST-elevation, P2Y12 receptor inhibitor, percutaneous coronary intervention, renin- angiotensin-aldosterone inhibitors, secondary prevention, smoking cessation, statins, stent, thienopyridines, troponins, unstable angina, and weight management. Additionally, the GWC reviewed documents related to non-ST-elevation acute coronary syndrome (NSTE-ACS) previously published by the ACC and AHA. References selected and published in this document are representative and not all-inclusive. 1.2. Organization of the GWC The GWC was composed of clinicians, cardiologists, inter- nists, interventionists, surgeons, emergency medicine special- ists, family practitioners, and geriatricians. The GWC included representatives from the ACC and AHA, American Academy of Family Physicians, American College of Emergency Physicians, American College of Physicians, Society for 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 IIa; 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. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e349 Cardiovascular Angiography and Interventions (SCAI), and Society of Thoracic Surgeons (STS). 1.3. Document Review and Approval This document was reviewed by 2 official reviewers each nominated by the ACC and AHA; 1 reviewer each from the American Academy of Family Physicians, American College of Emergency Physicians, SCAI, and STS; and 37 individ- ual content reviewers (including members of the American Association of Clinical Chemistry, ACC Heart Failure and Transplant Section Leadership Council, ACC Cardiovascular Imaging Section Leadership Council, ACC Interventional Section Leadership Council,ACC Prevention of Cardiovascular Disease Committee, ACC Surgeons Council, Association of International Governors, and Department of Health and Human Services). Reviewers RWI information was distributed to the GWC and is published in this document (Appendix 2). This document was approved for publication by the gov- erning bodies of the ACC and the AHA and endorsed by the American Association for Clinical Chemistry, SCAI, and the STS. 1.4. Scope of the CPG The 2014 NSTE-ACS CPG is a full revision of the 2007 ACCF/AHA CPG for the management of patients with unsta- ble angina (UA) and non-ST-elevation myocardial infarc- tion (NSTEMI) and the 2012 focused update.8 The new title, Non-ST-Elevation Acute Coronary Syndromes, emphasizes the continuum between UA and NSTEMI. At presentation, patients with UA and NSTEMI can be indistinguishable and are therefore considered together in this CPG. In the United States, NSTE-ACS affects >625000 patients annually,* or almost three fourths of all patients with acute coronary syndrome (ACS).9 In selecting the initial approach to care, the term ischemia-guided strategy has replaced the pre- vious descriptor, initial conservative management, to more clearly convey the physiological rationale of this approach. The task of the 2014 GWC was to establish a contempo- rary CPG for the optimal management of patients with NSTE- ACS. It incorporates both established and new evidence from published clinical trials, as well as information from basic science and comprehensive review articles. These recommen- dations were developed to guide the clinician in improving outcomes for patients with NSTE-ACS. Table 2 lists docu- ments deemed pertinent to this effort and is intended for use as a resource, thus obviating the need to repeat extant CPG recommendations. The GWC abbreviated the discussion sections to include an explanation of salient information related to the recommenda- tions. In contrast to textbook declaratory presentations, expla- nations were supplemented with evidence tables. The GWC also provided a brief summary of the relevant recommenda- tions and references related to secondary prevention rather than detailed reiteration. Throughout, the goal was to provide the clinician with concise, evidence-based contemporary rec- ommendations and the supporting documentation to encour- age their application. 2. Overview Of ACS 2.1. Definition of Terms ACS has evolved as a useful operational term that refers to a spectrum of conditions compatible with acute myocar- dial ischemia and/or infarction that are usually due to an abrupt reduction in coronary blood flow (Figure 1). A key branch point is ST-segment elevation (ST-elevation) or new left bundle-branch block on the electrocardiogram (ECG), which is an indication for immediate coronary angiography to determine if there is an indication for reperfusion ther- apy to open a likely completely occluded coronary artery. Separate CPGs have been developed for ST-elevation myo- cardial infarction (STEMI).17 TheabsenceofpersistentST-elevationissuggestiveofNSTE- ACS (except in patients with true posterior myocardial infarc- tion [MI], Sections 3.3.2.4, 4.3.2, and 7.2.2). NSTE-ACS can be further subdivided on the basis of cardiac biomarkers of necro- sis (eg, cardiac troponin, Sections 3.2.4 and 3.4). If cardiac bio- markers are elevated and the clinical context is appropriate, the patient is considered to have NSTEMI34 ; otherwise, the patient is deemed to have UA. ST depression, transient ST-elevation, and/or prominent T-wave inversions may be present but are not required for a diagnosis of NSTEMI. Abnormalities on the ECG and elevated troponins in isolation are insufficient to make the diagnosis of ACS but must be interpreted in the appropri- ate clinical context. Thus, UA and NSTEMI are closely related conditions whose pathogenesis and clinical presentations are similar but vary in severity. The conditions differ primarily by whether the ischemia is severe enough to cause myocardial damage leading to detectable quantities of myocardial injury biomarkers. The term possible ACS is often assigned during initial evaluation if the ECG is unrevealing and troponin data are not yet available. UA can present without any objective data of myocardial ischemic injury (normal ECG and normal tropo- nin), in which case the initial diagnosis depends solely on the patient s clinical history and the clinician s interpretation and judgment. However, with the increasing sensitivity of troponin assays, biomarker-negative ACS (ie, UA) is becoming rarer.39 The pathogenesis of ACS is considered in the Third Universal Definition of Myocardial Infarction. 21 This statement defines MI caused by a primary coronary artery process such as spon- taneous plaque rupture as MI type 1 and one related to reduced myocardial oxygen supply and/or increased myocardial oxygen demand (in the absence of a direct coronary artery process) as a MI type 2 (Appendix 4, Table A and Section 3.4 for an addi- tional discussion on the diagnosis of MI). 2.2. Epidemiology and Pathogenesis In the United States, the median age at ACS presentation is 68 years (interquartile range 56 to 79), and the male-to-female ratio is approximately 3:2.40 Some patients have a history of stable angina, whereas in others, ACS is the initial presenta- tion of coronary artery disease (CAD). It is estimated that in the United States, each year, >780000 persons will experience an ACS. Approximately 70% of these will have NSTE-ACS.9 Patients with NSTE-ACS typically have more comorbidities, both cardiac and noncardiac, than patients with STEMI. *Estimate includes secondary discharge diagnoses. The hallmark of ACS is the sudden imbalance between myo- cardial oxygen consumption (MVO2 ) and demand, which is usuallytheresultofcoronaryarteryobstruction.Theimbalance may also be caused by other conditions, including excessive myocardial oxygen demand in the setting of a stable flow-lim- iting lesion; acute coronary insufficiency due to other causes (eg, vasospastic [Prinzmetal] angina [Section 7.11], coronary embolism, coronary arteritis); noncoronary causes of myo- cardial oxygen supply-demand mismatch (eg, hypotension, severe anemia, hypertension, tachycardia, hypertrophic car- diomyopathy, severe aortic stenosis); nonischemic myocardial injury (eg, myocarditis, cardiac contusion, cardiotoxic drugs); and multifactorial causes that are not mutually exclusive (eg, stress [Takotsubo] cardiomyopathy [Section 7.13], pulmonary embolism, severe heart failure [HF], sepsis).41 3. Initial Evaluation and Management 3.1. Clinical Assessment and Initial Evaluation: Recommendation Class I 1. Patients with suspected ACS should be risk strati- fied based on the likelihood of ACS and adverse Table 2. Associated CPGs and Statements Title Organization Publication Year/ Reference CPGs Stable ischemic heart disease ACC/AHA/AATS/PCNA/SCAI/STS 201410 Atrial fibrillation AHA/ACC/HRS 201412 Assessment of cardiovascular risk ACC/AHA 201313 Heart failure ACC/AHA 201314 Lifestyle management to reduce cardiovascular risk AHA/ACC 201315 Management of overweight and obesity in adults AHA/ACC/TOS 201316 ST-elevation myocardial infarction ACC/AHA 201317 Treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults ACC/AHA 201318 Acute myocardial infarction in patients presenting with ST-segment elevation ESC 201219 Device-based therapy ACC/AHA/HRS 201320 Third universal definition of myocardial infarction ESC/ACC/AHA/WHF 201221 Acute coronary syndromes in patients presenting without persistent ST-segment elevation ESC 201122 Coronary artery bypass graft surgery ACC/AHA 201123 Hypertrophic cardiomyopathy ACC/AHA 201124 Effectiveness-based guidelines for the prevention of cardiovascular disease in women AHA/ACC 201125 Percutaneous coronary intervention ACC/AHA/SCAI 201126 Secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease Assessment of cardiovascular risk in asymptomatic adults ACC/AHA 201028 Myocardial revascularization ESC 201029 Unstable angina and non ST-elevation myocardial infarction NICE 201030 Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care part 9: postcardiac arrest care Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure Statements Key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease Practical clinical considerations in the interpretation of troponin elevations ACC 201234 Testing of low-risk patients presenting to the emergency department with chest pain AHA 201035 Primary prevention of cardiovascular diseases in people with diabetes mellitus AHA/ADA 200736 Prevention and control of influenza CDC 200537 *The full-text SIHD CPG is from 2012.11 A focused update was published in 2014.10 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. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e351 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.38 outcome(s) to decide on the need for hospitalization and assist in the selection of treatment options.42 44 (Level of Evidence: B) Patients with suspected ACS must be evaluated rapidly to identify those with a life-threatening emergency versus those with a more benign condition. The goal of the initial evalua- tion focuses on answering 2 questions: 1. What is the likelihood that the symptoms and signs rep- resent ACS? 2. What is the likelihood of adverse clinical outcome(s)? Risk assessment scores and clinical prediction algorithms using clinical history, physical examination, ECG, and car- diac troponins have been developed to help identify patients with ACS at increased risk of adverse outcome(s). Common risk assessment tools include the TIMI (Thrombolysis In Myocardial Infarction) risk score,42 the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) risk score,43 the GRACE (Global Registry of Acute Coronary Events) risk and the NCDR-ACTION (National Cardiovascular Data Registry-Acute Coronary Treatment and Intervention Outcomes Network) registry (https://www.ncdr.com/webncdr/ action/). These assessment tools have been applied with vari- able efficacy to predict outcomes in patients presenting to the emergency department (ED) with undifferentiated chest pain ( pain encompasses not only pain, but also symptoms such as discomfort, pressure, and squeezing).45 48 The Sanchis score,49 Heart (History, ECG, Age, Risk Factors, and Troponin) score,51 and Hess prediction were developed specifically for patients in the ED with chest pain. Although no definitive study has demonstrated the superiority of risk assessment scores or clinical prediction rules over clinician judgment, determination of the level of risk on initial evaluation is imperative to guide patient man- agement, including the need for additional diagnostic testing and treatment. See Section 3.2.2 for a discussion of risk strati- fication variables. See Online Data Supplement 1 for additional information on clinical assessment and initial evaluation. 3.1.1. ED or Outpatient Facility Presentation: Recommendations Class I 1. Patients with suspected ACS and high-risk features such as continuing chest pain, severe dyspnea, syn- cope/presyncope, or palpitations should be referred immediately to the ED and transported by emer- gency medical services when available. (Level of Evidence: C) Class IIb 1. Patients with less severe symptoms may be considered for referral to the ED, a chest pain unit, or a facility capable of performing adequate evaluation depend- ing on clinical circumstances. (Level of Evidence: C) Patients with suspected ACS and high-risk features should be transported to the ED by emergency medical services when available. Hospitals and outpatient facilities should provide clearly visible signage directing patients transported by pri- vate vehicle to the appropriate triage area. Outpatient facili- ties should have the capacity for ECG and cardiac troponin measurements with immediate ED referral for those consid- ered to have ACS. 3.2. Diagnosis of NSTE-ACS Differential diagnosis of NSTE-ACS includes41 : Nonischemic cardiovascular causes of chest pain (eg, aortic dissection, expanding aortic aneurysm, pericardi- tis, pulmonary embolism) Noncardiovascular causes of chest, back, or upper abdominal discomfort include: Pulmonary causes (eg, pneumonia, pleuritis, pneumothorax) Gastrointestinal causes (eg, gastroesophageal reflux, esophageal spasm, peptic ulcer, pancreatitis, biliary disease) Musculoskeletal causes (eg, costochondritis, cervical radiculopathy) Psychiatric disorders Other etiologies (eg, sickle cell crisis, herpes zoster) In addition, the clinician should differentiate NSTE-ACS from acute coronary insufficiency due to a nonatherosclerotic cause and noncoronary causes of myocardial oxygen supply- (Section 2.2.2). NSTE-ACS most commonly presents as a pressure-type chest pain that typically occurs at rest or with minimal exertion The pain most frequently starts in the retrosternal area and can radiate to either or both arms, the neck, or the jaw. Pain may also occur in these areas indepen- dent of chest pain. Patients with NSTE-ACS may also present with diaphoresis, dyspnea, nausea, abdominal pain, or syn- cope. Unexplained new-onset or increased exertional dyspnea is the most common angina equivalent. Less common presen- tations include nausea and vomiting, diaphoresis, unexplained fatigue, and syncope. Factors that increase the probability of NSTE-ACS are older age, male sex, positive family history of CAD, and the presence of peripheral arterial disease, diabe- tes mellitus, renal insufficiency, prior MI, and prior coronary revascularization. Although older patients ( 75 years of age) and women usually present with typical symptoms of ACS, the frequency of atypical presentations is increased in these groups as well as in patients with diabetes mellitus, impaired renal function, and dementia.54,55 Atypical symptoms, includ- ing epigastric pain, indigestion, stabbing or pleuritic pain, and increasing dyspnea in the absence of chest pain should raise concern for NSTE-ACS.56 Psychiatric disorders (eg, somato- form disorders, panic attack, anxiety disorders) are noncardiac causes of chest pain that can mimic ACS.57 3.2.2. Physical Examination The physical examination in NSTE-ACS can be normal, but signs of HF should expedite the diagnosis and treatment of Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e353 this condition. Acute myocardial ischemia may cause a S4 , a paradoxical splitting of S2 , or a new murmur of mitral regur- gitation due to papillary muscle dysfunction. However, these signs may also exist without NSTE-ACS and thus are nonspe- cific. The coupling of pain on palpation suggesting musculo- skeletal disease or inflammation with a pulsatile abdominal mass suggesting abdominal aortic aneurysm raises concern for nonischemic causes of NSTE-ACS. The physical exami- nation can indicate alternative diagnoses in patients with chest pain, several of which are life threatening. Aortic dissection is suggested by back pain, unequal palpated pulse volume, a difference of 15 mmHg between both arms in systolic blood pressure (BP), or a murmur of aortic regurgitation. Acute peri- carditis is suggested by a pericardial friction rub. Cardiac tam- ponade can be reflected by pulsus paradoxus. Pneumothorax is suspected when acute dyspnea, pleuritic chest pain, and dif- ferential breath sounds are present. A pleural friction rub may indicate pneumonitis or pleuritis. A 12-lead ECG should be performed and interpreted within 10 minutes of the patient s arrival at an emergency facility to assess for cardiac ischemia or injury.21 Changes on ECG in patients with NSTE-ACS include ST depression, tran- sient ST-elevation, or new T-wave inversion.21,58 Persistent ST-elevation or anterior ST depression indicative of true pos- terior MI should be treated according to the STEMI CPG.17 The ECG can be relatively normal or initially nondiagnostic; if this is the case, the ECG should be repeated (eg, at 15- to 30-minute intervals during the first hour), especially if symp- A normal ECG does not exclude ACS and occurs A normal ECG may also be associated with left circumflex or right coronary artery occlu- sions, which can be electrically silent (in which case posterior electrocardiographic leads [V7 ] may be helpful). Right- sided leads (V3 R to V4 R) are typically performed in the case of inferior STEMI to detect evidence of right ventricular infarc- tion. Left ventricular (LV) hypertrophy, bundle-branch blocks with repolarization abnormalities, and ventricular pacing may mask signs of ischemia/injury.62 3.2.4. Biomarkers of Myocardial Necrosis Cardiac troponins are the most sensitive and specific biomark- ers for NSTE-ACS. They rise within a few hours of symptom onset and typically remain elevated for several days (but may remain elevated for up to 2 weeks with a large infarction). A negative cardiac troponin obtained with more sensitive cardiac troponin assays on admission confers a >95% nega- tive predictive value for MI compared with high-sensitivity assays that confer a negative predictive value 99%.63 65 See Section 3.4 for a detailed review of biomarkers for the diag- nosis of MI. A chest roentgenogram is useful to identify potential pulmo- nary causes of chest pain and may show a widened mediasti- num in patients with aortic dissection. Computed tomography (CT) of the chest with intravenous contrast can help exclude pulmonary embolism and aortic dissection. Transthoracic echocardiography can identify a pericardial effusion and tamponade physiology and may also be useful to detect regional wall motion abnormalities. Transesophageal echocar- diography can identify a proximal aortic dissection. In low-risk patients with chest pain, coronary CT angiography can result in a more rapid, more cost-effective diagnosis than stress myocar- dial perfusion imaging.66 3.3. Prognosis Early Risk Stratification: Recommendations See Table 4 for a summary of recommendations from this section. Class I 1. In patients with chest pain or other symptoms sug- gestive of ACS, a 12-lead ECG should be performed and evaluated for ischemic changes within 10 min- utes of the patient s arrival at an emergency facility.21 (Level of Evidence: C) 2. If the initial ECG is not diagnostic but the patient remains symptomatic and there is a high clinical sus- picion for ACS, serial ECGs (eg, 15- to 30-minute in- tervals during the first hour) should be performed to detect ischemic changes. (Level of Evidence: C) 3. Serial cardiac troponin I or T levels (when a con- temporary assay is used) should be obtained at pre- sentation and 3 to 6 hours after symptom onset (see Section 3.4, Class I, #3 recommendation if time of symptom onset is unclear) in all patients who pres- ent with symptoms consistent with ACS to identify a rising and/or falling pattern of values.21,64,67 71 (Level of Evidence: A) 4. Additional troponin levels should be obtained beyond 6 hours after symptom onset (see Section 3.4, Class I, #3 recommendation if time of symptom onset is un- clear) in patients with normal troponin levels on seri- al examination when changes on ECG and/or clinical presentation confer an intermediate or high index of suspicion for ACS.21,72 74 (Level of Evidence: A) 5. Risk scores should be used to assess prognosis in pa- tients with NSTE-ACS.42 44,75 80 (Level of Evidence: A) Class IIa 1. Risk-stratification models can be useful in manage- (Level of Evidence: B) 2. It is reasonable to obtain supplemental electrocardio- graphic leads V7 in patients whose initial ECG is nondiagnostic and who are at intermediate/high risk of ACS.82 84 (Level of Evidence: B) Class IIb 1. Continuous monitoring with 12-lead ECG may be a reasonable alternative in patients whose initial ECG is nondiagnostic and who are at intermediate/high risk of ACS.85,86 (Level of Evidence: B) 2. Measurement of B-type natriuretic peptide or N-ter- minal pro B-type natriuretic peptide may be consid- ered to assess risk in patients with suspected ACS.87 91 (Level of Evidence: B) 3.3.1. Rationale for Risk Stratification and Spectrum of Risk: High, Intermediate, and Low Assessment of prognosis guides initial clinical evaluation and treatmentandisusefulforselectingthesiteofcare(coronarycare unit, monitored step-down unit, or outpatient monitored unit), antithrombotic therapies (eg, P2Y12 inhibitors, platelet glycopro- tein [GP] IIb/IIIa inhibitors [Sections 4.3.1.2 and 5.1.2.2]), and invasive management (Sections 4.4.2.1, 4.3.1, 4.4, 4.4.4, 4.4.5). There is a strong relationship between indicators of ischemia due to CAD and prognosis (Table 3 and Figure 2). Patients with a high likelihood of ischemia due to CAD are at greater risk of a major adverse cardiac event (MACE) than patients with a lower likelihood of ischemia due to CAD. Risk is highest at the time of presentation but remains elevated past the acute phase. By 6 months, NSTE-ACS mortality rates may equal or exceed those By 12 months, rates of death, MI, and recurrent instability in contemporary registries are >10%. Early events are related to the ruptured coronary plaque and thrombosis, and later events are more closely associated with the pathophysiology of chronic atherosclerosis and LV systolic function.92 98 3.3.2. Estimation of Level of Risk At initial presentation, the clinical history, anginal symptoms and equivalents, physical examination, ECG, renal function, and cardiac troponin measurements can be integrated into an estimation of the risk of death and nonfatal cardiac ischemic events (Table 3 and Figure 2).42,78 3.3.2.1. History: Angina Symptoms and Angina Equivalents In patients with or without known CAD, clinicians must deter- mine whether the presentation is consistent with acute isch- emia, stable ischemic heart disease, or an alternative etiology. Factors in the initial clinical history related to the likelihood of acute ischemia include age, sex, symptoms, prior history of CAD, and the number of traditional risk factors.99 105 The characteristics of angina include deep, poorly localized chest or arm pain that is reproducibly associated with exertion or emotional stress.106 Angina is relieved promptly (ie, in <5 minutes) with rest and/or short-acting nitroglycerin. Patients with NSTE-ACS may have typical or atypical anginal symp- toms, but episodes are more severe and prolonged, may occur at rest, or may be precipitated by less exertion than the patient previously experienced. Some patients have no chest pain but present solely with dyspnea or with arm, shoulder, back, jaw, neck, epigastric, or ear discomfort.107 109 Features not characteristic of myocardial ischemia include: Pleuritic pain (sharp or knifelike pain provoked by res- piration or cough); Primary or sole location of discomfort in the middle or lower abdomen; Pain localized by the tip of 1 finger, particularly at the LV apex or costochondral junction; Pain reproduced with movement or palpation of the chest wall or arms; Brief episodes of pain lasting a few seconds or less; Pain that is of maximal intensity at onset; and Pain that radiates into the lower extremities. Evaluation should include the clinician s impression of whether the pain represents a high, intermediate, or low likeli- hood of acute ischemia. Although typical characteristics increase the probability of CAD, atypical features do not exclude ACS. In the Multicenter Chest Pain Study, acute ischemia was diagnosed in 22% of patients who presented to the ED with sharp or stabbing pain and in 13% of those with pleuritic pain.110 Seven percent of patients whose pain was reproduced with palpation had ACS. The ACI- TIPI (Acute Cardiac Ischemia Time-Insensitive Predictive Instrument) project found that older age, male sex, chest or left arm pain, and chest pain or pressure were the most important findings, and each increased the likelihood of ACS.111,112 The relief of chest pain with nitroglycerin is not predic- tive of ACS. One study reported that sublingual nitroglycerin relieved symptoms in 35% of patients with documented ACS compared with 41% of patients without ACS.113 The relief of chest pain by gastrointestinal cocktails (eg, mixtures of liq- uid antacids, and/or viscous lidocaine, and/or anticholinergic agents) does not predict the absence of ACS.114 3.3.2.2. Demographics and History in Diagnosis and Risk Stratification A prior history of MI is associated with a high risk of obstruc- tive and multivessel CAD.115 Women with suspected ACS are less likely to have obstructive CAD than men. When obstructive CAD is present in women, it tends to be less severe than it is in It has been suggested that coronary microvascular dis- ease and endothelial dysfunction play a role in the pathophysi- ology of NSTE-ACS in patients with nonobstructive CAD.116 Older adults have increased risks of underlying CAD,117,118 mul- tivessel CAD, and a worse prognosis (Section 7.1). A family history of premature CAD is associated with increased coronary artery calcium scores119 and increased risk of 30-day cardiac events in patients with ACS.120,121 Diabetes mellitus, extracardiac (carotid, aortic, or peripheral) arterial disease, and hypertension are major risk factors for poor out- comes in patients with ACS (Section 6.2) with both STEMI122 The current or prior use of aspirin at presentation is associated with increased cardiovascular risk,42 likely reflecting the greater probability that patients who have been prescribed aspirin have an increased cardiovascular risk profile and/or prior vascular Table 3. TIMI Risk Score* for NSTE-ACS TIMI Risk Score All-Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia Requiring Urgent Revascularization Through 14 d After Randomization, % *The TIMI risk score is determined by the sum of the presence of 7 variables at 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. CAD indicates coronary artery disease; ECG, electrocardiogram; Ml, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndromes; and TIMI, Thrombolysis In Myocardial Infarction. Modified with permission from Antman et al.42 Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e355 disease. Smoking is associated with a lower risk of death in primarily because of the younger age of smokers with ACS and less severe CAD. Overweight and/or obesity at ACS presentation are associated with lower short-term risk of death. The obesity paradox may be a function of younger age at presentation, referral for angiography at an earlier stage of dis- ease, and more aggressive management of ACS.123 These indi- viduals, especially those with severe obesity (body mass index >35), have a higher long-term total mortality risk.124 129 Cocaine use can cause ACS by inducing coronary vaso- spasm, dissection, thrombosis, positive chronotropic and hypertensive actions, and direct myocardial toxicity (Section Methamphetamines are also associated with ACS.131 Urine toxicology screening should be considered when sub- stance abuse is suspected as a cause of or contributor to ACS, especially in younger patients (<50 years of age).132 3.3.2.3. Early Estimation of Risk The TIMI risk score is composed of 7, 1-point risk indicators rated on presentation (Table 3).42 The composite endpoints increase as the score increases. The TIMI risk score has been validated internally within the TIMI 11B trial and in 2 separate cohorts of patients from the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non Q-Wave Coronary The TIMI risk score calculator is available at www.timi.org. The TIMI risk index is useful in predicting 30-day and 1-year mortality in patients with NSTE-ACS.134 For patients with a TIMI risk score of 0 and normal high-sen- sitivity cardiac troponin 2 hours after presentation, accelerated diagnostic protocols have been developed that predict a very low rate of 30-day MACE (Section 3.4.3).65 The GRACE risk model predicts in-hospital and post- discharge mortality or MI.44,78,79,81 The GRACE tool was developed from 11389 patients in GRACE and validated in subsequent GRACE and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) IIb cohorts. The sum of scores is applied to a reference nomogram to determine all-cause mortality from hospital discharge to 6 months. The GRACE clinical applica- tion tool is a web-based downloadable application available at http://www.outcomes-umassmed.org/grace/ (Figure 2).44,135 Among patients with a higher TIMI risk score (eg, 3), there is a greater benefit from therapies such as low-molecular- weight heparin (LMWH),133,136 platelet GP IIb/IIIa inhibitors,137 and an invasive strategy.138 Similarly, the GRACE risk model can identify patients who would benefit from an early invasive Patients with elevated cardiac troponin benefit from more aggressive therapy, whereas those without elevated car- diac troponins may not.140 This is especially true for women in whom some data suggest adverse effects from invasive thera- pies in the absence of an elevated cardiac troponin value.141 Although B-type natriuretic peptide and N-terminal pro B- type natriuretic peptide are not useful for the diagnosis of ACS per se (but rather HF, which has many etiologies), they add The 12-lead ECG is pivotal in the decision pathway for the eval- uation and management of patients presenting with symptoms suggestive of ACS.58,59,85 Transient ST changes ( 0.5 mm [0.05 mV]) during symptoms at rest strongly suggest ischemia and underlyingsevereCAD.Patientswithoutacuteischemicchanges on ECG have a reduced risk of MI and a very low risk of in- hospital life-threatening complications, even in the presence of confounding electrocardiographic patterns such as LV hypertro- ST depression (especially horizontal or downsloping) is highly suggestive of NSTE-ACS.21,146,147 Marked symmetrical precordial T-wave inversion ( 2 mm [0.2 mV]) suggests acute ischemia, particularly due to a critical stenosis of the left anterior descending coronary artery148,149 ; it may also be seen with acute pulmonary embolism and right-sided ST-T changes. Nonspecific ST-T changes (usually defined as ST devia- tion of <0.5 mm [0.05 mV] or T-wave inversion of <2 mm [0.2 mV]) are less helpful diagnostically. Significant Q waves 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 at an emergency facility, in patients whose symptoms suggest ACS I C 21 Perform serial ECGs at 15- to 30-min intervals during the first hour in symptomatic patients with initial nondiagnostic ECG I C N/A Measure cardiac troponin (cTnI or cTnT) in all patients with symptoms consistent with ACS* I A 21, 64, 67 71 Measure serial cardiac troponin I or T at presentation and 3 6 h after symptom onset* in all patients with symptoms consistent with ACS Use risk scores to assess prognosis in patients with NSTE-ACS I A 42 44, 75 80 Risk-stratification models can be useful in management IIa B 42 44, 75 81 Obtain supplemental electrocardiographic leads V7 in patients with initial nondiagnostic ECG at intermediate/high risk for ACS IIa B 82 84 Continuous monitoring with 12-lead ECG may be a reasonable alternative with initial nondiagnostic 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 87 91 *See Section 3.4, 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; cTnI, 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. Figure 2. Global Registry of Acute Coronary Events Risk Calculator for In-Hospital Mortality for Acute Coronary Syndrome. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e357 are less helpful, although by suggesting prior MI, they indi- cate a high likelihood of significant CAD. Isolated Q waves in lead 3 are a normal finding. A completely normal ECG in a patient with chest pain does not exclude ACS, because 1% to 6% of such patients will have a MI, and at least 4% will have Fibrinolytic therapy is contraindicated for patients with ACS without ST-elevation, except for those with electro- cardiographic evidence of true posterior MI (ie, ST-elevation in posterior chest leads [V7 ]). This can be evaluated when acute myocardial infarction (AMI) is suspected but electrocardiographic changes are modest or not present82 84 ; a transthoracic echocardiogram to evaluate for posterior wall motion abnormalities may also be helpful in this setting. Alternative causes of ST-T changes include LV aneurysm, pericarditis, myocarditis, bundle-branch block, LV hypertro- phy, hyperkalemia, Prinzmetal angina, early repolarization, apical LV ballooning syndrome (Takotsubo cardiomyopathy, Section 7.13), andWolff-Parkinson-White conduction. Central nervous system events and therapy with tricyclic antidepres- sants or phenothiazines can cause deep T-wave inversion. 3.3.2.5. Physical Examination The physical examination is helpful in assessing the hemodynamic impact of an ischemic event. Patients with suspected ACS should have vital signs measured (BP in both arms if dissection is sus- pected)andshouldundergoathoroughcardiovascularexamination. Patients with evidence of LV dysfunction on examination (eg, rales, gallop) or acute mitral regurgitation have a higher likelihood of severe underlying CAD and are at high risk of a poor outcome. In the SHOCK (Should we Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) study, NSTEMI accounted for Other trials have reported lower percentages.92,151 The physical examina- tion may also help identify comorbid conditions (eg, occult GI bleeding) that could impact therapeutic risk and decision making. See Online Data Supplement 2 for additional information on risk stratification. 3.4. Cardiac Biomarkers and the Universal Definition of MI: Recommendations See Table 5 for a summary of recommendations from this sec- tion and Online Data Supplement 3 for additional information on cardiac injury markers and the universal definition of AMI. 3.4.1. Biomarkers: Diagnosis Class I 1. Cardiac-specific troponin (troponin I or T when a contemporary assay is used) levels should be mea- sured at presentation and 3 to 6 hours after symp- tom onset in all patients who present with symptoms consistent with ACS to identify a rising and/or falling (Level of Evidence: A) 2. Additional troponin levels should be obtained beyond 6 hours after symptom onset in patients with normal troponins on serial examination when electrocardio- graphic changes and/or clinical presentation con- fer an intermediate or high index of suspicion for (Level of Evidence: A) 3. If the time of symptom onset is ambiguous, the time of presentation should be considered the time of onset for assessing troponin values.67,68,72 (Level of Evidence: A) Class III: No Benefit 1. With contemporary troponin assays, creatine kinase myocardial isoenzyme (CK-MB) and myoglobin are not useful for diagnosis of ACS.158 164 (Level of Evidence: A) 3.4.2. Biomarkers: Prognosis Class I 1. The presence and magnitude of troponin elevations are useful for short- and long-term prognosis.71,73,165,166 (Level of Evidence: B) Class IIb 1. It may be reasonable to remeasure troponin once on day 3 or day 4 in patients with MI as an index of infarct size and dynamics of necrosis.164,165 (Level of Evidence: B) 2. Use of selected newer biomarkers, especially B-type natriuretic peptide, may be reasonable to provide additional prognostic information.87,88,167 171 (Level of Evidence: B) Cardiac troponins are the mainstay for diagnosis of ACS and for risk stratification in patients with ACS. The primary diagnostic biomarkers of myocardial necrosis are cardiac troponin I and cardiac troponin T. Features that favor troponins for detection of ACS include high concentrations of troponins in the myo- cardium; virtual absence of troponins in nonmyocardial tissue; high-release ratio into the systemic circulation (amount found in blood relative to amount depleted from myocardium); rapid release into the blood in proportion to the extent of myocardial injury; and the ability to quantify values with reproducible, inexpensive, rapid, and easily applied assays. The 2012 Third Universal Definition of MI provides criteria that classify 5 clini- cal presentations of MI on the basis of pathological, clinical, and prognostic factors.21 In the appropriate clinical context, MI is indicated by a rising and/or falling pattern of troponin with 1 value above the 99th percentile of the upper reference level and evidence for serial increases or decreases in the levels of The potential consequences of emerging high- sensitivity troponin assays include increases in the diagnosis of influenced by the definition of an abnormal tro- The recommendations in this section are formu- lated from studies predicated on both the new European Society of Cardiology/ACC/AHA/World Health Organization criteria21 and previous criteria/ redefinitions of MI based on earlier-gener- ation troponin assays (Appendix 4, Table A). 3.4.3. Cardiac Troponins See Online Data Supplement 4 for additional information on cardiac troponins. Of the 3 troponin subunits, 2 subunits (troponin I and troponinT) are derived from genes specifically expressed in the myocardium. Cardiac troponin measurements provide highly sensitive results specific for detecting cardiomyocyte necrosis.34,173 Highly sensitive assays can identify cardiac troponin not only in the blood of patients with acute cardiac injury, but also in the blood of most healthy peo- As assay sensitivity increases, a greater proportion of patients will have detectable long-term elevations in troponin, thus requiring consideration of serial changes for the diagnosis of MI.Cliniciansshouldbeawareofthesensitivityofthetestsusedfor troponin evaluation in their hospitals and cutpoint concentrations for clinical decisions. Markedly elevated values are usually related to MI, myocarditis, rare analytical factors, or chronic elevations in patients with renal failure and in some patients with HF. CPGs endorse the 99th percentile of the upper reference level as the appropriate cutpoint for considering myocardial For the diagnosis of acute myocardial necrosis, it is important to determine not only the peak troponin value, but also serial changes: 1. A troponin value above the 99th percentile of the upper reference level is required. Additionally, evidence for a serial increase or decrease 20% is required if the initial value is elevated.21,178 2. For any troponin values below or close to the 99th percentile, evidence for acute myocardial necrosis is indicated by a change of 3 standard deviations of the variation around the initial value as determined by the 3. Clinical laboratory reports should indicate whether sig- nificant changes in cardiac troponin values for the par- ticular assay have occurred. Absolute changes in nanograms per liter of high-sensitivity cardiac troponin T levels appear to have a significantly higher diagnostic accuracy for AMI than relative changes and may distinguish AMI from other causes of high-sensitivity cardiac troponin T elevations.71 This has also been suggested for some Troponins are elevated in MI as early as and many medical centers obtain troponins at 3 hours. Depending on the assay, values may not become abnormal for up to 12 hours. In the vast majority of patients with symptoms suggestive ofACS, MI can be excluded or confirmed within 6 hours, because very few patients present immediately after symptom onset. In high-risk patients, mea- surements after 6 hours may be required to identify ACS. Solitary elevations of troponin cannot be assumed to be due to MI, because troponin elevations can be due to tachyarrhyth- mia, hypotension or hypertension, cardiac trauma, acute HF, myocarditis and pericarditis, acute pulmonary thromboembolic disease, and severe noncardiac conditions such as sepsis, burns, respiratory failure, acute neurological diseases, and drug toxicity (including cancer chemotherapy). Chronic elevations can result from structural cardiac abnormalities such as LV hypertrophy or ventricular dilatation and are also common in patients with renal Patients with end-stage renal disease and no clini- cal evidence of ACS frequently have elevations of cardiac tropo- With conventional assays, this is more common with cardiac troponin T than with cardiac troponin I.180 In the diagnosis of NSTEMI, cardiac troponin values must manifest an acute pat- tern consistent with the clinical events, including ischemic symp- toms and electrocardiographic changes. Troponin elevations may persist for up to 14 days or occasionally longer. There is a paucity of guidelines for establishment of reinfarction during the acute infarct period on the basis of troponin measurements. References suggest that an increase of >20% of previous troponin levels or an absolute increase of high-sensitivity cardiac troponin T values (eg, >7 ng/L over 2 hours) may indicate reinfarction.183 185 During pregnancy, troponin values are within the normal range in the absence of cardiovascular morbidities. There is controversy as to whether troponin levels are elevated in pre- eclampsia, eclampsia, or gestational hypertension.186 189 When present, cardiac troponin elevations reflect myocardial necrosis. Point-of-care troponin values may provide initial diagnostic information, although their sensitivity is substantially below that of central laboratory methods.154,155,190 192 In addition, the rigorous quantitative assay standardization needed for routine diagnosis favors central laboratory testing. Troponin elevations convey prognostic assessment beyond that of clinical information, the initial ECG, and the predischarge In addition, troponin elevations may provide infor- mationtodirecttherapy.Patientswithcardiactroponinelevations Table 5. Summary of Recommendations for Cardiac Biomarkers and the Universal Definition of MI Recommendations COR LOE References Diagnosis Measure cardiac-specific troponin (troponin I or T) at presentation and 3 6 h after symptom onset 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 electrocardiographic changes and/or intermediate/high risk clinical features Consider time of presentation the time of onset with ambiguous symptom onset for assessing troponin values With contemporary troponin assays, CK-MB and myoglobin are not useful for diagnosis of ACS III: No Benefit A 158 164 Prognosis Troponin elevations are useful for short- and long-term prognosis I B 71, 73, 165, 166 Remeasurement of troponin value once on d 3 or 4 in patients with MI may be reasonable as an index of infarct size and dynamics of necrosis BNP may be reasonable for additional prognostic information IIb B 87, 88, 167 171 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 MI, myocardial infarction. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e359 are at high risk and benefit from intensive management and early High risk is optimally defined by the changing pattern as described in Section 3.4.3. Cardiac troponin elevations correlate with estimation of infarct size and risk of death; persistent elevation 72 to 96 hours after symptom onset may afford relevant information in this regard.164 Elevations of cardiac troponin can occur for multiple reasons other than MI. In these cases, there is often substantial risk of adverse outcomes, as troponin elevation indicates cardiomyocyte necrosis.181 3.4.4. CK-MB and Myoglobin Compared With Troponin Previously, CK-MB was used for early evidence of myocar- dial injury. 