ACP medicine, 3rd Edition

Cardiovascular Medicine

Acute Myocardial Infarction

Peter B. Berger MD1

Professor of Medicine, and Director of Interventional Cardiology

James L. Orford MB, CHB, MPH2

Consulting Cardiologist

1Duke University School of Medicine

2Mayday University Hospital, London

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

April 2007

In the 1970s, coronary angiography demonstrated that almost all cases of acute myocardial infarction were caused by thrombotic occlusion of a coronary artery. This discovery has led to the development of therapies to restore coronary blood flow in the occluded artery, which has dramatically reduced the morbidity and mortality associated with acute myocardial infarction.


In the past decade, the number of people who die each year of myocardial infarction has decreased significantly. Both in-hospital mortality and out-of-hospital mortality have declined as a result of substantial increases in the use of aspirin, heparin, thrombolytic therapy, and coronary angioplasty, as well as a reduction in the risk factors for coronary artery disease (e.g., hypertension, hyperlipidemia, smoking, and sedentary lifestyle) [see Risk-Factor Modification, below]; however, it must be emphasized that there is, unfortunately, persistent discordance between existing guidelines for management of acute coronary artery disease syndromes and current clinical practice.1,2

Despite these advances, approximately 1.5 million people in the United States suffer acute myocardial infarction each year, and nearly 500,000 of these patients die of coronary artery disease.3 Nearly half of these deaths occur before the patients receive medical care either from emergency medical technicians or in a hospital.3,4


The factors responsible for the sudden thrombotic occlusion of a coronary artery have only recently been elucidated.5,6,7 Atherosclerotic plaques rich in foam cells (lipid-laden macrophages) are susceptible to sudden plaque rupture and hemorrhage into the vessel wall, which may result in the sudden partial or total occlusion of the coronary artery. Although severe stenosis of a coronary artery (i.e., stenosis ≥ 70% of the diameter of the artery) is generally required to produce anginal symptoms, such stenoses tend to have dense fibrotic caps and are less prone to rupture than mild to moderate stenoses, which are generally more lipid laden. Studies of patients in whom angiography was performed before and after a myocardial infarction revealed that in most cases, acute coronary artery occlusion occurred at sites in the coronary artery circulation with stenoses of less than 70%, as demonstrated on the preinfarction angiogram.8 Although patients who have unstable anginal syndromes with increasingly frequent and severe angina are clearly at increased risk for myocardial infarction, the ability of physicians to predict which patients with stable anginal syndromes are likely to experience infarction and which coronary artery stenoses are likely to result in acute thrombotic occlusion is poor.


According to the World Health Organization, the diagnosis of myocardial infarction requires at least two of the following three criteria: (1) a clinical history of ischemic-type chest discomfort, (2) serial electrocardiographic tracings indicative of myocardial infarction, and (3) a rise and fall in serum cardiac markers.9 However, the advent and widespread adoption of novel diagnostic tools, including highly sensitive and specific serologic biomarkers and precise imaging techniques, have necessitated reevaluation of this established definition. The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction has integrated these diagnostic modalities and published updated definitions of acute myocardial infarction, evolving or recent myocardial infarction, and established myocardial infarction that more accurately reflect current clinical practice [see Table 1].10

Table 1 Clinical Definitions of Myocardial Infarction as Determined by the Joint European Society of Cardiology/American College of Cardiology Committee10

Acute, Evolving, or Recent Myocardial Infarction     Biochemical markers of myocardial necrosis (i.e., typical rise and gradual fall of troponin or more rapid rise and fall of CK-MB) with at least one of the following:
   Ischemic symptoms
   Development of pathologic Q waves on the ECG
   ECG changes indicative of ischemia (ST segment elevation or depression)
   Coronary artery intervention (e.g., primary coronary angioplasty)
    Pathologic findings of an acute myocardial infarction
Established Myocardial Infarction
    Development of new pathologic Q waves on serial ECGs; the patient may or may not remember previous symptoms; biochemical markers of myocardial necrosis may have normalized, depending on the length of time that has passed since the infarct developed
    Pathologic findings of a healed or healing myocardial infarction

CK-MB—creatine kinase-myocardial band

Clinical Manifestations

Patients with acute myocardial infarction often describe a heaviness, pressure, squeezing, or tightness in the chest that has persisted for more than 30 minutes. The discomfort may radiate or be located primarily in the arms, neck, or jaw. Chest pain, particularly severe or stabbing chest pain, and pain that causes writhing are unusual for coronary artery ischemia and should lead the clinician to consider causes other than myocardial infarction. Many patients with acute myocardial infarction, particularly those with inferior infarction, are diaphoretic; nausea and emesis are common as well. Dyspnea is also a common associated symptom. Syncope may occur and is more frequent with inferior than anterior infarction, in part because of the more frequent occurrence of bradyarrhythmias, heart block, and tachy arrhythmias with inferior infarction. Elderly patients with infarction often present with symptoms that differ from the symptoms of infarction in younger patients; more than half of elderly patients present with shortness of breath as their main complaint, and many others present with dizziness or symptoms of arrhythmia rather than the classic symptoms of acute myocardial infarction.11

Approximately two thirds of patients describe the new onset of angina or a change in their anginal pattern in the month preceding infarction.12 However, in approximately one fourth of patients, myocardial infarction is associated with only mild symptoms or no symptoms at all.13

Physical Examination

The patient with acute myocardial infarction often appears anxious and in distress. Vital signs are often normal, but sinus tachycardia is not uncommon. The pulse may be rapid or slow if arrhythmias are present. Either hypotension caused by left or right ventricular dysfunction or arrhythmia or hypertension caused by adrenergic discharge may be present. The respiratory rate may be elevated because of anxiety or pain or because of hypoxia in patients with significant congestive heart failure. The jugular venous pressure may be elevated, reflecting right ventricular dysfunction caused by right ventricular involvement (more common with inferior infarction); arrhythmia in which atrioventricular dissociation is present may produce so-called cannon A waves, which are abnormally high jugular venous waves caused by atrial systole occurring when the atrioventricular valves are closed. The lung examination is typically normal, but moist rales indicative of congestive heart failure resulting from left ventricular dysfunction may be present. The cardiac examination may reveal a dyskinetic apical pulsation on palpation; a fourth and, less commonly, a third heart sound may be audible. The murmur of ischemic mitral regurgitation may be present. If a left bundle branch block is present, abnormal splitting of the second heart sound may be heard.

It must be emphasized that the physical examination in acute myocardial infarction is generally most useful in excluding other potentially serious causes of the patient's chest discomfort, including pulmonary embolism, aortic dissection, spontaneous pneumothorax, pericarditis, and cholecystitis, rather than in confirming a diagnosis of acute myocardial infarction.


ECG is a valuable tool both in confirming the diagnosis of acute myocardial infarction and in selecting the most appropriate therapy for the patient. Although rhythm and conduction disturbances may be present, the presence and type of repolarization abnormalities are most useful in identifying myocardial infarction. If ST segment elevation is present in a patient with chest pain typical of acute myocardial infarction, the likelihood that the patient has acute myocardial infarction is greater than 90%.14 Other findings, such as ST segment depression, T wave inversion, and bundle branch block, are less specific but may also support a diagnosis of acute myocardial infarction, particularly when typical symptoms are present [see Figure 1]. Fully 50% of patients with myocardial infarction do not have ST segment elevation on their ECGs, although the ECG is seldom normal even at an early stage.15 In such patients, the ECG can help predict complications and early mortality.16 Patients with ST segment depression are at high risk; 30-day mortality in such patients is nearly as high as in patients with anterior ST segment elevation.17 Patients with other nonspecific ECG abnormalities are at lesser risk; those with normal ECGs who suffer infarction generally have the best prognosis [see Figure 2]. Regardless of the findings on the initial ECG, the most important element in the evaluation of a patient with suspected acute myocardial infarction is the patient's description of symptoms. All patients suspected of having acute myocardial infarction should be admitted to the hospital and receive rapid and appropriate therapy.


Figure 1. Relation between the initial electrocardiographic changes and the development of infarction in 1,715 patients strongly suspected of having an acute myocardial infarction. Each column shows the total number of patients and the number of patients later found to have had an infarction. Although infarction is less frequently confirmed in patients without ST segment elevation than in those with ST segment elevation, even patients with normal ECG findings may suffer acute myocardial infarction.14


Figure 2. Thirty-day mortality in patients with suspected acute myocardial infarction from placebo-controlled trials of thrombolytic therapy on the basis of their initial ECGs. Patients with ST segment depression are at high risk, nearly as high as patients with anterior ST segment elevation. The mortality among such patients is not reduced (and may be increased) by thrombolytic therapy. Patients with other nonspecific electrocardiographic abnormalities are at lesser risk, and those with normal ECG findings have the best prognosis.

Laboratory Findings

Injury to myocardial cells results in the release of intracellular enzymes into circulating blood, permitting their detection by blood tests. Traditionally, the serum cardiac marker creatine kinase (CK) and an isoenzyme, creatine kinase-myocardial band (CK-MB), which are found in high concentration in myocardial cells, have been used to diagnose myocardial infarction in its earliest stages.18 Rapid assays of these enzymes have been developed, permitting the determination of the blood levels of these enzymes within 30 to 60 minutes. Drawbacks to the use of CK-MB include its lack of specificity for cardiac muscle and the time required for CK-MB levels to rise during myocardial infarction. CK and CK-MB usually require at least 3 hours of profound ischemia to rise above normal levels; patients who present early in their infarction would not be expected to have elevated CK levels. Furthermore, patients may have only partial obstruction of the infarct-related artery, or there may be extensive collateralization of the infarct-related artery, which further delays the release of these enzymes. In patients suspected of having acute myocardial infarction, it is not appropriate to delay treatment until an elevation of CK or CK-MB is present, because the goal of treatment is to prevent injury to the myocardium. The challenge facing physicians is to identify patients suffering myocardial infarction even before CK becomes elevated, because these patients require emergency therapy and stand to benefit the most from reperfusion therapy.

To overcome these limitations and more accurately and rapidly identify patients in need of emergency reperfusion therapy, other blood tests have been developed to help identify patients with ischemia. Myoglobin is a low-molecular-weight heme protein found in cardiac muscle. Its advantage for diagnosis is that it is released more rapidly from infarcted myocardium than is CK-MB. However, myoglobin is also found in skeletal muscle, and the lack of specificity is a drawback.19 Troponin is a cardiac-specific marker for acute myocardial infarction; an increase in serum levels of troponin occurs soon after myocardial cell injury. An elevated cardiac troponin level on admission is a predictor of subsequent cardiac events.20,21 Changes to the definition of acute myocardial infarction reflect the increased emphasis on these specific biomarkers of myocardial injury [see Table 1].10

Imaging Studies


Echocardiography may be useful in identifying patients with myocardial infarction in the emergency department. Regional wall motion abnormalities occur within seconds of coronary occlusion and well before myocyte necrosis,22,23,24,25,26 and most patients with acute myocardial infarction have regional wall motion abnormalities readily seen on echocardiography. However, echo cardiographic evidence of myocardial infarction is not required in patients with symptoms and electrocardiographic evidence typical of acute myocardial infarction, and treatment should not be delayed, so that an echocardiogram can be performed. Similarly, wall motion abnormalities are not specific for acute myocardial infarction and may be caused by ischemia or prior infarction. Echocardiography may be useful in patients with left bundle branch block or abnormal ECGs without ST segment elevation whose symptoms are atypical and in whom the diagnosis is uncertain.27

Radionuclide Imaging

Perfusion imaging with both thallium and sestamibi in the emergency department has been reported to be both sensitive and specific in the evaluation of patients in whom the diagnosis is uncertain.27,28,29 A prospective randomized trial of 2,475 patients found that resting technetium-99m sestamibi imaging reduced unnecessary hospitalization in patients with acute ischemia without reducing admission of patients with acute ischemia.30

Emergent Therapy

Treatments have been developed that reduce the morbidity and mortality of acute myocardial infarction, particularly when initiated early; it is therefore important to avoid delay in administering therapy.4,31 Much of the emphasis on reducing delay has focused on the time between a patient's presentation to the emergency department and the administration of reperfusion therapy. The 2004 ACC/AHA guidelines recommended that all initial therapy be carried out in the emergency department based upon a predetermined, institution-specific, written protocol.31 A patient with symptoms suggestive of myocardial infarction should be evaluated within 10 minutes after arrival in the emergency department. Early steps should include the assessment of hemodynamic stability by measurement of the patient's heart rate and blood pressure; the performance of a 12-lead ECG; and the administration of oxygen by nasal prongs, I.V. analgesia (most commonly morphine sulfate), oral aspirin, and sublingual nitroglycerin if the blood pressure is greater than 90 mm Hg. The challenge facing physicians who work in emergency departments is that more than 90% of patients who present to the emergency department complaining of chest pain are not suffering myocardial infarction; many do not have a cardiac etiology for their chest pain.

All patients with definite or suspected myocardial infarction should be admitted to the hospital, undergo preparation for I.V. access, and be placed on continuous ECG monitoring. High-risk patients should be admitted to a coronary care unit. In many hospitals, patients at low risk for major complications are admitted to a telemetry unit, where emergency medical care can be quickly administered, rather than to a coronary care unit. Tachyarrhythmias and bradyarrhythmias may occur even in low-risk patients, particularly in the first 24 hours. Lidocaine, atropine, an external or internal pacemaker, and a defibrillator should be readily available.


Oxygen is generally recommended for all patients with acute myocardial infarction for the first several hours after admission and is mandatory for patients with pulmonary congestion or evidence of oxygen desaturation.


Aspirin should be given to all patients as soon as a diagnosis of myocardial infarction is made.17 In the second International Study of Infarct Survival (ISIS-2), aspirin was found to be nearly as effective as streptokinase, reducing 30-day mortality 23% in 17,000 patients with acute myocardial infarction; the benefit was additive in patients receiving both aspirin and streptokinase [see Figure 3].17 Other studies have revealed similar benefit from immediate aspirin therapy.32


Figure 3. Mortality at 35 days in 17,187 cases of suspected acute myocardial infarction in the second International Study of Infarct Survival (ISIS-2). In this study, aspirin reduced 30-day mortality by 23% and was nearly as effective as streptokinase; the benefit was additive in patients receiving both aspirin and streptokinase.17

Patients should be maintained on aspirin indefinitely. Prolonged administration of aspirin in patients with a history of myocardial infarction is associated with a 25% reduction in death, nonfatal reinfarction, and stroke.32


Pain relief should be among the initial therapies offered to patients with acute myocardial infarction. Persistent chest discomfort is generally caused by ongoing myocardial ischemia; although the ultimate goal of therapy is to eliminate ischemia, analgesia should be administered without delay. In addition to making patients more comfortable, pain relief may reduce the outpouring of catecholamines characteristic of the early stages of acute myocardial infarction and thereby reduce myocardial oxygen demand. Intravenous morphine sulfate is commonly used for pain relief in this setting.

Reperfusion Therapy

Reperfusion may be achieved by percutaneous coronary intervention (PCI) (previously referred to as primary coronary angioplasty, percutaneous transluminal coronary angioplasty [PTCA], or balloon angioplasty) or thrombolytic therapy.

Reperfusion Strategies and Outcomes

Importance of Time to Reperfusion

Many important predictors of early clinical outcome in myocardial infarction are independent of treatment. Most of the early mortality is explained by factors such as the age of the patient, initial heart rate and blood pressure, initial Killip classification [see Table 2], and infarct location. However, the time to administration of reperfusion therapy is a critical determinant of outcome and one of the few determinants of early clinical outcome under the control of the physician. Many studies have revealed that patients with myocardial infarction treated most rapidly have a lower mortality and, among survivors, reduced infarct size [see Figure 4].33 This observation has led to recommendations that the time between a patient's presentation to the emergency department and the administration of thrombolytic therapy not exceed 60 minutes; ideally, this period should not exceed 30 minutes.34 The most critical interval is the time between symptom onset and the achievement of reperfusion, not the time to the initiation of therapy. Thus, therapy that takes longer to initiate may actually be superior if it achieves reperfusion more rapidly than another therapy that can be initiated more rapidly (e.g., thrombolytic therapy). The ACC/AHA task force gave a class I recommendation to the use of PCI for any patient with an acute ST-segment elevation myocardial infarction (STEMI) who presents within 12 hours of symptom onset and who can undergo the procedure within 90 minutes of presentation by clinicians skilled in the procedure.31 When primary PCI is not available or its implementation is delayed, use of thrombolytic therapy is recommended. The ACC/AHA task force gave a class I recommendation to the use of thrombolytic therapy for any patient with an acute STEMI without contraindications for thrombolysis, who presents to a facility without the capability for expert, prompt intervention with primary PCI within 90 minutes of first medical contact.31 The delay from patient arrival to administration of thrombolytics should be less than 30 minutes.31Reperfusion therapy, whether PCI or thrombolytics, should not await the availability of results of cardiac biomarkers. The immediate implementation of reperfusion therapy without awaiting biomarker data was given a class I recommendation.31

Table 2 Killip Classification of Acute Myocardial Infarction

Class I

No clinical heart failure

Class II

Findings consistent with mild or moderate heart failure (e.g., isolated S3 gallop, bilateral rales in up to 50% of lung fields)

Class III

Pulmonary edema, rales in all lung fields, acute mitral regurgitation

Class IV

Cardiogenic shock (e.g., stuporous state of consciousness, systolic blood pressure < 90 mm Hg, decreased urine output, pulmonary edema, and cold, clammy skin)


Figure 4. Many studies have revealed lower mortality (a) and reduced infarct size among survivors (b) of myocardial infarction treated most rapidly. The equation shows the linear relation between infarct size and time to treatment.33(APSIM—APSAC dans l'Infarctus du Myocarde; Bassand—Bassand study; MITI—Myocardial Infarction Triage and Intervention; TPAT—Tissue Plasminogen Activator, Toronto trial; WWIC—Western Washington Intracoronary streptokinase trial; WWIV—Western Washington Intravenous streptokinase trial; WWTPA—Western Washington Tissue Plasminogen Activator trial)

The importance of avoiding hospital delay in performing primary coronary angioplasty was evident in the Global Use of Strategies to Open Occluded Arteries (GUSTO-IIb) substudy, which compared primary coronary angioplasty with tissue plasminogen activator (t-PA) therapy.35There was a clear relation between the length of time until angioplasty was performed after enrollment in the study and 30-day mortality [see Figure 5]. Analysis of 27,080 patients in the second National Registry of Myocardial Infarction also revealed a relation between time to treatment with primary PTCA and survival, even after adjusting for other mortality risk factors.36 In that study, the volume of patients treated with angioplasty at the hospital was also a predictor of outcome; a lower mortality was seen at hospitals in which a high number of patients with acute myocardial infarction were treated with coronary angioplasty. There have been studies in which unacceptably high mortality was seen at hospitals when primary angioplasty was not performed rapidly; reducing delay led to a reduction in mortality.37Therefore, as is the case with thrombolytic therapy, the speed with which reperfusion is achieved appears to be an important determinant of clinical outcome. The best reperfusion therapy (coronary angioplasty or thrombolytic therapy) is not necessarily the one that can be most rapidly initiated but, rather, the one that achieves coronary patency most rapidly. In general, the therapy that restores flow most rapidly should be preferred.38,39,40


Figure 5. Relation between the time from study enrollment to the first balloon inflation and 30-day mortality in the GUSTO-IIb substudy. Patients assigned to angioplasty in whom angioplasty was not performed are also shown.35 (PTCA—percutaneous transluminal coronary angioplasty)

Transfer for Primary Angioplasty versus Immediate Thrombolytic Therapy

Time to reperfusion is an important modifiable predictor of clinical outcome for both thrombolysis and primary angioplasty, although it has the greatest impact on patients treated with thrombolytic therapy. An alternative treatment strategy for patients with STEMI initially assessed at a hospital without on-site cardiac surgery facilities is immediate transfer for primary PCI.

The PRAGUE-2 investigators randomized 850 patients with acute STEMI presenting within 12 hours to a hospital without a catheterization laboratory to either immediate thrombolysis or transfer for primary PCI.41 The investigators determined that in the acute phase of STEMI, long-distance transport from a community hospital to a facility with PCI is safe and is associated with decreased mortality in patients presenting more than 3 hours after symptom onset. Similarly, the Danish Trial in Acute Myocardial Infarction (DANAMI)-2 trial investigators concluded that immediate transfer for primary PCI, in preference to immediate thrombolysis, was safe and efficacious.42

However, data from these trials need to be understood within the context of the individual trial designs and their actual conduct. The maximum transport distance in the PRAGUE-2 trial was 120 kilometers, and the time from transport to balloon inflation was only 97 ± 27 minutes. In the DANAMI-2 trial, the time from arrival to initiation of treatment in the thrombolysis arm of the study was 51 minutes, whereas the time required to transfer patients for primary PCI was 155 minutes (P < 0.0001). It is reasonable to assume that the reported benefit associated with this particular treatment strategy in the aforementioned randomized, controlled clinical trials (i.e., PRAGUE-2 and DANAMI-2) can be realized only if similar transfer times and door-to-balloon times are reproduced in clinical practice; the findings of the NRMI 4 investigators are not reassuring in this regard.

Coronary Angiography after Uncomplicated Myocardial Infarction

The role of coronary angiography after uncomplicated myocardial infarction remains controversial for patients who have received thrombolytic therapy. Coronary angiography in patients initially treated with thrombolytic agents has been studied in the second Thrombolysis in Myocardial Infarction (TIMI II) study, the Should We Intervene Following Thrombolysis? (SWIFT) study, the Treatment of Post-thrombolytic Stenoses (TOPS) study, and, most recently, a German study.43,44,45,46 It is clear from these studies that patients treated with thrombolytic therapy in whom complications do not occur are at low risk for reinfarction and death after discharge and that the routine performance of coronary angiography and coronary angioplasty does not reduce the occurrence of these adverse events. Despite the publication of these well-designed studies, there has been considerable reluctance among physicians to accept their results, and there remains considerable variability throughout the United States and the world in the frequency with which coronary angiography is performed in such patients.

Many cardiologists feel more comfortable caring for patients who have suffered a myocardial infarction if the patient's coronary anatomy is known. Patients at low risk may be discharged from the hospital more rapidly. Patients who have left mainstem or multivessel disease, particularly those who have reduced ventricular function, may be referred for coronary artery bypass surgery or percutaneous revascularization. Patients with persistent occlusion of the infarct-related artery may benefit from revascularization because of favorable effects on remodeling, a reduction in ventricular arrhythmia, and the improved ability of the infarct-related artery to provide collateral blood flow to other coronary arteries in the future. Nonetheless, until the benefits of cardiac catheterization are demonstrated in asymptomatic patients after an uncomplicated myocardial infarction, a conservative strategy is recommended in patients who have been given thrombolytic therapy, and coronary angiography is recommended only for patients with hemodynamic instability or for patients in whom spontaneous or exercise-induced ischemia occurs; such a strategy is safe and is associated with a good clinical outcome.

Patients who are not given thrombolytic therapy are at higher risk for reinfarction and death than those receiving thrombolytic therapy. The role of coronary angiography in patients with acute myocardial infarction not receiving thrombolytic therapy has not been studied. In such patients whose infarctions are complicated by hemodynamic compromise or postinfarction chest pain or in patients in whom multivessel disease or reduced ventricular function is believed to be present, coronary angiography is probably helpful. It remains unclear whether coronary angiography should be performed in patients not treated with thrombolytic therapy who do not have these high-risk characteristics. It is impossible to be definitive about recommendations in the absence of appropriate studies, and not surprisingly, practice patterns vary widely throughout the United States and the world in such patients.

Reperfusion Therapy in Patients without ST Segment Elevation

Primary PTCA has not been appropriately studied in patients without ST segment elevation, and it is not possible to be definitive about its use in this setting. However, regardless of the findings on ECG, PTCA is widely believed to be beneficial in patients with ischemic-type chest discomfort that persists despite medical therapy. Many patients with prolonged chest pain without ST segment elevation are not suffering from myocardial infarction; the likelihood that infarction is present is increased if repolarization abnormalities are present on the ECG and the patient has risk factors for coronary artery disease. In patients with critical coronary artery stenoses, immediate PTCA or bypass surgery may be appropriate. In patients without significant coronary artery disease, immediate angiography can also be extremely useful and can lead to the withdrawal of cardiac medications, discharge from the coronary care unit, and appropriate diagnostic evaluation, in many cases as an outpatient. Immediate angiography is recommended in all patients with hypotension, severe congestive heart failure, or cardiogenic shock regardless of the initial ECG results, because immediate revascularization appears to reduce mortality in this setting.47 In addition, there is a compelling case to be made for routine invasive evaluation of all patients who are admitted with unstable angina or non-ST segment elevation myocardial infarction (NSTEMI).48

In the TIMI-IIIb study, an early intervention strategy was compared with a conservative strategy in 3,000 patients with either unstable angina, recent non-Q wave myocardial infarction, or prolonged chest pain without ST segment elevation on ECG.49 Patients were randomized to receive either early angiography or medical therapy; only those patients who subsequently experienced recurrent chest pain or had an exercise test underwent angiography. Although death and myocardial infarction occurred with similar frequency in the two groups, the study showed that the initial hospitalization was longer and the need for rehospitalization more frequent in the group receiving conservative therapy. More recently, in the second Fragmin and Fast Revascularization during Instability in Coronary Artery Disease (FRISC-II) trial, an early invasive strategy was shown to reduce both mortality and myocardial infarction at 1 year.50 In the Treat Angina with Aggrastat [tirofiban] and Determine Cost of Therapy with Invasive or Conservative Strategy—Thrombolysis in Myocardial Infarction-18 (TACTICS-TIMI-18) study, an early invasive strategy was found to reduce the combined end point of death or myocardial infarction.51 In both the FRISC-II and TACTICS-TIMI-18 studies, patients at greatest risk, such as those with positive troponin values and with ST segment depression at study entry, had the highest event rates and derived the greatest benefit from an invasive strategy.

The 2002 ACC/AHA unstable angina guideline update has summarized the data regarding early invasive versus early conservative strategies in patients with unstable angina or NSTEMI and issued an updated set of recommendations to guide clinical decision making in this setting [see Table 3].52

Table 3 Class I Recommendations for the Use of an Invasive Strategy in the Management of Patients with Unstable Angina or Non-ST Segment Elevation Myocardial Infarction

An early invasive strategy is recommended for patients who have unstable angina or non-ST segment elevation myocardial infarction (NSTEMI) without serious comorbidity and who have any of the following high-risk indicators (level of evidence: A):
 Recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemic therapy
 Elevated levels of troponin T or troponin I
 New or presumably new ST segment depression
 Recurrent angina/ischemia with symptoms of congestive heart failure, an S3 gallop, pulmonary edema, worsening rales, or new or worsening mitral regurgitation
 High-risk findings on noninvasive stress testing
 Depressed left ventricular systolic function (e.g., ejection fraction < 0.40 on noninvasive study)
 Hemodynamic instability
 Sustained ventricular tachycardia
 Percutaneous coronary intervention within 6 mo
 Prior coronary artery bypass grafting
In the absence of any of these findings, an early conservative strategy or an early invasive strategy may be offered in hospitalized patients without contraindications for revascularization (level of evidence: B)

Note: Class I recommendations pertain to conditions for which there is evidence or general agreement that a given procedure is useful and effective. Level A evidence (highest)—Derived from multiple randomized clinical trials. Level B evidence (intermediate)—Derived from limited number of randomized clinical trials, nonrandomized studies, or observational registries.

Thrombolytic Therapy

Thrombolytic therapy has been widely studied in prospective, randomized, controlled trials involving more than 50,000 patients and has been proved to reduce mortality 29% in patients with ST segment elevation treated within 6 hours after the onset of chest pain [see Figure 6].53 The survival benefit of thrombolytic therapy is maintained for years.54 The benefit of thrombolytic therapy is achieved through rapid restoration of blood flow in an occluded coronary artery.55,56,57


Figure 6. Data from five controlled megatrials of thrombolytic therapy large enough to detect a mortality difference between the thrombolytic and nonthrombolytic control arms of the trials. Pooled data from these five trials (not shown) reveal a 29% mortality reduction in patients treated within 6 hours of symptom onset.53 (AIMS—APSAC International Mortality Study; ASSET—Anglo-Scandinavian Study of Early Thrombosis; GISSIµgruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico; GISSI-2µgruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Myocardico; ISAM—Intravenous Streptokinase in Acute Myocardial Infarction; NS—not significant)

Thrombolytic therapy is strongly recommended for patients with ST segment elevation in two or more contiguous leads who have had less than 6 hours of chest pain; for patients with classic symptoms of infarction in whom a bundle branch block precludes detection of ST segment elevation53; and for patients presenting with 6 to 12 hours of chest pain, although the expected benefits for this last group of patients are fewer. The potential benefits should be weighed against the potential risks in patients with relative contraindications to thrombolytic therapy (see below).17,58 It is important to calculate the duration of infarction as the time from the last pain-free interval. The infarct-related artery often opens and closes spontaneously during the early stages of infarction, which the patient may experience as alternating pain-free and painful intervals; the window of benefit from thrombolytic therapy may be greater than 12 hours if antegrade flow was even briefly restored.

Contraindications to Thrombolytic Therapy

Contraindications to thrombolytic therapy include all conditions that predispose a patient to significant bleeding. The most feared bleeding complication is intracerebral hemorrhage, which is fatal in over half of cases. Risk factors for intracerebral bleeding include advanced age, low body weight, hypertension, warfarin use, and previous stroke.53,59 Patients with gastrointestinal bleeding and those who have recently undergone surgery are also at increased risk for bleeding. Even when risk factors for bleeding are present, however, the potential benefits of thrombolytic therapy may still outweigh the risks. For example, although the elderly have a higher risk of intracerebral bleeding than younger patients, elderly patients should certainly be considered candidates for thrombolytic therapy, because their increasing absolute mortality results in a greater reduction in absolute mortality with thrombolytic therapy than is seen in younger patients.53

In patients with ECG findings other than ST segment elevation or bundle branch block, thrombolytic therapy has been found to be either of no use or deleterious; its use is not recommended in such patients.17,53

Choice of Thrombolytic Agent

Many different thrombolytic regimens have been proved effective for the treatment of acute myocardial infarction, and many more are being studied. In principle, the preferred thrombolytic regimen would restore normal antegrade blood flow to an occluded coronary artery most rapidly and in the greatest number of patients, would have the lowest reocclusion rate, and would be associated with the lowest risk of severe hemorrhagic complications. The first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO-I) trial evaluated four thrombolytic regimens to determine which was associated with the greatest overall survival and stroke-free survival at 30 days: (1) a regimen of front-loaded, weight-adjusted t-PA and I.V. heparin, (2) a regimen of streptokinase and I.V. heparin, (3) a regimen of streptokinase and subcutaneous heparin, and (4) a combination of I.V. t-PA and streptokinase given concurrently with I.V. heparin. Front-loaded t-PA was found to be moderately superior to the other thrombolytic regimens [see Figure 7].56 However, because of the approximately 10 times greater cost of t-PA than I.V. streptokinase and the low margin of superiority of t-PA (one life saved per thousand patients treated), some physicians prefer the less expensive streptokinase therapy, particularly for patients at low risk of dying (such as those with uncomplicated inferior infarctions) and the elderly, who are more likely to have hemorrhagic complications with t-PA than with streptokinase; t-PA is associated with a greater frequency of intracerebral hemorrhage than streptokinase.56 The recommendation of streptokinase in these patient groups is largely driven by its lower cost; if the costs of t-PA and streptokinase were similar, t-PA would most likely be the preferred therapy in all patient subgroups, with the possible exception of those at increased risk for intracerebral hemorrhage, in whom streptokinase might be preferred.


Figure 7. The frequency of death or disabling stroke in the 30 days after enrollment in 41,021 patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO-I) trial. Front-loaded t-PA was found to be superior to the other thrombolytic regimens.56

Streptokinase therapy is contraindicated in patients who have recently received a dose of streptokinase because of antibodies that form against the drug; these antibodies limit the efficacy of repeat doses and increase the risk of allergic reactions. It has been suggested that the drug not be readministered for at least 2 years.

New thrombolytic agents are continuously being developed in the hope of finding safer and more effective therapies. One such agent, reteplase, is a recombinant tissue plasminogen activator (rt-PA) that is a mutant of alteplase. Reteplase is easier to administer than alteplase; because of its longer half-life, it can be administered as two 10 mU boluses given 30 minutes apart, with concomitant aspirin and I.V. heparin administration. Several pilot studies suggest that reteplase has an early patency rate that is superior to the patency rates of streptokinase and alteplase. In the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial, 6,010 patients with acute myocardial infarction received either reteplase or streptokinase within 12 hours after the onset of symptoms.60 Mortality at 35 days, the primary end point of the study, was 9.02% for patients given reteplase, compared with 9.53% for patients given streptokinase, a nonsignificant difference (95% confidence interval, 1.98 to 0.96). This lack of significant difference indicates that reteplase was at least as effective as streptokinase.

In the GUSTO-III trial, reteplase was compared with t-PA in 15,059 patients with acute myocardial infarction who presented within 6 hours of symptom onset.61 Patients received either reteplase or an accelerated infusion of t-PA. For patients receiving reteplase, the mortality at 30 days was 7.47%, compared with 7.24% for patients receiving t-PA (P = 0.54; odds ratio, 1.03; 95% confidence interval, 0.91 to 1.18). The mortality rates with the two agents were therefore similar, and the two agents are probably, although not definitely, equivalent in efficacy.

Combination Therapy

Combination therapy, defined as the use of a thrombolytic agent and a glycoprotein IIb/IIIa inhibitor, has been proposed as an alternative to thrombolytic therapy alone for the primary treatment of STEMI. This strategy is supported by data from a number of trials that demonstrated improved rates of TIMI-3 flow after combination therapy, as compared with thrombolytic therapy alone.62,63 However, the results of two randomized, controlled trials evaluating clinical outcomes after the respective aforementioned reperfusion strategies have been somewhat disappointing.

The GUSTO-V trial randomized 16,588 patients who presented within 6 hours after symptom onset with STEMI to either standard-dose reteplase or half-dose reteplase and full-dose abciximab.64 At 30 days, the incidence of death in the reteplase arm was 5.9%, compared with 5.6% in the combination-therapy arm (P = 0.43), suggesting no mortality benefit associated with combination therapy. However, five of 16 prespecified secondary end points were reduced to a statistically significant degree (P < 0.05), suggesting a beneficial impact of combination therapy on the incidence of recurrent ischemic events and the mechanical and electrical complications of acute myocardial infarction (e.g., nonfatal reinfarction, recurrent ischemia, ventricular fibrillation, sustained ventricular tachycardia, and atrioventricular block). However, these clinical benefits were offset by an increased incidence of bleeding of any kind (13.7% with monotherapy versus 24.6% with combination therapy; P < 0.0001); severe or moderate, spontaneous, nonintracranial bleeding (1.9% versus 4.3%, P < 0.0001); severe bleeding (0.5% versus 1.1%; P < 0.0001), and bleeding sufficient to require blood transfusion (4.0% versus 5.7%; P < 0.0001). Furthermore, there were subgroups of patients in whom intracranial bleeding was increased by combination therapy; there was a significant (P = 0.033) association between age (< 75 or ≥ 75 years) and intracranial hemorrhage in the combination-therapy arm.

The Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-3 trial randomized 6,095 patients to one of three treatment regimens: full-dose tenecteplase and enoxaparin, half-dose tenecteplase and weight-adjusted low-dose unfractionated heparin infusion plus 12-hour infusion of abciximab, or full-dose tenecteplase and weight-adjusted unfractionated heparin infusion for 48 hours.65 In-hospital mortality was not significantly different between the three groups. The abciximab treatment regimen reduced in-hospital rates of reinfarction and refractory ischemia. Although rates of intracranial hemorrhage were similar, other types of major bleeding were significantly higher in the abciximab arm of the trial. The enoxaparin arm suggested that there is a higher rate of intracranial bleeding in the elderly; this finding was corroborated by the ASSENT-PLUS study, which necessitated a change in dose of enoxaparin when administered with a thrombolytic agent in elderly patients.66

Primary Coronary Angioplasty

In prospective, randomized trials comparing primary coronary angioplasty [see Figures 8a and 8b] with different thrombolytic agents, primary coronary angioplasty was associated with a lower morbidity and mortality than thrombolytic therapy.67,68,69,70,71 Although most of the individual trials were too small to detect statistically significant differences in mortality, pooled data from these trials suggest that primary coronary angioplasty is the preferred therapy for acute myocardial infarction at institutions where it can be performed without delay [see Figure 9].72


Figure 8. (a) Left anterior oblique view of an occluded left anterior descending artery in a patient suffering an acute anterior myocardial infarction. (b) Patency was restored with direct coronary angioplasty 17 minutes after the patient had arrived in the catheterization laboratory, and the patient had immediate resolution of his symptoms.


Figure 9. Results from a quantitative review of 23 randomized trials of primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction.72 Clinical outcome was improved in patients who received angioplasty.

The GUSTO-IIb trial was designed to be large enough to confirm the reduction in mortality found in the smaller randomized trials.73 The results of the study indicate that compared with thrombolytic therapy, primary coronary angioplasty is associated with a lower mortality, reinfarction rate, and frequency of stroke in the 30 days after enrollment [see Figure 10]. However, the degree of benefit associated with primary coronary angioplasty was much smaller than that seen in the earlier randomized studies; this finding was in part related to the lower frequency with which patients assigned to undergo angioplasty in GUSTO-IIb actually underwent the procedure and in part related to the lower frequency with which normal antegrade coronary blood flow was achieved in patients who did undergo coronary angioplasty.


Figure 10. Results from the GUSTO-IIb substudy trial comparing primary coronary angioplasty and accelerated t-PA indicate that primary angioplasty was associated with a lower mortality, reinfarction rate, and frequency of stroke in the 30 days after enrollment than was accelerated t-PA.73 (NS—not significant)

The consistency of the results favoring primary coronary angioplasty and the greater speed and frequency with which coronary angioplasty can restore flow to an occluded coronary artery support the conclusion that primary coronary angioplasty is preferable to thrombolytic therapy at institutions where it can be performed quickly with a high success rate.74 Studies have shown that excessive delay in performing primary coronary angioplasty and operator inexperience lead to a higher mortality than that seen when primary coronary angioplasty is performed rapidly by experienced operators.36 It has been recommended that primary angioplasty be performed only in hospitals where a high success rate and low complication rate can be demonstrated and where primary angioplasty is performed in at least 80% to 90% of patients in whom acute myocardial infarction is confirmed.72,75 The need for surgical backup is controversial, as excellent results have been obtained at centers without surgical backup.76 However, surgical backup is recommended because approximately 5% of patients with acute myocardial infarction who undergo immediate coronary angiography require emergency surgery either for angioplasty that has failed or, more commonly, because lethal coronary anatomy precludes primary angioplasty.

Immediate transfer for primary angioplasty is an alternative treatment strategy for patients with STEMI initially assessed at a hospital without on-site cardiac surgery facilities.

Antiplatelet Therapy

Aspirin and clopidogrel therapy

Aspirin should be given to patients with suspected STEMI as early as possible and continued indefinitely. True aspirin allergy is the only exception to this recommendation.31 The 2004 ACC/AHA guidelines gave a class I recommendation to the use of clopidogrel in all patients treated with primary PCI.31 Clopidogrel may be given in a loading dose of 300 mg or 600 mg; limited trial data suggest that 600 mg works within 2 to 3 hours and that outcomes may be better than with 300 mg. There are no data available regarding the combination of fibrinolytic agents and clopidogrel, but ongoing trials will provide this information. However, clopidogrel is probably indicated in patients receiving fibrinolytic therapy who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance.

Glycoprotein IIb/IIIa inhibitor therapy

The 2004 ACC/AHA guidelines gave a class IIa recommendation to treatment with abciximab as early as possible prior to PCI (with or without implantation of stents) in patients with STEMI.31 This recommendation was based on several studies including the Randomized, Placebo-Controlled Trial of Abciximab with Primary Angioplasty for Acute Myocardial Infarction (RAPPORT), the Intracoronary Stenting and Antithrombotic Regimen-2 (ISAR-2) study, the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL) study, and, most recently, the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) study.77,78,79,80 The results of the four studies differ, in part because the trials used different end points, in part because of the high frequency of noncompliance with the protocol in some trials, and in part because of differences in the treatments utilized (balloon angioplasty alone versus balloon angioplasty followed by stent placement).

The largest of the four studies, the CADILLAC study, found that abciximab is beneficial at reducing major adverse events, but the benefit appeared to be limited to patients undergoing balloon angioplasty without stent placement. The apparent lack of benefit following treatment with abciximab in patients in the CADILLAC trial who received a coronary stent is contrary to the results of the ISAR-2 and ADMIRAL trials, in which abciximab was found to be beneficial in patients receiving stents. There are data suggesting that stent placement in the setting of acute myocardial infarction slightly reduces the frequency with which normal antegrade blood flow in the infarct-related artery is achieved.81This would suggest that glycoprotein IIb/IIIa inhibitors should be beneficial in this setting. Taken together, the results of these studies that are currently available suggest that abciximab is beneficial in patients with acute myocardial infarction but that the benefit in patients undergoing balloon angioplasty alone may differ from that in patients who undergo balloon angioplasty with stent placement. Clearly, however, stents markedly reduce the frequency with which a repeat revascularization procedure is needed in the months after the angioplasty procedure.81 The combined use of stents and platelet glycoprotein inhibitors may maximize the frequency with which normal antegrade blood flow is achieved while reducing the need for repeat procedures in the following year.

One study compared the outcome of thrombolytic therapy using t-PA with that of primary angioplasty utilizing both stents and abciximab.82The reduction in infarct size was far greater in the group undergoing primary angioplasty; the clinical outcome was also better in the patients who underwent angioplasty.

Coronary Artery Bypass Surgery

Coronary artery bypass surgery can restore blood flow in an occluded infarct-related artery. However, because of the time required to perform coronary angiography and to transport patients to the operating room, reperfusion is achieved more slowly with bypass surgery than with thrombolytic therapy and primary coronary angioplasty.83 Emergency coronary artery bypass surgery should generally be reserved for patients in whom immediate angiography reveals coronary anatomy that precludes primary coronary angioplasty; for patients in whom angioplasty has failed; and for patients with a ventricular septal defect, severe mitral regurgitation, or myocardial rupture.

Rescue Coronary Angioplasty

Depending on the regimen used, only 33% to 60% of patients treated with thrombolytic therapy have restoration of normal antegrade flow in the infarct-related artery 90 minutes after the initiation of therapy.55 Accordingly, immediate coronary angiography has been studied to determine whether patients with persistent occlusion of the infarct-related artery benefit from coronary angioplasty; this procedure has been termed rescue angioplasty. A single small, randomized trial has examined the clinical outcome of patients with anterior infarction and coronary occlusion that persist despite thrombolytic therapy.84 Patients were randomized to either undergo rescue coronary angioplasty or receive continued medical therapy alone. The results of the trial suggested improved outcome with rescue angioplasty, although the benefits were not compelling. Three additional randomized trials evaluated the role of rescue angioplasty.85,86,87 Analyzed together, the four trials suggest that rescue angioplasty offers benefit, although the data are not compelling. Although use of coronary stents and platelet glycoprotein inhibitors improves the results of percutaneous revascularization procedures and would be expected to further increase the benefit of angioplasty after failed thrombolytic therapy, this has not yet been proved. There are insufficient data to recommend immediate angiography and angioplasty in all patients early after thrombolytic therapy. Immediate angiography is most likely to be beneficial in patients with large myocardial infarctions in whom persistent pain, ST segment elevation, or hemodynamic compromise is present more than 90 minutes after the administration of a thrombolytic agent.

The routine performance of angioplasty immediately after the administration of thrombolytic therapy in all patients with a significant residual stenosis (not just those patients with occluded coronary arteries) has been well studied in three prospective, randomized trials and has been found to be either of no benefit or deleterious.43,88 Angioplasty should not be routinely performed in such patients.

Stents appear to improve the ability to achieve arterial patency early after thrombolytic therapy, as compared with balloon angioplasty alone89; therapy with a glycoprotein IIb/IIIa inhibitor may also do so, although an increase in bleeding has been seen when glycoprotein IIb/IIIa inhibitors are used early after full-dose thrombolytic therapy.90 Data from several pilot studies suggest that the combination of a fibrin-specific thrombolytic agent, either t-PA or reteplase, combined with the glycoprotein IIb/IIIa inhibitor abciximab, may actually facilitate the performance of angioplasty rather than reduce its safety and efficacy, as was seen when balloon angioplasty was performed after thrombolytic therapy.62,63 Hence, the term facilitated angioplasty has been coined for the routine performance of angioplasty after the combination of half-dose thrombolytic therapy with a glycoprotein IIb/IIIa inhibitor.

The Plasminogen-activator Angioplasty Compatibility Trial (PACT) investigators randomized 606 patients to a reduced dose of a short-acting fibrinolytic regimen (50 mg bolus of reteplase) or a placebo followed by immediate angiography with angioplasty, if needed.91 In the group receiving reduced-dose reteplase, there was no increase in the incidence of stroke or major bleeding, and convalescent left-ventricular ejection fraction was higher, as evidenced by a patent infarct-related artery (TIMI-3 flow) on arrival in the catheterization laboratory (62%) or a TIMI-3 flow that was achieved by angioplasty within 1 hour after administration of the drug bolus (58%). However, only 12% of successful angioplasty procedures resulted in a patent infarct-related artery within 1 hour, because of routine delay in transfer to the catheterization laboratory, and there was no difference between the two treatment groups by a traditional intention-to-treat analysis.

The Southwest German Study in Acute Myocardial Infarction III (SIAM III) investigators randomized 163 patients initially treated with thrombolysis at a community hospital with no on-site PCI facilities either to hospital transfer and immediate stenting within 6 hours of thrombolysis or to delayed, elective stenting approximately 2 weeks after acute myocardial infarction.92 Transfer and immediate stenting were associated with a statistically significant reduction in the incidence of the composite primary end point (i.e., death, reinfarction, ischemic events, and target-lesion revascularization at 6 months), as compared with delayed stenting (25.6% versus 50.6%; P = 0.001). The difference in outcome was driven by events occurring during the 2 weeks that patients waited for elective stenting in the deferred PCI group. This trial design does not address whether PCI performed 1 to 2 days after thrombolytic therapy, as is usual in the United States, is as effective as PCI performed immediately after thrombolytic therapy. A randomized trial that analyzed the use of combination therapy (half-dose thrombolytic therapy with full-dose abciximab) before routinely performing primary PCI was reported.93 In the Bavarian Reperfusion Alternatives Evaluation (BRAVE) Trial, patients with STEMI were randomly assigned to receive either half-dose reteplase and full-dose abciximab or abciximab alone, and all patients underwent PCI as rapidly as possible. No advantage was seen with combination therapy; in fact, more bleeding complications occurred in this group. The results argue against the use of a facilitated PCI approach using the combination regimen of reteplase and abciximab.

Adjunctive Medical Therapy

Intravenous Heparin

The need for I.V. heparin after thrombolytic therapy varies with the thrombolytic agents used. A retrospective analysis of the GUSTO-I trial suggested that I.V. heparin with a partial thromboplastin time of 50 to 70 seconds was associated with the best clinical outcome in patients treated with t-PA.94 Data from GUSTO-I also suggest that I.V. heparin is not required when I.V. streptokinase is used, although heparin is recommended in patients with large anterior infarctions to prevent the development of apical mural thrombus and embolization.56 In patients in whom I.V. heparin is not administered, subcutaneous heparin should be administered during the period of bed rest to reduce the risk of deep vein thrombosis.95

The optimal duration of I.V. heparin therapy is unclear. Standard practice was to administer I.V. heparin for 3 to 5 days, although patients are now often discharged after only 3 days. It is recommended that heparin be discontinued more than 24 hours before patient discharge from the hospital because of the possibility of a rebound effect and recurrent thrombosis within 24 hours after cessation of heparin therapy.96

Randomized studies from the prethrombolytic era suggested that administration of I.V. heparin reduces mortality and reinfarction in patients not treated with thrombolytic agents.95 Aspirin and beta blockers were not routinely administered in those early trials; consequently, the true benefits of heparin when these drugs are administered are unknown. However, on the basis of the early data, I.V. heparin is generally recommended for patients with suspected myocardial infarction who are not treated with thrombolytic therapy.75

Low-Molecular-Weight Heparin

Low-molecular-weight heparins (depolymerized unfractionated heparin with a mean molecular weight of approximately 5,000) have a number of potential pharmacokinetic advantages over the parent molecule, including decreased binding to plasma proteins, decreased sensitivity to platelet factor 4, enhanced factor Xa activity, and improved bioavailability. These factors are associated with a predictable dose-response relationship and, combined with the ease of administration (once or twice daily S.C. dosing regimens) and lower rates of heparin-induced thrombocytopenia, have increased investigators? interest in low-molecular-weight heparins in preference to unfractionated heparin for the treatment of myocardial infarction. The results of four large randomized trials comparing three different low-molecular-weight heparins with unfractionated heparin have suggested that low-molecular-weight heparin is at least as effective in reducing ischemic events in patients with NSTEMI acute coronary syndromes. Following patients with STEMI, the second trial of Heparin and Aspirin Reperfusion Therapy (HART II) and the Acute Myocardial Infarction-Streptokinase (AMI-SK) trial demonstrated evidence of improved rates of reperfusion when the low-molecular-weight heparin enoxaparin was combined with t-PA or streptokinase, respectively.97,98 The ASSENT-3 trial compared three regimens: full-dose tenecteplase and enoxaparin, full-dose tenecteplase and unfractionated heparin, and half-dose tenecteplase and abciximab for the treatment of thrombolytic-eligible STEMI; the study revealed that enoxaparin fared better than unfractionated heparin in terms of 30-day mortality, in-hospital reinfarction, and in-hospital refractory ischemia (P = 0.0001) at 30 days.99 However, at 1 year, the benefits had diminished, and the mortality with enoxaparin was identical to that with unfractionated heparin. In addition, when the data from ASSENT-3 and ASSENT-3-PLUS (a study examining the administration of tenecteplase with enoxaparin in the prehospital setting) were pooled, a marked and prohibitive increase in the risk of intracerebral hemorrhage was seen in the elderly.66,99 As a result, ongoing trials utilizing enoxaparin with a fibrinolytic agent have adjusted the dose of enoxaparin downward in elderly patients. At present, the adjunctive anticoagulant that should be administered with fibrinolytic therapy and its optimal dose are not known.

Direct Thrombin Inhibitors

Direct thrombin inhibitors are an attractive alternative to indirect thrombin inhibitors, such as heparin or low-molecular-weight heparins, particularly because they block both circulating and clot-bound thrombin. A collaborative meta-analysis of phase-3 trials of direct thrombin inhibitors for the treatment of acute coronary artery syndromes demonstrated superiority over unfractionated heparin for the prevention of the composite end point of death or myocardial infarction.100 The Hirulog and Early Reperfusion or Occlusion (HERO)-2 trial demonstrated a similar benefit in a comparison of bivalirudin with heparin in patients with STEMI.101 Bivalirudin was associated with a 30% reduction in the incidence of reinfarction, but mortality did not decrease; however, the bivalirudin arm of the study exhibited a trend toward more bleeding events.

Beta Blockers

The 2004 ACC/AHA guidelines recommended that oral beta blockers be administered to all STEMI patients for whom treatment is not contraindicated, irrespective of whether they are undergoing fibrinolytic therapy or primary PCI.31 Early administration of beta blockers is recommended because it may reduce infarct size by reducing heart rate, blood pressure, and myocardial contractility, all of which diminish myocardial oxygen demand. Meta-analysis of the effects of early administration of I.V. beta blockers in 27,486 patients with acute myocardial infarction enrolled in 28 randomized trials revealed a 14% reduction in mortality during the first week of therapy; reinfarction was reduced by 18%.102

The TIMI-II study compared immediate beta-blocker therapy with deferred beta-blocker therapy in acute myocardial infarction; all patients also received I.V. t-PA.103 Results indicated that immediate beta-blocker therapy reduced the incidence of nonfatal reinfarction and recurrent ischemia, compared with oral metoprolol therapy begun on the sixth hospital day; as in earlier studies, only about 40% of patients with acute myocardial infarction were eligible for acute beta-blocker therapy.43 There are also data suggesting that immediate beta-blocker therapy reduces the risk of intracranial hemorrhage after lytic therapy.104

In patients in whom contraindications preclude early beta-blocker therapy, reevaluation should take place before discharge. Many patients will no longer have contraindications at the time of discharge. Patients without contraindications should be routinely started on beta-blocker therapy before discharge from the hospital. The optimal duration of benefit remains unclear, but it appears that the benefit of beta-blocker therapy is maintained for years. Patients with the largest infarctions benefit the most from the use of beta blockers. Current recommendations are that beta-blocker therapy be continued indefinitely in the absence of contraindications or side effects.

Angiotensin-Converting Enzyme Inhibitors

Several large randomized, controlled clinical trials evaluating the use of angiotensin-converting enzyme (ACE) inhibitors early after acute myocardial infarction have been performed; all but one trial revealed a significant reduction in mortality. Meta-analysis of these large trials and many smaller trials, which together included over 100,000 patients, suggested a 6.5% reduction in deaths, with an absolute reduction in mortality of 4.6 deaths per 1,000 patients among those treated with an ACE inhibitor.105 All patients with significant ventricular dysfunction (an ejection fraction < 40%) without contraindications should be treated with an ACE inhibitor; treatment should begin within the first 48 hours of infarction and be increased cautiously to avoid hypotension. If hypotension results from the early administration of ACE inhibitors, short-term mortality may be increased.106

The benefit of ACE inhibitors is clear in patients with large anterior infarctions and an ejection fraction less than 40%; whether patients with an ejection fraction greater than 40% benefit from ACE inhibitor therapy is less clear. However, the results of two large trials suggest that patients with a normal ejection fraction after myocardial infarction, as well as even patients with coronary artery disease without a previous myocardial infarction, have a reduction in mortality when treated with an ACE inhibitor. In the Heart Outcomes Prevention Evaluation (HOPE) study, 9,297 patients 55 years of age or older with vascular disease (or with diabetes and another cardiovascular risk factor) without a low ejection fraction or congestive heart failure were randomly assigned to receive either the ACE inhibitor ramipril or placebo for a mean of 5 years.107 The reduction in the combined end point of death from cardiovascular causes, myocardial infarction, or stroke with ramipril was remarkable; it occurred in 17.7% of placebo-treated patients versus 14.1% of patients receiving ramipril (relative risk, 0.78; 95% confidence interval, 0.70 to 0.86; P < 0.001). A statistically significant reduction was also present in the individual end points of cardiovascular death, myocardial infarction, and stroke. The study was stopped prematurely by the Data Safety Monitoring Board when clear evidence of a beneficial effect of ramipril was found. These findings are supported by the results of the European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease (EUROPA) trial, which randomized 12,218 patients with stable coronary artery disease and no evidence of congestive heart failure to 8 mg of perindopril or conventional therapy.108 Treatment with perindopril was associated with a highly statistically significant reduction in the incidence of fatal and nonfatal myocardial infarction at 4 years. Whether these favorable results are unique to tissue-specific ACE inhibitors or represent a class effect is unknown.

Intravenous Nitroglycerin

Randomized studies examining the role of I.V. nitroglycerin in acute myocardial infarction revealed beneficial effects on left ventricular function and a reduction in infarct size and mortality.109 However, these studies were small and were performed before the reperfusion era. To determine whether nitroglycerin therapy is beneficial in patients treated with reperfusion, 58,050 patients with acute myocardial infarction in the fourth International Study of Infarct Survival (ISIS-4) were randomized to receive either oral controlled-release mononitrate therapy or placebo; thrombolytic therapy was administered to patients in both groups.105 The results of this study revealed no benefit to the routine administration of oral nitrate therapy in this setting. Similar results were seen among 19,000 patients in the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) study, in whom I.V. nitroglycerin was administered for the first 24 hours, followed by transdermal nitrates.110 Whether these disappointing results in the ISIS-4 and GISSI-3 trials were caused by the routes of administration of the nitroglycerin preparation or the administration of thrombolytic therapy is unknown. However, on the basis of existing data, it does not appear that the routine administration of nitroglycerin to patients receiving early thrombolytic therapy is beneficial. I.V. nitroglycerin is probably most likely to be beneficial in patients with persistent or recurrent chest pain after reperfusion therapy and in patients in whom reperfusion therapy is not administered.

Prophylactic Antiarrhythmic Therapy

Previously, routine prophylactic antiarrhythmic therapy with I.V. lidocaine was recommended for all patients in the early stages of acute myocardial infarction. However, studies have revealed that prophylactic therapy with lidocaine does not reduce and may actually increase mortality because of an increase in the occurrence of fatal bradyarrhythmia and asystole.111 Neither I.V. lidocaine nor other antiarrhythmic agents are recommended as prophylactic therapy for patients without malignant ventricular ectopy.111,112

Statin Therapy

Statin therapy in the early management of acute myocardial infarction is under investigation; current evidence indicates such therapy may be beneficial. A study of more than 300,000 patients in the National Registry of Myocardial Infarction found that statin use within the first 24 hours of admission for acute myocardial infarction was associated with a significantly lower rate of early complications and in-hospital mortality.113 Statin therapy in the follow-up management of acute myocardial infarction is recommended.31,114,115 The 2004 ACC/AHA gave a class I recommendation to the initiation of statin therapy prior to hospital discharge in all STEMI patients [see Secondary Prevention,below].31,114,115

Calcium Channel Antagonists

Calcium channel antagonists should not be routinely administered for acute myocardial infarction. Calcium channel antagonists have been studied in prospective, double-blind, placebo-controlled trials; and neither verapamil,116,117 nifedipine,118,119 nor diltiazem120 appears to reduce postinfarction mortality. Verapamil and diltiazem may be useful in patients with preserved left ventricular function and no heart failure in whom contraindications to beta blockers exist.121,122 However, the data are insufficient to recommend the routine administration of these agents. On the basis of existing data, treatment with calcium channel blockers should be reserved for patients with ischemia that persists despite use of aspirin, beta blockers, nitrate therapy, and I.V. heparin and for patients with other indications for their administration.


Magnesium has been studied in many prospective, randomized trials of acute myocardial infarction, and the results have been conflicting. Magnesium is involved in hundreds of enzymatic steps and produces systemic and coronary vasodilatation, inhibits platelet function, and reduces reperfusion injury. Meta-analysis of seven prospective, randomized trials revealed a significant reduction in mortality with the use of magnesium (odds ratio, 0.44; confidence interval, 0.27 to 0.71).123 In ISIS-4, in which 58,050 patients were randomized to receive either I.V. magnesium or no magnesium, there was no reduction in 30-day mortality.105 It is possible that the later administration of magnesium in this study, compared with the previous studies, and the concomitant use of thrombolytic therapy in 70% of patients contributed to the lack of efficacy of magnesium in ISIS-4; only one third of patients in the LIMIT-2 study received thrombolytic therapy. Therefore, on the basis of the existing evidence, current recommendations are that magnesium not be routinely given to patients in whom reperfusion therapy is administered. It is possible that magnesium is of benefit, particularly in patients not receiving reperfusion therapy. Magnesium is clearly indicated in patients with myocardial infarction who have torsade de pointes-type ventricular tachycardia and in patients with magnesium deficiency.

Complications of Acute Myocardial Infarction

Ventricular Arrhythmias

Ventricular arrhythmias are a frequent cause of death in the earliest stages of acute myocardial infarction. The development of coronary care units, continuous ECG surveillance, and defibrillators in the 1960s led to a reduction in mortality from acute myocardial infarction through the prompt identification and treatment of ventricular arrhythmia; and emergency medical technicians have reduced outpatient mortality in the earliest minutes of myocardial infarction. In cities with well-developed emergency response systems, such as Seattle, Washington, and Rochester, Minnesota, where the average response time is less than 5 minutes, survival of patients with myocardial infarction complicated by cardiac arrest has increased.4 In fact, long-term survival of patients who have undergone rapid defibrillation after out-of-hospital cardiac arrest is similar to that of age-, sex-, and disease-matched patients who did not have out-of-hospital cardiac arrest; the quality of life of the majority of survivors is similar to that of the general population.124

Ventricular Fibrillation

In the setting of acute myocardial infarction, ventricular fibrillation is often described as either primary, when it occurs in the absence of hypotension or heart failure, or secondary, when hypotension or heart failure is present. Primary ventricular fibrillation occurs in approximately 3% to 5% of patients with acute myocardial infarction; the peak incidence is in the first 4 hours of infarction. Primary ventricular fibrillation is infrequent more than 24 hours after symptom onset. Mortality is increased in patients who suffer this complication.125,126 In patients who are successfully resuscitated and survive to hospital discharge, however, the long-term prognosis does not appear to be affected.125 Although lidocaine was shown to reduce the occurrence of primary ventricular fibrillation, mortality in patients receiving lidocaine increased because of an increase in fatal bradycardia and asystole; therefore, prophylactic lidocaine is no longer recommended if defibrillation can rapidly be performed.111 Beta blockers may reduce the early occurrence of ventricular fibrillation and should be administered to patients who have no contraindications.

Hypokalemia is a risk factor for primary ventricular fibrillation and should be rapidly corrected if present. When ventricular fibrillation occurs, rapid defibrillation with 200 to 300 joules should be attempted, and repeated shocks of 360 joules should be administered. The Advanced Cardiac Life Support (ACLS) guidelines recommend medical therapy, including epinephrine, lidocaine, and bretylium; in addition, I.V. amiodarone should be considered in patients in whom defibrillation is initially unsuccessful.

Secondary ventricular fibrillation is associated with a high mortality, in part because of the underlying hypotension and heart failure. Treatment must be aimed not only at terminating the arrhythmia but also at treating the hemodynamic abnormalities and their causes.

Ventricular Tachycardia

Ventricular tachycardia (three or more consecutive ventricular ectopic beats) is common in patients with acute myocardial infarction; however, short runs of nonsustained ventricular tachycardia are no longer believed to predispose a patient to sustained ventricular tachycardia or ventricular fibrillation. In patients in whom sustained or hemodynamically significant ventricular tachycardia occurs, prompt electrical cardioversion should be performed. If the ventricular tachycardia is monomorphic, synchronic cardioversion with 100 joules should first be attempted. As with ventricular fibrillation, polymorphic ventricular tachycardia should be treated with unsynchronized discharge. Prolonged runs of asymptomatic ventricular tachycardia can be initially treated with I.V. lidocaine, procainamide, or amiodarone. These medications may also be helpful in reducing recurrent ventricular tachycardia.

Atrial Arrhythmia

Atrial Fibrillation

Atrial fibrillation is the most common atrial arrhythmia in acute myocardial infarction, occurring in 10% to 16% of patients. Atrial fibrillation may result either from an acute increase in left atrial pressure caused by left ventricular dysfunction or from atrial ischemia as a result of occlusion of a coronary artery (usually the right coronary artery) proximal to the origin of atrial branches. The incidence of atrial fibrillation is decreased in patients given thrombolytic therapy.56

The treatment of atrial fibrillation in acute myocardial infarction should be similar to the treatment of atrial fibrillation in other settings. When there is hemodynamic compromise caused by loss of atrial systole or a rapid ventricular response with a reduction in cardiac output, cardioversion should be performed immediately. In patients with preserved left ventricular function in whom the atrial fibrillation is well tolerated, beta-blocker therapy is indicated. Verapamil and diltiazem may also be effective in such patients. In patients with congestive heart failure, digoxin is a reasonable alternative and may slow the ventricular response. If atrial fibrillation recurs, antiarrhythmic agents may be used, although their impact on clinical outcomes is unproved. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) investigators randomized 4,060 patients to either rhythm-control or rate-control treatment strategies.127 The rhythm-control strategy achieved no survival advantage over the rate-control strategy and there were both fewer hospital admissions and fewer adverse drug reactions in the rate-control group.

Bradyarrhythmias and Heart Block

Sinus bradycardia is common in acute myocardial infarction, particularly in patients with inferior myocardial infarction. However, treatment with atropine and a temporary pacemaker is required infrequently and, generally, only in patients with significant hemodynamic compromise manifested by increased angina, hypotension, or congestive heart failure.

High-degree (second- or third-degree) heart block occurs in approximately 20% of patients with inferior infarction; it is uncommon with infarction at other sites.128 About half of the cases of heart block seen with inferior infarction are Wenckebach-type second-degree heart block; the remainder are cases of third-degree heart block. The heart block is often easily treated with atropine, but a temporary pacemaker is required in as many as 50% of cases. The heart block generally lasts for hours to days; placement of a permanent pacemaker is needed in fewer than 1% of cases. However, the development of heart block with inferior infarction is associated with a threefold to fourfold increase in in-hospital mortality over inferior infarction without heart block.128,129 The increased mortality appears to result from the association between heart block and more severe left and right ventricular infarction rather than from the heart block itself or treatment of the heart block.

Heart block during anterior infarction is uncommon, occurring in fewer than 1% of cases. It is generally associated with extensive left ventricular myocardial infarction involving the conduction system below the atrioventricular node and carries a very poor prognosis.

Mitral Regurgitation

Mitral regurgitation may result from injury to any of the components of the mitral valve apparatus, including the papillary muscles and ventricular walls to which they attach. Mild mitral regurgitation is common in acute myocardial infarction and is present in nearly 50% of patients. Severe mitral regurgitation caused by acute myocardial infarction is rare and generally results from partial or complete rupture of a papillary muscle. The characteristic murmur of severe chronic mitral regurgitation may not be present with acute rupture of a papillary muscle. Instead, a decrescendo systolic murmur is often present, extending less throughout systole as systemic arterial pressure falls and left arterial pressure rises. In many cases, the significance of the murmur is not recognized. The blood supply of the anterior papillary muscle arises from branches of both the left anterior descending and the circumflex arteries; therefore, rupture of the anterior papillary muscle is rare. However, the posterior papillary muscle receives blood only from the dominant coronary artery (the right coronary artery in nearly 90% of patients); thrombotic occlusion of this artery may cause rupture of the posterior papillary muscle, resulting in severe mitral regurgitation. Severe mitral regurgitation is 10 times more likely to occur with inferior infarction than with anterior infarction. Acute severe mitral regurgitation is poorly tolerated and generally results in pulmonary edema, often with cardiogenic shock. Prompt surgical repair is recommended. Although the mortality associated with mitral valve surgery is high in this setting, approaching 50%, survival appears to be greater than with medical therapy alone. Therapy aimed at reducing left ventricular afterload, such as use of I.V. nitroprusside and an intra-aortic balloon pump, reduces the regurgitant volume and increases forward blood flow and cardiac output and may be helpful as a temporizing measure.

Ventricular Septal Defects

Ventricular septal defects are slightly more frequent in patients with anterior infarction than in patients with inferior infarction. The characteristic holosystolic murmur of ventricular septal defects may be difficult to distinguish from that of severe mitral regurgitation; however, ventricular septal defects are generally better tolerated and less frequently result in severe congestive heart failure. Surgical repair is recommended and results in the best outcome when repaired emergently in the hemodynamically compromised patient. As with acute severe mitral regurgitation, therapy aimed at reducing afterload, including I.V. nitroprusside and an intra-aortic balloon pump, may be beneficial. Repair of the septum is generally more difficult when associated with inferior infarction, because there may not be a viable rim of myocardial tissue beneath the defect to facilitate repair. The surgical mortality associated with repair of a postinfarction ventricular septal defect is approximately 20% but is largely related to the age of the patient, whether cardiogenic shock is present, the infarction site, and the severity of the underlying coronary artery disease.

Myocardial Rupture

As more and more patients survive the acute phase of myocardial infarction because reperfusion therapy reduces myocardial infarct size, myocardial rupture has increased in frequency as a cause of early death. Myocardial rupture has been reported to account for more than 20% of in-hospital deaths in some series in the thrombolytic era. Physicians must have a heightened awareness of the diagnosis if a patient is to survive this catastrophic occurrence, because emergency surgery is required. Symptoms suggestive of rupture include repetitive vomiting, pleuritic chest pain, restlessness, and agitation. ECG evidence of rupture includes a deviation from the normal pattern of ST segment and T wave evolution. Resolution of ST segment elevation and T wave inversion, with maximal T wave negativity in the leads with maximal ST segment elevation, should normally occur; however, in patients with rupture, there is progressive or recurrent ST segment elevation and persistently positive T wave deflections or reversal of initially inverted T waves.130 Echocardiography can quickly confirm the diagnosis. Even when emergency surgery is performed, fewer than 50% of patients survive to discharge.

Right Ventricular Infarction

Right ventricular infarction occurs in approximately one third of patients with acute inferior left ventricular infarction and is hemodynamically significant in approximately 50% of affected patients.131 Hemodynamically significant right ventricular infarction associated with anterior infarction or isolated right ventricular infarction is rare. The classic findings associated with hemodynamically significant right ventricular infarction are hypotension with clear lung fields and an elevated jugular venous pressure, often with the Kussmaul sign. Although nearly all patients with right ventricular infarction suffer both right and left ventricular infarction, the characteristic hemodynamic findings of right ventricular infarction generally dominate the clinical course and must be the main focus of therapy. Right ventricular involvement during inferior myocardial infarction is associated with a significant increase in mortality, and aggressive attempts at early reperfusion should be pursued.128,131 Prompt recognition of right ventricular involvement is clinically important because therapy that reduces right ventricular filling, such as use of nitrates or diuretics, should be avoided. Volume therapy should be administered to maintain cardiac output; in patients whose hypotension is refractory to volume therapy, dopamine may be beneficial. Heart block, which occurs in as many as 50% of patients with right ventricular infarction, should be treated rapidly, and maintenance of atrioventricular synchrony with dual atrial and ventricular pacing is often required to maintain filling of the ischemic noncompliant right ventricle and an adequate cardiac output.

Cardiogenic shock resulting from right ventricular infarction is generally reversible with these measures. Improvement in right ventricular function generally occurs over time, particularly in patients in whom reperfusion therapy was successful in achieving vessel patency.125 In patients who survive the initial hospitalization, left ventricular function is the most potent predictor of long-term outcome.


Extensive infarction of the anterior wall and apex of the left ventricle leads to thrombus formation in the apex of the left ventricle in approximately 30% of patients; systemic embolization occurs in about 15% of these patients. Left ventricular thrombus formation is much less common after inferior infarction. The thrombus generally appears within the first several days after infarction; it is more likely to embolize and cause stroke if it is pedunculated, protrudes into the left ventricular cavity, or is mobile. Left ventricular thrombus is an indication for anticoagulation with I.V. heparin, followed by warfarin therapy for 3 to 6 months.

Therapy that reduces infarct size, such as thrombolytic therapy, reduces the frequency of thrombus formation and therefore the risk of systemic embolization and stroke. However, in 0.3% to 1.0% of patients, thrombolytic therapy causes hemorrhagic stroke, most commonly in the 24 hours after its administration, which is fatal in more than 50% of cases. Hemorrhagic stroke is rare in acute myocardial infarction except as a consequence of thrombolytic therapy, although an ischemic stroke may become hemorrhagic because of thrombolytic, antiplatelet, and anticoagulation therapy. Hemorrhagic stroke, the most feared complication of thrombolytic therapy, is more likely in elderly patients; in patients with low body weight, with hypertension, or who have previously had a stroke; and in those on warfarin.53,59 Although thrombolytic therapy decreases the risk of ischemic stroke, there is a slight net increase in the overall risk of stroke because of the risk of hemorrhagic stroke. Primary coronary angioplasty is believed to reduce the incidence of ischemic stroke without increasing the risk of hemorrhagic stroke.

Predischarge Exercise Testing

In patients with spontaneous postinfarction angina, congestive heart failure, hypotension, or malignant ventricular arrhythmia, exercise testing should generally be deferred and coronary angiography should be performed. However, in patients without these high-risk characteristics, exercise testing is generally recommended before discharge from the hospital to assess a patient's functional capacity and ability to return to activities of daily living and work.132 Most data indicating that predischarge exercise testing can identify patients at increased risk for cardiac events after discharge are from the prethrombolytic era, when the risk of adverse cardiac events was much higher. In the modern era, in which thrombolytic therapy or primary coronary angioplasty is frequently performed and in which aspirin, beta blockers, ACE inhibitors, and lipid-lowering agents are routinely administered—all of which reduce the frequency of adverse events in the years after discharge—it is difficult to identify patients at risk, because the adverse event rate is so low. Nonetheless, exercise testing is generally recommended to provide a measure of comfort to both the patient and the physician, to help determine the appropriateness of medical therapy, and to facilitate entry of the patient into a cardiac rehabilitation program.

Although predischarge exercise testing has been the standard of care in the United States for some time, only recently has a study examined whether therapy based on the results of a predischarge exercise test improves clinical outcome. The Danish Trial in Acute Myocardial Infarction (DANAMI) was the first study to examine the usefulness of exercise testing in patients treated with thrombolytic agents (a low-risk group) and to provide support for what has been the standard of care in the United States [see Figure 11].133 The results of this study revealed that clinical outcome was improved in patients who received angiography and coronary angioplasty, compared with those who received medical therapy alone. Use of the results of exercise testing to decide whether or not to employ revascularization in patients without spontaneous angina is less common outside of the United States.


Figure 11. In the Danish Acute Myocardial Infarction (DANAMI) study, 1,008 patients treated with thrombolytic therapy in whom exercise-induced ischemia was present on a predischarge exercise test were randomized to receive either coronary angioplasty or medical therapy alone. Clinical outcome was improved in patients in the invasive arm of the study. (NS—not significant)

Patients with acute myocardial infarction who do not receive thrombolytic therapy or do not undergo primary angioplasty are at greater risk for adverse events after discharge from the hospital, and predischarge exercise testing is of even greater utility in such patients.

Prognostic variables indicating increased risk during exercise testing are exercise-induced angina or ST segment depression, particularly when it occurs during exercise at a low work load, and an abnormal drop in systolic blood pressure. However, electrocardiographic, symptomatic, and scintigraphic risk markers of ischemia (e.g., ST segment depression, angina, or a reversible perfusion defect) are less sensitive for identifying morbid and fatal outcomes than markers of left ventricular dysfunction or heart failure (e.g., exercise duration, impaired systolic blood pressure response, and peak left ventricular ejection fraction).134 The patients at greatest risk are those unable to exercise; such patients have the highest mortality after discharge.135

The type of exercise test that should be performed has been the subject of controversy. It is generally recommended that only simple treadmill testing be performed before discharge; in patients with abnormalities in the baseline ECG, stress testing with perfusion imaging or stress echocardiography may be helpful. In patients without widespread abnormalities on the ECG, perfusion imaging or stress echocardiography is generally deferred until at least 4 weeks after discharge, when a more vigorous exercise test can be performed. Whether the predischarge treadmill test should be a low-level test or a more vigorous symptom-limited test is unclear. It has been shown that a symptom-limited Bruce protocol exercise test detects ischemia more frequently than a submaximal test; however, it is not known which test has the greater positive and greater negative predictive value for identifying patients at risk. Currently, a lower-level exercise test is preferred, although a more vigorous test may be appropriate in patients likely to resume a more active and vigorous lifestyle shortly after discharge and in whom a low-level test may not cause the patient to expend the amount of energy he or she will be using during activities of daily living.

There has been concern that the use of beta blockers before the predischarge exercise test may mask the presence of significant coronary artery disease and prevent the identification of high-risk patients. This concern does not appear to be significant enough to outweigh the benefits of early beta-blocker therapy.

Secondary Prevention


Lipid-Lowering Therapy

Recent studies have demonstrated that in patients with coronary artery disease, lipid-lowering therapy with HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors reduces not only fatal and nonfatal infarction but also mortality from all causes. The Scandinavian Simvastatin Survival Study revealed a 42% reduction in cardiac mortality and a 30% reduction in all-cause mortality in 4,444 men and women with coronary artery disease over the 5.4 years of the study.136 The reductions in mortality were similar in patients in the lowest and those in the highest quartiles of serum low-density lipoprotein (LDL) cholesterol. It has been demonstrated that postinfarction patients with an LDL cholesterol level at or above 130 mg/dl benefit from lipid-lowering therapy within as little as 2 years after the initiation of such therapy.137 Initial measurement of cholesterol should be made within 24 hours after myocardial infarction; measurement of lipids 24 hours or more after myocardial infarction can be misleading in that cholesterol levels may be reduced below baseline levels during this period and remain low for up to 1 month. Early initiation of statins may be more beneficial than later initiation.138 Exercise, weight reduction in overweight patients, avoidance of dietary saturated fat and cholesterol, and smoking cessation have all been reported to favorably influence blood lipid levels and should be recommended whether or not lipid-lowering medications are prescribed [see CE:III Reducing Risk of Injury and Disease and CE:IV Diet and Exercise].

Anticoagulation Therapy

Several prospective, randomized trials revealed that warfarin therapy reduces mortality after discharge from the hospital in patients with acute myocardial infarction. However, in these studies, in which warfarin therapy was compared with placebo, aspirin was not administered in either arm of the study.139,140 The Coumadin Aspirin Reinfarction Study (CARS) revealed that the risk of reinfarction in patients treated with aspirin alone was similar to that in patients treated with aspirin and either low-dose (1 mg) or higher-dose (3 mg) warfarin.141Warfarin is also ineffective at preventing coronary reocclusion in patients in whom thrombolytic therapy was successful.142 Routine warfarin therapy is not currently recommended to prevent reinfarction in patients who have survived myocardial infarction.

Antiarrhythmic Therapy

Although Holter monitoring before discharge can help identify patients at increased risk for sudden cardiac death, antiarrhythmic therapy has not been shown to decrease the risk of death in such patients, and in fact, it increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST).143 Since CAST, several prospective, randomized studies have been performed that have examined the role of amiodarone in patients at increased risk for sudden death. Taken together, the results of those studies do not indicate that amiodarone reduces mortality. Further studies are needed before the routine use of amiodarone can be recommended in high-risk patients, such as those included in these trials.

Automated, Implantable Cardioverter-Defibrillator

Automated implantable cardioverter-defibrillators are of proven benefit in patients with coronary artery disease, reduced left ventricular ejection fraction, nonsustained ventricular tachycardia, and inducible ventricular tachycardia.144 It has been pro- posed that patients with a prior myocardial infarction and advanced left ventricular dysfunction may benefit from prophylactic implantation of a defibrillator (in the absence of electrophysiologic testing to induce arrhythmias). The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II investigators randomized 1,232 patients with a prior myocardial infarction and a left ventricular ejection fraction of 0.30 or less to an implantable defibrillator or conventional medical therapy. During an average follow-up of 20 months, the mortality rates were 19.8% in the conventional-therapy group and 14.2% in the defibrillator group (P = 0.016). Prophylactic implantation of a defibrillator is a recommended therapy in this patient population.145

Risk-Factor Modification

An important and often neglected aspect of medical care after a myocardial infarction is the identification and modification of risk factors for atherosclerosis. Hypertension and hypercholesterolemia should be treated. Cessation of smoking has been shown to prolong life in patients who have survived a myocardial infarction; behavior modification and group therapy can increase the likelihood of kicking the habit. Cardiac rehabilitation and the establishment of a healthier lifestyle with an exercise program146 can further reduce the likelihood of a return to smoking. Hypercholesterolemia should be aggressively treated as described above.

Although there are few data that conclusively indicate that patients who participate in a cardiac rehabilitation program after discharge have increased survival, an exercise rehabilitation program appears to improve a patient's sense of well-being and hasten return to work and leisure activities. A cardiac rehabilitation program can also help improve diet and aid weight reduction in overweight patients, help smokers refrain from smoking, and help establish an exercise program that the patient can maintain long after the formal rehabilitation program has ended. In summary, participation in a cardiac rehabilitation program often leads to the establishment of a healthier lifestyle.

Long-term Prognosis

Long-term prognosis after myocardial infarction is determined primarily by the severity of left ventricular dysfunction, the presence and degree of residual ischemia, and the potential for malignant ventricular arrhythmia. These adverse prognostic factors are related to each other but are also independently associated with death after discharge. Age is also an important determinant of outcome. Most deaths that occur in the first year after discharge occur in the first 3 months, a fact that stresses the importance of assessing risk and optimizing therapy before discharge from the hospital. However, there can be substantial improvement in ventricular function in the weeks and months after acute myocardial infarction, particularly in patients in whom early reperfusion was achieved. Therefore, measurement of ventricular function 2 to 3 months after myocardial infarction is a more accurate predictor of long-term prognosis than measurement of left ventricular function in the acute stages.


Figures 1, 2, 3, 4, 5, 6, 7, 8, and 11

Marcia Kammerer.


  1. Rogers WJ, Canto JG, Lambrew CT, et al: Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the U.S. from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3. J Am Coll Cardiol 36:2056, 2000
  2. Eagle KA, Goodman SG, Avezum A, et al: Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: Findings from the Global Registry of Acute Coronary Events (GRACE). Lancet 359:373, 2002
  3. Mortality from coronary heart disease and acute myocardial infarction—United States, 1998. MMWR Morb Mortal Wkly Rep 50:90, 2001
  4. Patient/bystander recognition and action: rapid identification and treatment of acute myocardial infarction (NIH Publication No 93-3303). National Heart Attack Alert Program (NHAAP). National Heart, Lung, and Blood Institute. National Institutes of Health, Bethesda, Maryland, 1993
  5. Fuster V: Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 90:2126, 1994
  6. Libby P: Molecular bases of the acute coronary syndromes. Circulation 91:2844, 1995
  7. Libby P: Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 104:365, 2001
  8. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al: Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 12:56, 1988
  9. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al: Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Circulation 90:583, 1994
  10. Myocardial infarction redefined: a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 36:959, 2000
  11. Aronow WS: Prevalence of presenting symptoms of recognized acute myocardial infarction and of unrecognized healed myocardial infarction in elderly patients. Am J Cardiol 60:1182, 1987
  12. Kouvaras G, Bacoulas G: Unstable angina as a warning symptom before acute myocardial infarction. Q J Med 64:679, 1987
  13. Kannel WB, Abbott RD: Incidence and prognosis of unrecognized myocardial infarction: an update on the Framingham study. N Engl J Med 311:1144, 1984
  14. Karlson BW, Herlitz J, Edvardsson N, et al: Eligibility for intravenous thrombolysis in suspected acute myocardial infarction. Circulation 82:1140, 1990
  15. Grijseels EW, Deckers JW, Hoes AW, et al: Prehospital triage of patients with suspected acute myocardial infarction. Evaluation of previously developed algorithms and new proposals. Eur Heart J 16:325, 1995
  16. Cragg DR, Friedman HZ, Bonema JD, et al: Outcome of patients with acute myocardial infarction who are ineligible for thrombolytic therapy. Ann Intern Med 115:173, 1991
  17. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Second International Study of Infarct Survival Collaborative Group. Lancet 2:349, 1988
  18. Roberts R, Kleinman N: Earlier diagnosis and treatment of acute myocardial infarction necessitates the need for a “new diagnostic mind-set.” Circulation 89:872, 1994
  19. Zabel M, Hohnloser SH, Koster W, et al: Analysis of creatine kinase, CK-MB, myoglobin, and troponin T time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation 87:1542, 1993
  20. Ohman EM, Armstrong P, Califf RM, et al: Risk stratification in acute ischemic syndromes using serum troponin T. The GUSTO Investigators. J Am Coll Cardiol 25(suppl):148A, 1995
  21. Ravkilde J, Nissen H, Horder M, et al: Independent prognostic value of serum creatine kinase isoenzyme MB mass, cardiac troponin T and myosin light chain levels in suspected acute myocardial infarction: analysis of 28 months of follow-up in 196 patients. J Am Coll Cardiol 25:574, 1995
  22. Hauser AM, Gangadharan V, Ramos RG, et al: Sequence of mechanical, electrocardiographic and clinical effects of repeated coronary arterial occlusion in human beings: echocardiographic observation during coronary angioplasty. J Am Coll Cardiol 5:193, 1985
  23. Sabia P, Abbott RD, Afrookteh A, et al: Importance of two-dimensional echocardiographic assessment of left ventricular systolic function in patients presenting to the emergency room with cardiac-related symptoms. Circulation 84:1615, 1991
  24. Fleischmann KE, Lee TH, Come PC, et al: Echocardiographic prediction of complications in patients with chest pain. Am J Cardiol 79:292, 1997
  25. Talreja D, Gruver C, Sklenar J, et al: Efficient utilization of echocardiography for the assessment of left ventricular systolic function. Am Heart J 139:394, 2000
  26. St John Sutton M, Pfeffer MA, Plappert T, et al: Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: the protective effects of captopril. Circulation 89:68, 1994
  27. Hilton TC, Thompson RC, Williams HJ, et al: Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol 23:1016, 1994
  28. Duca MD, Giri S, Wu AH, et al: Comparison of acute rest myocardial perfusion imaging and serum markers of myocardial injury in patients with chest pain syndromes. J Nucl Cardiol 6:570, 1999
  29. Radensky PW, Hilton TC, Fulmer H, et al: Potential cost effectiveness of initial myo cardial perfusion imaging for assessment of emergency department patients with chest pain. Am J Cardiol 79:595, 1997
  30. Udelson JE, Beshansky JR, Ballin DS, et al: Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia. JAMA 288:2693, 2002
  31. Antman EM, Anbe DT, Armstrong PW, et al: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 110:588, 2004
  32. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists Collaboration. Br Med J 296:320, 1988
  33. Weaver WD: Time to thrombolytic treatment: factors affecting delay and their influence on outcome. J Am Coll Cardiol 25(suppl 7):3S, 1995
  34. Emergency department rapid identification and treatment of patients with acute myocardial infarction. National Heart Attack Alert Program Coordinating Committee 60 minutes to Treatment Working Group. Ann Emerg Med 23:311, 1994
  35. Berger PB, Ellis SG, Holmes DR Jr, et al: The relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myo cardial infarction: results from the global use of strategies to open occluded arteries in acute coronary syndromes (GUSTO-IIb) trial. Circulation 100:14, 1999
  36. Cannon CP, Gibson CM, Lambrew CT, et al: Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 283:2941, 2000
  37. Caputo RP, Ho KKL, Stoler RC, et al: Effect of continuous quality improvement on the delivery of primary percutaneous transluminal coronary angioplasty for acute myo cardial infarction. Am J Cardiol 79:1159, 1997
  38. Jhangiana AH, Jorgenson MB, Kotlewski A, et al: Community practice of primary angioplasty for myocardial infarction. Am J Cardiol 80:209, 1997
  39. Patel S, Reese C, O'Connor RE, et al: Adverse outcomes accompanying primary angioplasty (PTCA) for acute myocardial infarction (AMI)—dangers of delay. J Am Coll Cardiol 27(suppl A):62A, 1996
  40. Rosman HS, Ciolino D, Nerenz D, et al: Primary PTCA and thrombolysis for acute myocardial infarction: observations from the community. J Am Coll Cardiol 27(suppl A):26A, 1996
  41. Widimsky P, Budesinsky T, Vorac D, et al: Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial—PRAGUE-2. Eur Heart J 24:94, 2003
  42. Andersen HR, Nielsen TT, Rasmussen K, et al: A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 349:733, 2003
  43. Immediate versus delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. The TIMI Study Group. JAMA 260:2849, 1988
  44. SWIFT trial of delayed elective intervention v conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. SWIFT Study Group. BMJ 302:555, 1991
  45. Ellis SG, Mooney MR, George BS, et al: Randomized trial of late elective angioplasty versus conservative management for patients with residual stenoses after thrombolytic treatment of myocardial infarction. Treatment of Post-Thrombolytic Stenoses (TOPS) Study Group. Circulation 86:1400, 1992
  46. Zeymer U: The ALKK Trial. Oral presentation at the Late Breaking Clinical Trials Session of the 49th Annual Scientific Sessions of the American College of Cardiology, March 2000
  47. Berger PB, Holmes DR Jr, Stebbins AL, et al: Impact of an aggressive invasive catheterization and revascularization strategy on mortality in patients with cardiogenic shock in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial: an observational study. Circulation 96:122, 1997
  48. Prasad A, Mathew V, Holmes DR, et al: Current management of non-ST-segment-elevation acute coronary syndrome: reconciling the results of randomized controlled trials. Eur Heart J 24:1544, 2003
  49. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB Trial. The TIMI IIIB Investigators. Circulation 89:1545, 1995
  50. Wallentin L, Lagerqvist B, Husted S, et al: Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. Lancet 356:9, 2000
  51. Cannon CP, Weintraub WS, Demopolous LA, et al: Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 344:1879, 2001
  52. Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction - summary article: A report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 40:1366, 2002
  53. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists? (FTT) Collaborative Group. Lancet 343:311, 1994
  54. French JK, Hyde TA, Patel H, et al: Survival 12 years after randomization to streptokinase: the influence of thrombolysis in myocardial infarction flow at three to four weeks. J Am Coll Cardiol 34:62, 1999
  55. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. The GUSTO Angiographic Investigators. N Engl J Med 329:1615, 1993
  56. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO Investigators. N Engl J Med 329:673, 1993
  57. Simes RJ, Topol EJ, Holmes DR Jr, et al: Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: importance of early and complete infarct artery reperfusion. Circulation 91:1923, 1995
  58. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6 to 24 hours after onset of acute myocardial infarction. Lancet 342:759, 1993
  59. de Jaegere PP, Arnold AA, Balk AH, et al: Intracranial hemorrhage in association with thrombolytic therapy: incidence and clinical predictive factors. J Am Coll Cardiol 19:289, 1992
  60. Randomised double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate the equivalent. International Joint Efficacy Comparison of Thrombolytics. Lancet 346:329, 1995
  61. A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. N Engl J Med 337:1118, 1997
  62. Antman EM, Giugliano RD, Gibson CM, et al: Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI 14) Trial. Circulation 99:2720, 1999
  63. Ohman EM, Lincoff AM, Bode C, et al: Enhanced early reperfusion at 60 minutes with low-dose reteplase combined with full-dose abciximab in acute myocardial infarction: preliminary results from the GUSTO-IV Pilot (SPEED) Dose-ranging Trial (abstr). Circulation 98(suppl I):I-504, 1998
  64. Topol EJ: Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 357:1905, 2001
  65. Assessment of the Safety and Efficacy of a New Thrombolytic regimen (ASSENT-3) Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomized trial of acute myocardial infarction. Lancet 358:605, 2001
  66. Wallentin L, Goldstein P, Armstrong PW, et al: Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 108:135, 2003
  67. O'Neill W, Timmis G, Bourdillon P, et al: A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 314:812, 1986
  68. de Boer MJ, Hoorntje JCA, Ottervanger JP, et al: Immediate coronary angioplasty versus intravenous streptokinase in acute myocardial infarction: left ventricular ejection fraction, hospital mortality, and reinfarction. J Am Coll Cardiol 23:1004, 1994
  69. de Boer MJ, Suryapranata H, Hoorntje JC, et al: Limitation of infarct size and preservation of left ventricular function after primary coronary angioplasty compared with intravenous streptokinase in acute myocardial infarction. Circulation 90:753, 1994
  70. Zijlstra F, de Boer MJ, Hoorntje JCA, et al: A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 328:680, 1993
  71. Grines CL, Browne KF, Marco J, et al: A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 328:673, 1993
  72. Keeley EC, Boura JA, Grines CL: Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 361:13, 2003
  73. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. N Engl J Med 336:1621, 1997
  74. Berger PB, Bell MR, Holmes DR Jr, et al: Time to reperfusion with direct coronary angioplasty and thrombolytic therapy in acute myocardial infarction. Am J Cardiol 73:231, 1994
  75. Ryan TJ, Anderson JL, Antman EM, et al: ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee of Management of Acute Myocardial Infarction). J Am Coll Cardiol 28:1328, 1996
  76. Wharton TP, McNamara SN, Fedele FA, et al: Primary angioplasty for the treatment of acute myocardial infarction: experience at two community hospitals without cardiac surgery. J Am Coll Cardiol 33:1257, 1999
  77. Brener SJ, Barr LA, Burchenal JE, et al: Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation 98:73, 1998
  78. Neumann FJ, Blasini R, Schmitt C, et al: Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after placement of coronary-artery stents in acute myocardial infarction. Circulation 98:2695, 1998
  79. Montalescot G, Barragan P, Wittenberg O, et al: Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 344:1895, 2001
  80. Stone GW, Grines CL, Cox DA, et al: Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 346:957, 2002
  81. Grines CL, Cox DA, Stone GW, et al: Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 341:1949, 1999
  82. Schomig A, Kastrati A, Dirschinger J, et al: Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. N Engl J Med 343:385, 2000
  83. Berger PB, Stensrud PE, Daly RC, et al: Emergency coronary artery bypass surgery following failed coronary angioplasty: time to reperfusion and other procedural characteristics. Am J Cardiol 76:565, 1995
  84. Ellis SG, Ribeiro da Silva E, Heyndrickx G, et al: Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 90:2280, 1994
  85. Belenkie I, Traboulsi M, Hall CA, et al: Rescue angioplasty during myocardial infarction has a beneficial effect on mortality: a tenable hypothesis. Can J Cardiol 8:357, 1992
  86. Widimsky P, Groh L, Ascherman M, et al: The “PRAGUE” study: a national multicenter randomized study comparing primary angioplasty vs thrombolysis vs both in patients with acute myocardial infarction admitted to the community hospitals: results of the pilot phase (abstr). Eur Heart J 19(suppl):56, 1998
  87. Vermeer F, Brunninkhuis L, van de Berg E, et al: Prospective randomized comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: a safety and feasibility study. Heart 82:426, 1999
  88. Simoons ML, Arnold AE, Betriu A, et al: Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1:197, 1988
  89. Dirschinger J, Kastrati A, Neumann FJ, et al: Influence of balloon pressure during stent placement in native coronary arteries on early and late angiographic and clinical outcome: a randomized evaluation of high-pressure inflation. Circulation 100:918, 1999
  90. Miller JM, Smalling R, Ohman EM, et al: Effectiveness of early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase) during acute myocardial infarction: results from the GUSTO-III trial. Am J Cardiol 84:779, 1989
  91. Ross AM, Coyne KS, Reiner JS, et al: A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial. PACT investigators. Plasminogen-activator Angioplasty Compatibility Trial. J Am Coll Cardiol 34:1954, 1999
  92. Scheller B, Hennen B, Hammer B, et al: Beneficial effects of immediate stenting after thrombolysis in acute myocardial infarction. J Am Coll Cardiol 42:634, 2003
  93. Kastrati A, Mehilli J, Schlotterbeck K, et al: Early administration of reteplase plus abciximab versus abciximab alone in patients with acute myocardial infarction referred for percutaneous coronary intervention. JAMA 291:947, 2004
  94. Granger CB, Hirsh J, Califf RM, et al: Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation 93:870, 1996
  95. Chesebro JH, Fuster V: Antithrombotic therapy for acute myocardial infarction: mechanisms and prevention of deep venous, left ventricular, and coronary artery thromboembolism. Circulation 74:1, 1986
  96. Granger CB, Miller JM, Bovill EG, et al: Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation 91:1929, 1995
  97. Ross AM, Molhoek P, Lundergan C, et al: Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II). Circulation 104:648, 2001
  98. Simoons M, Krzeminska-Pakula M, Alonso A, et al: Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myo cardial infarction. The AMI-SK study. Eur Heart J 23:1282, 2002
  99. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 358:605, 2001
  100. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data. Direct Thrombin Inhibitor Trialists?. Collaborative Group. Lancet 359:294, 2002
  101. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Lancet 358:1855, 2001
  102. Gersh BJ, Rahimtoola SH: Acute myocardial infarction. Pharmacological Management of Acute Myocardial Infarction. Warnica JW, Ed. Elsevier, New York, 1991, p 205
  103. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) phase II trial. The TIMI Study Group. N Engl J Med 320:618, 1989
  104. Barron HV, Rundle AC, Gore JM, et al: Intracranial hemorrhage rates and effect of immediate beta-blocker use in patients with acute myocardial infarction treated with tissue plasminogen activator. Participants in the National Registry of Myocardial Infarction-2. Am J Cardiol 85:294, 2000
  105. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Fourth International Study of Infarct Survival Collaborative Group. Lancet 345:669, 1995
  106. Sigurdsson A, Swedberg K: Left ventricular remodelling, neurohormonal activation and early treatment with enalapril (CONSENSUS II) following myocardial infarction. Eur Heart J 15(suppl B):14, 1994
  107. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145, 2000
  108. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Lancet 362:782, 2003
  109. Judgutt BI, Warnica JW: Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications: effect of timing, dosage, and infarct location. Circulation 78:906, 1988
  110. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lancet 34:1115, 1994
  111. MacMahon S, Collins R, Peto R, et al: Effects of prophylactic lidocaine in suspected acute myocardial infarction: an overview of results from the randomized, controlled trials. JAMA 260:1910, 1988
  112. Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA 270:1589, 1993
  113. Fonarow GD, Wright RS, Spencer FA, et al: Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol 96:611, 2005
  114. Schwartz GG, Olsson AG, Ezekowitz MD, et al: Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 285:1711, 2001
  115. Cannon CP, Braunwald E, McCabe CH, et al: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495, 2004
  116. Gheorghiade M: Calcium channel blockers in the management of myocardial infarction patients. Henry Ford Hosp Med J 39:210, 1991
  117. Held PH, Yusuf S: Effects of beta-blockers and calcium channel blockers in acute myocardial infarction. Eur Heart J 14(suppl F):18, 1993
  118. Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT): A randomized intervention trial of nifedipine in patients with acute myocardial infarction. The Israeli SPRINT Study Group. Eur Heart J 9:354, 1988
  119. Goldbourt U, Behar S, Reicher-Reiss H, et al: Early administration of nifedipine in suspected acute myocardial infarction. The Secondary Prevention Reinfarction Israel Nifedipine Trial 2 Study. Arch Intern Med 153:345, 1993
  120. The effect of diltiazem on mortality and reinfarction after myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group. N Engl J Med 319:385, 1988
  121. Gibson RS, Hansen JF, Messerli F, et al: Long-term effects of diltiazem and verapamil on mortality and cardiac events in non-Q-wave acute myocardial infarction without pulmonary congestion: post hoc subset analysis of the multicenter diltiazem postinfarction trial and the second Danish verapamil infarction trial studies. Am J Cardiol 86:275, 2000
  122. Boden WE, van Gilst WH, Scheldewaert RG, et al: Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomised placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT). Lancet 355:1751, 2000
  123. Teo KK, Yusuf S, Collins R, et al: Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomised trials. BMJ 303:1499, 1991
  124. Bunch TJ, White RD, Gersh BJ, et al: Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation. N Engl J Med 348:2626, 2003
  125. Berger PB, Ruocco NA, Ryan TJ, et al: Incidence and prognostic significance of ventricular tachycardia and ventricular fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the TIMI II trial. J Am Coll Cardiol 22:1773, 1993
  126. Behar S, Goldbourt U, Reicher-Reiss H, et al: Prognosis of acute myocardial infarction complicated by primary ventricular fibrillation. Am J Cardiol 66:1208, 1990
  127. Wyse DG, Waldo AL, DiMarco JP, et al: A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 347:1825, 2002
  128. Berger PB, Ryan TJ: Inferior infarction: high risk subgroups. Circulation 81:401, 1990
  129. Berger PB, Ruocco NA, Frederick MM, et al: The incidence and significance of heart block during inferior infarction: results from the TIMI II trial. J Am Coll Cardiol 20:533, 1992
  130. Oliva PB, Hammill SC, Edwards WD: Cardiac rupture, a clinically predictable complication of acute myocardial infarction: report of 70 cases with clinicopathologic correlations. J Am Coll Cardiol 22:720, 1993
  131. Zehender M, Kasper W, Kauder E, et al: Right ventricular infarction as an independent predictor of prognosis after acute inferior myocardial infarction. N Engl J Med 328:981, 1993
  132. Flapan AD: Management of patients after their first myocardial infarction. BMJ 309:1129, 1994
  133. Madsen JK, Grande P, Saunamaki K, et al: Danish Multicenter Randomized Study of Invasive Versus Conservative Treatment in Patients with Inducible Ischemia after Thrombolysis in Acute Myocardial Infarction (DANAMI). Danish Trial in Acute Myo cardial Infarction. Circulation 96:748, 1997
  134. Shaw LJ, Peterson ED, Kesler K, et al: A metaanalysis of predischarge risk stratification after acute myocardial infarction with stress electrocardiographic, myocardial perfusion, and ventricular function imaging. Am J Cardiol 78:1327, 1996
  135. Chaitman BR, McMahon RP, Terin M, et al: Impact of treatment strategy on predischarge exercise test in the Thrombolysis in Myocardial Infarction (TIMI) II trial. Am J Cardiol 71:131, 1993
  136. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Scandinavian Simvastatin Survival Study Group. Lancet 344:1383, 1994
  137. Sacks FM, Pfeffer MA, Moye LA, et al: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 335:1001, 1996
  138. Stenestrand U, Wallentin L: Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 285:430, 2001
  139. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Lancet 343:499, 1994
  140. Smith P, Arnesen H, Holme I: The effect of warfarin on mortality and reinfarction after myocardial infarction. J Engl J Med 323:147, 1990
  141. Randomised double-blind trial of fixed, low-dose warfarin with aspirin after myo cardial infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators. Lancet 350:389, 1997
  142. Meijer A, Verheugt FWA, Wester CPJP, et al: Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study: results of the APRICOT study. Circulation 87:1524, 1993
  143. Epstein AE, Hallstrom AP, Rogers WL, et al: Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: the original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 270:2451, 1993
  144. Moss AJ, Hall WJ, Cannom DS, et al: Improved survival with an implanted defi brillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 335:1933, 1996
  145. Moss AJ, Zareba W, Jackson Hall W, et al: Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 346:877, 2002
  146. Rana JS, Mukamal KJ, Morgan JP, et al: Obesity and the risk of death after acute myocardial infarction. Am Heart J 147:841, 2004

Editors: Dale, David C.; Federman, Daniel D.