In 1912, James Herrick theorized that myocardial infarction resulted from the sudden occlusion of a coronary artery by a thrombus.1 In the 1970s, coronary angiography confirmed that thrombotic occlusion of a coronary artery is the cause of acute myocardial infarction in nearly all cases. 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. Epidemiology In the past decade, the number of people dying 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 thrombolytic therapy, coronary angioplasty, aspirin, and heparin and a reduction in the risk factors for coronary artery disease.2 Despite these advances, approximately 1.5 million people in the United States suffer acute myocardial infarction each year, and 500,000 die. Nearly half of these deaths occur before the patient receives medical care either from emergency medical technicians or in a hospital.3,4 Pathogenesis The factors responsible for the sudden thrombotic occlusion of a coronary artery have only recently been elucidated. 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.5 Although severe stenosis of a coronary artery (> 70 percent diameter stenosis) 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 occlusion occurred at sites in the coronary circulation with stenoses of less than 70 percent on the preinfarction angiogram.6,7 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 stenoses are likely to result in acute thrombotic occlusion is poor. Diagnosis 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.3,8

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 ischemia and should lead the clinician to consider etiologies other than myocardial infarction. Many patients with acute myocardial infarction, particularly those with inferior infarction, are diaphoretic; nausea and emesis are frequent 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 tachyarrhythmia with inferior infarction. Elderly patients with infarction often present with symptoms atypical 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.9 Approximately two thirds of patients describe the new onset of angina or a change in their anginal pattern in the month preceding infarction.10 However, in approximately one fourth of patients, myocardial infarction is associated with only mild symptoms or no symptoms at all.11 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 common 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, however, 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, among others, rather than in confirming a diagnosis of acute myocardial infarction.

ELECTROCARDIOGRAPHY

The electrocardiogram is a valuable tool to both confirm the diagnosis and select the most appropriate therapy for the patient with acute myocardial infarction. 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 percent.12,13 Other findings such as ST segment depression, T wave inversion, and bundle branch block are less specific but may also be supportive of a diagnosis of acute myocardial infarction, particularly when typical symptoms are present [see Figure 1].12 Fully 50 percent of patients with myocardial infarction do not have ST segment elevation on their electrocardiogram; among such patients, the electrocardiogram can help predict complications and short-term mortality.14-18 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.16,17 Those with other nonspecific electrocardiographic abnormalities are at lesser risk, and 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 patients with suspected acute myocardial infarction is the patients’ description of their symptoms. All patients suspected of having acute myocardial infarction should be admitted to the hospital and receive rapid and appropriate therapy.

LABORATORY FINDINGS

Injury to myocardial cells results in the release of intracellular enzymes into circulating blood, permitting their detection by blood tests. Traditionally, creatine kinase (CK) and an isoenzyme, CK-MB, found in high concentration in myocardial cells, have been used to diagnose myocardial infarction in its earliest stages.19-22 Rapid assays of these enzymes have been developed, permitting the analysis of blood for 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 three hours of profound ischemia to rise above normal levels; patients who present early in their infarction would not be expected to have elevation of CK. Furthermore, patients may have partial occlusion of the infarct artery or extensive collateralization of the infarct 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 the CK becomes elevated, as 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 more rapidly released from infarcted myocardium than is CK-MB. However, myoglobin is also found in skeletal muscle, and the lack of specificity is a drawback.23 Troponin is a cardiac-specific marker for acute myocardial infarction; an increase in serum levels of troponin occurs early after myocardial cell injury. An elevated cardiac troponin level on admission has been reported to be a predictor of subsequent cardiac events.24,25 The ultimate role of this assay in the emergency department evaluation of patients remains unclear. A simple automated analysis of the white blood cell count has been shown to increase the ability to accurately diagnose myocardial infarction in patients with chest pain but no ST segment elevation on the ECG. A relative lymphocytopenia (a lymphocyte decrease to < 20.3 percent of leukocytes) is an independent predictor of acute myocardial infarction in such patients.26 The presence of both a relative lymphocytopenia and an elevated rapid CK-MB level in these patients may be particularly helpful in identifying myocardial infarction.

IMAGING STUDIES

Echocardiography Echocardiography may be useful in identifying patients with myocardial infarction in the emergency department.27,28 Most patients with acute myocardial infarction have regional wall motion abnormalities readily seen on echocardiography; however, echocardiographic evidence of myocardial infarction is not required in patients with symptoms and electrocardiographic evidence typical of acute myocardial infarction, and echocardiography should not be performed in such patients. Echocardiography is probably most 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. The utility of echocardiography in such patients has been demonstrated.29 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.29-31 However, the time required to perform these tests limits their usefulness, and their ultimate value in this setting remains unclear. Emergent Therapy Now that treatments have been developed that reduce the morbidity and mortality of acute myocardial infarction, particularly when initiated early, the importance of avoiding delay in administering them has been recognized.4,32 Although the greatest delay in treatment of acute myocardial infarction is usually the time that it takes a patient to seek medical care, 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. A patient with symptoms suggestive of myocardial infarction should be evaluated within 10 minutes and certainly no longer than 20 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, of I.V. analgesia (most commonly morphine sulfate), of oral aspirin, and of sublingual nitroglycerin if the blood pressure is less than 90 mm Hg. The challenge facing physicians who work in emergency departments is that more than 90 percent of patients who present to the emergency room complaining of chest pain are not suffering myocardial infarction; many do not have a cardiac etiology for their chest pain.33,34 All patients with definite or suspected myocardial infarction should be admitted to the hospital, be prepared for intravenous access, and undergo 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 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 to all patients. oxygen Oxygen is generally recommended for all acute myocardial infarction patients for the first several hours after admission and is mandatory for patients with pulmonary congestion or evidence of oxygen desaturation.

ASPIRIN

Aspirin should be given to all patients as soon as a diagnosis of myocardial infarction is made. 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 percent in 17,000 patients with acute myocardial infarction; the benefit was additive in patients receiving both aspirin and streptokinase. Other studies have revealed similar benefit from immediate aspirin therapy.35 The beneficial effect of aspirin is the result of its antiplatelet effect via the rapid inhibition of thromboxane A2 production. Patients should be maintained on aspirin indefinitely. Prolonged administration of aspirin in patients with a history of myocardial infarction is associated with a 25 percent reduction in death, nonfatal reinfarction, and stroke.35

ANALGESIA

Pain relief should be among the initial therapies offered to patients with acute myocardial infarction. Although persistent chest discomfort is generally caused by ongoing myocardial ischemia–and reducing ischemia is the ultimate goal of therapy–analgesia should also 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 in this setting.

Reperfusion Therapy THROMBOLYTIC THERAPY

Once the patient has been diagnosed as having acute myocardial infarction, it is imperative to initiate therapy as rapidly as possible to restore normal antegrade blood flow in the occluded artery. Thrombolytic therapy has been widely studied in prospective, randomized, controlled trials involving more than 200,000 patients and has been proved to reduce mortality 29 percent in patients with ST segment elevation treated within six hours of the onset of chest pain. The survival benefit of thrombolytic therapy is maintained for years. The benefit of thrombolytic therapy is achieved through rapid restoration of coronary blood flow in an occluded coronary artery. Thrombolytic therapy is strongly recommended for patients with ST segment elevation in two or more contiguous leads with less than six hours of chest pain; for patients with classic symptoms of infarction in whom a bundle branch block is present that precludes detection of ST segment elevation; for patients presenting with six to 12 hours of chest pain, although the expected benefits are less and the actual benefits should be weighed against the risks in patients with relative contraindications to thrombolytic therapy. It is important to calculate the duration of infarction as the time from the last pain-free interval. The infarct 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 even 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 prior stroke. Patients with gastrointestinal bleeding and recent surgery are also at increased risk for bleeding. When risk factors for bleeding are present, however, the potential benefits of thrombolytic therapy may still outweigh the risks. For example, although the elderly are at increased risk for intracerebral bleeding compared with younger patients, elderly patients should certainly be considered candidates for thrombolytic therapy, because their increasing absolute mortality results in a greater absolute mortality reduction with thrombolytic therapy than is seen in younger patients. 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 thrombolytic regimen that restores normal antegrade blood flow to an occluded coronary artery most rapidly and in the greatest number of patients, has the lowest reocclusion rate, and is associated with the lowest risk of severe hemorrhagic complications would be preferred. The first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO-1) trial evaluated four thrombolytic regimens to determine which was associated with the greatest overall survival and stroke-free survival at 30 days: (1) a front-loaded, weight-adjusted tissue plasminogen activator (t-PA) regimen consisting of a bolus of 15 mg and then 0.75 mg/kg (up to a total of 50 mg) over 30 minutes and 0.5 mg/kg (up to a total of 35 mg) over the next 60 minutes, with intravenous heparin (a bolus of 5,000 units and then 1,000 U/hr) to maintain an activated partial thromboplastin time of 60 to 85 seconds; (2) 1.5 million units of streptokinase over 60 minutes with the same doses of intravenous heparin as in the first regimen; (3) 1.5 million units of streptokinase over 60 minutes with subcutaneous heparin (12,500 units twice daily beginning four hours after the start of thrombolytic therapy); and (4) a combination of intravenous t-PA (1.0 mg/kg over 60 minutes, not to exceed 90 mg, with 10 percent given as a bolus) and streptokinase (1 million units over 60 minutes) given concurrently with the same doses of intravenous heparin as in the first regimen. Front-loaded t-PA was found to be superior to the other thrombolytic regimens. Earlier studies comparing t-PA and streptokinase, which had suggested similar efficacy between the two drugs, differed from the GUSTO-1 study in that the earlier studies administered a lower dose of t-PA over a longer period of time and did not administer intravenous heparin, which increases the early patency of the infarct artery with t-PA. However, because of the approximately 10-times-greater cost of t-PA compared with intravenous streptokinase and the low margin of superiority (one life saved per thousand patients treated), many 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.41 The recommendation of streptokinase in these patient groups is largely driven by its lower cost; if the cost 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. Streptokinase therapy is contraindicated in patients who have recently received a dose of streptokinase because of antibodies that form against the drug, limiting the efficacy of repeat doses and increasing the risk of allergic reactions. It has been suggested that the drug not be readministered for at least two years.

DIRECT CORONARY ANGIOPLASTY

Coronary angioplasty without antecedent thrombolytic therapy, termed direct or primary coronary angioplasty, has been studied in the treatment of acute myocardial infarction. After many nonrandomized studies suggested that direct coronary angioplasty was able to rapidly restore normal antegrade blood flow in an initially occluded coronary artery, a randomized study of direct coronary angioplasty was performed in which direct coronary angioplasty compared favorably with intracoronary thrombolytic therapy. Subsequent studies have compared direct coronary angioplasty with intravenous t-PA and streptokinase when it became clear that intravenous thrombolytic therapy was more rapid and efficacious than intracoronary thrombolysis. Prospective, randomized trials comparing direct coronary angioplasty with different thrombolytic agents indicate that direct coronary angioplasty is associated with a lower morbidity and mortality than thrombolytic therapy. Although most of the individual trials were too small to detect statistically significant differences in mortality, pooled data from these trials suggest that direct coronary angioplasty is the preferred therapy for acute myocardial infarction at institutions where it can be performed without delay. The consistency of the results favoring direct coronary angioplasty and the greater speed and frequency with which coronary angioplasty can restore flow to an occluded coronary artery support the conclusion that percutaneous transluminal coronary angioplasty (PTCA) is preferable to thrombolytic therapy at institutions where it can be performed quickly with a high angiographic success rate. The need for surgical backup is controversial, as excellent results have been obtained at centers without surgical backup. However, surgical backup is recommended because approximately five percent of patients with acute myocardial infarction who undergo immediate coronary angiography require emergency surgery either for failed angioplasty or because lethal coronary anatomy precludes PTCA. Although the initial studies comparing direct coronary angioplasty with different thrombolytic therapies were performed primarily at high-volume tertiary medical centers, the Global Use of Strategies to Open Occluded Arteries (GUSTO)-2b trial was an international study in which 1,100 patients were enrolled at hospitals that might more accurately reflect the performance of direct coronary angioplasty in the community. The study was sized to determine whether the mortality reduction present in the smaller randomized trials could be confirmed. The preliminary results of the study indicate that direct coronary angioplasty was associated with a lower mortality, reinfarction rate, and frequency of stroke in the 30 days after enrollment than thrombolytic therapy. However, the degree of benefit associated with direct coronary angioplasty was much smaller than in the earlier randomized studies; the reasons for this difference are unclear. The delay in performing direct angioplasty in the GUSTO-2b study appears to have been greater than in the earlier randomized studies, and the frequency with which normal antegrade flow was restored in the infarct artery appears to have been lower. Further analyses must be performed before the differences in outcome between the earlier randomized studies and the GUSTO-2b study can be fully understood. Because of concerns that the routine use of direct PTCA might actually delay reperfusion in certain medical centers, direct PTCA is currently recommended only in medical centers in which the procedure can be initiated (arterial access achieved) within 60 to 90 minutes, where a high success rate and low complication rate can be demonstrated, and where PTCA is performed in at least 80 to 90 percent of patients with acute myocardial infarction brought to the catheterization laboratory. Although reocclusion and renarrowing of the infarct artery are both associated with adverse outcome and appear to be less frequent with direct PTCA than with thrombolytic therapy, the most important aspect of the initial treatment should be the speed with which normal flow can be restored in the infarct artery. Ideally, physicians should recommend the therapy (thrombolytic therapy or direct PTCA) that is able to restore normal antegrade blood flow in the most infarct arteries most rapidly at their hospital. CORONARY ARTERY BYPASS SURGERY Coronary artery bypass surgery can also restore blood flow in an occluded infarct artery. Emergency bypass surgery has been reported in many small retrospective analyses to be an effective treatment in acute myocardial infarction and was found to be beneficial in a prospective, randomized trial in which it was compared with medical therapy that did not include reperfusion therapy. However, as a result of the time required to perform coronary angiography and transport patients to the operating room, reperfusion is achieved more slowly with bypass surgery than with thrombolytic therapy and direct coronary angioplasty. Emergency coronary artery bypass surgery should generally be reserved for patients in whom immediate angiography reveals coronary anatomy precluding direct coronary angioplasty; for patients with failed angioplasty; and for patients with a ventricular septal defect, severe mitral regurgitation, or myocardial rupture.

REPERFUSION STRATEGIES AND OUTCOMES

 Importance of Time to Reperfusion Many important predictors of early clinical outcome in myocardial infarction are independent of treatment, such as the age of the patient and whether the patient has suffered a prior myocardial infarction, has undergone coronary artery bypass surgery, or has impaired ventricular function. 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 a lower mortality and, among survivors, reduced infarct size in patients with myocardial infarction treated most rapidly. This observation has led to recommendations that the time between a patient’s presentation to the emergency room and the administration of thrombolytic therapy not exceed 60 minutes and ideally not exceed 30 minutes. The National Heart Attack Alert Program Coordinating Committee, 60 Minutes to Treatment Working Group, recommends critical time intervals between the onset of symptoms and the administration of reperfusion therapy along with a modification of these intervals to emphasize that the most critical interval is the time between symptom onset and the achievement of reperfusion and not the time to the initiation of therapy. Thus, therapy that takes longer to initiate (such as direct coronary angioplasty) may actually be superior if it achieves reperfusion more rapidly than another therapy that can be initiated more rapidly (such as thrombolytic therapy).

REPERFUSION THERAPY IN PATIENTS WITHOUT ST SEGMENT ELEVATION

Thrombolytic therapy has been studied in patients with electrocardiographic findings other than ST segment elevation or bundle branch block and has been found to be either of no use or deleterious; its use is not recommended in such patients. Direct 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 persistent ischemic-type chest discomfort despite medical therapy. Many patients with prolonged chest pain without ST segment elevation are not suffering myocardial infarction; the likelihood that infarction is present increases in such patients if repolarization abnormalities are present on the ECG and the patient has risk factors for coronary artery disease. In patients with critical coronary stenoses, immediate PTCA or bypass surgery may be appropriate. In patients without significant coronary 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, as immediate revascularization appears to reduce mortality in this setting. In the Thrombolysis in Myocardial Infarction (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 the ECG. Patients were randomized to early angiography and revascularization medical therapy, followed by exercise testing and angiography in only those patients with recurrent chest pain or a positive exercise test. The study was limited in its ability to evaluate a strategy of immediate angiography specifically in patients with prolonged chest pain without ST segment elevation. Such patients were a minority of patients in the trial because the study was a two-by-two factorial design in which intravenous t-PA was also evaluated, which reduces the efficacy of coronary angioplasty–and nearly as many patients underwent coronary angiography in the conservative group as in the invasive-strategy group. The TIMI IIIB study did show, however, that the initial hospitalization was longer and the need for rehospitalization more frequent in the conservative-strategy group. Other than the avoidance of thrombolytic therapy, patients with ST segment elevation on the initial ECG should be given the same pharmacological therapy as those without. Rescue Coronary Angioplasty Depending on the regimen used, only 33 to 60 percent of patients treated with thrombolytic therapy have restoration of normal antegrade flow in the infarct artery 90 minutes after the initiation of therapy. Accordingly, immediate coronary angiography has been recommended in patients after thrombolytic therapy so that those with persistent occlusion of the infarct artery can be identified and can undergo coronary angioplasty; this has been termed rescue angioplasty. A single, small randomized trial has examined the clinical outcome of patients with anterior infarction and persistent coronary occlusion despite thrombolytic therapy. Patients were randomized to either rescue coronary angioplasty or continued medical therapy alone. The results of the trial suggested improved outcome with rescue angioplasty, although the study was small and the benefits were not compelling. There are insufficient data to recommend immediate angiography and angioplasty in all patients 90 minutes after treatment with thrombolytic therapy; it 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 been found to be either of no benefit or deleterious.68-70 Angioplasty should not be routinely performed in such patients. Adjunctive Medical Therapy

INTRAVENOUS HEPARIN

The need for intravenous heparin after thrombolytic therapy varies with the thrombolytic agents. A recent retrospective analysis of the GUSTO-1 trial suggested that intravenous heparin with a partial thromboplastin time of 50 to 70 seconds was associated with the best clinical outcome in patients treated with t-PA. Data from GUSTO-1 also suggest that intravenous heparin is not required when intravenous streptokinase is used, although heparin is recommended in patients with large anterior infarctions to prevent the development of apical mural thrombus and embolization. Intravenous heparin has also been studied with the thrombolytic agent anisoylated plasminogen streptokinase activator complex (APSAC) and does not increase early patency with that agent. In patients in whom intravenous heparin is not administered, prophylactic therapy with subcutaneous heparin to reduce the risk of deep vein thrombosis should be administered during the period of bed rest. If intravenous heparin is administered, the optimal duration of therapy is unclear. Standard practice has been to administer intravenous heparin for three to five days. It is recommended that heparin not be discontinued less than 24 hours after patient discharge from the hospital because of the possibility of a rebound effect and an increased risk of recurrent thrombosis in the 24 hours after cessation of heparin therapy. Randomized studies from the prethrombolytic era suggested administration of intravenous heparin reduces mortality and reinfarction in patients not treated with thrombolytic therapy. Aspirin and beta blockers were not routinely administered in those early trials, so the true benefits of heparin when these drugs are administered are unknown. However, on the basis of these early data, intravenous heparin is recommended for patients with suspected myocardial infarction not treated with thrombolytic therapy.

BETA-BLOCKER THERAPY

Numerous studies of beta-blocker therapy in patients with acute myocardial infarction have documented significant reductions in in-hospital and long-term mortality. Early administration of beta-blocking agents has been promoted 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 intravenous beta blockers in 27,486 patients with acute myocardial infarction enrolled in 28 randomized trials revealed a 14 percent mortality reduction in the first week of therapy; reinfarction was reduced 18 percent. The second Thrombolysis in Myocardial Infarction (TIMI II) study compared immediate with deferred beta-blocker therapy in acute myocardial infarction. In this study, all patients also received intravenous t-PA. 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 percent of patients with acute myocardial infarction were eligible for acute beta-blocker therapy. It is recommended that all patients with acute myocardial infarction without contraindications receive intravenous beta blockers as early as possible, whether or not they receive reperfusion therapy. In patients in whom contraindications preclude early beta-blocker therapy, reevaluation should take place before discharge. Many patients with contraindications at the time of presentation will no longer have them 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, together including over 100,000 patients, suggests a 6.5 percent reduction in death with an absolute mortality reduction of 4.6 deaths per 1,000 patients among those treated with an ACE inhibitor. All patients with significant ventricular dysfunction (an ejection fraction < 40 percent) 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. The benefit is most clear in patients with large anterior infarctions and an ejection fraction less than 40 percent. Whether patients with normal ventricular function benefit from ACE inhibitor therapy is less clear. If hypotension results from the early administration of ACE inhibitors, short-term mortality may be increased.

INTRAVENOUS NITROGLYCERIN

Randomized studies examining the role of intravenous nitroglycerin in acute myocardial infarction revealed beneficial effects on left ventricular function and a reduction in infarct size and mortality. However, these studies were small and 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 either oral controlled-release mononitrate therapy or placebo; thrombolytic therapy was administered to patients in both groups. 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 intravenous nitroglycerin was administered for the first 24 hours followed by transdermal nitrates. Whether these disappointing results were caused by the routes of administration of the nitroglycerin preparation or the administration of thrombolytic therapy in the ISIS-4 and GISSI-3 trials 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. Intravenous 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 intravenous 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. Neither intravenous lidocaine nor other antiarrhythmic agents are recommended as prophylactic therapy for patients without malignant ventricular ectopy.

CALCIUM CHANNEL ANTAGONISTS

Therapy with calcium channel antagonists should not be routinely administered in acute myocardial infarction. Calcium channel antagonists have been studied in prospective, double-blind, placebo-controlled trials, and neither verapamil, nifedipine nor diltiazem appears to reduce postinfarction mortality. Verapamil may be useful in patients with preserved left ventricular function and no heart failure in whom contraindications to beta blockers exist; diltiazem reduced the occurrence of nonfatal myocardial infarction in the two weeks after acute myocardial infarction in a single study. 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 persistent ischemia despite use of aspirin, beta blockers, nitrate therapy, and intravenous heparin and for patients with other indications for their administration.

MAGNESIUM

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. Seven prospective randomized studies revealed an impressive mortality reduction associated with intravenous magnesium; meta-analysis of these trials revealed a significant mortality reduction with the use of magnesium (odds ratio = 0.44, confidence interval = 0.27 to 0.71). Subsequently, the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) revealed a 25 percent mortality reduction with use of magnesium in over 2,000 patients who had acute myocardial infarction. However, in ISIS-4, in which 58,050 patients were randomized to receive either intravenous magnesium or no magnesium, there was no reduction in 30-day mortality. It is possible that the later administration of magnesium in this study compared with the prior studies and the concomitant use of thrombolytic therapy in 70 percent 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. A subsequent small randomized trial reexamined the role of magnesium in patients in whom reperfusion therapy was not administered and did find a mortality reduction associated with its use. 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 remains possible that magnesium is of benefit in patients not receiving reperfusion therapy. Further studies are planned to evaluate the use of magnesium in patients with acute myocardial infarction. Magnesium is clearly indicated in myocardial infarction patients with 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 electrocardiographic surveillance, and defibrillators in the 1960s led to a reduction in the mortality from acute myocardial infarction through the prompt identification and treatment of ventricular arrhythmia. More recently, 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, where the average response time is less than five minutes, survival from myocardial infarction complicated by cardiac arrest is increased. 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 three to five percent of patients with acute myocardial infarction; the peak incidence is in the first four hours of infarction. Primary ventricular fibrillation is infrequent more than 24 hours after symptom onset. Although it was believed that primary ventricular fibrillation was easily treated and was not associated with an increased in-hospital mortality, recent studies indicate that mortality is increased in patients who suffer this complication. In those who are successfully resuscitated and survive to hospital discharge, however, the long-term prognosis does not appear to be affected. Although lidocaine has been shown to reduce the occurrence of primary ventricular fibrillation, mortality in patients receiving lidocaine was increased because of an increase in fatal bradycardia and asystole, and prophylactic lidocaine is no longer recommended if defibrillation can rapidly be performed. 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, and intravenous amiodarone should be considered in patients in whom defibrillation is initially unsuccessful. Secondary ventricular fibrillation is associated with a high mortality, at least in part because of the underlying hypotension and heart failure. Treatment must be aimed not only at terminating the arrhythmia but also at the hemodynamic abnormalities and their causes. Ventricular Tachycardia Ventricular tachycardia (three or more consecutive ventricular ectopic beats) is common in 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 intravenous 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 percent 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 treated with thrombolytic therapy. 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. Intravenous verapamil and diltiazem may also be effective in such patients. In patients with reduced ventricular function and, in particular, those with congestive heart failure, digoxin can slow the ventricular response. Although less effective than beta blockers or calcium channel blockers in that regard, digoxin is preferred because of its positive inotropic effect, in contrast to the negative inotropic effect of the other agents. If atrial fibrillation recurs, antiarrhythmic agents may be used, although their impact on clinical outcome has not been studied. 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 infrequently required 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 percent of patients with inferior infarction; it is uncommon with infarction at other sites. About half of the heart block seen with inferior infarction is Wenckebach-type second-degree heart block; the remainder is third-degree heart block. The heart block is often easily treated with atropine but may require a temporary pacemaker in as many as 50 percent of cases. The heart block generally lasts for hours to days; placement of a permanent pacemaker is needed in fewer than one percent 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. 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 one percent 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 percent 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 percent 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 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 percent, survival appears to be greater than with medical therapy alone. Therapy aimed at reducing left ventricular afterload, such as intravenous 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 intravenous 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 percent 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 disease.

MYOCARDIAL RUPTURE As more and more patients survive the acute phase of myocardial infarction because of reperfusion therapy, which 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 percent of in-hospital deaths 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. Electrocardiographic 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 occur; however, instead, there is progressive or recurrent ST segment elevation and persistently positive T wave deflections or reversal of initially inverted T waves. Echocardiography can quickly confirm the diagnosis. Even when emergency surgery is performed, fewer than 50 percent 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 percent of affected patients. Hemodynamically significant right ventricular infarction associated with anterior infarction and 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 Kussmaul’s 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. Prompt recognition of right ventricular involvement is clinically important because therapy that reduces right ventricular filling, such as nitrates or diuretics, should be avoided. Volume should be administered to maintain cardiac output; in patients whose hypotension is refractory to volume therapy, dopamine may be beneficial. Heart block, which may occur in as many as 50 percent 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. In patients who survive the initial hospitalization, left ventricular function is the most potent predictor of long-term outcome.

STROKE 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 percent of patients; systemic embolization occurs in about 15 percent 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; if the thrombus is pedunculated or protrudes into the left ventricular cavity or is mobile, it is more likely to embolize and result in stroke. Left ventricular thrombus is an indication for anticoagulation with intravenous heparin followed by warfarin for three to six 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 percent of patients, thrombolytic therapy causes hemorrhagic stroke–most commonly in the 24 hours after its administration–which is fatal in more than 50 percent 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 anticoagulant therapy. Hemorrhagic stroke, the most feared complication of thrombolytic therapy, is more likely in elderly patients; in patients with low body weight, hypertension, or prior stroke; and in those on warfarin. 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. Direct coronary angioplasty is believed to reduce the incidence of ischemic stroke without increasing the risk of hemorrhagic stroke. Coronary Angiography after Uncomplicated Myocardial Infarction In patients who have not undergone direct coronary angioplasty, the role of coronary angiography after uncomplicated myocardial infarction remains controversial. Coronary angiography in patients initially treated with thrombolytic agents has been studied in the TIMI II study, the Should We Intervene Following Thrombolysis? (SWIFT) study, and the Treatment of Post-thrombolytic Stenoses (TOPS) study. 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 patients’ coronary anatomy is known. Patients with low-risk anatomy may be discharged from the hospital more rapidly. Those patients who have left main or multivessel disease and particularly those who have reduced ventricular function may be referred for coronary bypass surgery or percutaneous revascularization. Patients with persistent occlusion of the infarct artery may benefit from late revascularization because of favorable effects on remodeling, a reduction in ventricular arrhythmia, and the improved ability of the infarct 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 patients in whom multivessel disease or reduced ventricular function is believed to be present, coronary angiography may be 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 throughout the world in such patients. 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 low-risk patients without these high-risk characteristics, predischarge 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. 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 direct coronary angioplasty is frequently performed and 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 when 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. In the Danish trial in Acute Myocardial Infarction (DANAMI), 1,008 patients given thrombolytic therapy who had no spontaneous postinfarction angina underwent a predischarge exercise test. Patients in whom exercise-induced ischemia was present were randomized to receive either angiography and coronary angioplasty or medical therapy alone. Patients were followed for a mean of 2.4 years; only three percent of the conservative therapy group underwent revascularization during the follow-up period. The results of this study revealed that clinical outcome was improved in patients in the invasive arm of the study. The DANAMI study was the first to examine the utility 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. Revascularization in patients without spontaneous angina on the basis of the results of exercise testing is less common outside of the United States. Patients with acute myocardial infarction who do not receive thrombolytic therapy or undergo direct angioplasty are at greater risk for adverse events after discharge from the hospital, and predischarge exercise testing is likely to be of even greater utility in such patients. Prognostic variables indicating increased risk during exercise testing include exercise-induced angina or ST segment depression, particularly at a low work load; an abnormal drop in systolic blood pressure; and an inability to complete the exercise test. However, the highest-risk patients are those unable to exercise; such patients have the highest mortality after discharge. 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 four 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 negative predictive value for identifying patients at risk. Currently, a lower-level exercise test is preferred, although a more vigorous test might be appropriate in patients likely to resume a more active and vigorous lifestyle shortly after discharge and in whom a low-level test might 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 disease and prevent the identification of high-risk patients. This does not appear to be a significant concern or outweigh the benefits of early beta-blocker therapy.

Secondary Prevention PHARMACOTHERAPY Lipid-Lowering Therapy Recent studies have demonstrated that in patients with coronary artery disease, lipid-lowering therapy with HMG-CoA reductase inhibitors reduces not only fatal and nonfatal reinfarction but mortality from all causes. The Scandinavian Simvastatin Survival Study revealed a 42 percent reduction in cardiac mortality and a 30 percent reduction in all-cause mortality in 4,444 men and women with coronary artery disease over the 5.4 years of the study.113 The reduction in mortality was similar among patients in the lowest and highest quartiles of serum low-density lipoprotein (LDL) cholesterol. More recently, 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 two years of the initiation of such therapy. Initial measurement of cholesterol should be made within 24 hours of 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 one month. Exercise, weight reduction in overweight patients, avoidance of dietary saturated fat and cholesterol, and smoking cessation have all been reported to favorably influence blood lipids and should be recommended whether or not lipid-lowering medications are prescribed. Anticoagulant Therapy Several prospective, randomized trials revealed that warfarin (Coumadin) 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. Recently, 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 or higher-dose warfarin. Warfarin is also ineffective at preventing coronary reocclusion in patients in whom thrombolytic therapy was successful. At the present time, the routine administration of warfarin is not 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). Since CAST, several studies have been performed examining the role of amiodarone in patients at increased risk for sudden death. Five prospective, randomized studies–Basel Antiarrhythmic Study of Infarct Survival (BASIS), a Polish trial, a Spanish trial, the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), and the European Myocardial Infarction Amiodarone Trial (EMIAT)–have been performed, and the results of these studies taken together do not indicate that amiodarone reduced mortality in the patients enrolled in these trials. Further studies are needed before the routine use of amiodarone can be recommended in high-risk patients such as those included in these trials.

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 survival in patients surviving 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 program can further reduce the likelihood of a return to smoking. Several studies now reveal that treatment of hypercholesterolemia in patients who have suffered a myocardial infarction prolongs survival, even in patients with LDL cholesterol levels as low as 130 mg/dl.

CARDIAC REHABILITATION Although there are few data that conclusively indicate that patients who participate in a cardiac rehabilitation program after discharge increase their survival, an exercise rehabilitation program appears to improve patients’ sense of well-being and to hasten their return to work and leisure activities. A cardiac rehabilitation program can 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 should lead 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 three months, increasing 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 two to three months after myocardial infarction is a more accurate predictor of long-term prognosis than measurement of left ventricular function in the acute stages. PETER B. BERGER, M.D.

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