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Management of acute myocardial infarction: Evaluating the past, practicing in the present, elaborating the future
Management of acute myocardial infarction: Evaluating the past, practicing in the present, elaborating the future Dietmar Glogar, MD, FESC, Paul Yang, MD, and Giinter Steurer, MD Vienna, Austria
The management of acute myocardial infarction initially focused on treatment and/or prevention of complications. In the prethrombolytic era, therapeutic regimens mainly comprised the use of antianginal and antiarrhythmic drugs. The development of semi-invasive hemodynamically guided treatment concepts led to remarkable improvement in clinical outcome. After the introduction of the "wave-front phenomenon," multiple pharmacologic treatment strategies were developed with the goal of infarct size reduction. The use of thrombolytic agents reduced infarct size and improved prognosis of patients with acute myocardial infarction. Acute angioplastic intervention was introduced in specialized centers to achieve rapid restoration of coronary blood flow. The protection of the myocardium from reperfusion injury, however, remains an unresolved issue. Intravenous magnesium administration in conjunction with new and better recanalization techniques could therefore be a promising therapy strategy in patients with acute myocardial infarction. (Am Heart J 1996;132:465-70.)
Treatment of patients with acute myocardial infarction (AMI) has gone through a very long evolution, and the development of new and better strategies is ongoing. 1 In-hospital management of patients with symptoms of AMI started with patient surveillance and the treatment of infarct complications. 2, 3 In the 1970s, pulmonary artery catheterization of patients with AMI enabled hemodynamic measurements and guided pharmacologic therapy on the basis of hemodynamic values. 4-6 After routine hemodynamic monitoring was introduced in patients with acute ischemic syndromes, the development of new cardiac imaging techniques aroused interest in determining infarct size and developing treatment strategies to reduce infarct size.7, s In the 1980s the aggressive use of thrombolytic agents reduced the extent of infarct size and improved the prognosis of patients with AMI.9-13 However, the finding that fibrinolytic agents From the Department of Cardiology, University of Vienna Medical School. Reprint requests: Dietmar Glogar, MD, FESC, Department of Cardiology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/0/74322
resulted in incomplete and delayed revascularization in a cohort of patients attenuated the enthusiasm of the early thrombolytic era. 14 When it was found in large randomized trials that direct coronary angioplasty opens occluded coronary arteries more rapidly and in a greater number of patients compared with thrombolytic therapy, direct angioplasty was established as a substitute for thrombolysis.15-17 In addition to the enormous advances that have been achieved in restoring the patency of the infarctrelated artery, successful suppression of neurohumoral activation after AMI by angiotensin-converting enzyme (ACE) inhibitors has been found to prevent ventricular remodeling and improve the long-term outcome of patients with an infarction.iS'21 Lifestyle changes, including a reduction in cigarette smoking, maintenance of a diet lower in saturated fat and cholesterol, an increase in the level of exercise, and use of aspirin and lipid-lowering therapy, has further contributed to a decline in mortality from ischemic heart disease. 22-24 PREHOSPITAL MANAGEMENT
Early hospitalization of patients with AMI reduced mortality in the prehospital period and stimulated the development of ambulance systems and the formation of coronary care units. The Austrian health system and the Austrian Heart Foundation were early supporters of the installation of coronary care ambulances and helicopters staffed by medical teams or trained paramedics. Between 1970 and 1980, approximately 90 of 120 internal medicine departments in Austria were provided with coronary care units. 25 In the prethrombolytic era, the prehospital management of patients with AMI focused on oxygen supply, pain relief with analgesics, pre- and afterload reduction with nitrates, antithrombotic therapy with aspirin, and provision of facilities for resuscitation. 3 In the thrombolytic era, the prehospital administration of thrombolytic agents significantly improved the outcome of patients with AMI compared with inhospital thrombolytic therapy. 26 This treatment reg465
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imen, however, has not achieved widespread acceptance because of logistical reasons and the inability of most ambulance systems and hospitals to organize such prehospital care programs. CORONARY CARE UNIT
The establishment of coronary care units (CCUs) staffed by a trained medical team 24 hours a day enabled continuous monitoring of cardiac rhythm, noninvasive and invasive hemodynamics, arterial oxygen saturation, and blood chemistry in patients with acute myocardial ischemia. The widespread use of direct current (DC) defibrillators for resuscitation of patients with ventricular fibrillation, the reduction of ventricular filling pressure with the use of nitrates, the reduction of afterload with the use ofvasodilators, the treatment of pump failure with the use ofinotropic pharmacologic agents, and the management of tachyarrhythmias with lidocaine and bradyarrhythmias with pacemakers dramatically reduced in-hospital mortality in the early CCU era compared with that in the pre-CCU era. 3, 6 The invasive monitoring ofhemodynamicswith the use of a pulmonary artery balloon flotation catheter guided pharmacologic therapy. 27 In particular, the relationship between the left ventricular filling pressure and the cardiac index was used for hemodynamic classification and risk stratification in patients with AMIyS, 29 ANTIARRHY'I'HMIC THERAPY STRATEGIES
DC cardioversion is the therapy of choice for the management of primary ventricular fibrillation, the most important complication of AMI. 3° Failure of DC shock to restore sinus rhythm indicates a poor prognosis, 31 and it was found that adjunctive agents, including adrenaline, lidocaine, and bicarbonate, failed to improve prognosis. Prophylactic lidocaine therapy was used less frequently after it was observed that rhythm disorders are frequent in the early hours of acute infarction, but require aggressive treatment only if hemodynamic consequences are observed or ventricular tachycardia or fibrillation occurs.32 Heart block may develop in 6% to 14% of patients with AMI. In-hospital mortality is higher in patients in whom heart block develops, whereas the longterm prognosis of patients discharged from the hospital after AMI is similar whether or not acute heart block develops. 33, 34Despite the continuous decline of in-hospital mortality of patients with AMI as a result of improvement of the management of acute complications, mortality has remained considerably high. In the 1970s, an Austrian infarct study revealed an average mortality of between 20% and 30% in pa-
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tients with AMI, depending on the age and risk situation of the patient. 25 Spontaneous sustained ventricular tachycardia 48 hours after AMI and inducible ventricular tachycardia are late complications of AMI resulting from a fixed reentry circuit and have prognostic importance. The optimal management of patients with episodes of sustained ventricular tachycardia includes antiarrhythmic drug therapy with class III drugs, implantation of an intracardiac defibrillator, and antiarrhythmic surgery.35 Whereas initial studies of class III antiarrhythmic agents such as amiodarone suggested an improved survival rate in patients after myocardial infarction,35 this was not confirmed by recent prospective studies. 36 The Survival With Oral d-Sotalol (SWORD) trial ~ assessed the effect of d-sotalol on patients who survived AMI. The trial was discontinued when an association was found between d-sotalol medication and increased mortality risk. The implantable defibrillator has been shown to significantly reduce the incidence of sudden death in patients with ventricular arrhythmias and heart failure. However, doubts still exist about its ability to improve long-term survival rates. 35 PHARMACOLOGIC THERAPY FOR INFARCT SIZE REDUCTION
Since Reimer et al.37 introduced the "wave-front phenomenon" concept of infarct expansion in the late 1970s, multiple pharmacologic strategies have been developed to reduce infarct size. Several clinical triMs have demonstrated that early mortality is reduced by administration of intravenous ~-blockers, particularly atenolol and metoprolol, followedby oral treatment for varying periods. 3s Two mega-trials, the First International Study of Infarct Survival (ISIS-l) 39 (atenolol) and Metoprolol In Acute Myocardial Infarction (MIAMI)4° (metoprolol), have shown a 13% to 14% reduction in early mortality. Although mechanisms for early mortality reduction by ~-blockade are still unclear, results from clinical studies suggest that the most probable underlying mechanisms are limitation of infarct progression, reduction of infarct size, reduction of the incidence of reinfarction, and, to some extent, suppression of malignant ventricular arrhythmias, 39-41 The benefit achieved by early administration of ~-blockers translates into substantial long-term benefit. Maintenance of 6-blockers is thus recommended after AMI, although similar benefits may be achieved with other pharmacologic treatment strategies such as ACE inhibitors and lipid-lowering agents. It has been shown that when nitrates are admin-
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istered during the acute phase of the infarction, infarct expansion and mortality are reduced by approximately 30%. 42 Several clinical trials have revealed beneficial effects of nitrates, administered either intravenously or orally, with respect to mortality reduction, limitation of infarct size, preservation of the jeopardized myocardium, or improvement of ventricular function. 42, 43 In contrast, the ISIS-4 trial failed to indicate a long-term benefit of nitrate medication after acute infarction. 44 However, the results of the ISIS-4 trial did not change management strategies concerning AMI, and nitrates are still used during the acute stage and as chronic medication in symptomatic patients. Trials of antiischemic drugs, especially B-blockers and nitrates, were carried out before the use of thrombolysis and primary angioplasty became widespread. Whether ~-blockers, nitrates, and other pharmacologic agents provide beneficial effects in conjunction with thrombolytic therapy or primary mechanical reperfusion strategies remains to be determined in well-designed clinical trials. INTRAVENOUS THROMBOLYTIC THERAPY
In the early 1980s DeWood et al. 45 convincingly demonstrated that thrombotic occlusion occurs in the early phase of myocardial infarction. Plaque fissuring and/or disruption with subsequent thrombus formation, occlusion, or reocclusion of the vessel lumen have been established as the major pathomechanisms underlying acute ischemic syndromes. 46, 47 Consequently, lysis of the obstructing coronary thrombus has become the focus of research during the past decade. Although spontaneous clot lysis may occur in approximately 20% of myocardial infarctions, 45 in most cases it occurs too late to save the viable myocardium. Early reperfusion with the use ofthrombolytic agents has been shown to have favorable results for early and late survival, preservation of the ventricular function, and limitation of infarct size. 9, 4s-50 However, the first attempts at thrombolysis in the early 1970s turned out to be rather frustrating. The European Working Party 5i performed one of the first large-scale trials that studied the efficacy of systemic thrombolysis; in this trial, streptokinase was used in an infusion protocol for several hours, followed by anticoagulation with coumadin. Although a trend for improvement in the mortality rate was noted, there was also a high rate of bleeding complications and strokes. Issues of timing, dose, and duration of thrombolytic therapy remained unanswered. 51, 52 Intracoronary application of thrombolytic agents was first introduced as a viable treatment concept by
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Rentrop et aL 53 in the early 1980s. In these first series, intracoronary thrombolysis with streptokinase was effective in achieving patency in more than 80% of patients after 1 to 2 hours of treatment. The feasibility of intracoronary lysis in clinical settings remained questionable because of the limited availability of catheterization laboratories and the time wasted by the admitting institutions before treatment Was started. The first large trial of systemic thrombolytic therapy in patients with AMI, Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI), 9 reaffirmed the importance of early therapy by demonstrating a 23% reduction in in-hospital mortality among patients treated with intravenous streptokinase within 3 hours of the onset of chest pain and a 50% reduction in mortality among those treated within 1 hour after the onset of chest pain. 9 Since then, several trials have attempted to prove the superior efficacy of various thrombolytic agents and treatment protocols with respect to mortality and left ventricular function. The largest of these trials were GISSI-254 and ISIS-3, 55 both of which compared the efficacy of intravenous streptokinase and recombinant tissue plasminogen activator (rtPA). Data from these two trials, which included more than 60,000 patients, have shown equivalent survival rates with the use of either streptokinase or r-tPA. However, several large-scale trials demonstrated that the use ofr-tPA activator achieved more rapid, complete, and earlier thrombolysis. The Thrombolysis In Myocardial Infarction (TIMI) trials have shown that r-tPA is superior to streptokinase in achieving early reperfusion. 56 Compared with the standard thrombolytic regimen with streptokinase, a survival benefit was found when accelerated t-PA was given with intravenous heparin.i4, 57Among trials that dealt with a "frontloaded" r-tPA dose regimen, i0 the RAPID trial 5s demonstrated coronary patency in 78% of the patients after 60 minutes and in 95% of the patients after 14 days. ADJUNCTIVE THERAPY
Results of several trials suggest that the use of additional medication further increases the beneficial effects of thrombolytic therapy. 55, 59 In the ISIS-2 trial, 59 the combination of antiplatelet and thrombolytic therapy almost doubled the mortality reduction without causing a significant increase in bleeding complications. These results support the early addition of aspirin to intravenous streptokinase therapy. The administration of intravenous magnesium in AMI as shown in the Second Leicester Intravenous
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Magnesium Intervention (LIMIT-2) trial 6° resulted in an attenuation of left ventricular dysfunction and a reduction of mortality in the early post-infarction period compared with patients who received placebo. The dose regimen used in the LIMIT-2 trial was a bolus infusion of 8 mmol magnesium followed by an infusion of 65 mmol during a 24-hour period. To establish a therapeutic regimen of intravenously administered magnesium, the LIMIT-2 protocol was adopted for ISIS-4, a clinical mega-trial. 44 However, results from the ISIS-4 trial concerning the efficacy of magnesium therapy in AMI were disappointing and led to the so-called "ISIS-crisis." Consecutively, several reviews 61-62 and meta-analyses 63-65 of LIMIT-2, ISIS-4, other previous clinical trials indicated that the timing of magnesium therapy plays a pivotal role in the success of magnesium treatment. Thus the pharmacologic role of magnesium in AMI must be elucidated by additional clinical trials. PRIMARY ANGIOPLASTY
The use of balloon angioplasty as an alternative strategy to achieve reperfusion was first introduced by Hartzler et al.66 in the early 1980s. Since then several interventional centers have been performing primary or direct coronary angioplasty with a high rate of success and a low in-hospital mortality rate. The rate of infarct-vessel patency was consistently high in reported observation studies, 67 and a reduction in the incidence of hemorrhagic stroke and bleeding complications was noted. During the past few years, encouraging results have been reported from several randomized trials that compared primary angioplasty and intravenous thrombolysis with tissue-plasminogen activator or streptokinase)~, 17, 6s Although most of these trials failed to show an improvement of ejection fraction or infarct size (with the exception of the "Zwolle trial" by Zijlstra e t a ] . 17 that found an improvement of ejection fraction for primary angioplasty versus streptokinase), the rapid restoration of infarct vessel patency and flow, and the improved survival rates are evident with primary angioplasty. Improve: ments in interventional techniques and equipment, and compelling results of studies of new adjunctive pharmacologic agents such as glycoprotein IIb/IIIa receptor antagonists justify expectations of further refinement of acute interventional approach in highrisk patients, and particularly in patients with AMI. SUMMARY
Because of the recent development of many competing strategies for the management of AMI, we are currently confronted with the problem of being
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unable to recommend one particular strategy as the optimal means of managing AMI. Prospective randomized protocols usually involve treatment strategies performed under optimized conditions that may not be found in everyday life for the majority of patients. Therefore, the availability of local resources, the cost-effectiveness of strategies, and the optimal timing for specific treatment modalities must be taken into consideration when making a treatment choice. It will be necessary for future investigations to address the question of combined treatment strategies, such as the combination of several pharmacologic treatment modalities or the use of aggressive interventional strategies in combination with pharmacologic interventions. The concept of intravenous administration of magnesium in patients with AMI has evolved over time from an adjunctive treatment modality for the reduction of arrhythmias during the first hours of infarction to an effective pharmacologic treatment for the attenuation of reperfusion injury. Thus, in the near future we may observe a more widespread use of a combined treatment strategy involving early reperfusion by m e a n s of either primary angioplasty or thrombolysis together with early loading treatment with magnesium infusion. This treatment strategy may be followed by a medication protocol with ACE inhibitors, p-blockers, and lipid-lowering agents to achieve maximum long-term benefit.
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61. Antman EM. Randomized trials of magnesium in acute myocardial infarction: big numbers do not tell the whole story. Am J Cardiol 1995;75:391-3. 62. Antman EM. Magnesium in acute MI: timing is critical. Circulation 1995;92:2367-72. 63. Antman E, Lau J, Kupelnik B, Mosteller F, Chalmers T. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. JAMA 1992;268:240-8. 64. Seelig MS, Elin RJ. Reexamination of magnesium infusions in myocardial infarction, Am J Card,el t995;76:172-3. 65. Woods KL. Mega-trials and management of acute myocardial infarction. Lancet 1995;346:611-4. 66. Hartzler G, Rutherford B, McConahay D, Johnson WJ, McCallister B, Gura GJ, Conn R, Crockett J. Percutaneous transluminal coronary angioplasty, with and without thrombolytic therapy for treatment of acute myocardial infarction. Am Heart J 1983;106:965-73. 67. Eckman MH, Wong JB, Salem DN, Pauker SG. Direct angioplasty for acute myocardial infarction: a review of outcomes in clinical subsets. Ann Intern Med 1992;117:667-76. 68. Gibbons RJ, Verani MS, Behrenbeck T, Pellikka P, O'Conner MK~ Mahamarian JJ, Chesebro JH, Wackers FJ. Feasibility of tomographic 99m-Tc-bexakis-2-methoxy-2-methylpropyl-isonitril imaging for the assessment of myocardial area at risk and the effects of treatment in acute myocardial infarction. Circulation 1989;80:1277-86.
The management of acute myocardial infarction initially focused on treatment and/or prevention of complications. In the prethrombolytic era, therapeutic regimens mainly comprised the use of antianginal and antiarrhythmic drugs. The development of semi-invasive hemodynamically guided treatment concepts led to remarkable improvement in clinical outcome. After the introduction of the "wave-front phenomenon," multiple pharmacologic treatment strategies were developed with the goal of infarct size reduction. The use of thrombolytic agents reduced infarct size and improved prognosis of patients with acute myocardial infarction. Acute angioplastic intervention was introduced in specialized centers to achieve rapid restoration of coronary blood flow. The protection of the myocardium from reperfusion injury, however, remains an unresolved issue. Intravenous magnesium administration in conjunction with new and better recanalization techniques could therefore be a promising therapy strategy in patients with acute myocardial infarction. (Am Heart J 1996;132:465-70.)
Treatment of patients with acute myocardial infarction (AMI) has gone through a very long evolution, and the development of new and better strategies is ongoing. 1 In-hospital management of patients with symptoms of AMI started with patient surveillance and the treatment of infarct complications. 2, 3 In the 1970s, pulmonary artery catheterization of patients with AMI enabled hemodynamic measurements and guided pharmacologic therapy on the basis of hemodynamic values. 4-6 After routine hemodynamic monitoring was introduced in patients with acute ischemic syndromes, the development of new cardiac imaging techniques aroused interest in determining infarct size and developing treatment strategies to reduce infarct size.7, s In the 1980s the aggressive use of thrombolytic agents reduced the extent of infarct size and improved the prognosis of patients with AMI.9-13 However, the finding that fibrinolytic agents From the Department of Cardiology, University of Vienna Medical School. Reprint requests: Dietmar Glogar, MD, FESC, Department of Cardiology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/0/74322
resulted in incomplete and delayed revascularization in a cohort of patients attenuated the enthusiasm of the early thrombolytic era. 14 When it was found in large randomized trials that direct coronary angioplasty opens occluded coronary arteries more rapidly and in a greater number of patients compared with thrombolytic therapy, direct angioplasty was established as a substitute for thrombolysis.15-17 In addition to the enormous advances that have been achieved in restoring the patency of the infarctrelated artery, successful suppression of neurohumoral activation after AMI by angiotensin-converting enzyme (ACE) inhibitors has been found to prevent ventricular remodeling and improve the long-term outcome of patients with an infarction.iS'21 Lifestyle changes, including a reduction in cigarette smoking, maintenance of a diet lower in saturated fat and cholesterol, an increase in the level of exercise, and use of aspirin and lipid-lowering therapy, has further contributed to a decline in mortality from ischemic heart disease. 22-24 PREHOSPITAL MANAGEMENT
Early hospitalization of patients with AMI reduced mortality in the prehospital period and stimulated the development of ambulance systems and the formation of coronary care units. The Austrian health system and the Austrian Heart Foundation were early supporters of the installation of coronary care ambulances and helicopters staffed by medical teams or trained paramedics. Between 1970 and 1980, approximately 90 of 120 internal medicine departments in Austria were provided with coronary care units. 25 In the prethrombolytic era, the prehospital management of patients with AMI focused on oxygen supply, pain relief with analgesics, pre- and afterload reduction with nitrates, antithrombotic therapy with aspirin, and provision of facilities for resuscitation. 3 In the thrombolytic era, the prehospital administration of thrombolytic agents significantly improved the outcome of patients with AMI compared with inhospital thrombolytic therapy. 26 This treatment reg465
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imen, however, has not achieved widespread acceptance because of logistical reasons and the inability of most ambulance systems and hospitals to organize such prehospital care programs. CORONARY CARE UNIT
The establishment of coronary care units (CCUs) staffed by a trained medical team 24 hours a day enabled continuous monitoring of cardiac rhythm, noninvasive and invasive hemodynamics, arterial oxygen saturation, and blood chemistry in patients with acute myocardial ischemia. The widespread use of direct current (DC) defibrillators for resuscitation of patients with ventricular fibrillation, the reduction of ventricular filling pressure with the use of nitrates, the reduction of afterload with the use ofvasodilators, the treatment of pump failure with the use ofinotropic pharmacologic agents, and the management of tachyarrhythmias with lidocaine and bradyarrhythmias with pacemakers dramatically reduced in-hospital mortality in the early CCU era compared with that in the pre-CCU era. 3, 6 The invasive monitoring ofhemodynamicswith the use of a pulmonary artery balloon flotation catheter guided pharmacologic therapy. 27 In particular, the relationship between the left ventricular filling pressure and the cardiac index was used for hemodynamic classification and risk stratification in patients with AMIyS, 29 ANTIARRHY'I'HMIC THERAPY STRATEGIES
DC cardioversion is the therapy of choice for the management of primary ventricular fibrillation, the most important complication of AMI. 3° Failure of DC shock to restore sinus rhythm indicates a poor prognosis, 31 and it was found that adjunctive agents, including adrenaline, lidocaine, and bicarbonate, failed to improve prognosis. Prophylactic lidocaine therapy was used less frequently after it was observed that rhythm disorders are frequent in the early hours of acute infarction, but require aggressive treatment only if hemodynamic consequences are observed or ventricular tachycardia or fibrillation occurs.32 Heart block may develop in 6% to 14% of patients with AMI. In-hospital mortality is higher in patients in whom heart block develops, whereas the longterm prognosis of patients discharged from the hospital after AMI is similar whether or not acute heart block develops. 33, 34Despite the continuous decline of in-hospital mortality of patients with AMI as a result of improvement of the management of acute complications, mortality has remained considerably high. In the 1970s, an Austrian infarct study revealed an average mortality of between 20% and 30% in pa-
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tients with AMI, depending on the age and risk situation of the patient. 25 Spontaneous sustained ventricular tachycardia 48 hours after AMI and inducible ventricular tachycardia are late complications of AMI resulting from a fixed reentry circuit and have prognostic importance. The optimal management of patients with episodes of sustained ventricular tachycardia includes antiarrhythmic drug therapy with class III drugs, implantation of an intracardiac defibrillator, and antiarrhythmic surgery.35 Whereas initial studies of class III antiarrhythmic agents such as amiodarone suggested an improved survival rate in patients after myocardial infarction,35 this was not confirmed by recent prospective studies. 36 The Survival With Oral d-Sotalol (SWORD) trial ~ assessed the effect of d-sotalol on patients who survived AMI. The trial was discontinued when an association was found between d-sotalol medication and increased mortality risk. The implantable defibrillator has been shown to significantly reduce the incidence of sudden death in patients with ventricular arrhythmias and heart failure. However, doubts still exist about its ability to improve long-term survival rates. 35 PHARMACOLOGIC THERAPY FOR INFARCT SIZE REDUCTION
Since Reimer et al.37 introduced the "wave-front phenomenon" concept of infarct expansion in the late 1970s, multiple pharmacologic strategies have been developed to reduce infarct size. Several clinical triMs have demonstrated that early mortality is reduced by administration of intravenous ~-blockers, particularly atenolol and metoprolol, followedby oral treatment for varying periods. 3s Two mega-trials, the First International Study of Infarct Survival (ISIS-l) 39 (atenolol) and Metoprolol In Acute Myocardial Infarction (MIAMI)4° (metoprolol), have shown a 13% to 14% reduction in early mortality. Although mechanisms for early mortality reduction by ~-blockade are still unclear, results from clinical studies suggest that the most probable underlying mechanisms are limitation of infarct progression, reduction of infarct size, reduction of the incidence of reinfarction, and, to some extent, suppression of malignant ventricular arrhythmias, 39-41 The benefit achieved by early administration of ~-blockers translates into substantial long-term benefit. Maintenance of 6-blockers is thus recommended after AMI, although similar benefits may be achieved with other pharmacologic treatment strategies such as ACE inhibitors and lipid-lowering agents. It has been shown that when nitrates are admin-
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istered during the acute phase of the infarction, infarct expansion and mortality are reduced by approximately 30%. 42 Several clinical trials have revealed beneficial effects of nitrates, administered either intravenously or orally, with respect to mortality reduction, limitation of infarct size, preservation of the jeopardized myocardium, or improvement of ventricular function. 42, 43 In contrast, the ISIS-4 trial failed to indicate a long-term benefit of nitrate medication after acute infarction. 44 However, the results of the ISIS-4 trial did not change management strategies concerning AMI, and nitrates are still used during the acute stage and as chronic medication in symptomatic patients. Trials of antiischemic drugs, especially B-blockers and nitrates, were carried out before the use of thrombolysis and primary angioplasty became widespread. Whether ~-blockers, nitrates, and other pharmacologic agents provide beneficial effects in conjunction with thrombolytic therapy or primary mechanical reperfusion strategies remains to be determined in well-designed clinical trials. INTRAVENOUS THROMBOLYTIC THERAPY
In the early 1980s DeWood et al. 45 convincingly demonstrated that thrombotic occlusion occurs in the early phase of myocardial infarction. Plaque fissuring and/or disruption with subsequent thrombus formation, occlusion, or reocclusion of the vessel lumen have been established as the major pathomechanisms underlying acute ischemic syndromes. 46, 47 Consequently, lysis of the obstructing coronary thrombus has become the focus of research during the past decade. Although spontaneous clot lysis may occur in approximately 20% of myocardial infarctions, 45 in most cases it occurs too late to save the viable myocardium. Early reperfusion with the use ofthrombolytic agents has been shown to have favorable results for early and late survival, preservation of the ventricular function, and limitation of infarct size. 9, 4s-50 However, the first attempts at thrombolysis in the early 1970s turned out to be rather frustrating. The European Working Party 5i performed one of the first large-scale trials that studied the efficacy of systemic thrombolysis; in this trial, streptokinase was used in an infusion protocol for several hours, followed by anticoagulation with coumadin. Although a trend for improvement in the mortality rate was noted, there was also a high rate of bleeding complications and strokes. Issues of timing, dose, and duration of thrombolytic therapy remained unanswered. 51, 52 Intracoronary application of thrombolytic agents was first introduced as a viable treatment concept by
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Rentrop et aL 53 in the early 1980s. In these first series, intracoronary thrombolysis with streptokinase was effective in achieving patency in more than 80% of patients after 1 to 2 hours of treatment. The feasibility of intracoronary lysis in clinical settings remained questionable because of the limited availability of catheterization laboratories and the time wasted by the admitting institutions before treatment Was started. The first large trial of systemic thrombolytic therapy in patients with AMI, Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI), 9 reaffirmed the importance of early therapy by demonstrating a 23% reduction in in-hospital mortality among patients treated with intravenous streptokinase within 3 hours of the onset of chest pain and a 50% reduction in mortality among those treated within 1 hour after the onset of chest pain. 9 Since then, several trials have attempted to prove the superior efficacy of various thrombolytic agents and treatment protocols with respect to mortality and left ventricular function. The largest of these trials were GISSI-254 and ISIS-3, 55 both of which compared the efficacy of intravenous streptokinase and recombinant tissue plasminogen activator (rtPA). Data from these two trials, which included more than 60,000 patients, have shown equivalent survival rates with the use of either streptokinase or r-tPA. However, several large-scale trials demonstrated that the use ofr-tPA activator achieved more rapid, complete, and earlier thrombolysis. The Thrombolysis In Myocardial Infarction (TIMI) trials have shown that r-tPA is superior to streptokinase in achieving early reperfusion. 56 Compared with the standard thrombolytic regimen with streptokinase, a survival benefit was found when accelerated t-PA was given with intravenous heparin.i4, 57Among trials that dealt with a "frontloaded" r-tPA dose regimen, i0 the RAPID trial 5s demonstrated coronary patency in 78% of the patients after 60 minutes and in 95% of the patients after 14 days. ADJUNCTIVE THERAPY
Results of several trials suggest that the use of additional medication further increases the beneficial effects of thrombolytic therapy. 55, 59 In the ISIS-2 trial, 59 the combination of antiplatelet and thrombolytic therapy almost doubled the mortality reduction without causing a significant increase in bleeding complications. These results support the early addition of aspirin to intravenous streptokinase therapy. The administration of intravenous magnesium in AMI as shown in the Second Leicester Intravenous
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Magnesium Intervention (LIMIT-2) trial 6° resulted in an attenuation of left ventricular dysfunction and a reduction of mortality in the early post-infarction period compared with patients who received placebo. The dose regimen used in the LIMIT-2 trial was a bolus infusion of 8 mmol magnesium followed by an infusion of 65 mmol during a 24-hour period. To establish a therapeutic regimen of intravenously administered magnesium, the LIMIT-2 protocol was adopted for ISIS-4, a clinical mega-trial. 44 However, results from the ISIS-4 trial concerning the efficacy of magnesium therapy in AMI were disappointing and led to the so-called "ISIS-crisis." Consecutively, several reviews 61-62 and meta-analyses 63-65 of LIMIT-2, ISIS-4, other previous clinical trials indicated that the timing of magnesium therapy plays a pivotal role in the success of magnesium treatment. Thus the pharmacologic role of magnesium in AMI must be elucidated by additional clinical trials. PRIMARY ANGIOPLASTY
The use of balloon angioplasty as an alternative strategy to achieve reperfusion was first introduced by Hartzler et al.66 in the early 1980s. Since then several interventional centers have been performing primary or direct coronary angioplasty with a high rate of success and a low in-hospital mortality rate. The rate of infarct-vessel patency was consistently high in reported observation studies, 67 and a reduction in the incidence of hemorrhagic stroke and bleeding complications was noted. During the past few years, encouraging results have been reported from several randomized trials that compared primary angioplasty and intravenous thrombolysis with tissue-plasminogen activator or streptokinase)~, 17, 6s Although most of these trials failed to show an improvement of ejection fraction or infarct size (with the exception of the "Zwolle trial" by Zijlstra e t a ] . 17 that found an improvement of ejection fraction for primary angioplasty versus streptokinase), the rapid restoration of infarct vessel patency and flow, and the improved survival rates are evident with primary angioplasty. Improve: ments in interventional techniques and equipment, and compelling results of studies of new adjunctive pharmacologic agents such as glycoprotein IIb/IIIa receptor antagonists justify expectations of further refinement of acute interventional approach in highrisk patients, and particularly in patients with AMI. SUMMARY
Because of the recent development of many competing strategies for the management of AMI, we are currently confronted with the problem of being
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unable to recommend one particular strategy as the optimal means of managing AMI. Prospective randomized protocols usually involve treatment strategies performed under optimized conditions that may not be found in everyday life for the majority of patients. Therefore, the availability of local resources, the cost-effectiveness of strategies, and the optimal timing for specific treatment modalities must be taken into consideration when making a treatment choice. It will be necessary for future investigations to address the question of combined treatment strategies, such as the combination of several pharmacologic treatment modalities or the use of aggressive interventional strategies in combination with pharmacologic interventions. The concept of intravenous administration of magnesium in patients with AMI has evolved over time from an adjunctive treatment modality for the reduction of arrhythmias during the first hours of infarction to an effective pharmacologic treatment for the attenuation of reperfusion injury. Thus, in the near future we may observe a more widespread use of a combined treatment strategy involving early reperfusion by m e a n s of either primary angioplasty or thrombolysis together with early loading treatment with magnesium infusion. This treatment strategy may be followed by a medication protocol with ACE inhibitors, p-blockers, and lipid-lowering agents to achieve maximum long-term benefit.
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