Clinical History

The initial differentiation of ACS from other causes of chest pain is based on the chest pain history, physical examination, presence of risk factors for CAD, and the ECG. Certain chest pain characteristics are associated with decreased or increased likelihoods of ACS.¹¹ The feature that was found to be associated with the highest risk of a diagnosis of ACS is radiation of pain to one or both shoulders or arms. A prospective study of patients who presented to an emergency department for evaluation of chest pain determined that pain relief by nitroglycerin is not a useful indicator of the presence or absence of ACS.¹² Nitroglycerin relieved chest pain in 35% of patients with active CAD, compared with 41% of patients without active CAD (p > 0.2).¹²

Another literature review included 15 studies published from 1989 to 2002 that identified symptoms of ACS.¹³ Chest pain was the most common symptom among both men and women, but atypical symptoms were common, especially among women. Compared with men, women with ACS were significantly more likely to report back and jaw pain, nausea, vomiting, dyspnea, indigestion, and palpitations. A significant fraction of patients with acute MI do not complain of chest pain at the time of presentation.^14–16 A total of 1674 U.S. hospitals contributed patients to the National Registry of Myocardial Infarction (NRMI) 2.¹⁴ Among 434,877 patients with confirmed MI who were enrolled in the NRMI-2 registry between June 1994 and March 1998, 142,445 (33%) did not have chest pain at the time of presentation to the hospital. There were several notable differences between the groups who presented with and without chest pain. Only 23% of patients without chest pain had ST segment elevation on the initial ECG, compared with 47% of the patients with chest pain. The group of patients who presented without chest pain was older (74 versus 67 years) and had a higher proportion of women (49% versus 38%). A subsequent analysis of 1,143,513 patients who were enrolled in the registry found that the proportion of patients who presented without chest pain was significantly higher for women than men (42% versus 30.7%; p < 0.001).¹⁶ The gender differences in clinical presentation without chest pain diminished with increasing age.¹⁶

The absence of chest pain has a major impact on hospital management and outcomes, even among patients who present with ST segment elevation.14–16 A report from the GRACE registry compared 6385 patients with STEMI and typical symptoms with 541 patients whose presenting symptoms did not include chest pain.¹⁵ Patients without chest pain were significantly less likely to receive reperfusion therapy (i.e., fibrinolysis or primary PCI, β-blockers), and aspirin. Perhaps as a consequence of undertreatment, hospital mortality was significantly greater among patients with STEMI and no chest pain than among patients with chest pain (18.7% versus 6.3%; p > 0.001) (Fig. 30.1).

There is a longstanding belief that diabetes is associated with silent myocardial ischemia and painless MI due to autonomic neuropathy. Nevertheless, in the NRMI 2 registry, only 33% of the patients with painless MI had diabetes mellitus, and in the GRACE registry, only 32% of patients with painless ACS had diabetes.14,15

Physical Examination

The initial physical examination provides important prognostic information in patients with acute MI. Killip and Kimball published their classic study in 1967.¹⁷ Among 250 patients with acute MI, 81 patients (33%) had no heart failure (Killip class I), 96 (38%) had mild heart failure (Killip class II), 26 (10%) had pulmonary edema (Killip class III), and 47 (19%) had cardiogenic shock (Killip class IV). Respective mortality rates were 6%, 17%, 38%, and 81%. Although the overall mortality for acute MI has decreased since 1967, the Killip class on admission remains a powerful predictor of outcome among patients treated with reperfusion therapy.^18,19 DeGeare and coworkers¹⁹ performed an analysis of 2654 patients with acute MI who were enrolled in three primary angioplasty trials. Patients in Killip class IV were excluded. Increasing Killip class was associated with an increased need for intra-aortic balloon counterpulsation and a greater incidence of renal failure, major arrhythmias, and major bleeding. After controlling for confounding variables, the Killip class on admission remained a multivariate predictor of both in-hospital and 6-month mortality.

The physical examination also may provide clues to the diagnosis of causes of chest pain other than ACS. A pericardial friction rub may be audible in patients with pericarditis. Aortic dissection may be associated with diminished or absent pulses. Both diagnoses are important to exclude because they are contraindications to fibrinolytic therapy.

Electrocardiogram

The ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction include three Class I indications for an ECG.²⁰ The first is that all patients with chest discomfort or other symptoms suggestive of STEMI should have a 12-lead ECG within 10 minutes of arrival in the emergency department (and it should be interpreted by an experienced physician). The second is that serial ECGs should be performed at intervals of 5 to 10 minutes in patients with a nondiagnostic initial ECG if the patient remains symptomatic and there is a high clinical suspicion of STEMI. The third is that right-sided ECG leads should be obtained to screen for right ventricular MI in patients with inferior STEMI.

The electrocardiographic diagnosis of acute MI in the presence of a left bundle branch block (LBBB) is problematic.25,26 Angiographic studies have demonstrated a low prevalence of acute MI among patients with a new LBBB.^27–30 Analysis of the Mayo Clinic’s primary PCI database found that only 12 of 36 patients with a new LBBB and clinical symptoms suspicious for an MI met troponin criteria for an MI, resulting in emergency activation of the cardiac catheterization laboratory for a false-positive diagnosis of acute MI in two thirds of patients with a new LBBB.²⁸

Sgarbossa and associates³¹ devised an algorithm for the diagnosis of acute MI in patients with LBBB that used three electrocardiographic criteria: ≥ 1 mm ST segment elevation concordant with the QRS complex; ≥ 1 mm ST segment depression in leads V₁, V₂, or V₃; and ≥ 5 mm ST segment elevation discordant with the QRS complex. Several subsequent studies investigated the utility of the so-called Sgarbossa criteria.^26,29 A study that enrolled 83 patients with LBBB and symptoms suggestive of acute MI found that the ECG algorithm based on the Sgarbossa criteria had a sensitivity of only 10%.²⁶

Patients with an acute MI who present with an LBBB that is new or of indeterminate age have a worse prognosis than patients without an LBBB. A bundle branch block was present on the admission electrocardiogram in 4% of the patients with a suspected acute MI who were included in a meta-analysis of nine trials that randomized 58,600 patients to either a control group or fibrinolytic therapy.³² Mortality at 35 days for patients who were randomized to the control groups was greater among patients who presented with a bundle branch block (23.6%), compared with patients who had ST segment elevation in the anterior leads (16.9%) or inferior leads (8.4%), or ST segment depression 13.8%).³² Fibrinolytic therapy was associated with a 25% reduction in mortality among patients who presented with a bundle branch block on ECG.³² The publication did not provide information regarding the age of the bundle branch block or whether the meta-analysis was limited to patients with an LBBB or also included patients with a right bundle branch block.³² Among 3053 patients with an acute MI who were enrolled in the Primary Angioplasty in Myocardial Infarction (PAMI) trials, an LBBB was an independent predictor of in-hospital death (odds ratio 5.53; 95% confidence interval [CI] 1.89 to 16.1; p = 0.002).³³

Patients with LBBB and acute MI frequently have no chest pain at the time of presentation. Chest pain was not reported by 47% of the 29,585 patients with LBBB and acute MI who were enrolled in the National Registry of Myocardial (NRMI) 2 registry.³⁴ Patients who presented without chest pain were less likely to receive aspirin or a β-blocker and four times less likely to receive reperfusion therapy (odds ratio 0.25).³⁴ This may explain why patients with acute MI and LBBB who presented without chest pain had a 47% greater in-hospital mortality rate than patients who presented with chest pain (27% versus 18%; p < 0.001).³⁴

A new or presumably new LBBB in patients with symptom onset within the prior 12 hours was designated as a Class I indication for either fibrinolytic therapy or primary percutaneous coronary intervention (PCI) in the guidelines for the management of acute MI that were issued by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines in 2004.²⁰ According to the most recent revision of the practice guidelines for ST elevation MI, a new or presumably new LBBB “should not be considered diagnostic of acute MI in isolation.”²⁴ The risks of fibrinolytic therapy may be increased in patients with LBBB due to older age and a higher prevalence of hypertension. Therefore, the most prudent strategy in patients with LBBB and a suspected acute MI may be immediate coronary angiography, both to diagnose an acute coronary artery occlusion and to eliminate the risk of fibrinolytic therapy in patients who cannot benefit from it (i.e., patients with a non–ST segment elevation MI or a non-cardiac condition). A more detailed discussion of the management of patients with LBBB and suspected MI can be found in an excellent review article that was published in 2012.²⁵

The ECG provides additional important information in patients with acute MI. Patients with acute inferior STEMI who have ST segment depression in the precordial leads have larger infarctions, more complications post-MI, and a higher mortality rate than patients without precordial ST segment depression.³⁵ The presence of Q waves in the infarct territory on the initial ECG is an independent predictor of greater 30-day mortality irrespective of the infarct location or time between symptom onset and administration of fibrinolytic therapy.³⁶ Nevertheless, substantial myocardial salvage is possible despite Q waves on the initial ECG.³⁷

The electrocardiographic leads with ST segment elevation have been correlated with occlusions of the left anterior descending (LAD), left circumflex, or right coronary arteries.38,39 The number of leads with ST segment elevation before reperfusion therapy and the degree of resolution of ST segment elevation after either fibrinolytic therapy or primary angioplasty confer useful prognostic information. The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) trial investigators reported that in-hospital mortality was directly related to the number of leads with ST segment elevation for both the patients treated with streptokinase and the control group.⁴⁰ Treatment with streptokinase significantly reduced in-hospital mortality among patients with ST segment elevation in four or more leads, but not among patients with ST segment elevation that was confined to two or three leads⁴⁰ (Fig. 30.2). Early ST segment recovery is associated with improved infarct zone wall motion⁴¹ and greater myocardial salvage as assessed by technetium-99m sestamibi scintigraphy.⁴² Also, resolution of ST segment elevation within 90 minutes after either primary angioplasty or fibrinolytic therapy identifies patients with lower mortality at 30 days and 1 year and 5 years after STEMI.^43–46 Continuous ECG monitoring is customary for the detection of arrhythmias and conduction abnormalities.

It is important to recognize that ST segment elevation occurs in numerous conditions other than acute MI.⁴⁷ The list includes left ventricular hypertrophy, LBBB, acute pericarditis, hyperkalemia, Brugada syndrome, pulmonary embolism, and left ventricular apical ballooning syndrome (takotsubo cardiomyopathy)^47,48 (Fig. 30.3).

Cardiac Enzymes

Myocardial necrosis is accompanied by the release of several biochemical markers in circulating blood, including creatine kinase, myoglobin, troponins T and I, and lactate dehydrogenase. As noted previously, a typical rise and gradual fall of troponin or more rapid rise and fall of CK-MB are required to diagnose an acute, evolving, or recent MI.² The ACC/AHA guidelines, however, stress that decisions such as initiation of reperfusion therapy for patients with ST segment elevation and symptoms of STEMI should not be delayed until the results of serum cardiac biomarkers are available.⁴⁹

Although troponin has become the preferred biomarker for myocardial necrosis, numerous other causes of an elevated troponin have been recognized, and several may be associated with chest pain or ST segment elevation.⁵⁰ An elevated troponin in patients with pulmonary embolism is associated with right ventricular dysfunction and an increased risk of hypotension and death.^51–53 Elevated cardiac troponin also has been reported in patients with acute pericarditis, and patients with ST segment elevation were more likely to have an elevated troponin.⁵⁴

Echocardiography

Echocardiography may be a useful diagnostic tool under a variety of circumstances. A transesophageal echocardiogram may be useful to differentiate STEMI from aortic dissection. Both transthoracic and transesophageal echocardiography are useful in patients with congestive heart failure (CHF) or hypotension to evaluate left and right ventricular function, to rule out cardiac tamponade, and to diagnose ventricular septal rupture or mitral regurgitation (MR). Mitral regurgitation is frequent among patients with uncomplicated MI. Color Doppler echocardiography was performed within 48 hours of admission in a series of 417 consecutive patients with acute MI.⁵⁵ Mild mitral regurgitation was present in 121 patients (29%), moderate mitral regurgitation in 21 (5%), and severe mitral regurgitation in 4 (1%).⁵⁵ Patients with any mitral regurgitation had higher 30-day and 1-year mortality rates, and mitral regurgitation was independently associated with increased 1-year mortality.⁵⁵ Echocardiography performed within 30 days after acute MI revealed mitral regurgitation in 50% of a cohort of 773 patients.⁵⁶ Cardiac auscultation did not detect a murmur in 54% of patients with mild and 31% of patients with moderate or severe mitral regurgitation.⁵⁶ Among 30-day survivors of an MI, during a mean follow-up period of 4.7 years moderate or severe mitral regurgitation detected by echocardiography within 30 days of MI was associated with a 55% increase in the relative risk (RR) of death independent of age, gender, left ventricular ejection fraction (EF), and Killip class.⁵⁶

Hemodynamic Monitoring

The value of pulmonary artery catheterization in critically ill patients has been questioned.⁵⁷ The evidence base regarding the impact of pulmonary artery catheters on outcome in patients with acute MI is limited to retrospective studies because pulmonary artery catheterization in patients with acute MI has not been evaluated in a prospective, randomized, controlled trial.^58–60 Cohen and associates⁶⁰ performed a retrospective analysis of pulmonary artery catheterization in patients with ACS who were enrolled in two large international randomized clinical trials, Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) Ilb and GUSTO III. The study compared the outcomes in 735 patients who received PA catheters with those in 25,702 patients who did not. Except for patients with cardiogenic shock, mortality at 30 days was significantly greater among patients who received pulmonary artery catheters, both before and after adjustment for baseline differences and subsequent events that may have prompted insertion of a pulmonary artery catheter.

According to the ACC/AHA Guidelines, the Class I indications for pulmonary artery catheter monitoring are (1) progressive hypotension that either is unresponsive to fluid administration or is developing in a patient in whom fluid administration is contraindicated and (2) a suspected mechanical complication, such as a VSD or papillary muscle rupture, if an echocardiogram has not been performed.²⁰ Intra-arterial pressure monitoring is recommended for patients with systolic blood pressure less than 80 mm Hg, patients with cardiogenic shock, and patients receiving vasopressor and inotropic drugs.²⁰

Access site bleeding is a major risk of central line insertion in patients who have received fibrinolytic drugs. The femoral route is preferred, and noncompressible sites, such as the subclavian vein, are relatively contraindicated.

Diagnostic Cardiac Catheterization and Coronary Angiography

Conditions other than STEMI can cause ST segment elevation. Pericarditis, for example, is a relative contraindication to fibrinolytic therapy because of the risk of intrapericardial bleeding and tamponade. Therefore, urgent coronary angiography and primary angioplasty if indicated would be preferable to intravenous fibrinolytic therapy if there is any suspicion of pericarditis. Similarly, diagnostic cardiac catheterization should be performed if clinical findings and noninvasive studies are unable to differentiate aortic dissection from acute MI.

Right heart catheterization and contrast ventriculography can provide useful diagnostic information in patients with suspected acute MI. Measurement of right heart pressures is useful in patients with suspected right ventricular MI and in patients with hypotension. Measurement of the oxygen content of blood in the right atrium and pulmonary artery is useful in patients with a suspected VSD. A contrast left ventriculogram provides an assessment of regional and global left ventricular function and the competence of the mitral valve. Left ventriculography was performed during the index cardiac catheterization in 1976 (95%) of 2082 patients with acute MI who were enrolled in the Controlled Abciximab and Device Investigation to Lower Angioplasty Complications (CADILLAC) trial.⁶¹ Mild mitral regurgitation was present in 192 patients (9.7%), and moderate or severe mitral regurgitation was present in 58 patients (2.9%). Mitral regurgitation was not detected by physical examination in 50% of a cohort of 50 patients with acute MI and moderately severe or severe mitral regurgitation that was demonstrated by left ventriculography.⁶²

Numerous studies have addressed the role of routine early angioplasty after fibrinolytic therapy.63–68 A prospective cohort study of 21,912 patients with a first acute MI concluded that revascularization within 14 days of the acute MI was associated with a significant reduction in 1-year mortality (RR 0.47; 95% CI 0.37 to 0.60; p < 0.001).⁶³ Several randomized trials have shown beneficial effects of a routine invasive strategy immediately after fibrinolysis,⁶⁵ within 24 hours after fibrinolysis,⁶⁶ and 1 to 6 weeks after acute MI.⁶⁷ The most recent trials have provided support for the practice of routine early angioplasty after fibrinolytic therapy.^68–70 The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) enrolled 1059 patients with a “high-risk” STEMI who received fibrinolytic therapy at centers that did not have the capability to perform PCI.⁶⁸ The patients were randomized to either “standard” treatment (including rescue PCI or delayed angiography) or immediate transfer to another hospital for PCI within 6 hours after fibrinolysis. The primary end point—the composite of death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days—occurred in 11% of the patients who were assigned to routine early PCI, compared with 17.2% of the patients who were assigned to standard treatment (RR 0.64; 95% CI 0.47 to 0.87; p = 0.004). Borgia and colleagues⁶⁹ performed a meta-analysis of seven randomized, controlled trials that compared routine early PCI after successful fibrinolysis with PCI only for patients without evidence of reperfusion (rescue PCI). After a follow-up period of 30 days routine early PCI after successful fibrinolysis reduced the rates of reinfarction (odds ratio 0.55; 95% CI 0.36 to 0.82; p = 0.003), the combined end point of death and reinfarction (odds ratio 0.65; 95% CI 0.49 to 0.88; p = 0.004), and recurrent ischemia (odds ratio 0.25; 95% CI 0.13 to 0.49; p < 0.001). The benefits of early PCI persisted after 6 to 12 months of follow-up. D’Souza and associates⁷⁰ performed a meta-analysis of eight randomized trials that compared routine early PCI with ischemia-driven PCI after fibrinolysis in patients with STEMI. PCI within 24 hours after fibrinolytic therapy was associated with less re-infarction and recurrent ischemia.

The 2004 and 2007 Focused Update of the ACC/AHA Guidelines for the management of patients with STEMI include five Class I recommendations, two Class IIa recommendations, and one Class IIb recommendation for coronary angiography in patients with acute MI20,21 (Box 30.1). Coronary angiography is recommended in survivors of STEMI who are candidates for revascularization therapy with spontaneous ischemia, intermediate-risk or high-risk findings on noninvasive testing, hemodynamic or electrical instability, mechanical defects, prior revascularization, or high-risk clinical features.

General Considerations

Patients who present to the emergency department with an acute MI will usually be diagnosed and treated before admission to the intensive care unit (ICU). It is not unusual, however, for STEMI to occur in patients receiving ICU treatment for other conditions, such as gastrointestinal bleeding or respiratory failure, or undergoing surgical procedures. As in the patients who present to an emergency department (ED), prompt performance and interpretation of an ECG constitute a critical initial step in management. Continuous ECG monitoring for arrhythmias is routinely practiced. Patients usually are advanced from nothing-by-mouth (NPO [nil per os]) status to clear liquids to a low-fat, low-cholesterol diet as tolerated. Stool softeners should be employed to prevent the hemodynamic effects of constipation.

Oxygen

The effects of supplemental oxygen on ischemic injury was studied by Madias and colleagues.⁷¹ Seventeen patients with acute anterior MI who were not in cardiogenic shock underwent precordial ST segment mapping before and after inhalation of 100% oxygen for 1 hour. The mean arterial partial pressure of oxygen increased from 70 mm Hg on room air to 278 mm Hg during oxygen inhalation. During oxygen inhalation there was a 16% reduction in the sum of all ST segment elevation, with reversion to baseline after oxygen was discontinued. Two hundred patients with suspected acute MI were enrolled in a double-blind, randomized trial of supplemental oxygen versus compressed air.⁷² No apparent benefit was observed for oxygen therapy, and the mortality rate was higher in the oxygen group than in the control group (9/80 versus 3/77; p = NS). A meta-analysis of 3 trials that enrolled 387 patients found that the pooled relative risk of death for patients who were treated with oxygen compared to air was 2.88 (95% CI 0.88 to 9.83).²¹ Hyperoxia during inhalation of high concentrations of oxygen causes an increase in coronary vascular resistance and a decrease in coronary blood flow.⁷³

Although supplemental oxygen is routinely administered to patients with STEMI, according to the ACC/AHA guidelines the only Class I indication for this intervention is an arterial oxygen saturation less than 90%.²⁰ The guidelines also include a Class IIa indication: “It is reasonable to administer supplemental oxygen to all patients with uncomplicated STEMI during the first 6 hours.”²⁰ Randomized, controlled trials of oxygen therapy in patients with STEMI are planned.⁷⁴

Analgesia and Sedation

Relief of pain is an important goal in patients with acute MI. The 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction included several recommendations regarding analgesic drugs.²¹ According to the guidelines, morphine sulfate is the analgesic of choice for the management of pain associated with STEMI, and pain associated with STEMI is a Class I indication for intravenous morphine.²¹ There are no published randomized trials of morphine therapy in patients with acute MI. An analysis of the CRUSADE registry, however, revealed that use of morphine was associated with a 50% higher mortality in patients with NSTEMI even after risk adjustment.⁷⁵ One proposed mechanism of morphine’s adverse effect is opioid-induced cortisol deficiency.⁷⁶ Until additional data become available, it may be prudent to limit the use of morphine to patients with persistent pain despite treatment with nitrates and a β-adrenergic antagonist.

The abundant evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects in patients with cardiovascular disease has been reviewed in great detail in multiple publications, including a scientific statement from the American Heart Association and a meta-analysis of 31 trials that enrolled 116,429 patients.77–79 A Danish study of 58,432 patients who were hospitalized for a first-time acute MI between 1995 and 2002 found that treatment with either a selective cyclooxgyenase-2 inhibitor or a nonselective NSAID after discharge from the hospital significantly increased the risk of death.⁸⁰ A subsequent study by the same investigators found that even short-term treatment with NSAIDs was associated with an increased risk of death and recurrent MI in patients with a prior MI.⁸¹ One possible explanation for the adverse cardiovascular effects of NSAIDs is inhibition of the clinical benefits of aspirin. An analysis of the Physicians’ Health Study concluded that there was greater than a twofold increased risk of a first MI among healthy male U.S. physicians who were randomized to aspirin and also took other NSAIDs on > 60 days per year.⁸² An important pharmacologic study demonstrated that inhibition of platelet aggregation by aspirin was blocked when ibuprofen was administered before aspirin.⁸³ The 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction included two new recommendations regarding both nonselective and cyclooxygenase-2 selective NSAIDs: a Class I recommendation that patients routinely taking NSAIDs (except for aspirin) before a STEMI should have those agents discontinued at the time of presentation with STEMI; and a Class III recommendation that NSAIDs (except for aspirin) “should not be administered during hospitalization for STEMI because of the increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use.”²¹

Nitrates

The ability of sublingual or intravenous nitroglycerin to relieve chest pain in patients with acute MI is well documented.⁸⁴ The beneficial physiologic effects of nitrates include vasodilation of peripheral arteries and veins, causing reductions in pulmonary capillary wedge pressure (PCWP), mean arterial pressure, and peripheral vascular resistance, thereby decreasing left ventricular preload and afterload and myocardial oxygen demand.⁸⁵ Also, vasodilation of the coronary arteries may improve myocardial oxygen supply, especially in patients with a component of coronary spasm.⁸⁶ Severe hypotension and bradycardia have been observed after administration of either sublingual or intravenous nitroglycerin in patients with acute MI.⁸⁷ Patients with right ventricular MI may experience severe hypotension during administration of nitroglycerin because adequate right ventricular preload is required to maintain cardiac output. Nitroglycerin is contraindicated in patients who have taken phosphodiesterase inhibitors because they potentiate nitroglycerin-induced hypotension.⁸⁸

There are two Class I indications for nitroglycerin in patients with STEMI. Sublingual nitroglycerin (0.4 mg) every 5 minutes for a total of three doses is recommended for relief of ischemic discomfort.²⁰ Intravenous nitroglycerin is indicated for relief of ongoing ischemic discomfort, control of hypertension, or management of pulmonary congestion.²⁰ It has been proposed that intravenous nitroglycerin may limit myocardial infarct size and expansion.⁸⁹ Two large clinical trials, however, were unable to demonstrate significant improvements in mortality by the prolonged administration of nitroglycerin after acute MI.^90,91 The GISSI-3 trial enrolled 19,394 patients with acute MI.⁹⁰ Patients who were randomized to treatment with nitroglycerin received intravenous nitroglycerin for 24 hours, followed by transdermal nitroglycerin for 6 weeks.⁹⁰ Nitroglycerin did not reduce the 6-week rate of death or clinical heart failure. The Fourth International Study of Infarct Survival (ISIS-4) enrolled 58,050 patients with suspected acute MI in a 2 × 2 × 2 factorial study that included randomization to isosorbide mononitrate 60 mg daily or placebo for 28 days.⁹¹ No significant effect of nitroglycerin on mortality was found after 5 weeks or 1 year.

Several studies have investigated the effect of another nitrate, nitroprusside, on hemodynamics and outcome in patients with acute MI.92–95 Intravenous nitroprusside reduced PCWP and increased cardiac index in patients with acute MI.^92,93 A comparison of intravenous nitroprusside with intravenous nitroglycerin in 10 patients with acute anterior MI demonstrated that ST segment elevation increased during infusion of nitroprusside, whereas it decreased during infusion of nitroglycerin.⁹² Experimental data indicate that nitroprusside may exacerbate myocardial ischemia or injury by redistribution of myocardial blood flow from ischemic to nonischemic zones.⁹² A Veterans Administration Cooperative Study enrolled 812 patients with acute MI and a PCWP greater than 12 mm Hg in a double-blind, randomized trial of nitroprusside infused for 48 hours.⁹⁵ Compared with the placebo group, mortality at 13 weeks was increased by nitroprusside in patients whose infusions started within 9 hours of the onset of pain. A smaller European trial randomized 328 patients with acute MI to infusion of nitroprusside or 5% glucose.⁹⁴ The trial was terminated when 1-week mortality in the control group was significantly greater than in the nitroprusside group (10.9% versus 3.1%; p < 0.05). The use of nitroprusside in patients with acute MI should probably be reserved for patients with severe hypertension that is unresponsive to treatment with intravenous nitroglycerin.

Aspirin

The Second International Study of Infarct Survival (ISIS-2) provided definitive evidence that aspirin reduces mortality in patients with acute MI.⁹⁶ The study used a 2 × 2 factorial design to randomize 17,187 patients to four treatment groups: streptokinase, aspirin 160 mg daily for 1 month, both, or neither. Aspirin reduced the rate of in-hospital reinfarction both in the patients who received streptokinase and in the patients who did not receive fibrinolytic therapy. At 35 days, the vascular-cause mortality rate was 9.4% among the patients in the aspirin treatment group patients, compared with 11.8% among those in the placebo group, representing a 23% reduction (p < 0.00001). Aspirin also significantly reduced all-cause mortality. Also, the combination of aspirin and streptokinase reduced mortality more than did either agent alone. The effects of the initial dose of aspirin on short-term outcomes after fibrinolytic therapy were tested by analyzing the outcomes of 48,422 patients with STEMI who were enrolled in two large clinical trials, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I and GUSTO III.⁹⁷ Compared with an initial dose of 162 mg, an initial dose of 325 mg was associated with a significant increase in moderate or severe bleeding in-hospital, but the rates of reinfarction and death at 24 hours, 7 days, and 30 days were not significantly different.⁹⁷ Nevertheless, the ACC/AHA Practice Guidelines for the Management of Patients with STEMI recommend that patients who present with acute STEMI who have not taken aspirin should receive 162 to 325 mg of non-enteric-coated aspirin, and the aspirin tablets should be chewed.²⁰ Also, the 2011 update of the guidelines for PCI include a Class IIa recommendation that “After PCI, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses.”⁹⁸

Reocclusion of a patent infarct artery after successful fibrinolytic therapy is associated with higher in-hospital mortality, reduced event-free survival after hospital discharge, and long-term impairment of regional and global left ventricular function.99–102 There are conflicting opinions regarding aspirin’s effect on reocclusion of an infarct artery.^103,104 The Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT) study randomized 300 patients with an open infarct artery within 48 hours after fibrinolysis to three treatment groups: aspirin 325 mg daily, warfarin, or placebo.¹⁰⁵ Cardiac catheterization was performed 3 months later in 248 patients. The reocclusion rates were not significantly different: 32% (24/74) with placebo, 30% (24/81) with warfarin, and 25% (23/93) with aspirin. A pooled analysis of published studies estimated that the incidence of reocclusion after streptokinase or tissue plasminogen activator (tPA) is approximately 11% with aspirin, compared with 25% without aspirin.¹⁰³

Inhibitors of the Platelet P2Y₁₂ Receptor

The combination of aspirin with inhibitors of the platelet P2Y₁₂ receptor has been shown to be superior to aspirin alone in patients with a STEMI.106–108 The Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study enrolled 3491 patients who received fibrinolytic therapy for STEMI and randomized them to receive clopidogrel 75 mg daily or placebo in a double-blind fashion.¹⁰⁶ Coronary angiography performed at a median of 84 hours after randomization in each group demonstrated an occluded IRA in 18.4% of the placebo group patients, compared with 11.7% of the clopidogrel group patients (p < 0.001). PCI was performed during the index hospitalization in 1863 (53.4%) of the patients who were enrolled in the CLARITY trial.¹⁰⁸ The combined incidence of cardiovascular death, recurrent MI, or stroke from PCI to 30 days after randomization was significantly lower among patients who were treated with clopidogrel and aspirin compared with the patients who received aspirin alone (3.6% versus 6.2%; adjusted odds ratio 0.54; 95% CI 0.35 to 0.85; p = 0.008).¹⁰⁸ The Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) randomized 45,852 patients with suspected acute MI to receive treatment with aspirin 162 mg daily plus clopidogrel 75 mg daily or placebo.¹⁰⁷ The in-hospital mortality rate was significantly lower for the clopidogrel group than for the placebo group (7.5% versus 8.1%; p = 0.03). The CLARITY study used a clopidogrel loading dose of 300 mg; the COMMIT study did not employ a loading dose.

A multivariate-weighted logistic regression analysis of the outcomes of 8429 STEMI patients who were enrolled in 26 randomized clinical trials concluded that pretreatment with a loading dose of clopidogrel before primary PCI was an independent predictor of coronary artery patency before PCI (odds ratio 1.51; 95% CI 1.31 to 1.74; p < 0.0001) and decreased mortality after PCI (odds ratio 0.57; 95% CI 0.38 to 0.85; p = 0.0055).¹⁰⁹ Among patients with STEMI who were enrolled in the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial and underwent primary PCI, a clopidogrel loading dose of 600 mg (n = 2158), compared with 300 mg (n = 1153) was associated with significantly lower 30-day rates of mortality, reinfarction, and stent thrombosis, and was an independent predictor of freedom from major adverse cardiac events at 30 days.¹¹⁰

Prasugrel, another inhibitor of the platelet P2Y₁₂ receptor, was studied in patients with ACS, including patients with STEMI, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.111,112 The trial randomized 3534 patients with STEMI who were undergoing either primary PCI (PCI within 12 hours of symptom onset) or secondary PCI (PCI between 12 hours and 14 days after symptom onset) to either prasugrel (60 mg loading dose and 10 mg/day maintenance dose) or clopidogrel (300 mg loading dose and 75 mg maintenance dose) for 6 to 15 months.¹¹² The primary end point of cardiovascular death, nonfatal MI, or nonfatal stroke, was significantly less frequent at both 30 days and 15 months among patients who were randomized to prasugrel compared with patients who were randomized to clopidogrel.¹¹²

Ticagrelor, an inhibitor of the platelet P2Y₁₂ receptor, was studied in patients with ACS, including patients with STEMI, in the Study of Platelet Inhibition and Patient Outcomes (PLATO).113,114 The trial randomized 7544 patients with STEMI who were undergoing primary PCI to either ticagrelor (180 mg loading dose and 90 mg twice daily maintenance dose) or clopidogrel (300 mg loading dose and 75 mg maintenance dose) for 6 to 12 months.¹¹⁴ Compared with clopidogrel, treatment with ticagrelor reduced several secondary end points, including MI (hazard ratio 0.80; p = 0.03), total mortality (hazard ratio 0.82; p = 0.05), and definite stent thrombosis (hazard ratio 0.66; p = 0.03); major bleeding was not significantly different (hazard ratio 0.98; p = 0.76).¹¹⁴

The 2007 and 2009 focused updates of the ACC/AHA Practice Guidelines for the Management of Patients with STEMI include several new recommendations regarding antiplatelet therapy (Box 30.2).^21,22 The Class I recommendations include the following: (1) clopidogrel 75 mg/day orally should be added to aspirin in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. Treatment with clopidogrel should continue for at least 14 days. (2) A loading dose of a P2Y₁₂ inhibitor is recommended for STEMI patients for whom PCI is planned. The options include clopidogrel, prasugrel, and ticagrelor. Prasugrel is contraindicated in patients with a history of TIA or stroke and active pathologic bleeding. Also, prasugrel should not be administered to patients older than age 75 because of an increased risk of fatal and intracranial bleeding. Finally, the maintenance dose of prasugrel should be reduced to 5 mg daily in patients who weigh less than 60 kg.

Anticoagulant Therapy

The rationale for anticoagulant therapy in patients with STEMI includes promotion of infarct artery patency, and prevention of deep vein thrombosis, pulmonary embolism, left ventricular mural thrombus, and cerebral embolism. Left ventricular mural thrombus formation after acute MI occurs more commonly after anterior than nonanterior wall MI and is associated with an increased risk of systemic embolization.115,116 Data conflict regarding the incidence of left ventricular thrombus in patients who receive reperfusion therapy. The GISSI-2 study, in which all patients received fibrinolytic therapy, observed left ventricular thrombi in 51 of 180 consecutive patients with a first anterior acute MI who underwent serial echocardiography within 48 hours after the onset of symptoms and before hospital discharge.¹¹⁷ Another study, however, detected left ventricular thrombi in only 6.4% of patients with acute anterior MI who underwent echocardiography on days 1, 14, and 90 after MI.¹¹⁸ A double-blind, randomized trial compared a 10-day course of high-dose subcutaneous UFH (12,500 units every 12 hours) with low-dose subcutaneous UFH (5000 units every 12 hours) in the prevention of left ventricular thrombus in 221 patients with acute anterior MI who did not receive fibrinolytic therapy.¹¹⁹ Echocardiography 10 days after MI demonstrated left ventricular thrombi in 10 of 95 patients (11%) in the high-dose group and in 28 of 88 patients (32%) in the low-dose group (p = 0.0004). A meta-analysis of seven studies that enrolled 270 patients suggests that systemic anticoagulation in patients with mural thrombi reduces embolic complications.¹¹⁵

Clinical trials have evaluated both subcutaneous and intravenous unfractionated heparin (UFH) in patients with acute MI who were treated with various fibrinolytic agents. Randomized, controlled clinical trials have shown that adjunctive therapy with intravenous UFH increases the patency of the IRA after administration of tPA.120,121 A meta-analysis that included 68,000 patients who were enrolled in randomized trials that compared UFH plus aspirin with aspirin alone showed that only 5 lives were saved per 1000 patients who received UFH in addition to streptokinase.¹²² The meta-analysis was heavily influenced by two studies, GISSI-2¹²³ and ISIS-3,^124,125 that enrolled 62,067 patients who were randomly assigned to receive fibrinolytic therapy plus either aspirin alone or aspirin plus subcutaneous UFH. Another meta-analysis was limited to six randomized controlled trials that enrolled 1735 patients who received either intravenous UFH or no heparin after fibrinolytic therapy.¹²⁶ The analysis found that the addition of intravenous UFH to tPA or streptokinase had insignificant effects on mortality and reinfarction, but the risk of bleeding was significantly increased.¹²⁶

Several randomized clinical trials127–131 and meta-analyses^132,133 have been performed to compare low-molecular-weight heparin (LMWH) with placebo or UFH as adjuncts to fibrinolytic therapy in patients with STEMI. A meta-analysis of 16,943 patients who were enrolled in four randomized trials revealed that the end points of death or reinfarction at 7 days and at 30 days were significantly reduced by LMWH compared with placebo.¹³³ A meta-analysis of 7098 patients who were enrolled in six randomized trials revealed that LMWH, compared with UFH, reduced the rates of reinfarction during hospitalization and at 30 days, but the rates of death were not significantly different.¹³³ Neither meta-analysis included a subsequent trial, Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-TIMI 25, that compared enoxaparin, an LMWH, with UFH in patients with STEMI who received fibrinolytic therapy.^129,130 The study was a double-blind, randomized comparison of enoxaparin given subcutaneously twice daily until hospital discharge versus intravenous UFH for 48 hours in 20,506 patients with STEMI. A fibrinolytic agent was received by 99.7% of the patients: 55% received alteplase, 20% received streptokinase, 19% received tenecteplase, and 5.5% received reteplase. The primary end point, death or nonfatal recurrent MI through 30 days, occurred in 12% of patients in the UFH group and in 9.9% of patients in the enoxaparin group (p