Con: Surgery is not the preferred treatment for acute myocardial infarction

Con: Surgery Is Not the Preferred Treatment for Acute Myocardial Infarction L. A. J. Higginson, MD

N

OT SINCE THE clinical description of acute myocardial infarction by Herrick in 19 12’ have there been so many options available for the treatment of this problem. Despite these options, acute myocardial infarction remains the most common cause of death in industrialized countries, and mortality and morbidity rates among the survivors of infarction are unacceptably high. It has been very interesting to watch the attempts to reduce this mortality. In the 196Os, defibrillation and the development of coronary care units resulted in a significant improvement in mortality. In the 197Os, research in ischemic heart disease was dominated by an attempt to reduce myocardial oxygen demand in an attempt to reduce the extent of infarction. Despite impressive results in experimental models showing myocardial salvage, it became clear that reduction of myocardial oxygen requirements in patients delayed the evolution of infarction but did not limit overall extent. However, these studies did show conclusively that prognosis-early and late-is influenced primarily by the size of the infarct. Limiting the size of the initial infarct continues to be the primary goal in the 1990s. The purpose of this review is to debate the best way of salvaging ischemic but not necrotic myocardium. It is agreed that reperfusion is the most effective way to limit infarct size. It is also agreed that if significant salvage is to occur the time interval between the onset of coronary occlusion and reperfusion must be brief. In the experimental setting, this time interval is usually not more than 4 to 6 hours.’ Accordingly, any reperfusion strategy designed to limit infarct size, if it is to be widely applicable to patients with acute myocardial infarction, must be applied soon after the development of symptoms. From the Department of Cardiology, University of Ottawa Heart Institute, Ontario, Canada. Address reprint requests to L. A. J. Higginson, MD, Department of Cardiology, Room H-208. Heart Institute, Ottawa Civic Hospital, 1053 Carling Ave. Ottawa, Ontario Kl Y 4E9. Canada. o 1990 by W.B. Saunders Company. 0888-6296/90/0401-0022$03.00/0

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This review will argue that the most effective way of establishing early reperfusion in most patients with acute myocardial infarction is not surgery but thrombolytic therapy. The present time is considered the “thrombolytic era,” as suggested by a number of research activities. The first link in the chain was the elucidation that thrombosis is the most important cause of acute myocardial infarction. While two Russian physicians, Obraztsov and Strazhesko,3 described the first patients with myocardial infarction and coronary thrombosis, it was up to Dewood et al4 to solidify the knowledge that thrombosis played a critical role in the genesis of acute transmural myocardial infarction. Dewood et al performed coronary angiography in more than 300 patients during the early phases of acute myocardial infarction. They found that more than 85% of patients studied in the first 4 hours after the onset of chest pain had total occlusion of the coronary artery supplying the infarct area. The study also showed that the prevalence of complete occlusion decreased in patients who were studied 6 to 24 hours from the onset of symptoms. This observation laid to rest the contention that thrombosis was a passive phenomenon rather than the culprit in the genesis of myocardial infarction. The next important step was the consistent observation by many groups of investigators that the intracoronary infusion of streptokinase resulted in the recanalization of an obstructed coronary artery in 70% to 80% of patients with acute myocardial infarction. Although the era was introduced by the intracoronary use of streptokinase, it soon became apparent that the intracoronary administration of thrombolytic therapy would have little to offer the majority of patients with infarction. Only a small fraction of patients with acute myocardial infarction have access to a suitably staffed cardiac catheterization laboratory within the time constraints necessary to achieve substantial myocardial salvage. This is one of the most important reasons that widespread surgical revascularization in the setting of acute myocardial infarction is not feasible. Intracoronary streptoki-

Journal of Cardiorhoracic Anesthesia, Vol 4, No 1 (February), 1990: pp 136- 140

CON: SURGERY FOR ACUTE MYOCARDIAL INFARCTION

nase was also impractical because, even assuming that a catheterization laboratory was available, time was required to catheterize the patient and to administer the thrombolytic therapy. During this time, potentially salvageable myosites were dying. Widespread acceptance of thrombolytic therapy began with investigators showing that appropriate doses of intravenous thrombolytics could induce reperfusion, salvage ischemic myocardium, and reduce mortality in the acute setting of myocardial infarction. Research has provided new thrombolytic agents like recombinant tissue-plasminogen activator (rtPA), which have been shown to be more effective than streptokinase in opening occluded coronaries and to cause less systemic fibrinolysis. The enthusiasm for coronary thrombolysis has been aided by research refuting the theory that reperfusion may induce potentially deleterious consequences including hemorrhage, the noreflow phenomenon, and augmented reperfusion injury. Although hemorrhage and reperfusion injury do occur with the restitution of blood flow, damage occurs within the center of the jeopardized area and does not preclude a significant reduction of infarct size.5 Elucidating the thrombus as the cause of acute myocardial infarction, proving that thrombolytic therapy can dissolve this clot and induce reperfusion, the development of thrombolytic agents that can be given intravenously, and research minimizing the potentially deleterious consequences of reperfusion have set the stage for coronary thrombolysis in the last decade. There is no longer any doubt that intravenous thrombolytic agents limit left ventricular dysfunction and decrease both early and late Table 1. Important

study GISSI’

Large Clinical Trials of Intravenous

Drug SK, placebo

Dose 1.6 x 10Bpg

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mortality when given early in the course of myocardial infarction. The GISSI study6 was conducted throughout Italy and followed 11,806 patients who were randomized to streptokinase (SK) (1.5 x lo6 units over 1 hour) or conventional therapy. Hospital mortality was reduced from 13.0% to 10.7% (18% reduction)6 (Table 1). If the thrombolytic therapy was given within the first hour of symptoms, the reduction in mortality approached 50%. This improvement in mortality was maintained over the ensuing 1 year with a 7% mortality for both groups. The ISIS-II study randomized 17,187 patients who received either placebo, SK (1.5 x lo6 units over 1 hour), aspirin (160 mg daily for 1 month), both, or neither.7 The 5-week vascular mortality was reduced from 12.0% to 9.2%, which was a 25% risk reduction by SK compared with placebo. There was a reduction from 13.2% to 8% (42% risk reduction) by the combination of SK and aspirin, compared with no SK or aspirin. This improvement in mortality was also maintained over the ensuing year. An unexpected finding in this ISIS-II trial was that streptokinase and aspirin were capable of reducing mortality as late as 12 to 24 hours after the onset of symptoms. Further trials will be needed to define the time limits within which thrombolytic therapy may be beneficial. The AIMS trial’ used the thrombolytic agent anisoylated plasminogen streptokinase activator complex (APSAC), which has advantages over streptokinase in that it may be given intravenously over a few minutes. In this trial, 1,004 patients were randomized to APSAC or placebo, and at 30 days the mortality was reduced from 12.2% to 6.4%, a 50% odds reduction of mortality. The improvement was so dramatic Thrombolysis

” 5,860

for Acute Myooardial

Infarction

Mortality Assessed

Mortality Reduction 1%)

50%<3h

21 d

18

5 h median

5wk

Time to Therapy

5,852 IsI!x7

SK, aspirin

SK, aspirin, placebo

1.6 x 106cg

8,592

180 mg/d

8,587

23

25

both

4,292

42

8,595 AIMS*

APSAC, placebo

30 gg

502

t6h

30d

47

30d

28

502 ASSET’

rt-PA, placebo

100 mg

2,516 2,495

40%<3h

138

that the trial was stopped early by the data monitoring committee. The ASSET trial used intravenous rt-PA to examine its effect on l-month mortality.’ More than 5,000 patients were randomized to intravenous rt-PA or placebo. The l-month mortality was reduced by rt-PA from 9.8% to 7.2%, a 28% odds reduction. The European Cooperative trial compared rt-PA with placebo, and was designed to examine its effect on ventricular function and morbidity. Perhaps the lowest mortality ever seen in a large trial of unequivocal myocardial infarction was seen in this study. The mortality rate at 21 days was 3.7% with rt-PA and 6.8% with placebo. The reductions in mortality with all three major thrombolytic agents are similar and prove conclusively that intravenous thrombolytic agents given early in the course of transmural myocardial infarction reduce early and late mortality. What is the evidence that thrombolytic therapy improves left ventricular function? White et al,” using intravenous SK and assessing ventricular function 3 weeks after treatment, showed that global ejection fraction increased from 53% to 59% in the treated group. Intravenous t-PA was used in an Australian study” in which the agent was given less than 4 hours from the onset of symptoms. Ejection fraction was found to be significantly higher in treated patients (57.7%) compared with the control group (51.7%). This was significantly different for patients with either inferior or anterior myocardial infarction. From these studies and others, it is clear that the use of thrombolytic therapy limits the extent of infarction and results in improved left ventricular function as well as a decreased incidence in severity of late congestive heart failure. Severe congestive heart failure or cardiogenie shock complicating acute myocardial infarction may be a special subset in which emergency invasive intervention, including coronary artery bypass grafting, may be warranted. Patients with true cardiogenic shock have an in-hospital mortality approaching 90% without some form of intervention. Very little information is available regarding thrombolytic therapy and its value in these patients. A few small series of patients have been treated with coronary thrombolysis and angioplasty showing mortalities below 50%; how-

L. A. J. HIGGINSON

ever, confirmation of the benefits would require a randomized and controlled trial. Because of the extremely poor prognosis of these patients, immediate coronary arteriography is warranted, and consideration given to immediate angioplasty or coronary artery bypass grafting. Surgery is also essential in the patient who shows a mechanical complication of myocardial infarction including development of ventricular septal defect or severe mitral regurgitation. Realizing that after thrombolytic therapy there is frequently a persistent high-grade atherosclerotic obstruction in the coronary artery, is there a role for routine elective coronary arteriography after thrombolytic therapy, followed, if required, by mechanical revascularization with PTCA or coronary artery bypass grafting? Three large trials have now looked at the role of emergency angioplasty soon after the administration of thrombolytic therapy. The TAMI, TIMIIIA, and the European Cooperative Study all showed that obligatory immediate angioplasty offers no benefit after initial coronary thrombolysis; in fact, in clinically stable patients, acute intervention may be harmful.12-14 Emergency angioplasty or coronary artery bypass grafting after thrombolytic therapy should be considered only in those patients manifesting signs or symptoms of continued or recurrent ischemia or who have developed hemodynamic compromise. Although thrombolytic therapy effectively lyses occluding thrombi that initiate transmural myocardial infarction, the underlying atherosclerotic changes in the infarct-related artery are not altered by thrombolytic therapy. The most that can be obtained with thrombolytic therapy is a restoration in the coronary arterial bed to the condition that existed before occlusion, leaving some patients at risk of persistent ischemia with a 20% chance of repeat occlusion. It seems logical to prevent these potentially catastrophic complications by an invasive strategy. This would involve performing routine coronary arteriography after thrombolysis, followed by late percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting if critical narrowing persists. An alternative approach, admittedly more conservative, would be to restrict coronary arteriography and invasive strategy to patients who have recurrence of myocardial is-

CON: SURGERY FOR ACUTE MYOCARDIAL INFARCTION

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chemia clinically or in whom ischemia is provoked during a predischarge exercise test. These two strategies using PTCA as the invasive alternative were compared in the TIM1 phase-II trial. I5 In that trial, 3,262 patients were treated with rt-PA within 4 hours of the onset of chest pain thought to be secondary to myocardial infarction. Of this number, 1,636 were assigned to treatment according to an invasive strategy consisting of coronary arteriography 18 to 48 hours later, followed by PTCA if it was deemed suitable. In the other group, 1,626 patients were assigned to a conservative strategy in which coronary arteriography was performed only in patients with spontaneous angina or exerciseinduced ischemia. In the invasive strategy group, 928 (56.7%) had PTCA, and it was successful in 93.3% of the group. In the conservative group, only 2 16 (13.3%) underwent clinically indicated PTCA prior to discharge. The primary endpoint was examined at 42 days. Reinfarction or death occurred in 10.9% of the invasive strategy group and 9.7% of those assigned to the conservative strategy (P not significant). Similarly, there was no difference between the two groups in ejection fraction at rest or with exercise 6 weeks after randomization. Both strategies resulted in excellent overall results with a mortality of only 4.7% in the conservative strategy group. These results suggest that coronary arteriography should be restricted to patients with spontaneous or exercise-induced ischemia after

myocardial infarction, and that most patients can be treated with thrombolytic therapy in community hospitals without the need for transfer, cardiac catheterization, or PTCA. Although this strategy only included PTCA, it seems clear that the same would be true if bypass grafting had been the invasive therapy. Bypass grafting is still an important form of therapy for those patients who develop ischemia following myocardial infarction and are judged anatomically to be better bypass candidates than candidates for percutaneous angioplasty. The current therapy for acute evolving transmural myocardial infarction within the first few hours of symptom onset is thrombolytic therapy plus aspirin. Its use limits the extent of infarction, improves left ventricular function, decreases the incidence and severity of late congestive heart failure, and improves survival. Emergency, invasive intervention including angioplasty or coronary artery bypass grafting is not warranted in clinically stable patients. Coronary arteriography should be considered in patients who later develop spontaneous or exerciseinduced ischemia and in those who develop profound complications of the infarct, including cardiogenic shock or the mechanical complications of myocardial infarction. In these selected situations, coronary artery bypass grafting has an important role; however, in the majority of patients with myocardial infarction, emergency coronary artery bypass surgery offers no benefit.

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6. Gruppo Italian0 per lo studio della streptochinasi nell’infarto miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1:397-401, 1986 7. ISIS-2 (Second International Study of Infarct Survival) Collaborative group: Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS2. Lancet 2:349-360, 1988 8. AIMS Trial Study Group: Effect of intravenous APSAC on mortality after acute myocardial infarction: Preliminary report of a placebo-controlled clinical trial. Lancet 1:545-549, 1988 9. Wilcox RG, Von Der Liffe G, Olsson CG, For The ASSET Study Group: Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. AngloScandinavian Study of Early Thrombolysis (ASSET). Lancet 2:525-530, 1988 10. White HD, Norris RM, Brown MA, et al: Effect

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of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 317850-855, 1987 11. National Heart Foundation of Australia Coronary Thrombolysis Group. Coronary thrombolysis and myocardial salvage by tissue plasminogen activator given up to 4 hours after onset of myocardial infarction. Lancet 1:203-207, 1988 12. Top01 EJ, Califf RM, George BS and the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. A multicenter randomized trial of intravenous recombinant tissue plasminogen activator and immediate angioplasty in acute myocardial infarction. N Engl J Med 317:581-588, 1987 13. The TIM1 Research Group. Immediate vs de-

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layed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A results. JAMA 260:2849-2868,1988 14. Simoons ML, Arnold AER, Betriu A, et al for the European Cooperative Study Group for Recombinant TissueType Plasminogen Activator (r&PA). Thrombolysis with tissue plasminogen activator in acute myocardial infarction: No additional benefit from immediate percutaneous coronary angioplasty. Lancet 1:197-202, 1988 15. The TIM1 Study Group: Comparison of Invasive and Conservative Strategies after Treatment with Intravenous Tissue Plasinogen Activator in Acute Myocardial Infarction. Results of the thrombolysis in myocardial infarction (TIMI) Phase II Trial. N Engl J Med 320~618-627, 1989