1.1. Initial evaluation

• Suspect acute coronary syndrome (ACS) in patients presenting with typical symptoms of pressure-type chest pain originating in the retrosternal area with a duration of pain ≥ 10 minutes. Patients may present with a variety of symptoms.
• Refer patients with high-risk features (retrosternal chest pain/pressure, severe dyspnea, syncope/presyncope, or palpitations) immediately to the emergency department for evaluation of their symptoms (Strong recommendation).
• Perform the following tests as part of the initial evaluation
  • 12-lead electrocardiogram (ECG) within 10 minutes of patient arrival (Strong recommendation)
  • Cardiac troponin I or T at presentation (Strong recommendation)
  • If high sensitivity cardiac troponin test available use
    • rapid rule out protocol at 0 and 3 hours (Strong recommendation)
    • rapid rule out protocol at 0 and 1 hours if validated 0 hour/1 hour algorithm available (Strong recommendation)
    • repeat after 3-6 hours if first two tests are inconclusive (Strong recommendation)
  • If high sensitivity cardiac troponin not available, repeat cardiac troponin measurement 3-6 hours after symptom onset (Strong recommendation)
  • If patients present within 3 hours of symptom onset, repeat measurements at 3-6 hours after symptom onset.

1.2. Risk stratification and diagnosis

• Risk stratify patients (such as using GRACE or TIMI scores) with suspected acute coronary syndrome (ACS) (Strong recommendation).
  • Consider admission for all high-risk or intermediate-risk patients.
  • Consider observation for low-risk patients.
• A diagnosis of ST-elevation myocardial infarction (STEMI) is made by electrocardiogram (ECG).
  • Specific ECG criteria (in the absence of left ventricular hypertrophy or left bundle branch block [LBBB]) are a new ST elevation and either of:
    • ≥ 2 mm (0.2 millivolts [mV]) in men or ≥ 1.5 mm (0.15 mV) in women in leads V2-V3
    • ≥ 1 mm (0.1 mV) in 2 other contiguous chest leads or limb leads
  • See ST-elevation myocardial infarction (STEMI) for details on the management of these patients.
• A diagnosis of non-ST-elevation acute coronary syndrome (non-STE ACS) is made using multiple clinical criteria.
  • These include the absence of ECG criteria for STEMI and at least 1 of the following:
    • typical symptoms of ischemia
    • cardiac biomarkers (preferably cardiac troponin) have ≥ 1 value > 99th percentile of upper reference limit - if so, this is also called non-ST-elevation myocardial infarction (NSTEMI)
    • ECG shows new or presumed-new significant, or dynamic ST-segment T-wave changes, new LBBB, or pathological Q waves
    • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
    • identification of intracoronary thrombus by angiography or autopsy
  • See Acute coronary syndromes for details on the management of these patients.

1.3. Initial management

4.1. Clinical presentation

• characteristics of acute ischemia-associated pain^(3, 4)
  • typical characteristics of angina related to myocardial ischemia
    • pain starts in retrosternal area and may radiate to one or both arms, neck, or jaw
    • occurs at rest or with minimal exertion
    • ≥ 10 minutes in duration
    • may be new-onset angina or angina with increased intensity
    • unrelieved within < 5 minutes of rest or nitroglycerin
  • atypical presentations may include absence of chest pain but discomfort in other areas, such as
    • arm
    • shoulder
    • back
    • neck
    • jaw
    • epigastric
    • ear
  • pain characteristics NOT typically related to myocardial ischemia
    • pleuritic pain
    • location of pain in middle or lower abdomen
    • pain localized by tip of 1 finger, at left ventricular apex or costochondral junction
    • pain associated with movement or palpation of chest wall or arms
    • duration of pain < few seconds
    • maximum intensity of pain is at onset
    • pain radiates into lower extremities
  • anginal equivalents include
    • new-onset or increased exertional dyspnea is most common
    • nausea
    • vomiting
    • diaphoresis
    • abdominal pain
    • syncope
    • unexplained fatigue
  • patients may have nocturnal angina
• probability of acute coronary syndrome increased in older patients with⁽³⁾
  • male sex
  • positive family history of coronary artery disease (CAD)
  • prior myocardial infarction (MI)
  • prior coronary revascularization
  • peripheral arterial disease
  • diabetes mellitus
  • renal insufficiency
• see also Acute coronary syndromes

4.2. History

4.3. Physical

4.4. Utility of clinical features for diagnosis of acute coronary syndrome

•  no clinical features alone appear useful for diagnosing acute coronary syndrome or acute myocardial infarction in patients with acute chest pain
  • based on systematic review
  • systematic review of 170 studies evaluating clinical features and electrocardiogram (ECG) for diagnosis of acute coronary syndrome or acute myocardial infarction
  • no single clinical feature useful for ruling in or out acute coronary syndrome but features appearing most helpful were
    • pain on palpation in analysis of 3 studies
    • pleuritic pain in analysis of 3 studies
    • completely normal electrocardiogram in analysis of 11 studies
  • Reference - Health Technol Assess 2004 Feb;8(2):iii

•  clinical details have limited role in predicting acute coronary syndrome or acute myocardial infarction in patients presenting to emergency room with chest pain
  • based on cohort study
  • 893 patients assessed in emergency room and reviewed 6 months later for presence of acute coronary syndrome or acute myocardial infarction
  • 34 patients (3.8%) had acute myocardial infarction and 81 patients (9.1%) had acute coronary syndrome
  • features associated with increased likelihood of diagnosis of acute myocardial infarction
    • pain radiating to the shoulder or both arms (positive likelihood ratio 4.07)
    • exertional pain (positive likelihood ratio 2.35)
  • features associated with increased likelihood of diagnosis of acute coronary syndrome
    • exertional pain (positive likelihood ratio 2.06)
    • pain radiating to the shoulder, the left arm, or both arms (positive likelihood ratio 1.62)
  • chest wall tenderness associated with decreased likelihood of acute myocardial infarction
  • no association between acute coronary syndrome/acute myocardial infarction and
    • location of pain
    • nature of pain
    • presence of associated
      • nausea or vomiting
      • diaphoresis
  • Reference - Acad Emerg Med 2002 Mar;9(3):203

•  chest wall tenderness may suggest low likelihood of acute coronary event
  • based on systematic review
  • systematic review of 16 cohort studies evaluating 1 of 10 signs and symptoms for diagnostic accuracy in acute myocardial infarction or acute coronary syndrome
  • prevalence was 11.6% for acute myocardial infarction and 26.3% for acute coronary syndrome
  • absence of chest wall tenderness for diagnosis of
    • acute myocardial infarction had pooled sensitivity 92% (95% CI 86%-96%) in analysis of 4 studies
    • acute coronary syndrome had pooled sensitivity 94% (95% CI 91%-96%) in analysis of 2 studies
  • no other sign or symptom had sufficient diagnostic accuracy for use in diagnosis or exclusion of acute myocardial infarction or acute coronary syndrome
  • Reference - Br J Gen Pract 2008 Feb;58(547):105 full-text
•  no characteristic of chest pain history alone or in combination appear to provide accurate diagnosis of acute coronary syndrome or acute myocardial infarction without further testing
  • based on systematic review
  • systematic review of 4 studies evaluating chest pain characteristics for diagnosis of acute myocardial infarction
  • chest pain factors associated with increased likelihood of acute myocardial infarction (positive likelihood ratio)
    • radiation to both arms or shoulders (4.1)
    • radiation to right arm or shoulder (4.7)
    • associated with exertion (2.4)
    • radiation to left arm (2.3)
    • associated with diaphoresis (2)
    • associated with nausea or vomiting (1.9)
    • worse than previous angina or similar to previous myocardial infarction (1.8)
    • described as pressure (1.3)
  • chest pain factors associated with decreased likelihood of acute myocardial infarction
    • described as pleuritic
    • described as positional
    • described as sharp
    • reproducible with palpation
    • inframammary location
    • not associated with exertion
  • Reference - JAMA 2005 Nov 23-30;294(20):2623, commentary can be found in JAMA 2006 May 17;295(19):2248, correction can be found in JAMA 2006 May 17;295(19):2250
  • DynaMed commentary -- elements with positive likelihood ratios are relatively weakly predictive of acute myocardial infarction without further testing
•  presence of reproducible chest wall tenderness may help rule out acute coronary syndrome in patients with acute chest pain (level 2 [mid-level] evidence)
  • based on diagnostic cohort study with possible selection bias and nonstandardized test under investigation
  • 121 consecutive patients with acute chest pain had palpation to detect presence or absence of reproducible chest wall tenderness (defined as self-reported pain that could be provoked in same quality and intensity by digital palpation over the region of complaints over the chest)
  • patients were included in study only if study investigator present in emergency unit of hospital
  • application of pressure for testing reproducible chest wall tenderness nonstandardized
  • reference standard was measurement of cardiac troponin and/or electrocardiogram (ECG)
  • prevalence of acute coronary syndrome was 12% by reference standard
  • diagnostic performance of nonreproducible chest wall tenderness for detecting acute coronary syndrome
    • sensitivity 92.9% (95% CI 66.1%-98.8%)
    • specificity 48.6% (95% CI 38.8%-58.5%)
    • positive predictive value 19.1% (95% CI 10.6%-30.5%)
    • negative predictive value 98.1% (95% CI 89.9%-99.7%)
  • Reference - BMJ Open 2015 Jan 28;5(1):e007442 full-text
•  differences in sex-specific diagnostic performance of chest pain characteristics appear small, and chest pain characteristics alone or in combination without additional clinical information do not appear helpful in identification of acute myocardial infarction
  • based on prospective cohort study
  • 2,475 consecutive patients presenting to the emergency department with acute chest pain evaluated, and sex-specific diagnostic performance of 34 chest pain characteristics in the early diagnosis of acute myocardial infarction assessed
  • 20.7% diagnosed with acute myocardial infarction (83.2% of these patients had non-ST-elevation acute myocardial infarction)
  • 31 of 34 chest pain characteristics had similar likelihood ratios for diagnosis of acute myocardial infarction in men and women
  • accuracy of all chest pain characteristics in the diagnosis of acute myocardial infarction low for both men and women (positive likelihood ratios near 1)
  • similar results noted for combinations of chest pain characteristics
  • Reference - JAMA Intern Med 2014 Feb 1;174(2):241, editorial can be found in JAMA Intern Med 2014 Feb 1;174(2):249
•  number of cardiac risk factors may have little diagnostic value for acute coronary syndrome
  • based on retrospective cohort study
  • 10,806 patients presenting to emergency department for suspected acute coronary syndrome included
  • 871 patients (8%) had acute coronary syndrome
  • cardiac risk factors were diabetes, hypertension, smoking, hypercholesterolemia, and family history of coronary artery disease
  • compared to 0 risk factors, likelihood ratio for 1-5 risk factors ranges from 1.05 to 1.71
  • Reference - Ann Emerg Med 2007 Feb;49(2):145

•  female sex and tachycardia each associated with increased likelihood of acute coronary syndrome presentation without chest pain in younger patients
  • based on prospective cohort study
  • 1,015 adults (30% women) ≤ 55 years old (median age 49 years) hospitalized for acute coronary syndrome (ACS) evaluated
  • increased risk of ACS presentation without chest pain
    • for women (adjusted odds ratio [OR] 1.95, 95% CI 1.23-3.11)
    • with tachycardia (adjusted OR 2.07, 95% CI 1.2-3.56)
  • among women, mean number of symptoms in general 3.5 in patients without chest pain vs. 5.8 in patients with chest pain (p < 0.001) (similar results in men)
  • no significant differences in ACS type, troponin level elevation, or coronary stenosis comparing patients with or without chest pain
  • Reference - JAMA Intern Med 2013 Nov 11;173(20):1863, editorial can be found in JAMA Intern Med 2013 Nov 11;173(20):1861

5.1. Testing overview

• 12-lead electrocardiogram (ECG)
  • 12-lead ECG should be evaluated within 10 minutes of patient arrival (ACC/AHA Class I, Level C)
  • if initial ECG nondiagnostic and patient remains symptomatic, repeat ECG at 15-minute to 30-minute intervals (ACC/AHA Class I, Level B)
  • if initial ECG is nondiagnostic, additional options include (ACC/AHA Class IIa, Level B)
    • supplemental ECG leads V7-V9
    • continuous 12-lead ECG monitoring
• cardiac biomarkers
  • measure cardiac troponin I or T in all patients with chest pain consistent with acute coronary syndrome (ACC/AHA Class I, Level A)
    • at presentation
    • 3-6 hours after symptom onset
    • beyond 6 hours if patient has initial normal serial troponins, ECG changes, moderate-to-high risk
  • if determination of time of symptom onset is ambiguous, consider time of presentation as time of symptom onset for assessing troponin levels

• see Acute coronary syndromes for additional testing

5.2. Definition of Acute Coronary Syndrome

• definition of acute coronary syndrome⁽³⁾
  • acute coronary syndrome includes spectrum of ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina (UA)
  • UA/NSTEMI is defined, in an appropriate clinical setting (chest discomfort or anginal equivalent), often accompanied by
    • electrocardiographic (ECG) ST-segment depression or prominent T-wave inversion and/or
    • positive biomarkers of necrosis (for example, troponin) in the absence of ST-segment elevation
  • NSTEMI differentiated from UA by presence of myocardial necrosis
  •  STEMI is diagnosed by ECG in the absence of left ventricular hypertrophy or left bundle branch block (LBBB) in the presence of new ST elevation (at J point) and either of:
    • ≥ 2 mm (0.2 millivolts [mV]) in men or ≥ 1.5 mm (0.15 mV) in women in leads V2-V3
    • ≥ 1 mm (0.1 mV) in 2 other contiguous chest leads or limb leads
    • see ST-elevation myocardial infarction (STEMI)

• European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and World Heart Federation (ESC/ACCF/AHA/WHF) 2012 universal definition of myocardial infarction
  • criteria for acute myocardial infarction - evidence of myocardial necrosis in clinical setting consistent with acute myocardial ischemia, as evidenced by any of
    • detection of rise and/or fall of cardiac biomarkers (preferably cardiac troponin [cTn]) with ≥ 1 value > 99th percentile of upper reference limit plus at least 1 of
      • symptoms of ischemia
      • new or presumed-new significant ST-segment T-wave changes or new left bundle branch block (LBBB)
      • development of pathological Q waves on electrocardiogram (ECG)
      • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
      • identification of intracoronary thrombus by angiography or autopsy
    • cardiac death with symptoms suggestive of myocardial ischemia and presumed-new ischemic ECG changes or new LBBB, but death occurring before blood samples obtained or before appearance of cardiac biomarkers in blood
    • for percutaneous coronary intervention-related myocardial infarction
      • in patients with normal baseline cTn levels, elevation of cTn values > 5 times 99th percentile of upper reference limit
      • in patients with baseline values elevated and stable or falling, rise of cTn values > 20%
      • plus 1 of
        • symptoms suggestive of myocardial ischemia
        • new ischemic ECG changes
        • angiographic findings consistent with procedural complication
        • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
    • stent thrombosis-related myocardial infarction detected by coronary angiography or autopsy in setting of myocardial ischemia and with rise and/or fall of cardiac biomarker values with ≥ 1 value > 99th percentile of upper reference limit
    • for coronary artery bypass graft-related myocardial infarction
      • in patients with normal baseline cTn levels, elevations of cardiac biomarkers > 10 times 99th percentile of upper reference limit indicates periprocedural myocardial necrosis
      • plus 1 of
        • new pathological Q waves or new LBBB
        • angiographic documented new graft or new native coronary artery occlusion
        • imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  • criteria for prior myocardial infarction - any of
    • pathological Q waves with or without symptoms in absence of nonischemic causes
    • imaging evidence of region of loss of viable myocardium that is thinned and fails to contract in absence of nonischemic cause
    • pathological findings of prior myocardial infarction
  • Reference - Eur Heart J 2012 Oct;33(20):2551 full-text, J Am Coll Cardiol 2012 Oct 16;60(16):1581, Circulation 2012 Oct 16;126(16):2020 full-text, Nat Rev Cardiol 2012 Nov;9(11):620 or at ESC 2012

• invasive strategy refers to diagnostic coronary angiography with intent to perform revascularization if appropriate based on coronary anatomy⁽³⁾
• ischemia-guided strategy refers to deferring coronary angiography unless patient develops refractory/recurrent ischemia or hemodynamic instability⁽³⁾

5.3. Electrocardiography (ECG)

• American College of Cardiology/American Heart Association (ACC/AHA) recommendations for ECG evaluation of patients with suspected acute coronary syndrome^(1, 3)
  • prehospital 12-lead ECG by emergency medical service providers is reasonable for chest pain patients suspected of acute coronary syndrome (ACS) (in such cases use of validated computer-generated interpretation algorithms recommended) (ACC/AHA Class IIa, Level B)
  • 12-lead ECG should be done and evaluated by experienced emergency physician within 10 minutes of patient arrival in emergency department (ACC/AHA Class I, Level C)
  • if initial ECG nondiagnostic and patient remains symptomatic and high clinical suspicion for acute coronary syndrome, perform serial ECGs, initially at 15-minute to 30-minute intervals (ACC/AHA Class I, Level B)
  • if initial ECG is nondiagnostic, additional options include (ACC/AHA Class IIa, Level B)
    • supplemental ECG leads V7-V9 to rule out myocardial infarction due to left circumflex occlusion
    • continuous 12-lead ECG monitoring

• European Society of Cardiology (ESC) recommendations for ECG evaluation of patients with suspected acute coronary syndrome
  • obtain 12-lead ECG within 10 minutes after first medical contact and have evaluated by experienced physician immediately (ESC Class I, Level B)
  • if initial ECG nondiagnostic and patient remains symptomatic, obtain additional 12-lead ECG (ESC Class I, Level B)
  • if 12-lead ECG nondiagnostic and ongoing ischemia is suspected, obtain ECG with supplemental leads (V3R, V4R, V7-V9) (ESC Class I, Level C)
  • Reference - Eur Heart J 2016 Jan 14;37(3):267

• findings⁽³⁾
  • with diagnostic implications include
    • transient ST changes (≥ 0.5 mm [0.05 mV]) during symptoms at rest - suggestive of ischemia/underlying coronary artery disease
    • ST depression - suggestive of non-ST-elevation acute coronary syndrome
    • symmetrical precordial T-wave inversion (≥ 2 mm [0.2 mV]) - suggestive of acute ischemia, acute pulmonary embolism, or right-sided ST-T changes
  • not specific for acute coronary syndrome include
    • ST deviation < 0.5 mm (0.05 mV)
    • T-wave inversion < 2 mm (0.2 mV)
    • significant Q waves
    • isolated Q waves in lead 3

•  compared to initial ECG, serial ECG may improve detection of acute coronary syndromes
  • based on prospective cohort study
  • 1,000 adults admitted for chest pain suspicious for coronary ischemia had initial ECG on presentation and at least 1 hour of automated serial 12-lead ECG monitoring (SECG)
    • initial ECG considered diagnostic if evidence of acute injury or ischemia
    • SECG considered diagnostic if evolving or new injury or ischemia with ST-segment measurement every 20 minutes
  • diagnostic standard was discharge diagnosis on chart review
  • comparing initial ECG vs. SECG
    • for acute coronary syndromes
      • sensitivity 27.5% vs. 34.2% (p < 0.0001)
      • specificity 97.1% vs. 99.4% (p < 0.01)
    • for myocardial infarction
      • sensitivity 55.4% vs. 68.1% (p < 0 .0001)
      • specificity not significantly different
  • actual effect on care not shown
  • Reference - Ann Emerg Med 1998 Jan;31(1):3, commentary can be found in ACP J Club 1998 Jul-Aug;129(1):15
•  out-of-hospital ECG appears highly specific for acute myocardial infarction and moderately specific for acute cardiac ischemia (level 2 [mid-level] evidence)
  • based on systematic review of mostly low-to-moderate diagnostic cohort studies
  • systematic review of 11 studies evaluating out-of-hospital ECG in 7,508 patients with suspected acute myocardial infarction or acute cardiac ischemia
  • reference standards not stated
  • range of prevalence
    • 46%-92% for acute coronary ischemia
    • 14%-51% for acute myocardial infarction
  • diagnostic performance of out-of-hospital ECG for diagnosing
    • acute myocardial infarction in analysis of 10 studies
      • sensitivity 68% (95% CI59%-76%)
      • specificity 97% (95% CI 89%-92%)
    • acute coronary ischemia in analysis of 5 studies
      • sensitivity 76% (95% CI 54%-89%)
      • specificity 88% (95% CI 67%-96%)
  • Reference - Ann Emerg Med 2001 May;37(5):461
•  combination of prehospital ECG and hospital ECG appears to have higher sensitivity than prehospital ECG alone for detection of acute coronary syndrome (level 2 [mid-level] evidence)
  • based on retrospective cohort study
  • 620 patients with chest pain symptoms had 12-lead ECG during prehospital period
  • acute coronary syndrome diagnosed in 179 patients (29%)
  • comparing prehospital ECG alone vs. in conjunction with hospital ECG
    • sensitivity 65.4% vs. 79.9% (p < 0.001)
    • specificity 66.4% vs. 61.2% (p < 0.001)
  • Reference - J Electrocardiol 2012 May-Jun;45(3):266 full-text
•  in patients with normal ECG, presence or absence of chest pain during ECG does not appear useful for diagnosing or ruling out acute coronary syndrome
  • based on cohort study
  • 387 patients (mean age 56 years) admitted to emergency department with cardiopulmonary symptoms who had normal ECG
  • 67% had chest pain during ECG
  • acute coronary syndrome diagnosed in 16% of patients with chest pain vs. 20% of patients without chest pain (not significant)
  • Reference - Acad Emerg Med 2009 Jun;16(6):495
•  presence of ST elevation or depression ≥ 1 mm in leads V1-V3 may be associated with acute myocardial infarction in patients with LBBB but may not rule out myocardial infarction if absent
  • based on systematic review with incomplete assessment of study quality
  • systematic review of 11 studies evaluating utility of Sgarbossa ECG algorithm in 2,100 patients with left bundle branch block (LBBB) and suspected acute myocardial infarction
  • study quality was assessed based only on robustness of reference standard, which included use of high-specificity cardiac markers and other methods not stated
  • prevalence of acute myocardial infarction was 55%
  • Sgarbossa ECG algorithm score evaluated in 10 studies with 1,614 patients
    • score ≥ 3 (defined as concordant ST elevation ≥ 1 mm or ST depression ≥ 1 mm in leads V1 to V3)
      • summary sensitivity 20%
      • summary specificity 98%
      • summary positive likelihood ratio 7.9
      • summary negative likelihood ratio 0.8
    • score ≥ 2 (ST deviation ≥ 5 mm)
      • summary sensitivities 20%-79%
      • summary specificities 61%-100%
      • summary positive likelihood ratios 0.7-6.6
      • summary negative likelihood ratios 0.2-1.1
  • Reference - Ann Emerg Med 2008 Oct;52(4):329, commentary can be found in Ann Intern Med 2009 Feb 17;150(4):JC2

5.4. Cardiac biomarkers

5.5. Clinical prediction rules

•  combination of single negative troponin and electrocardiogram at admission plus clinical judgment may safely rule out acute myocardial infarction in patients presenting to emergency department with suspected cardiac chest pain (level 2 [mid-level] evidence)
  • based on diagnostic cohort study without independent validation
  • 458 patients (mean age 64 years, 59% men) presenting to emergency department with suspected cardiac chest pain occurring within previous 24 hours had clinical assessment including electrocardiogram (ECG) and cardiac troponin measurement
    • clinical judgment of likelihood of acute myocardial infarction was rated on 5-point Likert scale ("definitely not," "probably not," "not sure," "probably," and "definitely")
    • clinicians were not blinded to ECG or other clinical information when making clinical judgment, but were blinded to admission troponin level
  • reference standard for acute myocardial infarction was rise or fall ≥ 20 ng/L (0.02 mcg/L) in serial cardiac troponin testing with at least 1 measurement above 99th percentile of upper reference limit
  • 17.7% had adjudicated diagnosis of acute myocardial infarction
  • for diagnosis of acute myocardial infarction with clinical judgment defined as positive for rating of "not sure," "probably," or "definitely"
    • clinical judgment plus ECG and high-sensitivity troponin assay had
      • sensitivity 100%
      • specificity 22.8%
      • positive predictive value 21.5%
      • negative predictive value 100%
    • clinical judgment alone had
      • sensitivity 95.1%
      • specificity 31.8%
      • positive predictive value 23.1%
      • negative predictive value 96.8%
  • for diagnosis of acute myocardial infarction with clinical judgment defined as positive for rating of "probably" or "definitely"
    • clinical judgment plus ECG and high-sensitivity troponin assay had
      • sensitivity 100%
      • specificity 46.6%
      • positive predictive value 28.4%
      • negative predictive value 100%
    • clinical judgment alone had
      • sensitivity 71.6%
      • specificity 69.2%
      • positive predictive value 33.3%
      • negative predictive value 91.8%
  • consistent findings with use of standard troponin assay instead of high-sensitivity troponin assay
  • Reference - Emerg Med J 2014 Nov;31(11):872
•  ADAPT-ADP for possible cardiac chest pain in the emergency department increases rate of successful early discharge compared to standard diagnostic protocol (level 1 [likely reliable] evidence)
  • based on randomized trial
  • 542 adults (mean age 60.5 years, 62% male) with acute chest pain consistent with acute coronary syndrome for whom further observation and troponin testing planned randomized to 1 of 2 interventions and followed for 30 days
    • ADAPT accelerated diagnostic protocol (ADAPT-ADP)
      • ECG and troponin test upon arrival with calculation of modified Thrombolysis in Myocardial Infarction (TIMI) score
      • if no new ischemia on ECG, negative troponin, and modified TIMI score 0, patients moved to observation bed without ECG monitoring
      • repeat ECG and troponin at 2 hours - if all tests negative, patients classified as low risk and discharged
      • all patients discharged following normal 2-hour tests scheduled for outpatient follow-up stress test at 72 hours
      • if any diagnostic test positive, or TIMI score ≥ 1, patients not considered low risk and managed according to standard care diagnostic protocol
    • standard diagnostic protocol - ECG and troponin test on arrival at hospital, prolonged observation, and second troponin test 6-12 hours after onset of pain
  • successful early discharge within 6 hours (no major adverse cardiac event within 30 days) in 19.3% with accelerated diagnostic protocol vs. 11% with standard protocol (p = 0.008, NNT 12)
  • no significant difference in major adverse cardiac events
  • Reference - JAMA Intern Med 2014 Jan;174(1):51, editorial can be found in JAMA Intern Med 2014 Jan;174(1):59
•  EDACS-ADP identifies patients with suspected ACS who are at low risk of major adverse cardiac events within 30 days who are eligible for early discharge (level 1 [likely reliable] evidence)
  • based on prognostic cohort study with independent derivation and validation cohorts and additional retrospective validation cohort study
  • derivation cohort included 1,974 patients (mean age 61 years) in emergency department in Australia with chest pain or other symptoms consistent with acute coronary syndrome (ACS) for ≥ 5 minutes who were followed for major adverse cardiac events (MACE) for 30 days
    • MACE defined as composite of cardiac death, myocardial infarction (with or without ST-elevation), emergency revascularization, cardiac arrest, cardiogenic shock, or high-degree atrioventricular block
    • patients with unstable presentation (abnormal vital signs, ongoing pain, or crescendo pattern) were excluded due to high risk for MACE at baseline
  • 15.5% had MACE within 30 days of hospital presentation
  • Emergency Department Assessment of Chest pain Score (EDACS) developed using factors significantly associated with risk of acute myocardial infarction in derivation cohort (range -8 to 34 points)
    • age
      • 2 points if aged18-45 years
      • 2 additional points for each 5-year increase in age > 45 years (up to 20 points)
    • 4 points if patient aged 18-50 years and either known coronary artery disease or ≥ 3 risk factors (family history of premature coronary artery disease, dyslipidemia, diabetes, hypertension, or current smoker)
    • 6 points if male sex
    • 3 points if diaphoresis symptoms present
    • 5 points if pain at presentation radiates to arm or shoulder
    • -4 points if pain at presentation occurred or worsened with inspiration
    • -6 points if pain at presentation is reproduced by palpation
  • online calculator can be found at Edaculator
  • EDACS-Accelerated Diagnostic Protocol (EDACS-ADP) predicts low risk of MACE within 30 days if all of
    • EDACS score < 16
    • no new ischemia on electrocardiogram
    • negative troponin tests at 0 and 2 hours
  • validation cohorts
    • Australian validation cohort included 608 similar patients
    • Canadian validation cohort included 763 patients ≥ 25 years old (mean age 58 years; 62% male) presenting with anterior or lateral chest pain
    • 13% in Australian validation cohort and 10.4% in Canadian validation cohort had MACE within 30 days of hospital presentation
  • 42.2% in derivation cohort, 51.3% in Australian validation cohort, and 41.6% in Canadian validation cohort were classified as low risk
  • performance of EDACS-ADP for identifying patients at low risk of MACE at 30 days

    	Derivation Cohort	Australian Validation Cohort	Canadian Validation Cohort
    Sensitivity	99%	100%	100%
    Specificity	49.9%	59%	46.4%
    Positive predictive value	26.5%	26.7%	17.5%
    Negative predictive value	99.6%	100%	100%

  • References
    • derivation and Australian validation study Emerg Med Australas 2014 Feb;26(1):34
    • Canadian validation study Emerg Med J 2016 Sep;33(9):618
•  in patients with suspected acute myocardial infarction, EDACS-ADP correctly identifies more low-risk patients eligible for early discharge than ADAPT-ADP (level 1 [likely reliable] evidence)
  • based on randomized trial
  • 558 patients (mean age 59 years) with suspected acute myocardial infarction were randomized to evaluation using EDACS-ADP vs. ADAPT-ADP and followed for 30 days
  • treating physicians could use evaluation to aid discharge decision, but final clinical management at their discretion
  • successful early discharge defined as emergency room discharge within 6 hours and no MACE within 30 days
  • 11.8% had MACE within 30 days (adjudicated by blinded outcome assessors)
  • comparing EDACS-ADP vs. ADAPT-ADP
    • patients identified as low-risk of 30-day MACE 41.6% vs. 30.5% (95% CI for difference 2.8%-19.4%) (no low-risk patients had MACE)
    • successful early discharge in 32.3% vs. 34.4% (not significant)
  • Reference - Ann Emerg Med 2016 Jul;68(1):93 full-text
• prediction rule incorporating automated assay for heart-type fatty acid binding protein for stratifying risk of ACS and 30-day risk of major cardiac adverse events in patients with suspected cardiac chest pain can be found in Emerg Med J 2015 Oct;32(10):769

6.1. Ischemia-guided therapy vs. early invasive strategy

• recommendations for ischemia-guided therapy vs. early invasive therapy in patients with non-ST-elevation acute coronary syndrome
  • American College of Cardiology/American Heart Association (ACC/AHA) recommendations⁽³⁾
    • invasive strategy includes diagnostic coronary angiography with intent to perform revascularization if appropriate based on coronary anatomy
      • immediate invasive strategy indicated, unless contraindicated, in patients with non-ST-elevation acute coronary syndrome with (ACC/AHA Class I, Level A)
        • refractory angina
        • hemodynamic instability
        • electrical instability
      • early invasive strategy (≤ 24 hours post admission)
        • indicated, unless contraindicated, in patients with initial stabilization of non-ST-elevation acute coronary syndrome but increased risk for clinical events (ACC/AHA Class I, Level B)
        • not indicated in patients with
          • serious comorbidities, whereby risk may outweigh benefit of revascularization (ACC/AHA Class III, Level C)
          • acute chest pain and low likelihood of acute coronary syndrome (ACC/AHA Class III, Level C) who are also negative for cardiac biomarkers, particularly women (ACC/AHA Class III, Level B)
      • delayed invasive strategy (25-72 hours post admission) reasonable in patients with initial stabilization without high/intermediate risk for clinical events (ACC/AHA Class IIa, Level B)
    • ischemia-guided strategy involves deferring coronary angiography unless patient develops refractory/recurrent ischemia or hemodynamic instability
      • consider ischemia-guided strategy, unless contraindicated, for patients with initial stabilization of non-ST-elevation acute coronary syndrome with risk of clinical events (ACC/AHA Class IIb, Level B)
      • reasonable to use ischemia-guided strategy after clinical and patient preferences have been considered (ACC/AHA Class IIb, Level C)
    • summary of considerations for invasive and ischemia-guided strategies
      • immediate invasive strategy (within 2 hours)
        • refractory angina
        • signs or symptoms of heart failure or new or worsening mitral regurgitation
        • hemodynamic instability
        • recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy
        • sustained ventricular fibrillation or ventricular tachycardia
      • early invasive strategy (within 24 hours)
        • none of the above but Global Registry of Acute Coronary Events (GRACE) risk score > 140
        • temporal change in troponin
        • new or presumably new ST depression
      • delayed invasive strategy (within 25-72 hours)
        • none of the above but diabetes mellitus
        • renal insufficiency (glomerular filtration rate < 60 mL/minute/1.73 m²)
        • reduced left ventricular systolic function (ejection fraction < 0.4)
        • early postinfarction angina
        • percutaneous coronary intervention within 6 months
        • prior coronary artery bypass graft
        • GRACE risk score 109-140, Thrombolysis in Myocardial Infarction (TIMI) score ≥ 2
      • ischemia-guided strategy
        • low-risk score (TIMI score 0 or 1, GRACE score < 109)
        • low-risk troponin-negative female patients
        • patient or clinician preference in the absence of high-risk features
  • European Society of Cardiology (ESC) recommendations
    • immediate (< 2 hours) invasive strategy recommended in patients with ≥ 1 very high-risk features, including (ESC Class I, Level C)
      • hemodynamic instability or cardiogenic shock
      • recurrent or ongoing chest pain refractory to medical treatment
      • life-threatening arrhythmias or cardiac arrest
      • mechanical complications of myocardial infarction
      • acute heart failure with refractory angina or ST deviation
      • recurrent dynamic ST- or T-wave changes (particularly with intermittent ST-elevation)
    • early (< 24 hours) invasive strategy recommended in patients with ≥ 1 high-risk features, including (ESC Class I, Level A)
      • rise or fall in cardiac troponin compatible with myocardial infarction
      • dynamic ST- or T-wave changes (with or without symptoms)
      • Global Registry of Acute Coronary Event (GRACE) score > 140
    • invasive strategy (< 72 hours) recommended in patients with ≥ 1 intermediate-risk features, including (ESC Class I, Level A)
      • diabetes
      • renal insufficiency (estimated glomerular filtration rate [eGFR] < 60 mL/minute/1.73 m²)
      • left ventricular ejection fraction (LVEF) < 40% or heart failure
      • early post-infarction angina
      • recent CABG
      • GRACE score 110-139 (see acute coronary syndromes for information on Grace score)
      • recurrent symptoms
      • known ischemia on non-invasive testing
    • in patients without intermediate-risk features, and no recurrent symptoms, use non-invasive testing (preferably with imaging) before deciding on invasive testing (ESC Class I, Level A)
    • Reference - Eur Heart J 2016 Jan 14;37(3):267

6.2. Revascularization for acute coronary syndrome

• American College of Cardiology/American Heart Association (ACC/AHA) recommendations
  • recommendations for percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG) for patients with unstable angina/NSTEMI
    • coronary artery bypass graft (CABG) recommended
      • for patients with significant left main coronary artery disease (CAD) (> 50% stenosis) (ACC/AHA Class I, Level A)
      • for patients with 3-vessel disease (survival benefit greater in patients with left ventricular ejection fraction [LVEF] < 50%) (ACC/AHA Class I, Level A)
      • for patients when percutaneous revascularization not optimal or possible and ongoing ischemia not responsive to maximal nonsurgical therapy (ACC/AHA Class I, Level B)
    • other clinical scenarios
      • 1- or 2-vessel CAD
        • proximal left anterior descending CAD
          • percutaneous coronary intervention (PCI) or CABG recommended for patients with 2-vessel disease with significant proximal left anterior descending CAD and either abnormal left ventricular function (LVEF < 50%) or ischemia on noninvasive testing (ACC/AHA Class I, Level A)
          • CABG reasonable for patients with 1-vessel disease with significant proximal left anterior descending CAD (ACC/AHA Class IIa, Level B)
        • 1- or 2-vessel CAD regardless of extent of involvement of proximal left anterior descending CAD
          • PCI or CABG recommended if large area of viable myocardium and high-risk criteria on noninvasive testing (ACC/AHA Class I, Level B)
          • PCI or CABG reasonable if moderate area of viable myocardium and ischemia on noninvasive testing (ACC/AHA Class IIa, Level B)
          • Use new-generation drug eluting stents for patients undergoing PCI (ESC Class I, Level A)
      • multivessel CAD
        • PCI or CABG recommended for patients with suitable coronary anatomy, normal left ventricular function, and without diabetes mellitus (ACC/AHA Class I, Level A)
        • CABG recommended for multivessel coronary disease in patients without diabetes who have suitable coronary anatomy and normal left ventricular function (ACC/AHA Class I, Level A)
        • PCI may be considered in patients with 2- or 3-vessel disease, significant proximal left anterior descending CAD, and treated diabetes or abnormal left ventricular function, with anatomy suitable for catheter-based therapy (ACC/AHA Class IIb, Level B)
        • CABG or PCI with stenting reasonable for patients with multivessel disease and symptomatic myocardial ischemia (ACC/AHA Class IIb, Level B)
        • PCI of nonculprit lesions may be considered for patients having revascularization for non-ST-elevation acute coronary syndrome (ACC/AHA Class IIb, Level B)
      • PCI reasonable for patients who are not candidates for surgery and have any of
        • focal saphenous vein graft lesions or multiple stenoses who are poor candidates for reoperative surgery (ACC/AHA Class IIa, Level C)
        • significant unprotected left main CAD (> 50% diameter stenosis) who are candidates for revascularization but not eligible for CABG or who need emergent intervention at angiography for hemodynamic instability (ACC/AHA Class IIa, Level B)
• efficacy of revascularization for acute coronary syndrome
  • routine invasive strategy associated with similar overall mortality and major cardiac events, with reduced risk of rehospitalization, compared to selective invasive strategy, although early mortality may be higher with routine invasive strategy (level 2 [mid-level] evidence)
  • early revascularization early revascularization and deferred revascularization associated with similar risks of mortality or recurrent myocardial infarction, but early revascularization may reduce risk for refractory ischemia and major bleeding (level 2 [mid-level] evidence)
  • special populations
    • routine invasive strategy may reduce risk of rehospitalization in patients with chronic kidney disease (level 2 [mid-level] evidence)
    • early invasive approach may reduce risk of death or myocardial infarction in elderly patients with acute coronary syndrome, but increased risk of bleeding in patients > 75 years old (level 2 [mid-level] evidence)
• see Revascularization for acute coronary syndrome for additional information

6.3. Revascularization for ST-elevation acute myocardial infarction

• primary percutaneous coronary intervention (PCI)
  • recommended in patients with ST-elevation myocardial infarction (STEMI) and symptoms < 12 hours, when PCI can be done in timely fashion (ACCF/AHA Class I, Level A)
    • specifically within 90 minutes of first medical contact (or within 120 minutes of first medical contact if transfer needed to hospital with PCI capability) (ACCF/AHA Class I, Level B)
    • primary PCI may reduce mortality and rates of reinfarction and stroke compared to thrombolytics in patients with STEMI (level 2 [mid-level] evidence)
    • in STEMI patients presenting to hospitals without PCI capability, transfer for PCI may reduce 30-day mortality and rates of reinfarction and stroke compared to on-site thrombolysis (level 2 [mid-level] evidence)
  • recommended as soon as possible (regardless of time delay) if
    • STEMI and symptoms < 12 hours, and contraindication to fibrinolytic therapy (ACCF/AHA Class I, Level B)
    • STEMI and acute severe heart failure or cardiogenic shock (ACCF/AHA Class I, Level B); early revascularization improves survival (level 1 [likely reliable] evidence), but benefit may be limited to patients < 75 years old (level 2 [mid-level] evidence)
  • reasonable for patients with STEMI and ongoing ischemia 12-24 hours after symptom onset (ACCF/AHA Class IIa, Level B)
• urgent coronary artery bypass graft (CABG) indicated for patients with STEMI and coronary anatomy not amenable to PCI if ongoing or recurrent ischemia, cardiogenic shock, severe heart failure, or other high-risk features (ACCF/AHA Class I, Level B)
• delayed PCI (in patients treated with fibrinolysis or no reperfusion)
  • recommended if cardiogenic shock or acute severe heart failure (ACCF/AHA Class I, Level B)
  • recommended if ischemia on noninvasive ischemia testing (ACCF/AHA Class I, Level B) or spontaneous or provoked by minimal exertion during hospitalization (ACCF/AHA Class I, Level C)
  • reasonable for patients with evidence of failed reperfusion or reocclusion after fibrinolytic therapy (ACCF/AHA Class IIa, Level B); rescue PCI after failed thrombolysis may reduce risk for reinfarction and heart failure but increase risk for stroke (level 2 [mid-level] evidence)
  • reasonable 3-24 hours after successful fibrinolytic therapy (ACCF/AHA Class IIa, Level B); PCI within 24 hours after fibrinolysis associated with reduced reinfarction rates in patients with STEMI (level 2 [mid-level] evidence)
• adjunctive medications for PCI
  • give aspirin 162-325 mg before primary PCI (ACCF/AHA Class I, Level B)
  • give loading dose of P2Y12 inhibitor before or at time of primary PCI using 1 of
    • clopidogrel 600 mg (ACCF/AHA Class I, Level B), or 300 mg if thrombolytics received in prior 24 hours (ACCF/AHA Class I, Level C)
    • prasugrel 60 mg (ACCF/AHA Class I, Level B), but contraindicated if history of stroke or transient ischemic attack (ACCF/AHA Class III Harm, Level B)
    • ticagrelor 180 mg (ACCF/AHA Class I, Level B)
  • IV glycoprotein (GP) IIb/IIIa inhibitors are reasonable in selected patients (for example, patients with large thrombus burden or inadequate P2Y12 inhibitor loading) using 1 of abciximab (ACCF/AHA Class IIa, Level A), high-bolus-dose tirofiban (ACCF/AHA Class IIa, Level B), or double-bolus eptifibatide (ACCF/AHA Class IIa, Level B)
  • recommended anticoagulant therapy options for STEMI is either
    • unfractionated heparin in patients having primary PCI (ACCF/AHA Class I, Level C) or PCI after fibrinolytic therapy (ACCF/AHA Class I, Level C)
      • if GP IIb/IIIa inhibitor - 50-70 units/kg IV boluses to maintain activated clotting time 200-250 seconds
      • if no GP IIb/IIIa inhibitor - 70-100 units/kg IV boluses to maintain activated clotting time 250-300 seconds (by Hemotec) or 300-350 seconds (by Hemochron)
    • bivalirudin (0.75 mg/kg IV bolus, then 1.75 mg/kg/hour infusion) in patients having primary PCI (ACCF/AHA Class I, Level B); bivalirudin associated with reduced bleeding and mortality compared to heparin plus GP IIb/IIIa inhibitor (level 2 [mid-level] evidence)
  • after PCI continue aspirin indefinitely (ACCF/AHA Class I, Level A) and P2Y12 inhibitor for at least 12 months if stent (ACCF/AHA Class I, Level B)
• procedure considerations for PCI
  • radial approach associated with reduced mortality and vascular complications compared to femoral approach for primary PCI for STEMI (level 2 [mid-level] evidence)
  • multivessel revascularization (sequential or simultaneous) during hospitalization for STEMI associated with reduced long-term rate of repeat hospitalization or repeat revascularization compared to primary PCI for infarct-related artery alone (level 2 [mid-level] evidence) but PCI in noninfarct artery not recommended at time of primary PCI in patients without hemodynamic compromise (ACCF/AHA Class III Harm, Level B)
  • aspiration thrombectomy not routinely indicated for patients undergoing primary PCI
    • routine manual thrombus aspiration prior to PCI for STEMI may increase 30-day stroke risk and does not appear to reduce 6-month risk of cardiovascular events (level 2 [mid-level] evidence)
    • manual thrombus aspiration prior to PCI may not reduce 30-day or 1-year mortality in patients with STEMI (level 2 [mid-level] evidence)
  • stenting considered useful in primary PCI (ACCF/AHA Class I, Level A)
    • drug-eluting stent reasonable for patients able to tolerate and comply with dual antiplatelet therapy (ACCF/AHA Class I, Level C)
    • stenting may reduce angina and repeat target vessel revascularization in patients having coronary angioplasty for acute myocardial infarction (level 2 [mid-level] evidence)

• see Percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) for STEMI for additional information

6.4. Medications for initial management

• medications for initial management are given to relieve ischemia and prevent myocardial infarction and death⁽³⁾

• oxygen^(1, 3)
  • give supplemental oxygen if (ACC/AHA Class I, Level B)
    • arterial saturation < 90% (pulse oximetry useful for continuous measurement of oxygen saturation [SaO₂])
    • respiratory distress
    • other high-risk features for hypoxemia
  • reasonable to give supplemental oxygen to all patients during first 6 hours after presentation (ACC/AHA Class IIa, Level C)
•  anticoagulant therapy
  • for all patients with acute coronary syndrome
    • American College of Cardiology/American Heart Association (ACC/AHA) recommendations
      • give aspirin 162-325 mg (chewed) to patients with unstable angina/non-ST-elevation myocardial infarction (NSTEMI) as soon as possible after hospital presentation and continue indefinitely (maintenance dose 81-325 mg/day) in patients who tolerate it (ACC/AHA Class I, Level A)
      • if unable to take aspirin, give clopidogrel (ACC/AHA Class I, Level B) or ticagrelor (ACC/AHA Class I, Level B)
      • add anticoagulant therapy (unfractionated heparin (UFH), enoxaparin, bivalirudin, or fondaparinux) to antiplatelet therapy as soon as possible after presentation (ACC/AHA Class I, Level A)
    • European Society of Cardiology (ESC) recommendations
      • give aspirin at initial oral loading dose of 150-300 mg (in aspirin naive patients) and maintenance dose of 75-100 mg/day long-term regardless of treatment strategy (ESC Class I, Level A)
      • in addition to aspirin, give P2Y₁₂ inhibitor (tricagrelor, prasugrel, or clopidrogel) orally for 12 months unless patient has contraindications (such as excessive risk of bleeding) (ESC Class I, Level A)
      • give parenteral anticoagulation at time of diagnosis according to both ischemic and bleeding risks (ESC Class I, Level B)
    • efficacy
      • low-molecular-weight heparin may reduce risk of myocardial infarction but does not appear to reduce mortality in patients with acute coronary syndrome (level 2 [mid-level] evidence)
      • enoxaparin is more effective than UFH for reducing subsequent myocardial infarction in patients with ST-elevation myocardial infarction (level 1 [likely reliable] evidence) and possibly in patients with non-ST-elevation acute coronary syndrome (level 2 [mid-level] evidence)
  • for patients having initial conservative (noninvasive) strategy, start dual antiplatelet therapy with aspirin and anticoagulants plus
    • ticagrelor or clopidogrel (loading dose followed by daily maintenance dose) (ACC/AHA Class I, Level B; ACCP Grade 1B)
    • ticagrelor preferred over clopidogrel (ACC/AHA Class IIa, Level B; ACCP Grade 2B)
      • ticagrelor may reduce risk for death and myocardial infarction compared to clopidogrel in patients with acute coronary syndrome (level 2 [mid-level] evidence)
      • addition of clopidogrel to aspirin may reduce morbidity and mortality in acute coronary syndrome (level 2 [mid-level] evidence)
      • FDA recommends AGAINST coadministration of clopidogrel (Plavix) and omeprazole (Prilosec/Prilosec OTC); some studies find increased rate of adverse events from combination of gastric acid suppressing agents and clopidogrel (level 2 [mid-level] evidence) but randomized trial suggested addition of omeprazole to clopidogrel may reduce gastrointestinal events without increasing cardiovascular events (level 2 [mid-level] evidence)
  • for patients having initial invasive strategy, start dual antiplatelet therapy upstream of diagnostic angiography with aspirin and anticoagulants plus
    • ticagrelor or clopidogrel (loading dose followed by daily maintenance dose) (ACC/AHA Class I, Level B; ACCP Grade 1B)
    • ticagrelor preferred over clopidogrel (ACC/AHA Class IIa, Level B)
    • IV glycoprotein IIb/IIIa inhibitor (eptifibatide or tirofiban) in addition to aspirin and ticagrelor or clopidogrel in high-risk patients such as those with elevated troponin levels, diabetes, or significant ST-segment depression NOT at high risk for bleeding (ACC/AHA Class IIb, Level B)
      • glycoprotein IIb/IIIa inhibitors as initial medical treatment for non-ST-elevation acute coronary syndrome might reduce mortality at 30 days but may also increase major bleeding (level 2 [mid-level] evidence)
      • triple antiplatelet therapy including glycoprotein IIb/IIIa inhibitors associated with lower myocardial infarction rate than dual antiplatelet therapy in patients with non-ST-elevation acute coronary syndrome (level 2 [mid-level] evidence)
    • prasugrel 60 mg then 10 mg once daily (but consider 5 mg once daily if < 60 kg [132.3 lbs]) is an option at time of percutaneous coronary intervention (PCI) (ACC/AHA Class I, Level B; ACCP Grade 1B)
      • prasugrel associated with reduced rate of myocardial infarction but increased rate of major and fatal bleeding compared to clopidogrel in patients with acute coronary syndromes having PCI (level 2 [mid-level] evidence)
  • after further risk stratification and planning of revascularization approach, antiplatelet and anticoagulation therapy recommendations are modified
  • long-term antiplatelet therapy includes
    • aspirin indefinitely (ACC/AHA Class I, Level A)
    • ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for ≥ 1 year depending on prior treatment strategies (ACC/AHA Class I, Level B)
    • prasugrel 10 mg once daily for ≥ 1 year for patients with stent implantation (ACC/AHA Class I, Level B)
  • additional considerations
    • addition of direct factor Xa inhibitors to antiplatelet therapy for 6-13 months may reduce major adverse cardiovascular events but increase risk of clinically significant bleeding in patients with acute coronary syndrome (level 2 [mid-level] evidence); uncertain if any net clinical benefit
    • in patients with chronic kidney disease, antiplatelet therapy (for acute coronary syndrome or PCI) may increase risk for bleeding and may not reduce myocardial infarction, stroke, or mortality (level 2 [mid-level] evidence)
  • see Antiplatelet and anticoagulant drugs for acute coronary syndromes for details
• nitrates
  • American College of Cardiology/American Heart Association (ACC/AHA) recommendations^(1, 3)
    • reasonable for healthcare providers to advise patients who tolerate nitroglycerin to repeat nitroglycerin every 5 minutes for up to 3 doses while awaiting arrival of prehospital emergency medical service personnel (ACC/AHA Class IIa, Level C)
    • give sublingual nitroglycerin 0.3-0.4 mg every 5 minutes for total of 3 doses to patients with acute coronary syndrome and ongoing ischemic discomfort, then assess for need for IV nitroglycerin, if not contraindicated (ACC/AHA Class I, Level C)
    • IV nitroglycerin
      • indicated in first 48 hours after unstable angina/non-ST-elevation myocardial infarction (STEMI) for treatment of persistent ischemia, heart failure, or hypertension (ACC/AHA Class I, Level B)
      • should not preclude therapy with other proven mortality-reducing interventions (such as beta blockers or angiotensin-converting enzyme [ACE] inhibitors) (ACC/AHA Class I, Level B)
    • nitrates should not be given if use of phosphodiesterase inhibitor for erectile dysfunction within 24 hours (sildenafil) or 48 hours (tadalafil) (safe interval not yet determined for vardenafil) (ACC/AHA Class III, Level B)
    • additional contraindications to nitrates include (ACC/AHA Class III, Level C)
      • systolic blood pressure < 90 mm Hg or ≥ 30 mm Hg below baseline
      • severe bradycardia (< 50 beats/minute)
      • tachycardia (> 100 beats/minute) in absence of symptomatic heart failure
      • right ventricular infarction
    • before hospital discharge, give all patients sublingual or spray nitroglycerin and provide instructions for its use to treat ischemic symptoms (ACC/AHA Class I, Level C)
  • European Society of Cardiology (ESC) 2015 guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation
    • in patients with recurrent angina, uncontrolled hypertension, or signs of heart failure, give sublingual or IV nitrates for angina relief (ESC Class I, Level C )
    • in patients with suspected/confirmed vasospastic angina, avoid beta blockers and consider nitrates and calcium channel blockers (ESC Class IIa, Level B )
    • Reference - Eur Heart J 2016 Jan 14;37(3):267
• morphine⁽³⁾
  • if no contraindications, reasonable to give morphine sulfate IV if ischemic chest discomfort despite treatment with maximally tolerate anti-ischemic medications (ACC/AHA Class IIb, Level B)
• beta blockers^(1, 3)
  • start oral beta blocker within first 24 hours in patients who do not have any of (ACC/AHA Class I, Level A)
    • signs of heart failure
    • evidence of a low-output state
    • increased risk for cardiogenic shock; risk increases with
      • age > 70 years
      • systolic blood pressure < 120 mm Hg
      • sinus tachycardia > 110 beats/minute
      • heart rate < 60 beats/minute
      • increased time since symptom onset
    • other relative contraindications to beta blockade
      • PR interval > 0.24 seconds
      • second- or third-degree heart block
      • active asthma or reactive airway disease
  • sustained release metoprolol succinate, carvedilol, or bisoprolol recommended for patients with all of (ACC/AHA Class I, Level C)
    • non-ST-elevation acute coronary syndrome
    • stabilized heart failure
    • reduced systolic function
  • if patient initially has contraindications to beta blockers, reevaluate to determine subsequent eligibility (ACC/AHA Class I, Level C)
  • reasonable to continue beta blocker therapy in patients with normal left ventricular function (ACC/AHA Class IIa, Level C)
  • do not give IV beta blockers to patients who have risk factors for shock (ACC/AHA Class III, Level B)
  • in patients with ongoing ischemic symptoms, initiate beta blockers early if not contraindicated (ESC Class I, Level B ) (Eur Heart J 2016 Jan 14;37(3):267)
  • in patients with suspected/confirmed vasospastic angina, avoid beta blockers and consider calcium channel blockers and nitrates (ESC Class IIa, Level B ) (Eur Heart J 2016 Jan 14;37(3):267)
• nonsteroidal antiinflammatory drugs (NSAIDs)⁽³⁾
  • do not give nonsteroidal anti-inflammatory drugs (NSAIDs) (except aspirin) and discontinue prior NSAID use during hospitalization for unstable angina/NSTEMI due to increased risk of mortality or complications (ACC/AHA Class III, Level B)
• see Acute coronary syndromes for additional information

6.5. Discharge from emergency department or chest pain unit

• American College of Cardiology/American Heart Association (ACC/AHA) recommendations⁽³⁾
  • for patients with symptoms consistent with acute coronary syndrome (ACS) but with normal initial electrocardiogram (ECG) and cardiac troponin levels
    • reasonable to observe in chest pain unit or telemetry unit with serial ECG and cardiac troponin measurements at 3- to 6-hour intervals (ACC/AHA Class IIa, Level B)
    • reasonable to perform treadmill ECG (ACC/AHA Class IIa, Level A), stress myocardial perfusion study, or stress echocardiography before discharge or ≤ 72 hours after discharge (ACC/AHA Class IIa, Level B)
    • for patients with no history of coronary artery disease, reasonable to initially perform
      • coronary computed tomography (CT) angiography to assess coronary artery anatomy (ACC/AHA Class IIa, Level A)
      • rest myocardial perfusion imaging with technetium-99m radiopharmaceutical to rule out myocardial ischemia (ACC/AHA Class IIa, Level B)
  • for low-risk patients referred for outpatient testing, reasonable provide to provide instructions about activity level and follow-up with clinician, and reasonable to give medications, such as (ACC/AHA Class IIa, Level C)
    • daily aspirin
    • short-acting nitroglycerin
    • other appropriate medications (such as beta blockers)
• see Acute coronary syndromes for additional follow-up information

7.1. Global registry of acute coronary events (GRACE) score

•  GRACE risk calculator predicts 6-month postdischarge mortality after ACS (level 1 [likely reliable] evidence)
  • based on prognostic cohort study with independent derivation and validation cohorts
  • derivation cohort included 15,007 patients with acute coronary syndrome (ACS) discharged alive from hospital from 1999 to 2002 who had complete 6-month follow-up data
  • validation cohort included 7,638 patients with acute coronary syndrome admitted from 2002 to 2003
  • 6-month all-cause mortality was 4.8% in derivation and 4.7% in validation cohorts
  • risk score based on 9 factors (total score 0-210 points)

    Factors for Risk Score:

    Factor	Points for Risk Score
    Age	0 points if < 40 years old 18 points if 40-49 years old 36 points if 50-59 years old 55 points if 60-69 years old 73 points if 70-79 years old 91 points if 80-89 years old 100 points if ≥ 90 years old
    History of heart failure	24 points
    History of MI	12 points
    Resting heart rate	0 points if < 50 beats/minute 3 points if 50-69.9 beats/minute 9 points if 70-89.9 beats/minute 14 points if 90-109.9 beats/minute 23 points if 110-149.9 beats/minute 35 points if 150-199.9 beats/minute 43 points if ≥ 200 beats/minute
    Systolic blood pressure	24 points if < 80 mm Hg 22 points if 80-99.9 mm Hg 18 points if 100-119.9 mm Hg 14 points if 120-139.9 mm Hg 10 points if 140-159.9 mm Hg 4 points if 160-199.9 mm Hg 0 points if ≥ 200 mm Hg
    ST-segment depression	11 points
    Initial serum creatinine	1 point if < 0.4 mg/dL (35.4 mcmol/L) 3 points if 0.4-0.79 mg/dL (35.4-69.8 mcmol/L) 5 points if 0.8-1.19 mg/dL (70.7-105.2 mcmol/L) 7 points if 1.2-1.59 mg/dL (106.1-141 mcmol/L) 9 points if 1.6-1.99 mg/dL (141.4-176 mcmol/L) 15 points if 2-3.99 mg/dL (176.8-352.7 mcmol/L) 20 points if ≥ 4 mg/dL (353.6 mcmol/L)
    Elevated cardiac enzymes	15 points
    No in-hospital PCI	14 points
    Abbreviations: MI, myocardial infarction; PCI, percutaneous coronary intervention.

  • continuous curve to predict 6-month postdischarge mortality based on risk score (estimated from graph)
    • risk score < 130 points associated with risks from 1% to 5%
    • risk score 130-170 associated with risks from 5% to 20%
    • risk score 170-190 associated with risks from 20% to 35%
    • risk exceeds 50% shortly after risk score exceeds 200
  • Reference - JAMA 2004 Jun 9;291(22):2727, commentary can be found in ACP J Club 2004 Nov-Dec;141(3):80
• software to apply GRACE risk score can be found at University of Massachusetts Medical School
• additional GRACE derivation and validations cohorts
  • GRACE prediction model for 6-month risk of death and myocardial infarction after ACS was derived from 21,688 patients and validated in 22,122 patients (BMJ 2006 Nov 25;333(7578):1091 full-text), editorial can be found inBMJ 2006 Nov 25;333(7578):1079
  • GRACE prediction model validated in retrospective study of patients hospitalized for acute myocardial infarction (AMI) in Ontario, Canada 1999-2001 (Heart 2006 Jul;92(7):905)
  • GRACE model reported to provide accurate risk assessment on admission in analysis of 16,618 patients with suspected acute coronary syndrome (Am J Cardiol 2013 Jan 15;111(2):202)
•  postdischarge GRACE score is more accurate than admission GRACE score for 6-month prediction of death or myocardial infarction for patients with ACS in New Zealand (level 1 [likely reliable] evidence)
  • based on prognostic cohort study
  • 3,743 patients hospitalized with ACS in New Zealand were assessed by admission-to-6-month and discharge-to-6-month GRACE scores
  • 4.3% died and 7.2% were rehospitalized for myocardial infarction between admission and 6 months

    Performance of GRACE Scores for Prediction of Death and Combined Death or Myocardial Infarction:

    GRACE Score	Risk Category	Death		Death or Myocardial Infarction
    		Predicted	Observed	Predicted	Observed
    Admission-to-6-month	Low	1.5%	0.8%	11.3%	5.4%
    	Intermediate	4.2%	1.8%	11.3%	11.6%
    	High	17.1%	10.3%	35.4%	17.3%
    Discharge-to-6-month	Low	0.4%	0.7%	1.8%	6.4%
    	Intermediate	1.8%	1.6%	4.3%	7.3%
    	High	8.1%	6.4%	16.9%	15.1%
    Abbreviation: GRACE, global registry of acute coronary events.

  • admission-to-6-month GRACE scores for both death and death or myocardial infarction had strong discrimination but overestimated risk in all risk categories
  • postdischarge GRACE score had strong discrimination and good calibration
  • Reference - Heart 2014 Dec 15;100(24):1960
•  GRACE Freedom-from-Event score may predict risk of in-hospital adverse event (level 2 [mid-level] evidence)
  • based on retrospective prognostic cohort study with independent derivation and validation cohorts
  • derivation cohort included 16,127 patients and validation cohort included 7,970 patients (both from GRACE database 2001-2007)
  • in-hospital events included MI, arrhythmia, heart failure or shock, major bleeding, stroke or death (13,803 [85.6%] of inception cohort had in-hospital event data available)
  • factors protecting against risk of in-hospital events included
    • younger age
    • lower Killip class
    • unstable angina presentation
    • no hypotension
    • no ST deviation
    • no cardiac arrest at presentation
    • normal creatinine
    • decreased pulse rate
    • no hospital transfer
    • no history of diabetes, heart failure, peripheral arterial disease, or atrial fibrillation
    • prehospital use of statins
    • no chronic warfarin
  • in-hospital event rate in model development cohort
    • 40% in 3 deciles with lowest Freedom-from-Event scores
    • 13.7% in 3 deciles with intermediate Freedom-from-Event scores
    • 5.2% in 3 deciles with highest Freedom-from-Event score
  • Reference - Heart 2009 Jun;95(11):888
• addition of biomarkers to GRACE score
  • addition of high-sensitivity cardiac troponin or B-type natriuretic peptide to GRACE score may not further improve prediction of in-hospital and 1-year mortality (level 2 [mid-level] evidence)
    • based on retrospective cohort study
    • 370 patients with acute coronary syndrome (173 with unstable angina, 197 with acute myocardial infarction) followed for 1 year
    • no significant differences in performance of GRACE with addition of cardiac troponin or B-type natriuretic peptide measurements
    • Reference - Heart 2011 Sep;97(18):1479, editorial can be found at Heart 2011 Sep;97(18):1461
  • high GRACE score combined with high brain natriuretic peptide level may identify patients with ACS at risk of cardiovascular events
    • based on cohort study
    • 449 patients with acute coronary syndrome with admission GRACE score and brain natriuretic peptide (BNP) level included
    • 90 cardiovascular events (all-cause mortality, readmission with ACS or heart failure) occurred during 10-month follow-up
    • compared to those with low GRACE score and low BNP level, increased risk of cardiovascular events at 10 months in patients with
      • high GRACE score and high BNP level (relative risk [RR] 6, 95% CI 2.4-14.83)
      • high GRACE score and low BNP level (RR 2.40, 95% CI 0.76-7.56)
    • Reference - Heart 2009 Nov;95(22):1836
  • addition of biomarkers to GRACE score may improve prediction of ischemia and heart failure (level 2 [mid-level] evidence)
    • based on post hoc secondary analysis of ARCHIPELAGO trial
    • 419 patients with non-ST-elevation ACS had 9 inflammatory, ischemic, or neurohormonal biomarkers measured within 48 hours of symptom onset
    • ischemia in 11% and heart failure in 12% at 2-month follow-up
    • greater interleukin-6 levels associated with increased risk of ischemia (adjusted odds ratio [OR] 1.69, 95% CI 1.23-2.31)
    • increased risk of heart failure associated with
      • increased BNP (adjusted OR 3.16, 95% CI 1.99-5.03)
      • increased aldosterone (adjusted OR 1.57, 95% CI 1.14-2.16)
    • decreased risk of heart failure associated with increase in matrix metalloproteinase-9 (adjusted OR 0.64, 95% CI 0.46-0.88)
    • performance of GRACE score significantly improved with addition of
      • interleukin-6 for predicting ischemia
      • BNP, aldosterone and matrix metalloproteinase-9 to model including GRACE and BNP for predicting heart failure
    • Reference - Am J Cardiol 2010 Sep 1;106(5):650

7.2. Thrombolysis in myocardial infarction (TIMI) score

•  TIMI risk score (for unstable angina) predicts poor outcomes within 14 days (level 1 [likely reliable] evidence)
  • based on prognostic cohort study with independent derivation and validation cohorts
  • study based on patients in 2 randomized trials (TIMI, ESSENCE) of unfractionated heparin vs. enoxaparin in patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI)
  • derivation cohort included 1,957 patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) in TIMI IIB trial
  • validation cohort included 5,124 nonoverlapping patients from TIMI IIb and ESSENCE trials
  • composite endpoint included all-cause mortality, new or recurrent myocardial infarction, or severe recurrent ischemia requiring urgent revascularization within 14 days
  • composite endpoint occurred in 16.7% of derivation cohort
  • TIMI risk score derived using factors significantly associated with increased risk of composite endpoint in derivation cohort (total score 0-7, 1 point for each factor)
    • age > 65 years
    • at least 3 risk factors for coronary artery disease (CAD), including
      • family history
      • hypertension
      • diabetes
      • hypercholesterolemia
      • current smoker
    • prior coronary stenosis > 50%
    • ST-segment deviation on electrocardiogram (ECG) at presentation
    • at least 2 anginal events in prior 24 hours
    • use of aspirin in prior 7 days
    • elevated serum cardiac markers (creatine kinase-myocardial band [CK-MB] or cardiac troponin)
  • event rates in derivation cohort (all-cause mortality, new or recurrent myocardial infarction, or severe recurrent ischemia requiring urgent revascularization within 14 days) increased significantly with increasing TIMI risk score
    • score 0 or 1 - 4.7%
    • score 2 - 8.3%
    • score 3 - 13.2%
    • score 4 - 19.9%
    • score 5 - 26.2%
    • score 6 or 7 - 40.9%
  • similar trends in validation cohort
  • Reference - JAMA 2000 Aug 16;284(7):835, editorial can be found in JAMA 2000 Aug 16;284(7):876
  • TIMI risk score predicted 1-year risk of cardiovascular events in 7,656 patients with ACS and no obstructive CAD (Arch Intern Med 2006 Jul 10;166(13):1391)
•  TIMI and modified TIMI score > 0 has insufficient sensitivity to rule out death, myocardial infarction or revascularization within 30 days in patients with suspected acute coronary syndrome in emergency department (level 1 [likely reliable] evidence)
  • based on validation cohort study
  • 1,666 patients presenting to emergency department with suspected acute coronary syndrome were assessed with TIMI and modified TIMI scores
  • 219 patients (13%) died, had myocardial infarction, or coronary revascularization within 30 days
  • modified TIMI score (0-10 points)
    • 5 points for elevated cardiac biomarkers or electrocardiographic ST deviation > 0.5 mm or both are present
    • 1 point for each of 5 other TIMI risk factors
  • death, myocardial infarction, or coronary revascularization within 30 days in validation cohort

    Predictive Performance of TIMI and Modified TIMI by Score:

    Cutoff Score	Statistic	TIMI	Modified TIMI
    < 1	Sensitivity	96%	96%
    	Specificity	23%	23%
    < 2	Sensitivity	74%	82%
    	Specificity	54%	53%
    < 3	Sensitivity	51%	71%
    	Specificity	81%	78%
    < 4	Sensitivity	19%	61%
    	Specificity	96%	91%
    Abbreviations: TIMI, thrombolysis in myocardial infarction.

  • Reference - Emerg Med J 2014 Apr;31(4):281
•  TIMI risk score appears insufficiently accurate to recommend as sole means for predicting outcomes for patients with suspected ACS in emergency department (level 2 [mid-level] evidence)
  • based on systematic review limited by heterogeneity
  • systematic review of 10 prospective cohort studies evaluating prognostic accuracy of TIMI risk score for predicting 30-day risk of AMI, coronary revascularization or death in 17,265 patients presenting to emergency department with potential ACS

    Diagnostic Accuracy of TIMI Risk Score for Predicting Adverse Cardiovascular Outcomes in Emergency Department Patients with Potential Acute Coronary Syndrome*:

    Cutoff Score	Sensitivity	Specificity
    > 0	97.2%	25%
    > 1	90.6%	51%
    > 2	79.7%	70.4%
    > 3	57.5%	85.5%
    > 4	33.2%	96.6%
    Abbreviation: TIMI, thrombolysis in myocardial infarction.  * In analysis of 8 trials with 15,660 patients.

  • Reference - CMAJ 2010 Jul 13;182(10):1039 full-text
•  TIMI risk index may predict in-hospital mortality (level 2 [mid-level] evidence)
  • based on retrospective cohort study
  • 337,192 patients with non-ST-elevation myocardial infarction (NSTEMI) from National Registry of Myocardial Infarction with NSTEMI included
  • TIMI risk index = [heart rate × (age/10)²] / systolic blood pressure
  • patient stratification included
    • 81,679 patients with ST-elevation myocardial infarction treated with reperfusion therapy (STEMI-RT)
    • 71,807 patients with ST-elevation myocardial infarction not treated with reperfusion therapy (STEMI-no RT)
    • 337,192 patients with NSTEMI
  • prediction of in-hospital mortality by TIMI risk index

    In-Hospital Mortality (Approximated from Graph) Stratified by TIMI Risk Index:

    TIMI Risk Index	NSTEMI	STEMI-RT	STEMI-no RT
    < 10	2%	1%	2.5%
    10 to < 20	2.5%	2%	5%
    20 to < 30	6%	5%	10%
    30 to < 40	10%	11%	17%
    40 to < 50	16%	20%	22%
    50 to < 60	20%	29%	30%
    60 to < 70	25%	40%	35%
    70 to < 80	29%	46%	40%
    80 or higher	36%	60%	52%
    Abbreviations: NSTEMI, non-ST-elevation myocardial infarction; STEMI-no RT, ST-elevation myocardial infarction not treated with reperfusion therapy; STEMI-RT, ST-elevation myocardial infarction treated with reperfusion therapy; TIMI, thrombolysis in myocardial infarction.

  • Reference - J Am Coll Cardiol 2006 Apr 18;47(8):1553, commentary can be found in ACP J Club 2006 Sep-Oct;145(2):52

7.3. Acute myocardial infarction in Switzerland (AMIS)

•  AMIS risk score can predict in-hospital mortality (level 1 [likely reliable] evidence)
  • based on prognostic cohort study with independent derivation and validation cohorts
  • derivation cohort included 7,520 patients with acute coronary syndrome
  • validation cohorts included 2,854 and 2,635 similar patients
  • AMIS risk score derived from data mining and machine learning algorithms included the following factors
    • age
    • Killip class
    • systolic blood pressure
    • heart rate
    • prehospital cardiopulmonary resuscitation
    • history of heart failure
    • history of cerebrovascular disease
  • online calculator can be found at AMIS-Plus
  • Reference - Heart 2009 Apr;95(8):662, commentary can be found in Heart 2009 Jul;95(14):1128

8.1. Guidelines

8.2. Review articles

• review of diagnostic strategies for suspected acute coronary syndrome can be found in Health Technol Assess 2013;17(1):v-vi, 1
• review of coronary artery disease and myocardial infarction can be found in N Engl J Med 2012 Jan 5;366(1):54, correction can be found in N Engl J Med 2012 Mar 8;366(10):970, commentary can be found in N Engl J Med 2012 Mar 29;366(13):1259
• review of treatment of unstable angina and non-ST-elevation myocardial infarction can be found in Tex Heart Inst J 2010;37(3):262 full-text
• review of acute coronary syndromes without ST-segment elevation can be found in BMJ 2007 Jun 16;334(7606):1265 full-text, commentary can be found in BMJ 2007 Jun 30;334(7608):1336
• case presentation of management of acute coronary syndromes can be found in JAMA 2010 Jan 6;303(1):54, commentary can be found in JAMA 2011 Nov 2;306(17):1911

8.3. MEDLINE search

• to search MEDLINE for (Acute coronary syndrome) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis