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Last Updated: 1/25/2013  

Acute Coronary Syndromes

Diagnosis
  • Ask patients about symptoms suggesting ACS, “typically” described as pressure, tightness or heaviness and radiates to the jaw, back or arm.

  • Obtain electrocardiogram immediately in all patients with suspected ACS.

  • Measure CK-MB and troponin T or I upon initial evaluation of patients with presumed ACS.

  • Consider using a diagnostic tool that combines history, physical exam, and laboratory data to aid in early risk stratification.

  • Use stress testing or consider coronary CT angiography in patients stratified as low-risk.

Therapy
  • Give aspirin therapy promptly and continue in all patients with suspected ACS.

  • Proceed directly to coronary angiography in patients with STEMI who present to experienced centers or can be transferred to a referral center in order to perform a primary percutaneous intervention.

  • Administer a thrombolytic agent as an alternative to primary percutaneous interventions in suitable candidates with STEMI.

  • Give anticoagulant therapy with unfractionated heparin, low-molecular-weight heparin or bivalirudin, to moderate- and high-risk patients with ACS.

  • Administer clopidogrel or a newer P2Y12 receptor inhibitor in selected patients with ACS.

  • Consider administering glycoprotein IIb/IIIa antagonists in addition to aspirin and an anticoagulant in patients with high-risk NSTEMI, as adjunctive therapy in patients with STEMI undergoing primary percutaneous intervention, or as an alternative to P2Y12 receptor inhibitors.

  • Administer β-blockers early to patients with suspected ACS unless there are significant contraindications; give a nonselective β-blocker to patients with left ventricular dysfunction after an MI.

  • Administer nitroglycerin to with ACS with ongoing chest discomfort.

  • Administer an ACE inhibitor early in the course of ACS.

  • Prescribe high-potency HMG-CoA reductase inhibitors (statins) in patients with ACS and continue after hospitalization, with goal LDL<100 mg/dL.

  • Strongly advise all tobacco users who have had an acute coronary event to quit smoking.

  • Aim for glycemic control (glucose <180 mg/dL) in patients with diabetes.

Elicit a history of chest discomfort symptoms that suggest ACS. 
  • Obtain a detailed history including the character, intensity, location, radiation, and duration of chest discomfort as well as exacerbating and ameliorating factors.

  • Understand that ‘typical’ chest discomfort suggesting ACS is described as pressure, tightness, or heaviness and radiates to the jaw, back, or arm.

  • Ask about associated symptoms such as nausea, lightheadedness, diaphoresis, and shortness of breath.

  • Recognize factors that increase risk for CAD such as age, gender, common cardiac risk factors (i.e., smoking, hypertension, dyslipidemia [elevated total or LDL cholesterol, low HDL cholesterol], diabetes, obesity), previously documented CAD, or a family history of CAD.

  • Recognize that coronary patients can have atypical symptoms such as dyspnea, fatigue, nausea, abdominal discomfort, or syncope, especially those with diabetes or the elderly.

  • See table Prevalence of History and Physical Examination Elements in Patients with Acute Coronary Syndromes.

Evidence
  • A 2005 systematic review evaluated the diagnostic accuracy of specific qualities of chest pain for the diagnosis of MI. Qualities which increased the likelihood of MI included radiation to the right arm (LR, 4.7) or to both arms (LR, 4.1). Association with exertion, nausea, vomiting, or diaphoresis were all weakly predictive with likelihood ratio around 2 (1).

  • A prospective study of 893 patients presenting to the ED with chest pain found that exertional pain (LR, 2.4) and radiation to the shoulder or arms (LR, 4.1) were moderately predictive of ACS and that chest wall tenderness (LR, 0.3) was moderately predictive of noncardiac chest pain (2).

  • The 2011 update to the 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction from the American College of Cardiology and the American Heart Association describes possible symptoms associated with ACS, including chest, arm, shoulder, jaw, ear, or epigastric discomfort, dyspnea, nausea, diaphoresis, and fatigue (3).

  • Strong clinical predictors of angiographic CAD are age, gender, and the character of the chest discomfort. Typical angina characterized by substernal discomfort, onset that is exertional, and relief with rest or nitroglycerin is associated with as high as a 94% probability of CAD in certain patients (4).

Rationale
  • A detailed history is fundamental to the diagnosis of ACS.

Comments
  • Recognize that myocardial ischemia is associated with the classic symptoms of severe retrosternal chest pressure in only about 25% of patients, whereas 25% of patients have chest discomfort that mimics heartburn pain, 25% have ischemia that is clinically silent, and the remaining patients complain of stabbing or sharp chest pain, chest pain reproducible by palpation, or jaw, neck, back, and left arm discomfort. Women and elderly patients may have more atypical symptoms.

Perform a thorough physical exam to inform early risk stratification and assist in the diagnosis of ACS. 
Evidence
  • Multiple analyses of correlates of poor outcomes in patients with acute MI have found that hypotension, tachycardia, and findings consistent with HF are independent predictors of death (5; 6; 7; 8).

Rationale
  • The physical exam can expose signs that highly suggest myocardial ischemia or findings that are more subtle or unremarkable.

  • Increased levels of circulating catecholamines may cause severe hypertension.

  • New murmurs suggest valvular incompetence, possibly caused by papillary muscle dysfunction or rupture.

  • A new S4 gallop can represent impaired relaxation associated with decreased diastolic compliance.

  • A new S3 gallop can represent impaired systolic function associated with extensive myocardial damage.

  • HF may be present if ischemia results in left ventricular diastolic or systolic dysfunction or valvular incompetence.

  • Other nonspecific signs include hypotension, bradycardia, tachycardia, and tachypnea.

Obtain an ECG immediately in all patients with suspected ACS. 
Evidence
  • In the GUSTO IIA trial, both ECG changes and elevation of cardiac proteins were shown to be reliable predictors of 30-day mortality in patients with MI treated with thrombolytics. There were 855 patients studied within 12 hours of the onset of symptoms. Cardiac troponin T levels, CK-MB levels, and ECGs were analyzed in a blinded fashion. Death within 30 days was significantly higher in patients with elevated troponin T levels (>0.1 ng/mL) than in patients with lower levels of troponin T (11.8% vs. 3.9%, P<0.001). The troponin T level was the variable most strongly related to 30-day mortality followed by the electrocardiographic category and the CK-MB level (9).

  • A retrospective analysis of the presenting ECGs of patients enrolled in GUSTO-IIb evaluated the ability of ECG findings at presentation to predict death or myocardial reinfarction during the first 30 days of follow-up. Poor outcomes at 30 days were lowest in patients with T-wave inversions (5.5%) and highest in patients with both ST-segment elevations and depressions (12.4%). This finding remained significant in the multivariate model; ST-segment elevations and depressions were associated with an odds ratio of 2.27 (10).

  • In one study, 322 patients with transmural MI with ST-segment elevation were admitted within 24 hours of infarction and underwent coronary arteriography. Total coronary occlusion was observed in 110 of 126 patients (87%) who were evaluated within 4 hours of the onset of symptoms (11).

  • Data from 7115 patients in the Multicenter Chest Pain Study showed that the probability of acute MI among patients with chest pain and initially normal or nonspecific ECGs was 3% overall and ranged from less than 1% to 17% (12).

  • In a UK study of 151 patients, standard ECG criteria for ST-segment elevation and depression had a sensitivity of 84% and specificity of 93% for acute MI when compared with a diagnostic gold standard of contrast-enhanced MRI (13).

  • The 2011 update to the 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction from the American College of Cardiology and American Heart Association recommends an ECG within 10 minutes of presentation in patients with possible ACS (3).

Rationale
  • Initial management is determined by the early risk stratification of these patients.

  • The treatment options for STEMI include immediate thrombolysis and/or PCI. In contrast, the initial management options for the other categories do not require revascularization as urgently.

Comments
  • The diagnostic yield of the ECG is improved if a tracing can be recorded during an episode of chest discomfort.

Measure CK-MB and troponin T or I upon initial evaluation of patients with presumed ACS. 
  • Measure serum cardiac markers of myocardial necrosis (myoglobin, CK-MB, and troponin T or I), recognizing the release kinetics from the time of chest pain onset.

  • If initial markers are normal, repeat measurements at 6 hours and 12 hours after onset of symptoms.

  • In patients with STEMI, proceed with management immediately pending receipt of cardiac marker results.

  • See table Laboratory and Other Studies for Acute Coronary Syndromes.

  • See table Release Kinetics of Cardiac Markers.

Evidence
  • A study evaluated the prognostic value of troponin I at presentation in 359 patients with NSTEMI and normal CK and CK-MB. Patients with elevated troponin I had increased risk of death or MI at both 2 days (3.9% vs. 0%; P=0.01) and 14 days (13.9% vs. 2.2%; P<0.0001) (14).

  • The GUSTO IIA trial showed that elevated troponin T was independently related to 30-day mortality in patients with acute MI treated with thrombolytics (9).

  • In a multicenter study, cardiac troponin I levels were analyzed in 1404 symptomatic patients. The mortality rate at 42 days was significantly higher in the 573 patients with cardiac troponin I levels of at least 0.4 ng/mL than in the 831 patients with cardiac troponin I levels below 0.4 ng/mL. There were statistically significant increases in deaths with increasing levels of cardiac troponin I (15).

  • In an ED study, both troponin I and T were assessed for rapid diagnostic value. In 773 patients without ST-segment elevation on their ECGs, troponin T and troponin I status (positive or negative) was determined. Troponin T and troponin I proved to be strong, independent predictors of cardiac events. The event rates in patients with negative tests were only 1.1% for troponin T and 0.3% for troponin I (16).

  • In the FRISC study group, the risk for cardiac events increased with increasing maximal levels of troponin T obtained in the initial 24 hours in 976 patients with unstable CAD (17).

  • The TRIM study group found elevated troponin T levels to be an independent predictor of risk in 232 patients with suspected ACS (18).

  • In a study of 1047 patients admitted with acute chest pain, elevated cardiac troponin I was found to be an independent predictor of major cardiac events (19).

  • In a 1997 study of 106 patients with the clinical diagnosis of unstable angina, ECG evidence of myocardial ischemia, and normal values of total CK over the initial 16 hours of observation found that elevated troponin I was associated with increased risk of death and MI in the short-term and for up to 1 year (20).

  • A 2009 study evaluated the diagnostic accuracy of new, sensitive cardiac troponin assays compared with conventional assays in 718 consecutive patients presenting with chest pain. The newer assays were more sensitive than the standard assay (21).

  • A 2009 multicenter study of the accuracy of a high-sensitivity troponin assay in 1818 patients with suspected acute MI found that the assay had sensitivity of 90.7% and specificity of 90.4% at a cutoff of 40 pg/mL at the time of admission. High-sensitivity troponin drawn 3 hours after presentation had sensitivity of 98.2% and specificity of 99.4% at a cutoff of 32 pg/mL (22; 23).

Rationale
  • During MI, the cardiac myocytes lose membrane integrity and leak proteins into the serum; by serially measuring cardiac marker proteins, the clinician can detect evidence of myocardial damage within the last 24 hours.

  • Elevation of cardiac markers is part of the universal definition of both Q-wave and non-Q-wave MI.

  • The choice of cardiac marker has evolved over time. Conventional troponin is considered the most accurate marker.

Comments
  • Detection of cardiac biomarkers (preferably troponin) is an integral part of the universal definition of myocardial infarction (24).

  • Newer assays with improved sensitivity may supplant the current markers.

Do not routinely obtain other cardiac biomarkers that may be diagnostically or prognostically associated with ACS. 
Evidence
  • Elevated serum values of CRP measured within the first 24 hours in patients with unstable angina were shown to correlate with an increased rate of death from cardiac causes (5.7% rate of death in patients with CRP <2.0 mg/L, 7.8% with CRP 2 to 10 mg/L, and 16.5% with CRP >10 mg/L) (25).

  • In 96 patients with unstable angina who underwent coronary angiography within 5 days of admission, the degree of complexity of a culprit lesion was shown to correlate to the degree of elevation of CRP (26).

  • In patients with unstable angina who received medical management only (i.e., no revascularization), CRP levels measured within the first week of discharge correlated with 90-day mortality and MI. CRP was found to be a sensitive (88%) and specific (81%) predictor of death or MI at 90 days in these patients (27).

  • In a prospective 11-month French study of 677 patients admitted to the ED with chest pain, heart fatty acid-binding protein and IMA did not provide additional diagnostic utility above the standard for the diagnosis of non-ST-segment elevation of ACS (28).

  • In a stratified analysis (by cystatin C concentration at baseline) of 1128 patients in the ICTUS trial, the highest tertile of cystatin C remained independently predictive of mortality (HR, 2.04 [CI, 1.02 to 4.10]; P=0.04) and spontaneous MI (HR, 1.95 [CI, 1.05 to 3.63]; P=0.04) (29).

  • A study found that in 487 consecutive patients presenting to the ED with symptoms suggestive of acute MI, the combination of troponin T and copeptin at initial presentation resulted in an area under the receiver-operating characteristic curve of 0.97 (CI, 0.95 to 0.98), which was significantly higher than the 0.86 (CI, 0.80 to 0.92) for troponin T alone (P<0.001). The combination of copeptin <14 pmol/L and troponin T ≤0.01 mcg/L had sensitivity of 98.8% and specificity of 77.1% for acute MI (30).

Rationale
  • Although these markers may have prognostic significance, they have no established clinical role.

  • CRP is an acute-phase reactant and can be elevated in many inflammatory conditions; it is thought to be an indicator for vulnerable coronary plaques.

  • BNP, N-terminal prohormone of BNP, copeptin, IMA, and other markers have been associated with diagnosis of ACS or as prognostic markers, but their utility is unclear.

Comments
  • Although a multimarker approach to risk stratification of ACS (e.g., simultaneous assessment of cardiac troponin I, CRP, and BNP) has been advocated as a potential advance over a single biomarker assessment, this approach needs further research.

Consider obtaining early echocardiography in patients with chest pain and suspected ACS. 
  • Consider obtaining echocardiography to detect regional wall motion abnormalities before serum marker results are known in any patient with a nondiagnostic echocardiogram in whom NSTEMI or unstable angina is suspected.

  • Use echocardiography to identify other nonischemic conditions that cause chest pain, such as:

    • Myocarditis

    • Valvular heart disease

    • Aortic dissection

    • Pulmonary embolism

    • Mechanical complications of acute infarction, such as mitral regurgitation, papillary muscle dysfunction or rupture, and VSD

  • See table Laboratory and Other Studies for Acute Coronary Syndromes.

Evidence
  • In one prospective study using 2-D echocardiography to diagnose acute MI by detecting regional wall motion abnormalities, 27 of 29 patients who had a regional wall motion abnormality and chest pain ruled in for an acute MI. Of 13 patients who went on to have a complication of acute MI, all had a regional wall motion abnormality on initial ECG (31).

Rationale
  • Echocardiography can show the progression from hypokinesis to akinesis during ischemia as well as show impaired myocardial relaxation during diastole.

  • Echocardiography findings of a new regional wall motion abnormality along with rise of cardiac markers greater than 99% of the upper limit of normal is consistent with the universal definition of MI.

  • An echocardiogram is valuable in diagnosing mechanical complications, such as papillary muscle dysfunction.

  • Echocardiography may aid in diagnosing other conditions that may simulate ACS, such as aortic dissection, pericarditis, or pulmonary embolism.

  • An echocardiogram demonstrating normal wall motion excludes extensive myocardial damage but does not rule out NSTEMI.

Comments
  • Note that echocardiography cannot definitely distinguish between ischemia and infarction, and cardiac markers need to be sent in order to assess acute myocardial damage.

  • Injury involving more than 20% of myocardial wall thickness is required before echocardiography can detect a segmental wall motion abnormality.

Consider using a diagnostic tool that combines history, physical exam, and laboratory data to aid in early risk stratification. 
  • Consider using one of the available diagnostic tools, such as the TIMI risk score and the GRACE risk prediction model, which combine history, physical exam, and laboratory data to aid in early risk stratification.

  • Use the tool if it aids in timely, accurate decision making.

Evidence
  • A 2000 study validated the TIMI risk score in 1957 high-risk patients. The TIMI score includes seven variables. The score was found to predict the risk of death or ischemic events, with rates rising with higher scores, ranging from 4.7% to 40.9% (32).

  • The GRACE risk prediction model predicts 6-month mortality in patients admitted with ACS (33).

Rationale
  • Generating an accurate pretest probability can aid in proper decision making for further diagnostic testing or therapeutic interventions.

Comments
  • The available tools vary in their ease of use, sensitivity, and specificity.

  • There are no well-validated, sensitive scoring schemes for low-risk patients.

  • A TIMI risk score calculator is available.

  • A GRACE risk score calculator is available.

Use stress testing or consider coronary CT angiography in patients stratified as low-risk. 
Evidence
  • According to 2002 AHA guidelines, exercise or pharmacologic stress testing should be an integral part of the evaluation of low-risk patients with unstable angina who have become symptom-free (34).

  • In a study of 276 patients undergoing ETT within 48 hours of presentation to the ED with chest pain, the ETT was normal in 195 patients (71.1%). During a 4-month follow-up period, none of these patients died and only 1 (0.5%) had a major cardiac event (35).

  • In a study of 1000 patients presenting to the ED with suspected cardiac chest pain and low-risk features, immediate exercise testing was negative in 64%. All of these patients were discharged from the ED, and at 30-days follow-up there were no deaths and only 1 patient (0.2%) had an MI (36).

  • A 2009 study evaluated the diagnostic accuracy of coronary CT angiography in 368 patients presenting with chest pain to the ED. Coronary CT angiography had sensitivity of 77% and specificity of 87% for ACS (37).

  • A 2012 trial randomized intermediate-risk patients presenting to the ED with chest pain to early coronary CT angiography or to standard ED evaluation. There were similar clinical outcomes in the groups, but the early CT group had fewer hospital admissions and shorter length of hospital stay. Costs were similar in the two groups (38).

  • A study of 1370 low-to-intermediate risk patients presenting with a possible ACS randomized the patients 2:1 to coronary CT angiography vs. standard care. The study found that patients receiving the angiography-based strategy were significantly more likely to be discharged from the ED (49.6% vs. 22.7%) and had shorter length of stay (6.8 hours, P<0.001). No patients with negative CT angiography died or had MI within 30 days (39).

Rationale
  • Use of exercise ECG testing is safe and effective in the rapid diagnosis and risk stratification of patients with unstable angina.

Comments
  • The optimal role for coronary CT angiography and its potential harms have not been fully characterized.

Consider the broad differential diagnosis in patients with suspected ACS. 
Evidence
  • Of the 3 million people admitted to the hospital annually for symptoms of an ACS, only approximately 30% will ultimately be diagnosed with an acute MI (43).

Rationale
  • Many conditions can mimic acute myocardial ischemia or infarction, and important consideration must be given to alternative diagnoses such as aortic dissection because the therapy is different and treatments such as thrombolytics are contraindicated and potentially hazardous.

Consult a cardiologist and other specialists to assist in choosing additional testing for patients in whom the diagnosis of ACS is uncertain. 
  • Consider consulting a cardiologist:

    • If the diagnosis of ACS is uncertain

    • To optimize diagnostic strategy

    • When invasive cardiac testing may be needed

  • Consider consulting a pulmonary, gastroenterology, or appropriate surgical specialist when a noncardiac etiology of chest pain is suspected and for help in confirming the diagnosis as needed.

Evidence
  • Consensus.

Rationale
  • Diagnostic tests for evaluating ACS do not have the same availability or accuracy in different institutions, particularly in using different imaging modalities for stress testing.

  • It is important to recognize the limitations of a specific test and to consult specialists with expertise in this area, particularly when invasive testing may be needed.

Comments
  • In institutions where exercise ECG is not routinely done, the sensitivity is likely to be lower than that reported in the literature.

Consult with a cardiologist for most patients with ACS, particularly patients who may require complex management. 
  • Consult a cardiologist in most patients with ACS for assistance with managing:

    • ST-segment elevation or new LBBB MI

    • Requirement for PCI

    • Complications including HF/LVD, dysrhythmias, or recurrent symptoms

  • Consider consulting a cardiologist for patients with ACS and at least one high-risk factor:

    • Elevated troponin T or I

    • New ST-segment depression

    • Recurrent angina/ischemia at rest or with low-level activity

    • HF

    • Ventricular tachycardia

    • Markedly abnormal stress test

    • PCI within 6 months or prior coronary bypass surgery

Evidence
  • A study shows that early involvement of a cardiologist in the care of patients with ACS is associated with improved outcomes and greater adherence to established guidelines for ACS management (125).

  • In an analysis of 8241 Medicare patients hospitalized with acute MI, risk-adjusted multivariate analysis showed that patients admitted by cardiologists had a 12% lower mortality at 1-year follow-up than patients admitted by other physician groups (P<0.001). Cardiologists also had the highest use of medications known to improve outcome, including thrombolytic agents and β-blockers (125).

Rationale
  • ACS is a broad spectrum of disease, and consultation with a cardiologist may improve management and clinical outcomes.

  • Early intervention can improve outcomes and reduce mortality in patients with ACS and high-risk features.

Hospitalize all but those patients with low suspicion of ACS for further evaluation and treatment. 
  • Hospitalize all patients with definite ACS and ST-segment elevation for consideration of immediate reperfusion therapy.

  • Hospitalize all patients with definite ACS and ongoing chest discomfort, positive cardiac markers, new ST-segment abnormalities, or hemodynamic abnormalities.

  • Hospitalize all patients with definite or possible ACS but negative initial ECG and cardiac markers:

    • Who require observation in a facility with cardiac monitoring, including the ED or a chest pain unit, and a repeat ECG and cardiac marker measurement every 6 to 12 hours (up to 24 hours) after the onset of symptoms

    • In whom ischemic heart disease is suspected but follow-up ECG and cardiac markers are normal and who should have a stress test before or shortly after discharge

  • See figure Algorithm for the Evaluation and Management of Patients Suspected of Having Acute Coronary Syndromes.

Evidence
  • In a study of 276 patients undergoing ETT, within 48 hours of presentation to the ED with chest pain, the ETT was normal in 195 patients (71.1%). During a 4-month follow-up period, none of these patients died and only 1 (0.5%) had a major cardiac event (35).

  • In a study of 1000 patients presenting to the ED with suspected cardiac chest pain and low-risk features, immediate exercise testing was negative in 64%. All of these patients were discharged from the ED, and at 30 days follow-up there were no deaths and only 1 patient (0.2%) had an MI (36).

  • A study of 1370 low-to-intermediate risk patients presenting with a possible ACS randomized the patients 2:1 to coronary CT angiography vs. standard care. The study found that patients receiving the angiography-based strategy were significantly more likely to be discharged from the ED (49.6% vs. 22.7%) and to have a shorter length of stay (6.8 hours, P<0.001). No patients with negative CT angiography died or had an MI within 30 days (39).

Rationale
  • Death associated with acute MI and high-risk unstable angina is concentrated within a relatively brief period of time.

  • Most serious cardiac events occur within 48 hours of the patient's arrival at the hospital with in-hospital mortality rates as high as 10% to 20% if no intervention is done.

Give aspirin therapy promptly and continue in all patients with suspected ACS. 
Evidence
  • In a randomized trial involving 555 patients hospitalized with unstable angina, aspirin therapy was associated with a 30% reduction in the risk of cardiac death or nonfatal MI, and a 43% reduction in all-cause mortality (44).

  • In a randomized trial involving 1266 men with unstable angina, aspirin therapy was associated with a 51% reduction in the risk of death or acute MI, and a 51% reduction in each of the endpoints considered separately (45).

  • The ISIS-2 study conclusively showed the efficacy of aspirin therapy alone for the treatment of acute MI when 17,187 patients were randomly assigned to receive either a 1-hour infusion of streptokinase, 1 month of enteric coated aspirin, both, or neither. Aspirin therapy alone showed a highly significant reduction in 5-week vascular mortality (odds reduction 23% ± 4 compared with placebo controls). Aspirin significantly reduced nonfatal reinfarction (1.0% vs. 2.0%) and nonfatal stroke (0.3% vs. 0.6%) and was not associated with significant increase in cerebral hemorrhage or bleeding requiring transfusion (46).

  • A 2012 guideline from the American College of Cardiology and the American Heart Association for the treatment of unstable angina and NSTEMI recommends that all patients receive aspirin as soon as possible and continue it indefinitely if it is tolerated (47).

  • A 2009 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI recommends the use of aspirin in addition to another antiplatelet medication and an anticoagulant in patients with STEMI (48).

Rationale
  • Aspirin reduces the incidence of MI in patients with unstable angina.

  • Aspirin reduces mortality in patients with acute unstable angina or acute MI.

  • Aspirin diminishes platelet aggregation by irreversibly inhibiting thromboxane A2.

  • The anti-inflammatory properties of aspirin may also contribute to its beneficial effects.

Proceed directly to coronary angiography in patients with STEMI and other high-risk subsets of patients with ACS who present to experienced centers or can be transferred to a referral center in order to perform a primary PCI. 
  • Consider immediate coronary angiography and PCI in patients with STEMI or new LBBB.

    • Primary angioplasty is superior to thrombolytic therapy in patients with acute STEMI and should be considered if it can be done in a timely fashion (within 2 hours of admission) by individuals skilled in the procedure and in a high-volume center.

    • Primary angioplasty is indicated in patients with a contraindication to thrombolytic therapy or in patients with cardiogenic shock.

  • Consider an early invasive strategy with diagnostic coronary angiography in patients with unstable angina/NSTEMI if any of the following high-risk features are present:

    • Recurrent angina/ischemia at rest or with a low level of activity despite anti-ischemic therapy

    • Elevated troponin T or I

    • New ST-segment depression

    • Recurrent angina/ischemia with HF or new or worsening mitral regurgitation

    • High-risk stress test results

    • Sustained ventricular tachycardia

    • PCI within 6 months

    • Prior coronary artery bypass surgery

  • Consider an early invasive strategy as an alternative to conservative therapy in patients without contraindication for revascularization and patients who repeatedly have ACS despite therapy and without evidence of ongoing ischemia.

  • See table Risk Stratification and Management of Patients With Acute Coronary Syndromes.

  • See figure Algorithm for the Evaluation and Management of Patients Suspected of Having Acute Coronary Syndromes.

  • See figure Left Anterior Descending Artery Stenosis.

  • See figure Stented Left Anterior Coronary Artery.

Evidence
  • A 2007 Cochrane review of thrombolysis compared with primary angioplasty for acute MI included 10 trials with 2573 participants. Patients receiving primary angioplasty had lower rates of short-term mortality (RRR, 32% [CI, 5% to 50%]), reinfarction (RRR, 52% [CI, 30% to 67%]), and stroke (RRR, 66% [CI, 28% to 84%]). Long-term impact was not clear. The review has not been updated, so it was withdrawn (49).

  • A 2003 systematic review and meta-analysis of thrombolysis compared with primary angioplasty for acute ST-segment elevation included 23 randomized trials with 7739 patients. Angioplasty was associated with lower rates of 30-day mortality (NNT, 50; P=0.0002), nonfatal reinfarction (NNT, 25; P<0.0001), and hemorrhagic stroke (NNT, 100; P=0.0004) (50).

  • A 2003 systematic review and meta-analysis of thrombolysis compared with transfer for primary angioplasty included six trials involving 3750 patients with acute MI. Transfer time was <3 hours in all studies. Transfer for primary angioplasty was associated with a 42% reduction in the composite endpoint of death, reinfarction, or stroke (P<0.001) (51).

  • A 2010 Cochrane review of early invasive strategy compared with a conservative strategy for patients with unstable angina and NSTEMI included five trials with 7618 participants. The invasive strategy resulted in fewer MIs after 3 to 5 years (RR, 0.78 [CI, 0.67 to 0.92]), less refractory angina in the short term and for up to a year, but twice the number of peri-procedure MI (52).

  • In the DANAMI-2 trial, 1129 patients with acute STEMI presenting to hospitals without invasive facilities were randomized to on-site thrombolysis with alteplase (rt-PA) or transfer to a referral center for primary coronary intervention. The primary outcome was the composite of death, reinfarction, or disabling stroke at 30 days. Compared with thrombolysis, transfer for primary PCI was associated with a significant reduction in the primary endpoint (8.5% vs. 14.2%; P=0.002) (53).

  • An early invasive strategy in patients with unstable angina or NSTEMI with high-risk features has been supported by various clinical trials including TIMI IIIB and FRISC II.

    • In TIMI IIIB, 1473 patients with unstable angina or NSTEMI were randomized to compare an early invasive strategy (early arteriography and revascularization if appropriate) vs. an early conservative strategy (arteriography and revascularization if initial medical therapy failed). The endpoint for the comparison of the two strategies (death, MI, or an unsatisfactory symptom-limited exercise stress test at 6 weeks) occurred in 18.1% of patients assigned to the early conservative strategy and 16.2% of patients assigned to the early invasive strategy (P=not significant). In the latter, the average length of initial hospitalization, incidence of rehospitalization within 6 weeks, and days of rehospitalization all were significantly lower (54).

    • In the FRISC II study, 2457 patients were randomly assigned to an early invasive or noninvasive treatment strategy. After 6 months, there was a decrease in the composite endpoint of death or MI of 9.4% in the invasive group, compared with 12.1% in the noninvasive group (RR, 0.78 [CI, 0.62 to 0.98]; P=0.031). There was a significant decrease in MI alone (7.8% vs. 10.1%; RR, 0.77 [CI, 0.60 to 0.99]; P=0.045) and not significantly lower mortality (1.9% vs. 2.9%; RR, 0.65 [CI, 0.39 to 1.09]; P=0.10). Symptoms of angina and readmission were halved by the invasive strategy. The greatest advantages were seen in high-risk patients (55).

  • In the SHOCK trial, 30-day and 6-month mortality was reduced by early revascularization with PTCA or CABG vs. aggressive medical therapy. These benefits were limited to patients aged under 75 years, and ‘medical therapy’ included insertion of an IABP (56).

  • A 2009 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI recommends that patients presenting with STEMI to a hospital with the capability for primary PCI receive PCI within 90 minutes of arrival. The guideline recommends that patients who cannot receive PCI within 90 minutes (either at the presenting facility or after transfer) be treated with thrombolysis (48).

  • A 2011 guideline for coronary angiography from the American College of Cardiology, the American Heart Association, and the Society for Cardiovascular Angiography and Interventions recommends immediate coronary angiography with PCI in patients with STEMI with severe HF or a large area of at-risk myocardium, in the absence of contraindications (57).

Rationale
  • Primary PCI is associated with a lower 30-day mortality rate and lower risk of hemorrhagic stroke vs. thrombolytic therapy.

  • Prompt transfer to a referral center for primary PCI may be beneficial in patients with ST-segment elevation or LBBB acute MI.

Administer a thrombolytic agent as an alternative to primary PCIs in suitable candidates with STEMI. 
  • Administer iv thrombolytic therapy to patients with ST-segment elevation or new LBBB MI and chest pain of less than 12 hours if not undergoing primary PCI.

  • Consider administering a thrombolytic agent to patients with persistent chest pain who present more than 12 hours after onset of chest pain.

  • Recognize that primary PCI is an alternative to thrombolytic therapy and may be associated with improved outcomes in selected patients.

  • See table Drug Treatment for Acute Coronary Syndromes.

Evidence
  • Numerous clinical trials (including ISIS-2, GUSTO, and GISSI) have shown a reduced mortality rate with thrombolytic use (compared with standard of care at the time which did not include primary PCI). A review of nine trials included 58,600 patients undergoing thrombolytic therapy vs. control for acute MI. Results showed a highly significant 18% reduction in 35-day mortality and a reduction of 21% among patients with ST-segment elevations (58).

  • The ISIS-2 trial consisted of 17,187 patients entering 417 hospitals up to 24 hours (median, 5 hours) after the onset of suspected acute MI. Patients were randomly assigned a 1-hour iv infusion of 1.5 million units of streptokinase, 1 month of enteric-coated aspirin, 160 mg/d, both active treatments, or placebo. Streptokinase alone and aspirin alone each produced a highly significant reduction in 5-week vascular mortality and the combination was significantly better than either agent alone. Their separate effects on vascular deaths appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents vs. 568/4300 (13.2%) among patients allocated neither (odds reduction: 42% SD 5 [Cl, 34% to 50%]). Patients allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8% vs. 2.9%), strokes (0.6% vs. 1.1%), and deaths (8.0% vs. 13.2%) than patients allocated neither. The differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up (46).

  • The GISSI trial was an unblinded trial of iv streptokinase in early acute MI. There were 11,806 patients in 176 coronary care units enrolled over 17 months. Patients admitted within 12 hrs after the onset of symptoms and with no contraindications to streptokinase were randomly assigned to receive streptokinase in addition to usual treatment. At 21 days, overall hospital mortality was 10.7% in streptokinase recipients vs. 13% in controls (NNT, 43; P=0.0002) (59).

  • In the ASSET trial, 5011 patients with suspected acute MI were randomized to receive alteplase (rt-PA) or placebo. At 1-month follow-up alteplase therapy was associated with a 26% relative reduction in all-cause mortality (60).

  • A 2009 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI recommends that patients presenting with STEMIs to a hospital with the capability for primary PCI receive PCI within 90 minutes of arrival. The guideline recommends that patients who cannot receive PCI within 90 minutes (either at the presenting facility or after transfer) be treated with thrombolysis, but that high-risk patients receiving thrombolysis be transferred to a PCI center for ongoing care (48).

Rationale
  • By lysing the clot that is limiting blood flow to the myocardium, thrombolytics restore perfusion to the ischemic area, reduce infarct size, and improve survival.

Comments
  • Thrombolysis does not prevent death or MI for ACS patients without ST-segment elevation.

  • Thrombolytic therapy should not be given to patients with STEMI who present more than 12 hours after symptom onset without ongoing chest pain, as the bleeding risk probably outweighs the potential benefits.

  • For patients with cardiogenic shock, thrombolytic therapy seems to be ineffective, and strong consideration should be given to percutaneous or surgical revascularization in these patients. The randomized SHOCK trial reported improved 6-month survival with early revascularization in patients aged under 75 years with cardiogenic shock due to acute MI (61).

  • The value of thrombolytic therapy in patients aged 75 years or older is controversial, but older age is not a contraindication to thrombolytic therapy in carefully selected patients.

Administer clopidogrel or a newer P2Y12 receptor-inhibitor in selected patients with ACS. 
  • Administer clopidogrel, prasugrel, or ticagrelor to patients with ACS who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance.

  • Administer clopidogrel or another P2Y12 receptor-inhibitor in addition to aspirin as soon as possible to patients with ACS for whom a noninterventional approach is planned, and continue for at least 1 month and for up to 9 months.

  • Administer clopidogrel or another P2Y12 receptor-inhibitor in addition to aspirin to patients with ACS for whom PCI is planned and who are not at high-risk for bleeding, and continue clopidogrel for up to 12 months.

  • Discontinue clopidogrel for 5 to 7 days before elective coronary bypass surgery.

  • Administer clopidogrel, 75 mg/d, in addition to aspirin in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not undergo reperfusion.

  • Consider prescribing a concomitant proton-pump inhibitor or H2 blocker in patients receiving dual antiplatelet therapy who are at high-risk for gastrointestinal bleeding.

  • Consider substituting a newer P2Y12 receptor-inhibitor, such as prasugrel or ticagrelor, for clopidogrel in select patients.

Evidence
  • A 2012 systematic review evaluated the effect of P2Y12 inhibitors on mortality and stroke in patients with ACS or in those undergoing PCI. Compared with placebo, clopidogrel led to lower rates of cardiovascular mortality (OR, 0.93 [CI 0.87 to 0.99]) and stroke (OR, 0.84 [CI 0.72 to 0.97]). Newer agents, compared with clopidogrel, reduced mortality (OR, 0.86 [CI 0.76 to 0.94]) but not stroke (62).

  • In the CURE trial, 12,562 patients with ACS were randomized to receive aspirin, 75 to 325 mg, alone or in combination with clopidogrel, 300 mg, as a loading dose followed by 75 mg/d for a period of 3 to 12 months. At 1-month follow-up there was a 20% relative risk reduction in the composite endpoint of cardiovascular death, MI, or stroke in the aspirin plus clopidogrel group; however, there was an absolute increase of 1% in the risk of major bleeding complications (63). At 12-months follow-up, the beneficial effects of clopidogrel persisted, with no excess in life-threatening hemorrhagic events after 1 month (64).

  • In PCI-CURE, a substudy of CURE, 2658 patients with ACS undergoing PCI were randomized to aspirin or aspirin plus clopidogrel before the intervention. At 30-days follow-up, there was a 31% reduction in death or MI in the clopidogrel plus aspirin group (65).

  • The COMMIT-CCS-2 study randomized 45,852 patients (93% with STEMI, 54% treated with fibrinolysis) within 24 hours of suspected MI to clopidogrel, 75 mg/d (without a loading dose) or placebo in addition aspirin, 162 mg/d. The study drug treatment was to continue until hospital discharge or up to 4 weeks. The composite primary endpoint of death, reinfarction, or stroke was reduced from 10.1% in the placebo group to 9.2% in the clopidogrel group (OR, 0.91 [CI, 0.86 to 0.97]; P=0.002). The benefit of clopidogrel was seen in both the subgroups of patients who did and did not receive fibrinolytic therapy. The co-primary endpoint of all-cause mortality was reduced from 8.1% in the placebo group to 7.5% in the clopidogrel group (OR, 0.93 [CI, 0.87 to 0.99]; P=0.03; NNT=167) (66).

  • A 2010 consensus statement from the ACCF/AHA and the American College of Gastroenterology on the use of proton-pump inhibitors and thienophyridines acknowledges that proton-pump inhibitors may reduce the efficacy of clopidogrel and suggests that the potential benefits and harms of proton-pump inhibitors be evaluated in patients with ACS requiring antiplatelet therapy (67).

  • A 2010 meta-analysis comparing newer P2Y12 inhibitors with clopidogrel included 48,599 patients (94% with ACS). Patients receiving newer agents had significantly lower rates of death (OR, 0.83 [CI, 0.75 to 0.92], P<0.001 for the whole cohort; OR, 0.85 [CI, 0.75 to 0.96], P=0.008 for any PCI; and OR, 0.78 [CI, 0.66 to 0.92], P=0.003 for PCI for STEMI). This encouraging result was balanced by an increase in major bleeding for any PCI (OR, 1.23 [CI, 1.04 to 1.46]; P=0.01), but not in PCI for STEMI (OR, 0.98 [CI, 0.85 to 1.13]; P=0.76) (68).

  • The TRITON-TIMI 38 trial randomized 13,608 patients to either prasugrel, 60 mg load, and 10 mg/d or clopidogrel, 300 mg load, and 75 mg/d, with a primary endpoint of death, MI, or stroke. More patients receiving clopidogrel met the primary endpoint compared with prasugrel (12.1% vs. 9.9%; P<0.001). However, patients receiving prasugrel had more bleeding (HR, 1.32 [CI, 1.03 to 1.68]; P=0.03) (69).

  • The PLATO trial randomized 18,624 ACS patients to ticagrelor, 180 mg load, followed by 90 mg bid, or clopidogrel, 300 mg load, followed by 75 mg/d. Ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, MI, or stroke (HR, 0.84 [CI, 0.77 to 0.92]; P<0.001) without an increase in the rate of overall major bleeding but with an increase in the rate of nonprocedure-related bleeding (70).

  • The CURRENT-OASIS 7 trial showed that, in patients with ACS who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, MI, or stroke (71).

  • A 2009 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI recommends the use of thienopyridines in the acute setting and for 1 year, with consideration of longer treatment in patients receiving drug-eluting stents (48).

  • A 2012 guideline from the American College of Cardiology and the American Heart Association for the treatment of unstable angina and NSTEMI recommends the use of these agents, and states that clopidogrel or ticagrelor should be continued for up to 12 months (47).

Rationale
  • Clopidogrel is a more potent antiplatelet agent than aspirin, and it provides additional antiplatelet activity when added to aspirin.

  • Prasugrel has more potent platelet inhibition than clopidogrel and has been shown to be particularly effective in diabetic or STEMI patients.

  • Ticagrelor has shown greater antiplatelet efficacy as compared with clopidogrel. It is not a prodrug and does not have to be metabolized to be active.

Comments
  • In patients after ACS who require anticoagulation with warfarin in addition to antiplatelet therapy, the 2012 guideline recommends an INR of 2.0 to 3.0 (47).

  • There is a clustering of adverse events in the initial 90 days after stopping clopidogrel among both medically treated and PCI-treated patients with ACS, suggesting the possibility of a clopidogrel rebound effect (72).

  • Clopidogrel increases bleeding among patients undergoing coronary bypass surgery within 5 days of receiving clopidogrel, but not among those receiving surgery later (63).

Give anticoagulant therapy with UFH, LMWH, or bivalirudin to moderate- and high-risk patients with ACS. 
Evidence
  • A 2008 Cochrane review of heparins (either UFH or LMWH) compared with placebo in patients with ACS included eight studies with 3118 participants. Heparins reduced MI (RR, 0.40 [CI, 0.25 to 0.63]), increased minor bleeding (RR, 6.80 [CI, 1.23 to 37.49]), and did not affect mortality (73).

  • Two landmark trials (TIMI IIB and ESSENCE) show enoxaparin to be superior to UFH for preventing death and cardiac ischemic events.

    • The TIMI IIB trial was conducted in two phases, an acute phase (3 days to 8 days) and a chronic outpatient phase (up to 43 days) and included 3910 patients with unstable angina or non-Q wave MI. In the acute phase, patients were randomized to weight-based continuous iv UFH for 3 or more days followed by placebo subcutaneous injections during the outpatient phase vs. uninterrupted antithrombin therapy with enoxaparin during both the acute (initial 30 mg iv bolus followed by injections of 1.0 mg/kg·12 h) and outpatient phases (injections every 12 hours of 40 mg for patients weighing <65 kg and 60 mg for patients weighing ≥65 kg). The primary endpoint (death, MI, or urgent revascularization) occurred by 8 days in 14.5% of patients in the UFH group and 12.4% of patients in the enoxaparin group (NNT, 48; P=0.048) and by 43 days in 19.7% of the UFH group and 17.3% of the enoxaparin group (NNT, 42; P=0.048). Rates of major hemorrhage were similar in the groups (74).

    • The ESSENCE trial evaluated the efficacy and safety of enoxaparin, 1 mg/kg·12 h, plus aspirin vs. continuous iv UFH plus aspirin in 3171 patients with unstable angina or non-Q wave MI. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and data were collected over 30 days. At 14 days, the primary endpoint (a composite risk of death, MI, or recurrent angina with electrocardiographic changes or prompting intervention), was significantly lower in patients assigned to enoxaparin compared with heparin (16.6% vs. 19.8%; NNT, 31; P=0.019). At 30 days, the composite risk of death, MI, or recurrent angina remained significantly lower in the enoxaparin group compared with the UFH group (19.8% vs. 23.3%; NNT, 29; P=0.016). The rate of revascularization procedures at 30 days was also significantly lower in patients assigned to enoxaparin (27.1% vs. 32.2%; P=0.001). The 30-day incidence of major bleeding complications were similar, but the incidence of minor bleeding was significantly higher in the enoxaparin group (13.8% vs. 8.8%; P<0.001) due primarily to injection-site ecchymosis (75).

  • A 2003 Cochrane review of the effect of LMWH compared with UFH in patients with ACS included seven studies with 11,092 participants. LMWH was associated with significant reductions in the occurrence of MI (RR, 0.83), need for revascularization procedures (RR, 0.88), and development of thrombocytopenia (RR, 0.64) relative to UFH. There were no differences in total mortality, recurrent angina, or major or minor bleeds between groups (76).

  • A 2007 meta-analysis compared enoxaparin with UFH and included over 49,000 patients from 12 trials looking at a primary endpoint of death, MI, or major bleeding at 30 days. Overall, there was a near-significant trend toward lower rates of the primary endpoint with enoxaparin (OR, 0.90; P=0.051). There was a significant benefit to enoxaparin among trials of patients with STEMI (OR, 0.84; P=0.015) but no benefit in trials of patients with NSTEMI (77).

  • The ACUITY trial randomized 13,819 patients with moderate- to high-risk NSTEMI to one of three regimens: bivalirudin alone, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or FH/LMWH plus a glycoprotein IIb/IIIa inhibitor. Both bivalirudin arms were considered noninferior to the heparin arm with respect to the composite ischemia endpoint (death, MI, or unplanned revascularization for ischemia), but the bivalirudin-alone arm had significantly lower rates of major bleeding (78).

  • The HORIZONS-AMI trial randomized 3602 STEMI patients undergoing primary PCI to compare bivalirudin with UFH plus glycoprotein IIb/IIIa inhibitors. Anticoagulation with bivalirudin alone, as compared with UFH plus glycoprotein IIb/IIIa inhibitors, resulted in a lower 30-day rate of net adverse clinical events defined as the combination of major bleeding or major adverse cardiovascular events, including death, reinfarction, target-vessel revascularization for ischemia, and stroke (9.2% vs. 12.1%; NNT, 35; P=0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; RR, 0.60; P<0.001) (79).

Rationale
  • The combination of anticoagulants and aspirin is beneficial in patients with ACS.

Consider administering glycoprotein IIb/IIIa antagonists in addition to aspirin and an anticoagulant in patients with high-risk NSTEMI, as adjunctive therapy in patients with STEMI undergoing primary PCI, or as an alternative to P2Y12 receptor-inhibitors.  
  • Administer abciximab, eptifibatide, or tirofiban in addition to aspirin and anticoagulants to patients with continuing ischemia, an elevated troponin level, or with other high-risk features, including angina at rest with ST-segment changes, HF, diabetes, or recent MI who do not have increased bleeding risk.

  • Administer an iv glycoprotein IIb/IIIa antagonist in addition to aspirin and an anticoagulant to patients in whom catheterization and PCI are planned; it may be administered just before PCI.

  • See table Drug Treatment for Acute Coronary Syndromes.

Evidence
  • A 2010 Cochrane review of the use of glycoprotein IIb/IIIa blockers with PCI or in patients with NSTEMI included 48 trials with 62,417 participants. When used in the initial management of NSTEMI, glycoprotein IIb/IIIa blockers did not reduce mortality, but reduced the rate of death or MI at both 30 days (OR, 0.92 [CI, 0.86 to 0.99]), and at 6 months (OR, 0.88 [CI, 0.81 to 0.96]) and increased severe bleeding (OR, 1.27 [CI, 1.12 to 1.43]) (80).

  • In the EPIC trial, 2099 patients with NSTEMI who required PCI either due to MI requiring rescue, early post-MI angina, unstable angina within 24 hours of admission, or vessels at high risk for closure were randomly assigned to receive bolus and continuous infusion of placebo, a bolus of abciximab then continuous infusion with placebo, or a bolus and infusion of abciximab. The primary endpoint was death, nonfatal MI, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an IABP for refractory ischemia. As compared with placebo, abciximab bolus and infusion resulted in a 35% reduction in the primary endpoint (81).

  • In the EPILOG trial, 2792 patients with NSTEMI undergoing urgent or elective percutaneous coronary revascularization were randomly assigned to receive abciximab with standard dose heparin, abciximab with low-dose heparin, or placebo with standard-dose heparin. The primary endpoint of death, MI, or urgent revascularization was 11.7% in the placebo group, 5.2% in the abciximab with low-dose heparin group, and 5.4% in the abciximab with standard-dose heparin (82).

  • In the EPISTENT trial, 2399 patients with NSTEMI were randomly assigned stenting plus placebo, stenting plus abciximab, or balloon angioplasty plus abciximab. The primary endpoint of death, MI, or need for urgent revascularization occurred in 10.8% of the placebo group, 5.3% of the stent plus abciximab group, and 6.9% of the balloon angioplasty plus abciximab group. Death and large MI occurred less in the abciximab groups (7.8% in the placebo group, 3.0% in the stent plus abciximab group, and 4.7% in the balloon angioplasty plus abciximab group) (83).

  • In the PRISM study, 3232 patients already receiving aspirin with accelerating angina were randomly assigned to iv tirofiban therapy for 48 hours or heparin therapy. The primary endpoint was a composite of death, MI, or refractory ischemia at 48 hours. The composite endpoint was reduced by 32% in the tirofiban group at 48 hours (84).

  • In PRISM-PLUS, 1915 patients with NSTEMI or unstable angina were randomly assigned to tirofiban, heparin, or both. All patients received aspirin if there was no contraindication. PCI was performed after 48 hours if indicated. The composite primary endpoint of death, MI, or refractory ischemia at 7 days was assessed. The study was stopped prematurely for the group receiving tirofiban alone due to increased mortality; however, the arm receiving tirofiban plus heparin had a lower frequency for the composite endpoint than the group receiving heparin alone (12.9% vs. 17.9%) (85).

  • PURSUIT was a trial of 10,948 patients with ischemic chest pain who had either ECG evidence of ischemia (other than persistent ST elevation) or elevated cardiac enzymes. Patients were randomly assigned to receive a bolus and infusion of either eptifibatide or placebo for 72 hours. The primary composite endpoint was death and nonfatal MI. As compared with the placebo group, the eptifibatide group had a 1.5% absolute reduction in the incidence of the primary endpoint (86).

  • The ISAR REACT 2 trial randomized 2022 high-risk NSTEMI patients undergoing PCI to abciximab iv for 12 hours vs. placebo. All patients also received clopidogrel, 600 mg, and aspirin, 500 mg. The primary composite endpoint of death, MI, or urgent target vessel revascularization occurring within 30 days after randomization was reached in 90 patients (8.9%) assigned to abciximab vs. 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (RR, 0.75 [CI, 0.58 to 0.97]; P=0.03). This benefit was more pronounced in the elevated troponin group. The ISAR REACT 2 trial was the first to show a benefit for glycoprotein IIb/IIIa antagonists in the context of clopidogrel (87).

  • A 2012 guideline from the American College of Cardiology and the American Heart Association for the treatment of unstable angina and NSTEMI recommends glycoprotein IIb/IIIa inhibitors in patients receiving an invasive strategy, either before or at the time of PCI (47).

  • A 2009 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI recommends the use of glycoprotein IIb/IIIa inhibitors at the time of PCI in select patients (48).

Rationale
  • The glycoprotein IIb/IIIa receptor antagonists block platelet aggregation.

Comments
  • All three glycoprotein IIb/IIIa antagonists are used in patients with ACS and in those undergoing PCIs. However, abciximab has a longer duration of action than tirofiban and eptifibatide in antagonizing platelet aggregation and may therefore be less desirable in patients who might need CABG.

Administer β-blockers early to patients with suspected ACS unless there are significant contraindications; give a nonselective β-blocker to patients with LVD after an MI.  
  • Initiate oral β-blocker therapy in the first 24 hours for patients who do not have any of the following:

    • Signs of HF

    • Evidence of a low-output state

    • Increased risk for cardiogenic shock

    • Other relative contraindications to β-blockade (PR interval >0.24 s, second- or third-degree heart block, active asthma, or reactive airway disease)

  • Re-evaluate patients with early contraindications within the first 24 hours of STEMI as candidates for β-blocker therapy as secondary prevention.

  • Consider administering iv β-blockers at presentation to patients with STEMI who are hypertensive and do not have any of the following:

    • Signs of HF

    • Evidence of a low-output state

    • Increased risk for cardiogenic shock

    • Other relative contraindications to β-blockade

  • Start carvedilol, 6.25 mg bid, beginning 3 to 21 days after MI in stable patients with LVEF ≤40% and no significant contraindications, titrating to a maximum dose of 25 mg bid over 4 to 6 weeks.

  • See table Drug Treatment for Acute Coronary Syndromes.

Evidence
  • A 2005 randomized, controlled trial compared early treatment with metoprolol to placebo in 45,852 patients with suspected acute MI. After 4 weeks of follow-up, metoprolol did not reduce the primary outcomes of overall mortality or the composite of death, reinfarction, or cardiac arrest, but patients receiving metoprolol had lower rates of reinfarction (NNT, 200; P=0.001) and ventricular fibrillation (NNT, 200; P=0.001) (88).

  • In the CAPRICORN trial, 1959 patients with documented acute MI and LVEF ≤40% were randomized to carvedilol or placebo beginning 3 to 21 days after MI. The initial dose of carvedilol was 6.25 mg bid, and the dose was increased as tolerated over a period of 4 to 6 weeks to a maximum dose of 25 mg bid. Ninety-eight percent of patients were also receiving an ACE inhibitor. Patients were followed for a mean of 1.3 years, and the primary endpoint was all-cause mortality or hospitalization for cardiovascular problems. Although there was no difference between carvedilol and placebo with respect to the primary endpoint (35% vs. 37%, respectively), carvedilol therapy was associated with a 23% reduction in all-cause mortality (P=0.03), a 25% reduction in cardiovascular mortality (P=0.02), a 41% reduction in recurrent nonfatal MI (P=0.01), and a 29% reduction in the combined endpoint of death or nonfatal MI (P=0.002) (89).

  • A 2009 systematic review assessed the effect of β-blockers on mortality in patients with ACS. Compared with placebo, nonselective β-blockers reduced mortality (RR, 0.73 [CI 0.64 to 0.82]) and vascular events (RR, 0.71 [CI 0.59 to 0.84]); β1-blockers showed a nonsignificant trend toward reduced mortality (RR, 0.82 [CI 0.67 to 1.01]) and vascular events (RR, 0.68 [CI 0.42 to 1.11]) (90).

  • A 2010 systematic review of the effect of β-blockers on in-hospital mortality in patients with ACS included 18 studies with 72,249 participants. Despite heterogeneity, the studies overall showed a trend toward a small reduction in in-hospital mortality (RR, 0.95 [CI, 0.90-1.01]). One included study showed that patients receiving β-blockers had higher rates of cardiogenic shock (91).

Rationale
  • β-blockers reduce mortality and hospitalization in patients with HF and reduced left ventricular systolic function (LVEF ≤40%).

  • Carvedilol provides nonselective blockade of α, β1, and β2 receptors, antagonizing the deleterious effects of sympathetic nervous system activation, reducing heart rate and systemic arterial pressure, and potentially attenuating adverse LV remodeling.

Comments
  • In patients with continuing or frequently occurring ischemia when β-blockers are contraindicated, a nondihydropyridine calcium antagonist (e.g., verapamil or diltiazem) may be used in the absence of severe LV dysfunction or other contraindications (92).

  • β-blockers may be harmful to patients who are at risk of cardiogenic shock.

Administer an ACE inhibitor early in the course of ACS.  
  • Administer an ACE inhibitor to patients within the first 24 hours of STEMI or with clinical HF in the absence of hypotension (systolic BP <100 mm Hg) or known contraindications to an ACE inhibitor.

  • Administer an ACE inhibitor to patients with acute MI and a LVEF <40% or patients with clinical HF due to left ventricular systolic dysfunction.

  • Consider administering an ACE inhibitor to all other patients within the first 24 hours of acute MI in the absence of hypotension or other contraindications.

  • Consider administering an ACE inhibitor in asymptomatic patients with mildly impaired left ventricular systolic function (EF 40% to 50%).

  • See table Drug Treatment for Acute Coronary Syndromes.

Evidence
  • A 1999 systematic review and meta-analysis evaluated the effect of ACE inhibitors in patients with acute MI and included 15 studies with 15,104 participants. Compared with placebo, ACE inhibitors lowered mortality (OR, 0.83 [CI, 0.71 to 0.97]) (93).

  • In the ISIS-4 trial, 58,050 patients with suspected acute MI were randomly assigned within the first 24 hours to receive either 1 month of oral captopril (6.25 mg initial dose titrated up to 50 mg bid) vs. placebo. There was a significant 7% proportional reduction in 5-week mortality in the captopril group, and the largest benefit was among patients with anterior infarction. The data further suggested that early therapy was important, as the deaths occurring in the placebo group occurred within the first 7 days (94).

  • The GISSI-3 trial used oral lisinopril in 19,394 patients admitted with acute MI. Patients were randomly assigned to 6 weeks of oral lisinopril (5 mg initial dose and then 10 mg/d) or open control. Lisinopril, started within 24 hrs from acute MI symptoms, produced significant reductions in overall mortality (OR, 0.88 [CI, 0.79 to 0.99]) and in the combined outcome measure of mortality and severe ventricular dysfunction (0.90 [CI, 0.84 to 0.98]). Again, 60% of lives saved were during the first 5 days of treatment, emphasizing the need for early initiation of treatment (95).

  • The SAVE trial was a randomized, double-blind, placebo-controlled clinical trial of 2231 patients 3 to 16 days post-MI with EFs of ≤40% without overt HF or symptoms of myocardial ischemia. The investigators assessed the effect of ACE inhibitors on postinfarction death and ventricular dilation. Patients were randomly assigned to receive either captopril or placebo and were followed for an average of 42 months. Mortality from all causes was significantly reduced in the captopril group compared with the placebo group, with a 19% risk reduction. In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21% for death from cardiovascular causes, 37% for the development of severe HF, 22% for HF requiring hospitalization, and 25% for recurrent MI (96).

  • In the AIRE study, 2006 patients with clinical HF after acute MI were randomized to receive ramipril or placebo and followed for an average of 15 months. Ramipril was associated with a 27% relative reduction in the risk of death from any cause, and a 19% relative reduction in the risk of death, severe HF, stroke, or recurrent MI (97).

Rationale
  • ACE inhibitor therapy can attenuate ventricular remodeling resulting in a reduction in the development of HF and death.

  • ACE inhibitor therapy may also reduce the risk of recurrent MI and other vascular events.

Consider an ARB as an alternative to an ACE inhibitor in patients with HF or LVD after acute MI. 
Evidence
  • In the VALIANT trial, 14,703 patients with acute MI complicated by clinical HF and/or LV EF ≤35% by ECG or contrast ventriculography (≤40% by radionuclide angiography) were randomly assigned to receive captopril (target dose, 50 mg tid), valsartan (target dose, 160 mg bid), or both drugs within 10 days after infarction. Median follow-up was 24.7 months, and the primary endpoint was all-cause mortality. Compared with captopril, valsartan was associated with equivalent mortality and recurrent cardiovascular event rates, but fewer patients in the valsartan group required permanent discontinuation of study medication due to side effects. The combination of captopril and valsartan did not improve survival but was associated with an increased incidence of side effects (98).

  • In the OPTIMAAL trial, 5,477 patients aged 50 years or older with an acute MI complicated by HF or a new anterior Q-wave MI were randomized to captopril, 50 mg tid, or losartan, 50 mg/d. During a mean follow-up of 2.7 years, all-cause mortality was 16% in the captopril group and 18% in the losartan group (P=0.07). Losartan was tolerated better than captopril, and significantly fewer patients in the losartan group discontinued study medication due to side effects (99).

Rationale
  • Like ACE inhibitors, ARBs can improve clinical outcomes in patients with acute MI complicated by HF, LV systolic dysfunction, or both.

Comments
  • Because the value of early treatment with ACE inhibitors following acute MI has been documented in clinical trials involving more than 100,000 patients, ACE inhibitors remain the first-choice agents in this population. However, based on the results of the VALIANT and OPTIMAAL trials, ARBs are a suitable alternative in patients who are unable to tolerate ACE inhibitors.

  • The VALIANT trial showed equivalent outcomes with captopril and valsartan, but the OPTIMAAL trial failed to show that losartan was equivalent to captopril; therefore, valsartan is the preferred ARB in the post-MI setting.

Administer nitroglycerin to patients with ACS who have ongoing chest discomfort. 
  • Administer iv nitroglycerin for the first 24 to 48 hours to patients with:

    • Unstable angina

    • Acute uncomplicated MI with ongoing chest discomfort

    • MI complicated by HF, large anterior infarction, persistent ischemia, or hypertension

  • Adminster sublingual nitroglycerin to patients who present in office settings as an alternative.

  • Avoid nitroglycerin in marked bradycardia, tachycardia, or hypotension and use with extreme caution, if at all, in patients with suspected right ventricular infarction.

  • See table Drug Treatment for Acute Coronary Syndromes.

Evidence
  • Clinical trials such as GISSI-3 and ISIS-4 support the use of nitrates early in the setting of an ACS. Evidence from these trials shows that nitrates may reduce infarct size, improve regional myocardial function, prevent LV remodeling that occurs after a large transmural MI, and provides a small relative reduction in mortality rate (94; 95).

  • The GISSI-3 trial assessed the efficacy of lisinopril, transdermal nitroglycerin, and their combination in 19,394 patients with acute MI. Patients were randomly assigned to a 24-hour infusion of nitroglycerin (beginning within 24 hours of pain onset) followed by topical nitroglycerin (10 mg/d with a 10-hour nitrate-free period at night) for 6 weeks. There was an insignificant reduction in mortality in the nitrate-therapy-alone group when compared with control (6.52% vs. 6.92% respectively). However the combined use of lisinopril and nitrates led to a greater reduction in mortality at 6 weeks and 6 months when compared with the group that received no nitrates or lisinopril therapy alone (95).

  • Another randomized trial, ISIS-4, compared 28-day treatment with oral isosorbide mononitrate with placebo control in 58,050 patients with suspected acute MI. Nitrate therapy was associated with a nonsignificant reduction in 35-day mortality when compared with control (7.34% vs. 7.54% respectively) (94).

Rationale
  • The vasodilating action of nitroglycerin has been shown to result in combined preload and afterload reduction, decreased cardiac work, and lower myocardial oxygen requirements; additionally, the direct vasodilator effect on the coronary bed improves myocardial blood flow.

Prescribe high-potency HMG-CoA reductase inhibitors (statins) in patients with ACS and continue after hospitalization, with goal LDL <100 mg/dL.  
  • Initiate intensive therapy with a high-potency statin (atorvastatin or rosuvastatin) early in the setting of ACS.

  • Continue statin therapy after hospital discharge, with goal LDL <100 mg/dL.

  • Follow National Cholesterol Education Program guidelines.

  • See table Drug Treatment for Acute Coronary Syndromes.

Evidence
  • A 2007 systematic review of the benefit of intensive statin therapy compared with moderate statin therapy in patients with ACS and angina included six trials with 110,271 participants. In patients with ACS, intensive statin reduced mortality at 2 years (NNT, 91) (100).

  • A 2006 systematic review and meta-analysis of early intensive statin treatment in ACS included 13 trials with 17,963 participants. Early intensive statin use led to lower rates of death or cardiovascular events over 2 years (HR, 0.81 [CI, 0.77 to 0.87]), with benefit emerging after 4 months (101).

  • A 2006 systematic review of the effect of early statin treatment on short-term outcomes in ACS included 12 trials with 13,024 participants. The study found no benefit to early statins at 1 month and 4 months follow-up (102).

  • In the MIRACL study, 3086 patients with unstable angina or non-Q wave MI were randomly assigned to receive either atorvastatin, 80 mg/d, or placebo within 24 to 96 hours after hospital admission. Patients were followed for a total of 16 weeks, and the primary endpoint was a combination of death, nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergent rehospitalization. The results showed a 2.6% absolute risk reduction in the primary combined endpoint for the atorvastatin group. In addition, the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence requiring emergency rehospitalization (6.2% vs. 8.4%; RR, 0.74; [CI, 0.57 to 0.95]; P=0.02) (103).

  • In the PROVE IT-TIMI 22 trial, 4162 patients who had been hospitalized for ACS within the preceding 10 days were randomized to either pravastatin, 40 mg/d (standard therapy), or atorvastatin, 80 mg/d (intensive therapy). The rates of the primary endpoint of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke at 2 years were 26.3% in the pravastatin group and 22.4% in the atorvastatin group (NNT, 26; P=0.005) (104).

  • A further analysis of PROVE IT-TIMI 22 showed that atorvastatin, 80 mg, a more intensive low-density lipoprotein cholesterol-lowering agent, reduced both first and subsequent primary endpoint events compared with pravastatin, 40 mg, after ACS (105).

Rationale
  • Statin therapy reduces the risk of future coronary events.

Administer oxygen to patients with oxygen saturation <90%. 
  • Administer oxygen in patients with overt pulmonary edema or arterial oxygen saturation <90%.

  • Consider administering oxygen routinely in all patients with uncomplicated MI during the first 2 to 3 hours.

Evidence
  • It is not known whether oxygen supplementation limits myocardial damage or reduces complications or death. Some experimental results indicate that breathing oxygen may limit ischemic injury and reduce ST-segment elevation in patients with acute MI (106).

  • A 2010 Cochrane review of 387 patients found no conclusive evidence from randomized, controlled trials to support the routine use of inhaled oxygen in patients with acute MI (107).

  • The 2004 guideline from the American College of Cardiology and the American Heart Association recommended supplemental oxygen in patients with STEMI with oxygen saturation <90%. Subsequent guideline updates have not addressed the issue (108).

Rationale
  • Significant hypoxemia can be corrected with supplemental oxygen and may possibly limit ischemic myocardial injury.

Initiate bed rest with bedside commode privileges for at least the first 12 hours of hospitalization in patients with suspected ACS. 
  • Place patients on bed rest while ischemia is ongoing; mobilize patients to a chair and bedside commode when symptom-free.

  • Consider ordering a stool softener to reduce the risk of straining and associated Valsalva maneuvers.

Evidence
  • The 2004 guideline from the American College of Cardiology and the American Heart Association recommended bed rest with commode privileges for the first 12 to 24 hours in patients with STEMI. Subsequent guideline updates have not addressed the issue (108).

Rationale
  • Physical exertion and sympathetic stimulation increase myocardial oxygen demand that can increase the area of myocardial damage when coronary blood flow is limited.

  • The Valsalva maneuver causes changes in ventricular loading, predisposing the patient to ventricular arrhythmias.

Administer morphine to patients with persistent pain. 
  • Administer effective analgesia in patients with persistent symptoms after 3 sublingual nitroglycerin doses or in patients with recurrent symptoms.

  • Administer morphine sulfate intravenously at a rate of 2 to 4 mg every 5 minutes.

Evidence
  • Data show that acceleration of the heart rate, elevation of arterial pressure, and augmentation of cardiac contractility increases myocardial oxygen demand (109).

  • The 2007 guideline update from the American College of Cardiology and the American Heart Association recommended morphine for pain control in patients with STEMI. Subsequent guideline updates have not addressed the issue (110).

Rationale
  • Overactivity of the sympathetic nervous system adversely increases myocardial oxygen demand.

  • Morphine sulfate reduces sympathetic tone through a centrally mediated anxiolytic affect; morphine also reduces myocardial oxygen demand by reducing per-load and by a vagally-mediated reduction in heart rate.

Consider early initiation of eplerenone, a selective aldosterone blocker, in patients with LVD after MI. 
Evidence
  • In the EPHESUS trial, 6632 patients with acute MI, LV EF ≤40%, and clinical HF or diabetes were randomly assigned to receive eplerenone, 25 to 50 mg/d (n=3319) or placebo (n=3313) in addition to optimal medical therapy. Patients were randomly assigned within 3 to 14 days of acute MI and followed for a mean of 16 months. During this period, total mortality was reduced from 16.7% in the placebo group to 14.4% in the eplerenone group (RR, 0.85; P=0.008). Cardiovascular mortality was reduced from 14.6% to 12.3% (RR, 0.83; P=0.005), and the composite endpoint of all-cause mortality or hospitalization for cardiovascular events was reduced from 30.0% to 26.7% (RR, 0.87; P=0.002). Eplerenone was well tolerated, and the overall incidence of adverse events was similar in the two groups. Hyperkalemia was more common with eplerenone, but hypokalemia was more common with placebo. Gastrointestinal disorders were somewhat more common in patients receiving eplerenone (19.9% vs. 17.7%; P=0.02) (111).

  • Subanalysis from EPHESUS examined the relationship between eplerenone, serum potassium, and clinical outcomes. The use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in postacute MI patients with HF and LV systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (≥6.0 mEq/L) when periodic monitoring of serum potassium is instituted (112).

  • The 2004 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI recommends aldosterone blockade for patients post-MI who have EF <40%, are receiving an ACE inhibitor, have either diabetes or clinical HF and who do not have hyperkalemia or CKD. The issue has not been addressed in subsequent guideline updates (108).

Rationale
  • Despite treatment with ACE inhibitors and β-blockers, patients with impaired LV systolic function after MI are at increased risk for HF and death, in part due to progressive deterioration in LV performance resulting from ventricular structural remodeling.

  • Eplerenone limits collagen formation and ventricular remodeling after acute MI and also has a favorable effect on the neurohormonal profile.

Comments
  • Although spironolactone has previously been shown to reduce mortality and hospitalizations in patients with severe LV systolic dysfunction and NYHA class III or IV HF, the efficacy of spironolactone in patients with recent MI is unknown.

  • Aldosterone antagonists should not be used in patients with creatinine levels >2.0 to 2.5 mg/dL or preexisting hyperkalemia.

Educate patients about the importance of tight glycemic control. 
  • Consider referral to diabetic teaching programs and instruction on an ADA diet and weight reduction in order to achieve long-term tight diabetic control.

  • See module Diabetes Mellitus, Type 2

Evidence
  • Tight glucose control in diabetics during and after MI (DIGAMI study) has been shown to lower acute and 1-year mortality rates. A total of 620 patients with acute MI were studied: 306 randomly assigned to treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for ≥3 months (the tight control group) and 314 to conventional therapy. After 1 year, 57 subjects (18.6%) in the infusion group and 82 (26.1%) in the control group had died (relative mortality reduction 29%; P=0.027). The 3-month mortality rate was 6.5% in the infusion group vs. 13.5% in the control group (relative reduction 52%; P=0.046); the 1-year mortality rate was 8.6% in the infusion group vs. 18.0% in the control group (relative reduction 52%, P=0.02) (113).

  • In the DIGAMI-2 study, glucose-insulin infusion did not affect the outcome of patients with diabetes and acute MI, although the study was terminated prematurely owing to slow patient recruitment rate, and failed to achieve satisfactory glycemic control (114).

Rationale
  • Hyperglycemia contributes to microvascular disease and is a known risk factor for MI.

Comments
  • The role of aggressive metabolic control in the setting of acute MI remains controversial.

Consider placement of an IABP in specific subsets of patients with ACS for stabilization before angiography and revascularization or cardiogenic shock. 
  • Place an IABP as a stabilizing measure while awaiting angiography and revascularization in patients with:

    • Cardiogenic shock unresponsive to therapy

    • Acute MR or VSD

    • Recurrent intractable ventricular arrhythmias with hemodynamic instability

    • Refractory post-MI angina

  • See figure Ventricular Septal Defect.

Evidence
  • In a selected patient population, survival rates as high as 60% to 75% have been shown for cardiogenic shock treated with IABP within the first 24 hours (115; 116).

  • Survival rates for early repair accompanied by IABP in patients with acute VSD or MR are as high as 60% (117).

  • In patients with recurrent ischemia after MI, IABP can be used as a stabilizing measure before performing angiography and revascularization with PTCA or CABG (118).

  • In the SHOCK trial, over 800 patients with acute MI complicated by cardiogenic shock were placed in four treatment groups (and a no-thrombolytic-therapy group): no IABP, IABP only, thrombolytic therapy only, and thrombolytic therapy and IABP. Patients with IABP had a lower in-hospital mortality rate than patients who did not receive IABP (50% vs. 72%, P<0.001) (61).

Rationale
  • The IABP reduces afterload during ventricular systole and increases coronary perfusion during diastole.

  • IABPs are often placed while in the catheterization lab as most of these unstable patients are taken immediately to the catheterization lab at certain centers, particularly if the patient requires stabilization for surgery.

Strongly advise all tobacco users who have had an acute coronary event to quit smoking. 
  • Strongly advise all smokers to quit in the setting of ACS.

  • Offer patients referral to a smoking cessation program and consider prescribing nicotine patches, nicotine gum, or bupropion therapy.

  • See module Smoking Cessation.

Evidence
  • A 2007 randomized trial compared an intensive smoking cessation intervention with control advice in smokers with ACS. The intervention consisted of 12 or more weeks of intensive behavior modification therapy with medication as indicated. After 2 years follow-up, patients in the intensive intervention group had lower overall mortality (NNT, 11), as well as lower rates of hospitalization (NNT, 6) (119).

  • Men aged less than 60 years who continued to smoke had a risk of death from all causes, 5.4 times that of men who stopped smoking. The adverse effect of continued smoking was most pronounced in patients with unstable angina (120).

  • Bupropion was studied in a multicenter, randomized, double-blind, placebo-controlled study involving 450 smokers who had previously used bupropion in a smoking cessation attempt. Participants made regular clinic visits throughout the treatment phase during which they received brief counseling sessions to encourage abstinence from smoking. In participants receiving bupropion SR, 27% (61 of 226) reached the primary endpoint of continuous abstinence from smoking from weeks 4 through 7, compared with 5% (11 of 224) of participants receiving placebo (P<0.001). Significantly (P<0.001) more participants who received bupropion SR during the treatment phase remained continuously abstinent from the start of week 4 through month 6 (27 of 226; 12%), compared with participants who received placebo (5 of 224; 2%) (121).

Rationale
  • Smoking doubles risk of death after MI.

Aim for glycemic control (glucose <180 mg/dL) in patients with diabetes. 
  • Maintain reasonable glucose control (<180 mg/dL) using an insulin-based regimen while avoiding hypoglycemia in diabetic patients who have been hospitalized for ACS.

  • Consider referral to diabetic teaching programs and instruction on an ADA diet and weight reduction in order to achieve long-term tight diabetic control.

  • See module Diabetes Mellitus, Type 2.

Evidence
  • Tight glucose control in diabetics during and after MI (DIGAMI study) has been shown to lower acute and 1-year mortality rates. A total of 620 patients with acute MI were studied: 306 randomly assigned to treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for ≥3 months (the tight control group) and 314 to conventional therapy. After 1 year, 57 subjects (18.6%) in the infusion group and 82 (26.1%) in the control group had died (relative mortality reduction 29%, P=0.027). The 3-month mortality rate was 6.5% in the infusion group vs. 13.5% in the control group (relative reduction 52%, P=0.046); 1-year mortality rate 8.6% in the infusion group vs. 18.0% in the control group (relative reduction 52%, P=0.020) (113).

  • In the DIGAMI-2 study, glucose-insulin infusion did not affect the outcome of patients with diabetes and acute MI, although the study was terminated prematurely owing to slow patient recruitment rate, and failed to achieve satisfactory glycemic control (114).

  • A 2012 guideline from the American College of Cardiology and the American Heart Association for the treatment of unstable angina and NSTEMI states that it is reasonable to use insulin to maintain a glucose level <180 mg/dL in diabetic patients hospitalized with ACS while avoiding hypoglycemia (47).

  • A 2009 guideline from the American College of Cardiology and the American Heart Association for the management of STEMI states that it is reasonable to use insulin to maintain a glucose level of <180 mg/dL in patients with diabetes and STEMI (48).

Rationale
  • Hyperglycemia contributes to microvascular disease and is a known risk factor for MI.

Comments
  • The role of aggressive metabolic control in the setting of acute MI remains controversial.

Educate hypertensive patients with ACS about the importance of BP control. 
  • Aim for goal BP of <135/85 mm Hg (<130/80 mm Hg in patients with diabetes, CKD, or HF) and discuss with patients the importance of good control.

  • See module Essential Hypertension.

Evidence
  • According to JNC 7, hypertension is a known modifiable risk factor for cardiovascular disease, and CAD in particular (122).

  • A 2011 meta-analysis evaluated the effects of different antihypertensive agents on cardiovascular events and included nine randomized trials with 62,605 hypertensive participants. Calcium-channel blockers and ACE inhibitors were similar to diuretics and β-blockers in preventing cardiovascular events (123).

  • In the ALLHAT trial, antihypertensive treatment with a thiazide diuretic (chlorthalidone) was associated with improved cardiovascular outcomes relative to lisinopril or amlodipine, although there was no difference in overall mortality between groups (124).

Rationale
  • High BP is a known risk factor for MI.

Educate patients with ACS about the importance of long-term statin therapy. 
  • Inform all patients with ACS about cholesterol reduction, including patients who undergo revascularization.

  • Follow National Cholesterol Education Program guidelines recommending a goal LDL <100 mg/dL.

  • See module Lipid Disorders.

Evidence
  • A 2007 systematic review of the benefit of intensive statin therapy compared with moderate statin therapy in patients with ACS and angina included 6 trials with 110,271 participants. In patients with ACS, intensive statin therapy reduced mortality at 2 years (NNT, 91) (100).

Rationale
  • Cholesterol-lowering therapy after MI or unstable angina reduces vascular events and death.

Provide specific instructions on permissible types and level of activity. 
  • Encourage daily walking immediately after discharge.

  • Follow driving regulations depending on state law.

  • Counsel that sexual activity can be resumed in stable patients within 7 to 10 days.

  • Individualize instructions regarding strenuous activity (e.g., heavy lifting, climbing stairs, and yard work) to the patient, based on his or her performance on exercise testing.

Evidence
  • The 2004 guideline from the American College of Cardiology and the American Heart Association recommended regular exercise in patients with history of STEMI, and that a stress test be performed to guide the exercise. The issue has not been addressed in subsequent guidelines (108).

Rationale
  • Activity can be safely resumed early after an ACS and may be beneficial to patients' cardiovascular and emotional health.

Consider early cardiac catheterization for ACS in patients with recurrent symptoms, serious complications, or other intermediate- to high-risk features. 
  • Consider cardiac catheterization for patients with ACS who have:

    • Unstable angina or NSTEMI and recurrent ischemic symptoms

    • HF

    • LVD

    • Dysrhythmias

    • Persistent elevated cardiac protein levels

    • Persistent ischemic ECG abnormalities

    • Prior CABG

    • Hemodynamic instability

    • Other high-risk features

  • A delayed invasive strategy is reasonable for non-high-risk patients

  • See table Risk Stratification and Management of Patients With Acute Coronary Syndromes.

Evidence
  • A 2012 guideline from the American College of Cardiology and the American Heart Association for the treatment of unstable angina and NSTEMI recommends an early invasive strategy in patients who are clinically stable or at high risk (47).

  • The FRISC II study showed a significant reduction in death or MI at 6 months in patients with unstable angina randomly assigned to revascularization compared with patients who received noninvasive treatment (9.4% vs. 12.1%; P=0.031) (55).

  • A study involving 2220 patients showed that an early invasive approach (i.e., cardiac catheterization within 4 to 48 hours after presentation) vs. a conservative approach in combination with a glycoprotein IIb/IIIa inhibitor in patients with NSTEMI or unstable angina significantly reduces major cardiac events (126).

  • In the TIMI IIIB trial, fewer patients reached the primary endpoint of death, nonfatal MI, or failed exercise tolerance test in the group randomly assigned to early invasive therapy vs. a conservative approach (16.2% vs. 18.1%, respectively). However, this difference was not statistically significant (54).

  • In the TIMACS trial, over 3000 patients with unstable angina and NSTEMI were randomized to undergo angiography either within 24 hours of randomization (early intervention) or at 36 hours or more after randomization (delayed intervention). At 6 months, there was no significant difference in the rate of the composite primary endpoint of death, MI, or stroke (9.6% in the early-intervention group vs. 11.3%; P=0.15). High-risk patients (GRACE risk score >140) had a benefit with the early invasive strategy vs. delayed intervention (127).

Rationale
  • These complications or high-risk features of ACS are associated with more severe CAD and subsequent cardiac events.

  • Death, severe HF, and arrhythmias are early complications of reinfarction, and there is an increased incidence of cardiogenic shock or cardiac arrest.

Use exercise stress testing in post-MI patients without high-risk features for prognostic assessment. 
  • In stable patients post-MI without high-risk features (i.e., hypotension, HF, recurrent chest pain, inability to exercise), consider an exercise treadmill stress test with or without radionuclide imaging if the patient can exercise.

  • Consider a pharmacologic stress test if the patient cannot exercise.

  • Obtain a submaximal stress test 4 to 7 days post-MI, or a symptom-limited exercise test at 14 to 21 days post-MI.

    • A submaximal protocol has a predetermined endpoint of a heart rate of either 120 bpm, 70% of predicted maximum heart rate, or a peak MET level of 5.

    • A symptom-limited test continues until the patient shows signs or symptoms that require the test to be terminated (i.e., angina, fatigue, ST-segment depression ≥2 mm, ventricular arrhythmias, or ≥10 mm Hg drop in systolic BP from baseline).

  • Consider the addition of imaging (myocardial perfusion or ECG) to improve the sensitivity and specificity of the test, especially in LBBB, marked baseline ST-T wave abnormality, pacemaker dependency, left ventricular hypertrophy, use of digitalis and type 1 antiarrhythmics, and Wolff-Parkinson-White syndrome.

  • See table Risk Stratification and Management of Patients With Acute Coronary Syndromes.

Evidence
  • The 2004 guideline from the American College of Cardiology and the American Heart Association recommended regular exercise in patients with history of STEMI, and that a stress test be performed to guide the exercise. The issue has not been addressed in subsequent guidelines (108).

  • In one study, stable post-MI patients underwent assessment of left ventricular function and had adenosine tomography done early (5 ± 3 days) after infarction. Cardiac events occurred in 30 (33%) of 92 patients over 15.7 ± 4.9 months. Independent predictors of all events were quantified perfusion defect size (P<0.0001), absolute extent of left ventricular ischemia (P <0.000001), and EF (P<0.0001) (128).

Rationale
  • Early stress testing post-MI assesses functional capacity and efficacy of the patient's medical regimen, and can risk-stratify the patient according to likelihood of future cardiac events.

  • Predictors for future adverse events in post-MI patients include inability to exercise, exercise induced ST-segment depression, failure to achieve 5 METs during treadmill testing, and failure to increase systolic BP by 10 to 30 mm Hg during exercise.

Comments
  • The role and safety of exercise testing in evaluating patients after MI has been well established.

Watch for depression in all patients with history of ACS, and treat depression in patients who manifest it.  
  • Ask about depressive symptoms including:

    • Low mood

    • Lack of energy

    • Feelings of worthlessness or hopelessness

    • Change in eating or sleeping habits

    • Loss of interest in usual activities

    • Crying spells

Evidence
  • Among 222 patients with acute MI, 35 (15.8%) met criteria for major depression. During an 18-month follow-up period, major depression was associated with a marked increase in cardiac mortality by multivariate analysis (OR, 3.64; P=0.012) (129).

  • In a study of 430 patients with unstable angina, the presence of depressive symptoms was associated with an over four-fold risk of cardiac death or nonfatal MI during a 12-month follow-up period independent of other risk factors (130).

  • In the SADHART trial, 369 patients with major depression after ACS were randomized to sertraline, 50 to 200 mg/d or placebo and followed for 24 weeks. The incidence of severe adverse cardiovascular events during follow-up was 14.5% with sertraline and 22.4% with placebo (131).

  • In the ENRICHD trial, 2481 patients with depression or low perceived social support following acute MI were randomized to receive standard medical care or standard care supplemented with cognitive behavioral therapy. Although cognitive behavioral therapy led to improvements in depression and social isolation scores, there was no difference between groups in the composite outcome of death or recurrent MI during a mean follow-up period of 29 months (132).

Rationale
  • Approximately 20% of patients experience depression after acute MI and the presence of depression is associated with increased risk for recurrent hospitalization and death.

Continue secondary prevention measures as part of outpatient management. 
  • Address management of hypertension, diabetes, lipid lowering, smoking cessation, and an exercise program in cardiac rehabilitation as components of comprehensive follow-up of all post-MI patients (see Patient Counseling).

  • See module Coronary Heart Disease.

Evidence
  • The 2004 guideline from the American College of Cardiology/American Heart Association for the management of STEMI discusses the importance of a variety of secondary prevention measures. The issue has not been addressed in subsequent guidelines (108).

Rationale
  • Approximately 70% of coronary heart disease deaths and 50% of MIs occur in patients with previously established CAD.

Table Grahic Jump Location
 Prevalence of History and Physical Examination Elements in Patients with Acute Coronary Syndromes

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CategoryElementPatients with myocardial infarction (%)Patients with unstable angina (%)Notes
HistoryChest pressure, tightness, or heaviness; pain that radiates to the jaw, shoulders, back, one or both arms2430Features such as activity provoking chest discomfort, resolution with rest suggest angina; recent onset or increasing symptoms of chest discomfort or symptoms occurring at rest are consistent with unstable angina
HistoryHeartburn-like pain2321Can be associated with inferior ischemia
HistorySharp or stabbing chest pain517Less commonly anginal; consider musculoskeletal or respiratory etiology
HistoryChest pain reproducible by palpation8NAMore consistent with musculoskeletal pain
HistoryAssociated symptoms such as nausea, lightheadedness, diaphoresis, and shortness of breathVariableAtypical symptoms may be more common in women and the elderly
HistoryFactors that increase risk for CAD such as age, gender, smoking, hypertension, dyslipidemia, diabetes, obesity, previously documented CAD, or a family history of CADVariable
Physical examVital signs: tachycardia or bradycardiaVariableNonspecific finding
Physical examVital signs:
blood pressure
VariableExtreme hypertension, especially diastolic hypertension, can be caused by increased levels of circulating catecholamines while the patient is experiencing chest pain. Hypotension can be a sign of cardiogenic shock and is a poor prognostic indicator (see Killip classes below)
Physical examVital signs: Tachycardia, bradycardia,
irregular pulse, fever, tachypnea
VariableIrregular pulse can indicate atrial fibrillation secondary to ventricular infarct/ischemia
Physical examElevated jugular venous pressureVariableCan be indicative of a large territory of ischemia or infarction resulting in right-sided HF
Physical examCardiopulmonary exam: hemodynamic class
Killip Class I
Killip Class II
Killip Class III
Killip Class IV

85
10
<5
<5

Class I: no evidence of HF
Class II: bibasilar rales, ± S3 gallop
Class III: pulmonary edema
Class IV: cardiogenic shock
Presence of HF or cardiogenic shock are considered high-risk features
Physical examCardiac exam:
rub
VariableMay indicate acute pericarditis
Physical examCardiac exam:
new S3 or S4 gallops
VariableCan also be associated with systolic and diastolic dysfunction
Physical examCardiac exam:
new murmurs
VariableAcute mitral regurgitation is often heard as a loud early systolic murmur; papillary muscle dysfunction and associated mitral regurgitation due to myocardial ischemia is often heard as a late systolic apical murmur. A new, harsh holosystolic murmur at the left sternal border suggests ventricular septal rupture
Physical examBasilar ralesPulmonary congestion occurs in 30%-40% of patients
Physical examLower extremity edemaVariableCan be indicative of a large territory of ischemia or infarction resulting in right-sided HF
Table Grahic Jump Location
 Laboratory and Other Studies for Acute Coronary Syndromes

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TestSensitivity(%)Specificity (%)Notes
ECG Findings
New ST-segment elevation >1 mm or Q waves in ≥2 contiguous leads5090Likelihood of diagnosing a Q-wave infarction 77%
New ST-segment depressions, T wave inversions, or bothLikelihood of diagnosing a non-Q wave MI 20%-26%
Nonspecific ST-T wave changes with typical chest painLikelihood of diagnosing a non-Q wave MI 12%-21%
Serum Cardiac Markers
Myoglobin, measured 1-12 hrs after onset of chest pain70-9159-92 (92% at <2 hrs, 59% at 10-12 hrs)Most useful in early detection (<4 hours after presentation); low specificity due to presence in skeletal muscle. Not commonly used clinically
Creatine kinase-MB (immunochemical assay) with relative index
0-3 hrs
6-9 hrs
9-12 hrs

30
70
>97

96-100
96-100
96-100
Most useful when used in combination with troponin (40)
Troponin T
2 hrs
4 hrs
6 hrs
10 hrs
14 hrs
18 hrs

10.5
5.7
61.7
86.5
84.9
78.7

98.4
98.3
96.1
96.4
96.1
95.7
Very specific, remains elevated for several days. Troponin is a complex of three different protein subunits (T, I, and C). Troponin T is a regulatory protein that modulates myocardial contractions and is normally absent in serum (41).
Some data suggest that Troponin T may be less specific in instances of rhabdomyolysis and renal failure
Troponin I
2 hrs
4 hrs
6 hrs
10 hrs
14 hrs
18 hrs

15.8
35.7
57.5
92.3
90.6
95.7

96.8
94.2
94.3
94.6
92.2
93.4
Very specific, remains elevated for several days. Troponin I is an inhibiting protein that prevents muscle contraction in the absence of calcium and troponin C. Troponin T and I have similar release kinetics and duration of elevation in serum after myocardial damage, however troponin I appears to be more sensitive
EchocardiographyCan miss small areas of infarction and the age of a regional wall motion abnormality cannot be determined
Coronary CT angiography77%87%Studies have shown better sensitivity in stable patients (42). Has been shown to facilitate hospital discharge and shorten length of stay
Exercise ECG(to establish CAD after acute infarction has been excluded in patients admitted for presumed ACS)
ST-segment depression ≥0.5 mm
ST-segment depression ≥1.0 mm

86
65

77
89
Useful in patients considered low-risk for an ACS (i.e., atypical chest pain, normal cardiac markers, normal ECG)
Exercise myocardial perfusion imaging (thallium-201/sestamibi-99mTc)9072Useful in patients considered low-risk for an ACS (i.e., atypical chest pain, normal cardiac markers, normal ECG)
Exercise echocardiography8183Useful in patients considered low-risk for an ACS (i.e., atypical chest pain, normal cardiac markers, normal ECG)
Coronary arteriographyGold standard for documenting the presence and severity of coronary artery disease, but used therapeutically rather than diagnostically in patients with ACS

ACS = acute coronary syndrome; BNP = brain natriuretic peptide; CAD = coronary artery disease; CRP = C-reactive protein; ECG = electrocardiography; IMA = ischemia-modified albumin; LBBB = left bundle branch block; MI = myocardial infarction; UA = unstable angina.

Table Grahic Jump Location
 Differential Diagnosis of Acute Coronary Syndromes

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DiseaseCharacteristics
Myocardial infarctionTypically chest pressure or squeezing, jaw discomfort, or shoulder or arm discomfort, accompanied by dyspnea, diaphoresis, or other symptoms, precipitated or worsened by exertion, often in patients with risk factors for coronary artery disease
Early risk assessment is crucial to appropriate diagnosis and early treatment. Women and the elderly may have less typical symptoms
EsophagitisBurning-type chest discomfort, usually precipitated by meals, and not related to exertion; often accompanied by nausea, diaphoresis. Often positional; worse lying down, improved with sitting
Symptoms of esophageal disorders can be alleviated by sublingual nitroglycerin, which may confuse the differential with myocardial ischemia
Pericarditis and pericardial tamponadeSubsternal chest discomfort that can be sharp, dull, or pressure-like, often relieved with sitting forward. Usually pleuritic. Often there are symptoms of dyspnea alone or in association with chest discomfort
ECG abnormalities are often present, including ST-segment elevation (usually diffuse) or more specifically PR segment depression, also ST-segment depression (less frequent), nonspecific ST-T wave abnormalities, and T wave inversions. Echocardiography and right heart catheterization aids in the diagnosis of tamponade
Aortic dissectionFrequently substernal chest pain with radiation to the back, mid-scapular region. Often described as ‘tearing’ or ‘ripping’ type pain. Chest x-ray result may show a widened mediastinal silhouette, a pleural effusion, or both
Can have concomitant myocardial ischemia or infarction due to involvement of the coronary arteries (most commonly the right coronary artery)
PneumoniaUsually pleuritic chest pain. Often associated with dyspnea and cough. Most often other signs or symptoms of infection are present
CholecystitisOccasionally presents as chest discomfort, usually related to meals, not exertion. Diagnosis by imaging of upper abdomen with CT, ultrasound or MRI
PancreatitisOccasionally chest discomfort, more commonly mid-epigastric pain, often with accompanying symptoms of nausea and vomiting. Diagnosed with imaging of abdomen and laboratory tests
Clues to this diagnosis include significant alcohol ingestion history, abnormal amylase or liver enzymes
PneumothoraxChest x-ray or CT confirms the diagnosis
Musculoskeletal painTypically more reproducible chest pain. Should be a diagnosis of exclusion
Includes muscle strain, costochondritis, and fracture

CT = computed tomography; ECG = electrocardiography; MRI = magnetic resonance imaging.

Table Grahic Jump Location
 Drug Treatment for Acute Coronary Syndromes

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
Oral platelet inhibitors
FirstLineIconAspirin160-325 mg immediately, then 81 mg qdGI side effects, hypersensitivity reactions, minor bleedingAvoid with severe hepatic disease or severe CKD. Caution with: asthma, GI diseaseGive aspirin promptly and continue indefinitely
blackboxiconClopidogrel (Plavix)300 mg, then 75 mg qdBleeding, diarrhea, rare TTPblackboxicon Diminished effect in poor metabolizers. Avoid use of omeprazole or esomeprazole. Caution with hepatic diseaseUse if aspirin is contraindicated, or combined with aspirin in select patients
blackboxiconPrasugrel (Effient)60 mg loading dose, then 10 mg qdBleeding, bradycardia, hypotension, hypertension, hyperlipidemia, hypercholesterolemia, TTP, hypersensitivity reactions, nauseablackboxicon Bleeding risk. If <60 kg, reduce dose to 5 mg qd. Avoid if >75 years. Avoid with history of TIA or stroke. Caution with severe hepatic disease
Dipyridamole (Persantine)75-100 mg qidHeadache, dizziness, hypotension, abdominal distressCaution with severe hepatic diseaseUsed with warfarin or aspirin
blackboxiconTicagrelor (Brilinta)180 mg loading dose, then 90 mg bidDyspnea, headache, dizzinessblackboxicon Bleeding risk. Maintenance doses of aspirin >100 mg reduce effectiveness of ticagrelor. Avoid with severe hepatic impairment. Caution with moderate hepatic impairment. Many drug interactions due to CYP3A4 metabolism and inhibition, and P-glycoprotein inhibition
Anticoagulants
Unfractionated heparinPCI (without GP IIb/IIIa): 60-100 U/kg IV bolus to maintain ACT within 250-300 sec (HemoTec) or 300-350 sec (Hemochron). UA: 75 U/kg IV bolus, then 1250 U/hr IV. MI: 60 U/kg IV bolus, then 12 U/kg·hr IV to aPTT 1.5-2, or 7500 U SC q12hrBleeding, thrombocytopenia, elevated hepatic enzymesAvoid with: history of HIT, bovine or pork allergy. Monitor plateletsFor moderate- and high-risk patients. Dosing depends upon concomitant agents and procedures
blackboxiconLow-molecular-weight heparinsBleeding, thrombocytopenia, elevated hepatic enzymes, injection site reactions, allergic reactionsblackboxicon Spinal or epidural hematomas with neuraxial anesthesia or spinal puncture. Avoid with: history of HIT, pork allergy. Monitor thrombocytopeniaFor moderate- and high-risk patients
blackboxiconDalteparin (Fragmin)For NSTEMI or UA: 120 IU/kg SC q12hr
blackboxiconEnoxaparin (Lovenox)For NSTEMI or UA: 1 mg/kg SC q12hr. For STEMI, add a loading dose of 30 mg IV bolus and 1 mg/kg SCAnemia, fever, edema, nausea
Direct thrombin inhibitorsBleeding, hypotension, allergic reactions, nauseaFor patients with HIT
Argatroban (Acova)For PCI: 25 mcg/kg·min IV continuous infusion and a bolus of 350 mcg/kg IV via large bore over 3-5 min. Monitor ACTAngina, diarrheaAvoid with hepatic disease
Bivalirudin (Angiomax)For PTCA or PCI: 0.75 mg/kg IV bolus, then 1.75 mg/kg·hr IV infusionIf CrCl<30, reduce infusion to 1 mg/kg·hr
Factor Xa inhibitor
blackboxiconFondaparinux (Arixtra)2.5 mg SC qd for up to 8 daysEdema, thrombocytopenia, nausea, vomitingblackboxicon Spinal or epidural hematomas with neuraxial anesthesia or spinal puncture. Avoid if CrCl<30. Caution with: elderly, hepatic disease, moderate CKD
blackboxiconWarfarin (Coumadin)Initially, 5 mg PO qd. Adjust dose according to INR. Target INR 2-3. Continue heparin or LMWH until INR achieved for 2 daysSystemic cholesterol microembolization, uncommon skin necrosisblackboxicon Major or fatal bleeding. Monitor INR regularly. Avoid in pregnancy. Caution with: ITP, HIT, hepatic disease, protein C or S deficiency. Many drug interactions
Platelet glycoprotein IIb/IIIa inhibitorsBleeding, thrombocytopenia, hypotension, rare anaphylactoid reactions
Abciximab (ReoPro)PCI: 0.25 mg/kg IV bolus given 10-60 min before start, then 0.125 mcg/kg·min IV for 12 hr (maximum 10 µ/min). UA or NSTEMI: 0.25 mg/kg IV bolus, then 10 mcg/min IV infusionNausea, vomiting
Eptifibatide (Integrilin)UA or NSTEMI: 180 mcg/kg IV bolus. For PCI, repeat bolus in 10 min. Then, 2 mcg/kg·min infusionIf CrCl 10-50, reduce infusion to 1 mcg/kg·min. Avoid if CrCl<10
Tirofiban (Aggrastat)UA or NSTEMI: 0.4 mcg/kg·min IV for 30 min, then 0.1 mcg/kg·min infusionBradycardia, coronary artery dissectionIf CrCl<30, reduce infusions to 0.2 mcg/kg·min IV for 30 minutes, then 0.05 mcg/kg·min
ThrombolyticsBleeding, hypotensionAvoid with severe hypertension. Caution with: severe hepatic disease, CKDAlternative to PCI in suitable STEMI patients
Alteplase, tPA (Activase)Accelerated infusion: 15 mg IV bolus, then 50 IV over 30 min, then 35 mg IV over 60 min. Or, 3-hour infusion: 60 mg IV over 1 hr, then 20 mg/hr IV for 2 hrIf <67 kg, decrease dose
Reteplase (Retavase)10 U IV bolus over 2 min. Repeat in 30 min
Streptokinase (Streptase)IV: 1.5 million IU by IV infusion within 60 min. IC: 20,000 IU loading dose, then 2000 IU/min for 1 hrAllergic reactions (fever, shivering), tolerance or hypersensitivity with repeat use
Tenecteplase (TNKase)30-50 mg (based on weight) IV bolus over 5 secondsExtreme caution if >75 years
β-blockersBradycardia, CNS side effects, bronchospasm (particularly if nonselective), hypotension, AV block, diarrhea, nauseaCaution with: CKD, HF, depression, hyperthyroidismInitiate early in eligible patients
Carvedilol (Coreg, Coreg CR)Regular-release: 6.25 mg bid with food for 3-10 days, gradually increase to 25 mg bid. Extended-release: 20 mg qd in the AM with food for 3-10 days, gradually increase to 80 mg qdHyperglycemia, weight increaseAvoid with hepatic disease. Consider reduced dose in elderlyNonselective
blackboxiconMetoprolol (Lopressor)5 mg IV bolus every 2 minutes for 3 doses. Then, 50 mg PO q6hr for 48 hr. Maintenance dose is 50-100 mg bid (regular-release)blackboxicon (Oral): Abrupt withdrawal not advised. Consider reduced dose in hepatic diseaseβ1 selective
Non-dihydropyridine calcium-channel blockersBradycardia, hypotension, AV block, edema, asystole, CNS side effectsAvoid with: Wolff-Parkinson-White syndrome, advanced aortic stenosis. Caution with: HF, hepatic disease, reflux esophagitis. In elderly, start with low doseFor use if β-blockers are ineffective or contraindicated
Diltiazem (Cardizem)Regular-release: Initially 30-60 mg tid. Up to 360 mg total daily dose, dosed tid-qidGI side effects
Verapamil (Calan)80-120 mg q8hr. Maximum 480 mg total daily dose, dosed tid-qidConstipation, allergic-type reactionsCaution with: CKD, neuromuscular disease
Nitrate vasodilatorsHeadache, flushing, hypotension, bradycardia, tachycardiaAvoid with: severe anemia, increased intracranial pressure, closed-angle glaucoma. Caution with hepatic disease. Elderly should start with low dose
Nitroglycerin IV5 mcg/min IV infusion. Titrate by 5 mcg/min IV q3-5 min until clinical response, or to a dose of 20 mcg/min. Continue titrating to effective dose of 5-100 mcg/min IVAvoid with: constrictive pericarditis, restrictive cardiomyopathy, cardiac tamponade. Extreme caution with suspected right ventricular infarctionFor 24-48 hr with UA or eligible MI
Nitroglycerin (Nitrostat, NitroMist, Nitrolingual Pumpspray, Minitran, Nitrodur)Sublingual: 1 tablet (0.3 mg, 0.4 mg, or 0.6 mg) SL. May repeat q5min prn, up to 3 doses. Lingual spray or aerosol: 1-2 sprays (400-800 mcg) SL. May repeat q5min prn, up to 3 doses. 2% ointment: 15-30 mg q6-8hr. Transdermal patch: 1 patch (0.1-0.8 mg/hr) q24hr. Remove patch for 10-12 hr before next patchDermatologic adverse reactions, methemoglobinemia, toleranceExtreme caution with suspected right ventricular infarction. Caution with: constrictive pericarditis, restrictive cardiomyopathy, cardiac tamponadeFor angina
Isosorbide dinitrate (Isordil, Dilatrate-SR)Immediate-release: 5-60 mg bid-tid. Sustained-release: 40-160 mg qd. SL: 2.5-5 mg before activityNausea, tolerance
Isosorbide mononitrate (Monoket)Immediate-release: 10-20 mg bid, 7 hr apart. Extended-release: 30-60 mg qd in the AM. May increase to 120 mg qdTolerance
Morphine2-5 mg IV q3-5min prn for pain. May use maintenance dose of 4-8 mg IV q4-6hrRespiratory depression, hypotension, nausea, vomitingFor persistent symptoms following 3 SL nitroglycerin
blackboxiconAngiotensin-converting enzyme inhibitorsHypotension, cough, hyperkalemia, angioedema, anaphylactoid reactionsblackboxicon Pregnancy. Avoid if history of angioedemaAdminister early in select patients
blackboxiconCaptopril (Capoten)Initially 6.25-12.5 mg tid. Gradually up to 50 mg tidNot affected by hepatic disease. Decrease dose if CrCl<50Shortest-acting ACE inhibitor
blackboxiconEnalapril (Vasotec)Initially 2.5 mg qd. Gradually up to 10 mg bid
blackboxiconLisinopril (Prinivil, Zestril)5 mg qd for 2 days, then 10 mg qdNot affected by hepatic disease. Decrease dose if: elderly, hypotensive, or CrCl<30
blackboxiconRamipril (Altace)Initially 1.25-2.5 mg bid. Gradually up to 5 mg bidDecrease dose if CrCl<40
Angiotensin II-receptor antagonist
blackboxiconValsartan (Diovan)Initially 20 mg bid. Gradually up to 160 mg bidHeadache, hyperkalemia, rare anaphylactoid reactions and angioedemablackboxicon Pregnancy. Caution with: hepatic disease, severe CKD, history of angioedemaAlternative to ACE inhibitor in patients with HF or LVD after acute MI
Selective aldosterone receptor antagonist
Eplerenone (Inspra)25 mg qd, up to 50 mg qd within 4 weeksHyperkalemia, hyponatremia, endocrine effects, elevated hepatic enzymesAvoid with potent inhibitors of CYP3A4. Caution with: CKD, severe hepatic diseaseConsider early initiation in eligible patients
HMG-CoA reductase inhibitors (statins)Generally more effective if given at bedtimeRhabdomyolysis and acute renal failure, myalgia, myopathy, hepatotoxicity, diabetes, rare hypersensitivity reactions, rare peripheral neuropathyAvoid with: hepatic disease, pregnancy. Avoid concomitant use with cyclosporine or gemfibrozil. Use caution with fenofibrate or niacin. For most statins, additional drug interactions exist due to cytochrome P450 hepatic metabolism. Avoid large quantities (>1 quart daily) of grapefruit juice. Elderly may have an increased responseConsider early initiation in patients with ACS
Atorvastatin (Lipitor)10-80 mg qdIf taking a CYP3A4 inhibitor concomitantly, don't exceed 20 mg qd
Rosuvastatin (Crestor)5-40 mg qd. Can be taken in AM or PMIf CrCl<30, maximum dose 10 mg qd. Undergoes minimal hepatic metabolism. Use 5 mg starting dose with Asians
Simvastatin (Zocor)40 mg qhsIf CrCl<20, start with 5 mg qhs. Do not take a CYP3A4 inhibitor concomitantly. Caution with >20 mg in Chinese

FirstLineIcon = first-line agent; blackboxicon = black box warning; ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; ACT = activated clotting time; AM = morning; aPTT = activated partial thromboplastin time; AV = atrioventricular; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CYP = cytochrome P450; GI = gastrointestinal; GP = glycoprotein; HF = heart failure; HIT = heparin-induced thrombocytopenia; HMG-CoA = hydroxymethylglutaryl-coenzyme A; IC = intracoronary; IM = intramuscular; INR = international normalized ratio; ITP = idiopathic thrombocytopenic purpura; iv = intravenous; LMWH = low-molecular-weight heparin; LVD = left ventricular dysfunction; MI = myocardial infarction; min = minutes; NSTEMI = non-ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; PM = evening; PO = oral; prn = as needed; q12hr = every 12 hours; q4-6hr = every 4-6 hours; qd = once daily; qhs = every day at bedtime; qid = four times daily; SC = subcutaneous; SCr = serum; TTP = thrombotic thrombocytopenic purpura

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Release Kinetics of Cardiac Markers

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MarkerFirst rise, hourPeak, hourDuration, days
Myoglobin1-24-61
Creatine kinase
MB band
3-412-242-3
Troponin3-412-247-11
Table Grahic Jump Location
 Likelihood of Significant Coronary Artery Disease in Unstable Angina

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High LikelihoodIntermediate LikelihoodLow Likelihood
History of CADDefinite angina
Males aged ≤60
Females aged ≤70
Chest pain, probably not angina
Definite angina
Males aged ≥60
Females aged ≥70
Probable angina
Males aged ≥60
Females aged ≥70
One risk factor, but not in diabetic patient
Hemodynamic changes or ECG changes with painProbably not angina in DM or non-DM patients with ≥2 risk factorsT wave flattening or inverted <1 mm in leads with dominant R waves
Variant anginaVascular diseaseNormal ECG
ST-segment elevation or depression ≥1 mm from baselineST-segment depression of 0.5-1 mm
Marked symmetrical T-wave inversion in multiple chest leadsT-wave inversion ≥1 mm in leads with dominant R waves

High likelihood: greater than 85% chance of significant flow-limiting CAD being present

Intermediate likelihood: 15%-85% chance of significant flow-limiting CAD being present

Low likelihood: less than 15% chance of significant flow-limiting CAD being present

CAD = coronary artery disease; DM = diabetes mellitus; ECG = electrocardiography.

Table Grahic Jump Location
 Risk Stratification and Management of Patients With Acute Coronary Syndrome

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Extremely High- Risk FeaturesHigh-Risk FeaturesModerate-Risk FeaturesLow-Risk Features
Historical featuresRecurrent pain despite aspirin, heparin, and medical treatmentPresenting history of recurrent rest pain plus history of CAD/MIRecurrent ischemic rest pain plus history of CAD/MIRest ischemic pain, no history of CAD/MI
Lab and ECG featuresElevated troponin with acutely ischemic ECG, including ST elevations with chest pain or persistent new ST depressions >0.5 mmElevated troponin I plus acutely ischemic-appearing ECGNegative serial troponins with ECG showing nonspecific ST/T wave changesNegative serial troponins and normal (or unchanged) repeat ECG
TreatmentUrgent referral for acute coronary angiography with PCI in a high volume center vs. thrombolytics (only if ST-cluster or new LBBB) plus appropriate antiplatelet and anticoagulant therapyAdmission to the hospital plus dual antiplatelet and anticoagulant therapy, medical treatment followed by early inpatient investigation (e.g., coronary angiography vs. stress test)Admission to the hospital plus anticoagulant therapy, ASA followed by possible inpatient investigation (e.g., inpatient stress test)ASA, medical treatment (may include low-molecular-weight heparin), telemetry observation, then outpatient follow-up and investigation

ACS = acute coronary syndrome; ASA = acetylsalicylic acid; CAD = coronary artery disease; ECG = electrocardiography; GP = glycoprotein; LBBB = left bundle branch block; LMWH = low-molecular-weight heparin; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angiography.

Table Grahic Jump Location
 Electrocardiographic Localization of Acute Myocardial Infarction

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Anatomic LocationST-Segment ChangeIndicative ECG Leads
InferiorElevationII, III, aVF
AnteroseptalElevationV1-V3
Lateral and ApicalElevationV4-V5; possible elevations in I and aVL
Posterior*DepressionTall R waves in V1-V3
Right ventricular*ElevationV4R; tall R waves in V1-V3

*Often associated with inferior and/or lateral ST-elevation infarction.

  • Algorithm for the Evaluation and Management of Patients Suspected of Having Acute Coronary Syndromes Reprinted with permission from © 2001 American College of Cardiology and the American Heart Association, Inc. All rights reserved. This material is the exclusive property of and is provided by ACC/AHA and is protected under U.S. Copyright and international laws. Any use of this material, including downloading or copying from this web site [or CD ROM] for your personal use, will indicate your consent and agreement to the terms stated in this notice. No right, title or interest in the material is conveyed to you as a result of any such downloading or copying, and such downloaded or copied material may not be used for any commercial purpose.
  • Left Anterior Descending Artery Stenosis Coronary angiogram showing obstruction of the left anterior descending coronary artery.
  • Stented Left Anterior Coronary Artery Coronary angiogram showing stenting of an obstructed left anterior descending coronary artery.
  • Ventricular Septal Defect Echocardiogram of a patient with an acute ventricular septal defect following a myocardial infarction. The echocardiogram shows flow between the left and right ventricles through the interventricular septum.
  • Anterior ST-elevation Myocardial Infarctions Electrocardiogram showing changes consistent with acute anterior myocardial infarction.
  • Inferior ST-elevation Myocardial Infarction This electrocardiogram demonstrates Q waves and ST-segment elevation in leads II, III and aVF consistent with an acute inferior myocardial infarction.
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ACC

American College of Cardiology

ACE

angiotensin-converting enzyme

ACS

acute coronary syndrome

ACT

activated clotting time

AHA

American Heart Association

aPTT

activated partial thromboplastin time

ARB

angiotensin-receptor blocker

AV

atrioventricular

BBW

Black box warning

bid

twice a day

BNP

brain natriuretic paptide

BP

blood pressure

CABG

coronary artery bypass graft(ing)

CAD

coronary artery disease

CI

confidence interval

CK

creatine kinase

CKD

chronic kidney disease

CK-MB

myocardial muscle creatine kinase isoenzyme

CNS

central nervous system

CrCL

creatinine clearance

CRP

C-reactive protein

CT

computed tomography

CYP

cytochrome P450

DM

diabetes mellitus

ECG

electrocardiogram/electrocardiography

ED

emergency department

EF

ejection fraction

FTL

first-line agent

GI

gastrointestinal

GP

glycoprotein

GRACE

Global Registry of Acute Coronary Events

HDL

high-density lipoprotein

HF

heart failure

HIT

heparin-induced thrombocytopenia

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

HR

hazard ratio

IABP

intra-aortic balloon pump

IC

intracoronary

IM

intramuscular

IMA

ischemia-modified albumin

INR

international normalized ratio

ITP

idiopathic thrombocytopenic purpura

iv

intravenous

JNC 7

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

LBBB

left bundle branch block

LDL

low-density lipoprotein

LMWH

low-molecular-weight heparin

LV

left ventricle

LVD

left ventricular dysfunction

LVEF

left ventricular ejection fraction

MET

metabolic equivalent of task

MI

myocardial infarction

MR

mitral regurgitation

MRI

magnetic resonance imaging

NSTEMI

non-ST-segment elevation myocardial infarction

NYHA

New York Heart Association

OR

odds ratio

PCI

percutaneous coronary intervention

po

oral

prn

as needed

PTCA

percutaneous transluminal coronary angiography

PTT

partial thromboplastin time

qd

every day

qhs

every day at bedtime

qid

four times daily

RRR

relative reduction in risk

SC

subcutaneous

SCr

serum

SR

sustained release

STEMI

ST-segment elevation myocardial infarction

tid

three times daily

tPA

tissue plasminogen activator

TTP

thrombotic thrombocytopenic purpura

UA

unstable angina

UFH

unfractionated heparin

VSD

ventriculoseptal defect


Study name acronyms
ACUITY

Acute Catheterization and Urgent Intervention Triage Strategy

AIRE

Acute Infarction Ramipril Efficacy

ALLHAT

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

ASSET

Anglo-Scandinavian Study of Early Thrombolysis

COMMIT/CCS-2

Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study

CURE

Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events

CURRENT-OASIS 7

Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Syndromes

DANAMI-2

Danish Trial in Acute Myocardial Infarction-2

DIGAMI-2

Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction

ENRICHD

Enhancing Recovery in Coronary Heart Disease Patients

EPHESUS

Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

EPIC

Evaluation of 73E for the Prevention of Ischemic Complications

EPILOG

Evaluation of Percutaneous Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab Glycoprotein IIb/IIIa Blockade

EPISTENT

Evaluation of Platelet IIb/IIIa Inhibitor for Stenting

ESSENCE

Efficacy and Safety of Subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave Coronary Events

FRISC

FRagmin and Fast Revascularisation during InStability in Coronary artery disease

GISSI

Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico

GUSTO

Global Use of Strategies To Open Occluded Coronary Arteries

HORIZONS-AMI

Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction

ICTUS

Invasive versus Conservative Treatment in Unstable Coronary Syndromes

ISAR-REACT 2

Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2

ISIS

International Study of Infarct Survival

MIRACL

Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering

OPTIMAAL

Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan

PCI-CURE

Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events

PLATO

Platelet Inhibition and Patient Outcomes

PRISM

Platelet Receptor Inhibition in Ischemic Syndrome Management

PRISM-PLUS

Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms

PROVE IT-TIMI 22

Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22

PURSUIT

Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy

SADHART

Sertraline Antidepressant Heart Attack Randomized Trial

SAVE

Survival and Ventricular Enlargement

SHOCK

Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock

TIMACS

Timing of Intervention in Acute Coronary Syndromes

TIMI

Thrombolysis in Myocardial Ischemia

TRIM

Thrombin Inhibition in Myocardial Ischemia

TRITON-TIMI 38

Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction 38

VALIANT

Valsartan in Acute Myocardial Infarction


Guidelines

2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update). A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

ACC/AHA 2002 guideline update for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines)

2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction)

2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update). A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death

Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement

Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force

Hyperglycemia and acute coronary syndrome. A scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism

Management of cocaine-associated chest pain and myocardial infarction. A scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology

ACC/AHA Guidelines for the management of patients with ST-elevation myocardial infarction

2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention

ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.

2007 Focused Update of the ACC.AHA 2004 Guidelines for the management of Patients with ST-Elevation Myocardial Infarction

2009 Focused Updates: ACC/AHA guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update)

2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline)

2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

Third report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III)

Systematic Reviews

Systematic review: the comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft surgery

Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

Systematic review: comparing routine and selective invasive strategies for the acute coronary syndrome

Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease

Adult bone marrow–derived cells for cardiac repair: a systematic review and meta-analysis

Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis

Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300 000 persons

Angiotensin-converting enzyme insertion/deletion gene polymorphic variant as a marker of coronary artery disease: a meta-analysis

Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality

The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials

Home-based versus centre-based cardiac rehabilitation: Cochrane systematic review and meta-analysis.

Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies.

Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis.

Adequacy of reporting monitoring regimens of risk factors for cardiovascular disease in clinical guidelines: systematic review.

Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis.

Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials.

Indirect comparison meta-analysis of aspirin therapy after coronary surgery

Angiotensin receptor blockers and risk of myocardial infarction: systematic review

Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies

Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review

Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine

Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis

Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery

Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis

Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis

Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis

Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials

Efficacy of in-hospital multidimensional interventions of secondary prevention after acute coronary syndrome: a systematic review and meta-analysis

Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: a meta-analysis

Platelet glycoprotein IIb/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes (Cochrane Review)

Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials

Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials.

Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials

Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis.

Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview

Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials

Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2

Aspirin dose for the prevention of cardiovascular disease: a systematic review

Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials

Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis

Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis

Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis

Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths

Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies

Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis

Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis

Carotid bruits as a prognostic indicator of cardiovascular death and myocardial infarction: a meta-analysis

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

A systematic review of selective and non-selective beta-blockers for prevention of vascular events in patients with acute coronary syndrome or heart failure

Impact of clopidogrel and potent P2Y 12 -inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. A systematic review and meta-analysis.

DOI: 10.7326/d361
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Disclosures:
Helene Glassberg, MD is a speaker for pharmaceutical companies. Rozy Desai, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Sanjum S. Sethi, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Michael E. Farkouh, MD, MSc, FRCPC, FACC consults for Eli Lilly and AstraZeneca.
Deborah Korenstein, MD, FACP, Editor in Chief, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. Richard B. Lynn, MD, FACP, Editor, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.
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