A. Aspirin

All patients with definite or suspected myocardial infarction should receive aspirin at a dose of 162 mg or 325 mg at once regardless of whether thrombolytic therapy is being considered or the patient has been taking aspirin. Chewable aspirin provides more rapid blood levels. Patients with a definite aspirin allergy may be treated with clopidogrel 300 mg, though the onset of its effectiveness will be slower.

B. Thrombolytic Therapy

Thrombolytic therapy reduces mortality and limits infarct size in patients with acute myocardial infarction associated with ST segment elevation (defined as = 0.1 mV in two inferior or lateral leads or two contiguous precordial leads), or with new-onset LBBB. The greatest benefit occurs if treatment is initiated within the first 3 hours, when a 50% or greater reduction in mortality rate can be achieved.

The magnitude of benefit declines rapidly thereafter, but a 10% relative mortality reduction can be achieved up to 12 hours after the onset of chest pain. The survival benefit is greatest in patients with large-usually anterior-infarctions. Patients without ST segment elevation (previously labeled “non-Q wave” infarctions) generally have incomplete or partially recanalized occlusions and have not benefited from thrombolysis. Thrombolytic therapy has also not been shown to improve the prognosis of patients with prior coronary artery bypass grafting, presumably because it is ineffective in opening bypass grafts.

Major bleeding complications occur in 0.5-5% of patients, the most serious of which is intracranial hemorrhage. The major risk factors for intracranial bleeding are age over 65 years, hypertension at presentation, low body weight (< 70 kg), and the use of clot-specific thrombolytic agents (alteplase, reteplase, tenecteplase). Although patients over age 75 have a much higher mortality rate with acute myocardial infarction and, therefore, potentially greater benefit, the risk of severe bleeding is also much higher and the net benefit is less clear. Patients presenting more than 12 hours after the onset of chest pain may also derive a small benefit, particularly if pain and ST segment elevation persist, but rarely does this benefit outweigh the attendant risk.

Therefore, the current recommendation is to administer thrombolytic therapy to patients with ST segment elevation infarctions who are under 75 years of age and present within 6-12 hours of the onset of symptoms. Contraindications include previous Hemorrhagic stroke, other strokes, or cerebrovascular events within 1 year, known intracranial neoplasm, current blood pressure > 180 mm Hg systolic or 110 mm Hg diastolic, active internal bleeding (excluding menstruation), or suspected aortic dissection. Relative contraindications are blood pressure > 180/110 mm Hg at presentation, other intracerebral pathology not listed above as a contraindication, known bleeding diathesis, trauma within 2-4 weeks, major surgery within 3 weeks, prolonged (> 10 minutes) or traumatic Cardiopulmonary resuscitation, recent (within 2-4 weeks) internal bleeding, noncompressible vascular punctures, active diabetic retinopathy, pregnancy, active peptic ulcer disease, a history of severe hypertension, current use of anticoagulants (INR > 2.0-3.0), and prior allergic reaction or exposure within 2 years to streptokinase or anistreplase.

Five thrombolytic agents are available for acute myocardial infarction.

Streptokinase was the first thrombolytic agent to be extensively evaluated. It is less clot-specific and has subsequently proved to produce rapid but less effective coronary artery reopening than the newer agents, although the mortality differences are small. Streptokinase has a tendency to induce sometimes severe hypotension, particularly if infused rapidly. This can be managed by slowing or interrupting the infusion and administering fluids. There is little evidence that adjunctive heparin is beneficial in patients given streptokinase, unlike when it is administered with the more clot-specific agents. Allergic reactions, including anaphylaxis, occur in 1-2% of patients, and this agent should generally not be administered to patients with prior exposure.

Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC) is a conjugate of streptokinase that is inactive until the anisoyl group is hydrolyzed, which occurs gradually after injection (half-time 90 minutes). Thus, it can be injected as a bolus but will provide continuing thrombolytic activity. Otherwise, it has most of the same features of streptokinase, including the potential to produce allergic reactions and hypotension. Newer agents that can also be administered as boluses have largely supplanted it.

Alteplase (recombinant tissue plasminogen activator; t-PA) is a naturally occurring thrombolytic factor that is theoretically thrombus-specific. In the first GUSTO trial, which compared t-PA with streptokinase, the 30-day mortality rate with t-PA was one absolute percentage point lower (one additional life saved per 100 patients treated), though there was also a small increase in the rate of intracranial hemorrhage. An angiographic substudy confirmed a higher 90-minute patency rate and a higher rate of normal (TIMI grade 3) flow in patients. Alteplase has a shorter half-life than streptokinase and is associated with a higher rate of early reocclusion, thus necessitating the concomitant use of intravenous heparin. Alteplase has since become the most widely used thrombolytic therapy in the United States despite a considerably higher price than that of streptokinase.

Two additional clot-specific agents are now available. Reteplase is a recombinant plasminogen activator closely related to t-PA. In comparative trials it appears to have efficacy similar to that of alteplase, but it has a longer duration of action and can be administered as two boluses 30 minutes apart. Tenecteplase (TNK-t-PA) is a genetically engineered mutant of native t-PA that has reduced plasma clearance, increased fibrin sensitivity, and increased resistance to plasminogen activator inhibitor-1. It can be given as a single weight-adjusted bolus. In a large comparative trial, this agent was quite comparable to t-PA with regard to both efficacy and safety.

Selection of a thrombolytic agent: Although there continues to be heated discussion about which agent to use, the relatively small differences in efficacy between them are minor compared with the potential benefit of treating a greater proportion of appropriate candidates in a more prompt manner. The principal objective should be to administer a thrombolytic agent within 30 minutes of presentation-or even during transport. The evidence does suggest that the clot-specific agents (alteplase, reteplase, and tenecteplase) are marginally more effective than streptokinase, and thus they are generally favored by most cardiologists. These agents do produce slightly higher rates of intracranial bleeding and require intravenous coadministration of heparin, which also increases bleeding risk. As a result, streptokinase may be preferable in patients at higher risk of this complication, particularly older patients with elevated blood pressures. Streptokinase and anistreplase should be avoided in patients with previous allergic reactions or recent exposure to either. Because of their potential for substantially lowering blood pressure, they should also be avoided in patients who present with hypotension. The ability to administer tenecteplase as a single bolus is an attractive feature that may facilitate earlier treatment. The combination of a reduced-dose thrombolytic given with a platelet glycoprotein IIb/IIa antagonist has been investigated in several trials, with variable evidence of greater efficacy but a definite increase in bleeding complications.

Postthrombolytic management: After completion of the thrombolytic infusion, aspirin should be continued. Anticoagulation with intravenous heparin (60 units/kg bolus to a maximum of 4000 units, followed by an infusion of 12 units/kg/min adjusted to maintain an aPTT of 50-75 seconds) is continued for at least 24 hours after alteplase, reteplase, or tenecteplase but is optional in patients receiving streptokinase. Prophylactic treatment with antacids and an H2 blocker is indicated.

Reperfusion rates of 40-80% can be expected, determined primarily by the interval between onset of the infarction and treatment. Reperfusion is recognized clinically by the abrupt cessation of pain, the occurrence of ventricular arrhythmias (most characteristically accelerated idioventricular rhythm), the rapid evolution of the ECG to Q waves, and an early peak of CK (by 12 hours); however, all of these signs may be misleading. Even with anticoagulation, 10-20% of reperfused vessels will reocclude during hospitalization. This is usually recognized by the recurrence of pain and ST segment elevation and is treated by readministration of a thrombolytic agent or immediate angiography and PTCA.

The optimal management of myocardial infarction after thrombolysis is controversial but has been clarified considerably by the TIMI 2 trial. Patients with recurrent ischemic pain prior to discharge should undergo catheterization and, if indicated, revascularization. Asymptomatic, clinically stable patients should undergo predischarge evaluation to determine whether residual jeopardized myocardium is present. This can be accomplished by submaximal exercise or pharmacologic stress scintigraphy. Those with significantly positive tests or a low threshold for symptomatic ischemia should undergo angiography and revascularization where feasible. Patients with negative tests have an excellent prognosis without intervention, though they may require revascularization for symptoms at a later time.

C. Acute PTCA and Stenting for ST Segment Elevation Myocardial Infarction

Immediate coronary angiography and PTCA or stenting of the infarct-related artery is an increasingly utilized alternative to thrombolysis. It is the approach of choice in patients with absolute and many relative contraindications to thrombolytic therapy. The results of this approach in specialized centers are excellent, exceeding those obtainable by thrombolytic therapy even in good candidates, but this experience may not be generalizable to centers and operators with less experience or expertise. Stenting-in conjunction with platelet glycoprotein IIb/IIIa antagonists-is now widely used in acute myocardial infarction patients. In the subgroup of patients with cardiogenic shock, early catheterization and percutaneous or surgical revascularization is the preferred management, because thrombolysis has not improved their dismal prognosis. Because an acute interventional approach carries a lower risk of hemorrhagic complications, it may also be the preferred strategy in older patients.

D. Initial Management of Non-ST-Segment Elevation Myocardial Infarction

Patients presenting with an acute myocardial infarction without ST segment elevation or evolving Q waves generally do not have persistent thrombotic coronary occlusions (with the exception of LBBB or anterior ST segment depressions that may represent reciprocal changes from a true posterior infarction). Thrombolytic therapy is not appropriate in these patients, and in general their management should be similar to that of patients with unstable angina, who usually have the same underlying pathophysiology. This is described in the previous section, and includes aspirin, heparin, platelet glycoprotein IIb/IIIa antagonists, beta-blockers, and nitrates. As is the case with unstable angina, controversy continues over whether there is an advantage to a routine strategy of early coronary angiography, but patients with continuing or recurrent ischemia or very positive stress tests should undergo angiography and revascularization when appropriate.

E. General Measures

CCU monitoring should be instituted as soon as possible. Uncomplicated patients can be transferred to a telemetry unit after 24-48 hours. Activity should initially be limited to bed rest but can be advanced within 24 hours. Progressive ambulation should be started after 24-72 hours if tolerated. Low-flow oxygen therapy (2-4 L/min) should be given if oxygen saturation is reduced.

F. Analgesia

An initial attempt should be made to relieve pain with sublingual nitroglycerin. However, if no response occurs after two or three tablets, intravenous opioids provide the most rapid and effective analgesia and may also reduce pulmonary congestion. Morphine sulfate, 4-8 mg, or meperidine, 50-75 mg, should be given. Subsequent small doses can be given every 15 minutes until pain abates.

G. Beta-Adrenergic Blocking Agents

Several studies have shown modestly improved short-term survival when intravenous beta-blockers (metoprolol, 5 mg intravenously every 5 minutes for three doses) are given immediately after acute myocardial infarction. These agents reduce the duration of ischemic pain and the incidence of ventricular fibrillation. A favorable effect appears to persist even after thrombolytic therapy. Beta-blockade should be avoided in patients with decompensated heart failure, asthma, or high degrees of atrioventricular block.

H. Nitrates

Nitroglycerin is the agent of choice for recurrent ischemic pain and is useful in lowering blood pressure or relieving pulmonary congestion. However, routine nitrate administration is not recommended, since no improvement in outcome has been observed in the ISIS-4 or GISSI-3 trials, in which a total of over 70,000 patients were randomized to nitrate treatment or placebo.

I. Angiotensin-Converting Enzyme (ACE) Inhibitors
A series of trials (SAVE, AIRE, SMILE, TRACE, GISSI-III, and ISIS-IV) have shown both short- and long-term improvement in survival with ACE inhibitor therapy. The benefits are greatest in patients with low ejection fractions, large infarctions, or clinical evidence of heart failure, and only these patients should receive chronic ACE inhibitor therapy for postinfarction indications. Acute short-term treatment may improve survival in a broader group of patients, but this is uncertain. Treatment should be commenced carefully in the first postinfarction day if the patient is not hypotensive. When there is no evidence of heart failure or when a very large infarction is not present, ACE inhibitors should be considered only after the administration of thrombolytic therapy, aspirin, beta-blockers, and, if the patient has evidence of continuing ischemia, nitrates.

J. Antiarrhythmic Prophylaxis

The incidence of ventricular fibrillation in hospitalized patients is approximately 5%, with 80% of episodes occurring in the first 12-24 hours. Prophylactic lidocaine infusions (1-2 mg/min) prevent most episodes, but this therapy has not reduced the mortality rate and it increases the risk of asystole, so this approach is no longer recommended except in patients with nonsustained ventricular tachycardia. Intravenous magnesium sulfate has been effective in one study, but ISIS-4 did not report a benefit with routine magnesium administration.

K. Calcium Channel Blockers

There are no studies to support the use of calcium channel blockers in most acute myocardial infarction patients-and indeed, they have the potential to exacerbate ischemia and cause death from reflex tachycardia or myocardial depression. One exception is that diltiazem and verapamil appear to prevent reinfarction and ischemia in the subset of patients with non-Q wave infarction. Diltiazem is preferable because it causes less myocardial depression. The dosage is 240-360 mg daily. Otherwise, long-acting calcium channel blockers should be reserved for management of hypertension or ischemia as second- or third-line drugs after beta-blockers and nitrates.

L. Anticoagulation

With the exception of patients undergoing thrombolysis and subsequent heparin therapy, the use of full anticoagulation in the acute setting remains controversial. Patients who will be at bed rest or on limited activity status for some time should be given prophylaxis for deep vein thrombosis (5000 units of heparin subcutaneously every 12 hours) unless contraindicated. Aspirin, 325 mg daily, should be continued also unless contraindicated.

Preferences:
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