Myocardial Infarction and the Open-Artery Hypothesis
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《新英格兰医药杂志》
In patients with acute myocardial infarction, the prompt restoration of antegrade flow in the infarct-related coronary artery, whether accomplished pharmacologically1 or mechanically,2 improves left ventricular systolic function and reduces mortality. Initially, these salutary effects of reperfusion therapy were thought to be tightly linked: successful reperfusion salvaged ischemic but still viable myocardium, which led to improved left ventricular function and, in turn, improved survival. Conversely, reperfusion of the infarct-related artery more than 12 hours after the onset of infarction was thought not to achieve these beneficial results. However, several studies suggested that the effects of reperfusion on left ventricular function and survival might, to some extent, be independent of one another. In the Western Washington trial,3 fibrinolytic therapy (with streptokinase) improved survival without improving left ventricular function. In the Second International Study of Infarct Survival,4 streptokinase reduced mortality even when given 13 to 24 hours after the onset of chest pain, at a time when myocardial salvage was unlikely. These initial studies formed the basis for the so-called open-artery hypothesis: that the restoration of antegrade flow in the infarct-related artery days, weeks, or even several months after myocardial infarction would improve survival even though left ventricular function did not improve.
In a series of nonrandomized, retrospective studies of patients with a first myocardial infarction, long-term survival was found to be substantially better among those with antegrade flow in the infarct-related artery than among those whose infarct-related artery was persistently occluded. For example, among survivors of a first infarction with disease of only the infarct-related artery (i.e., single-vessel disease), the long-term prognosis for those with antegrade perfusion was excellent (none of 64 patients died during a follow-up period averaging 46 months), whereas the prognosis for those without antegrade flow was much worse (21 of 115 patients died during a follow-up of similar duration) (P<0.001).5 The left ventricular volumes and ejection fractions were similar among the patients in the two groups. Subsequent nonrandomized, retrospective studies involving patients with multivessel coronary artery disease after a first myocardial infarction showed that the prognosis for those with a patent infarct-related artery was markedly better than that for those with a persistently occluded infarct-related artery.6 Similar results have been reported by others, including the data on almost 1000 patients enrolled in the Survival and Ventricular Enlargement (SAVE) study.7 In that study of survivors of myocardial infarction with a left ventricular ejection fraction of 0.40 or less, the patency of the infarct-related artery was a powerful predictor of long-term survival, independently of the extent of coronary artery disease or left ventricular systolic function.
In the retrospective studies just cited, almost all the deaths were sudden, suggesting that the patients had died from an arrhythmia. Subsequent analyses showed that patients with a persistently occluded infarct-related artery after myocardial infarction were more likely than those with a patent artery to have late potentials, an indicator of an increased likelihood of subsequent ventricular tachycardia and fibrillation, on signal-averaged electrocardiography.8 Other studies9 showed that patients with a patent infarct-related artery after infarction were unlikely to have ventricular tachyarrhythmia that was inducible during invasive programmed electrical stimulation, whereas the absence of antegrade flow was often accompanied by inducible ventricular tachycardia or fibrillation. On the basis of these data, we and others hypothesized that antegrade perfusion of the infarct-related artery reduced electrical instability in the periinfarction region (the so-called border zone), where viable myocytes are interspersed with irreversibly damaged myocytes.
In our original study,5 in which 21 of 115 patients with persistently occluded infarct-related arteries died during follow-up, only 1 of those who died had been taking a beta-adrenergic blocker; a beta-blocker was thought to be contraindicated for the other 20 patients. In the 1980s, when these patients were being treated and followed, the use of beta-adrenergic blockers in general, and after myocardial infarction in particular, was not nearly as ubiquitous as it is today. Many patients had coexisting conditions (i.e., left ventricular systolic dysfunction, symptoms of heart failure, peripheral vascular disease, or insulin-dependent diabetes mellitus) that were thought to contraindicate the use of a beta-adrenergic blocker. Nowadays, patients with these conditions routinely receive one. In a subsequent analysis,10 we showed that survivors of myocardial infarction with a persistently occluded infarct-related artery had an excellent long-term prognosis, provided that treatment with a beta-adrenergic blocker was maintained: among 46 such patients treated with a beta-adrenergic blocker, only 1 died during an average follow-up of 54 months, whereas 20 of 67 patients who were not receiving a beta-adrenergic blocker died during a follow-up of similar duration (P=0.007). In essence, the prognosis among patients with a persistently occluded infarct-related artery who were treated with a beta-adrenergic blocker was as good as that among those whose infarct-related artery was patent. Thus, the prevention of lethal arrhythmias, accomplished by restoring antegrade flow in the occluded infarct-related artery or simply by giving a beta-adrenergic blocker, resulted in markedly improved survival.
The open-artery hypothesis, although not previously validated in a prospective, randomized study, has nonetheless been embraced by many practicing physicians. As a result, many patients whose infarct-related artery is shown to be occluded after myocardial infarction are referred for percutaneous coronary intervention (PCI) days or weeks after the acute event, in the belief that the restoration of antegrade flow will reduce morbidity and mortality.11 In this issue of the Journal, Hochman and colleagues12 report the results of a large randomized, prospective study assessing the open-artery hypothesis. Their study unequivocally shows that the restoration of antegrade flow reduces neither disease progression nor the rate of death: patients whose infarct-related artery was opened mechanically fared no better than those whose infarct-related artery remained occluded. The late restoration of antegrade flow did not reduce the incidence of death, reinfarction, or heart failure.
Why are the results of this study disparate from the previously published data? First, almost all the studies cited here were retrospective and not randomized; as a consequence, the analyses may have been confounded by unrecognized variables or selection bias. Second, the almost universal use of beta-adrenergic blockers in the study by Hochman et al. (in 86% of patients undergoing mechanical restoration of antegrade flow in the occluded infarct-related artery and in 89% of those not undergoing PCI) may have obscured the potential advantage of restoring antegrade flow in the occluded infarct-related artery for reducing rates of disease progression and death. In our studies, beta-adrenergic blockers were as effective as mechanical restoration of antegrade flow in improving survival among patients with a persistently occluded infarct-related artery after myocardial infarction. Unfortunately, Hochman et al. do not provide data on the minority of patients (146 who underwent PCI and 117 who did not) who were not given beta-adrenergic blockers; information about their long-term follow-up would be of great interest. For survivors of myocardial infarction in whom a beta-adrenergic blocker is contraindicated or cannot be tolerated, it is conceivable that the restoration of antegrade flow in a persistently occluded infarct-related artery may be beneficial.
How should the results of the study by Hochman et al. be incorporated into the care of patients after myocardial infarction? First, for most such patients without spontaneous or inducible myocardial ischemia in whom left ventricular systolic function is not depressed, routine coronary angiography, often performed previously to identify a persistently occluded infarct-related artery, is not warranted. Second, all survivors of myocardial infarction should receive a beta-adrenergic blocker indefinitely, unless, of course, they cannot tolerate it or there is a contraindication to its use. As the results of the study by Hochman et al. show, nowadays only a relatively small minority of such patients (10 to 15%) cannot be treated with beta-adrenergic blockers. This small minority may benefit from the mechanical restoration of antegrade flow in the occluded infarct-related artery days, weeks, or even several months after myocardial infarction.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Medicine (Cardiovascular Division), University of Texas Southwestern Medical Center, Dallas (L.D.H.); and the Department of Medicine (Cardiovascular Division), Johns Hopkins Medical Institutions, Baltimore (R.A.L.).
This article was published at www.nejm.org on November 14, 2006.
References
Gruppo Italiano per lo Studio della Streptochinasi Nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402.
Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673-679.
Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983;309:1477-1482.
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-360.
Cigarroa RG, Lange RA, Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J Cardiol 1989;64:155-160.
Lange RA, Cigarroa RG, Hillis LD. Influence of residual antegrade coronary blood flow on survival after myocardial infarction in patients with multivessel coronary artery disease. Coron Artery Dis 1990;1:59-63.
Lamas GA, Flaker GC, Mitchell G, et al. Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation 1995;92:1101-1109.
Lange RA, Cigarroa RG, Wells PJ, Kremers MS, Hillis LD. Influence of anterograde flow in the infarct artery on the incidence of late potentials after acute myocardial infarction. Am J Cardiol 1990;65:554-558.
Kersschot IE, Brugada P, Ramentol M, et al. Effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation: a prospective, randomized study. J Am Coll Cardiol 1986;7:1234-1242.
Glamann DB, Lange RA, Hillis LD. Beneficial effect of long-term beta blockade after acute myocardial infarction in patients without anterograde flow in the infarct artery. Am J Cardiol 1991;68:150-154.
Berger AK, Edris DW, Breall JA, Oetgen WJ, Marciniak TA, Molinari GF. Resource use and quality of care for Medicare patients with acute myocardial infarction in Maryland and the District of Columbia: analysis of data from the Cooperative Cardiovascular Project. Am Heart J 1998;135:349-356.
Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006;355:2395-2407.(L. David Hillis, M.D., an)
In a series of nonrandomized, retrospective studies of patients with a first myocardial infarction, long-term survival was found to be substantially better among those with antegrade flow in the infarct-related artery than among those whose infarct-related artery was persistently occluded. For example, among survivors of a first infarction with disease of only the infarct-related artery (i.e., single-vessel disease), the long-term prognosis for those with antegrade perfusion was excellent (none of 64 patients died during a follow-up period averaging 46 months), whereas the prognosis for those without antegrade flow was much worse (21 of 115 patients died during a follow-up of similar duration) (P<0.001).5 The left ventricular volumes and ejection fractions were similar among the patients in the two groups. Subsequent nonrandomized, retrospective studies involving patients with multivessel coronary artery disease after a first myocardial infarction showed that the prognosis for those with a patent infarct-related artery was markedly better than that for those with a persistently occluded infarct-related artery.6 Similar results have been reported by others, including the data on almost 1000 patients enrolled in the Survival and Ventricular Enlargement (SAVE) study.7 In that study of survivors of myocardial infarction with a left ventricular ejection fraction of 0.40 or less, the patency of the infarct-related artery was a powerful predictor of long-term survival, independently of the extent of coronary artery disease or left ventricular systolic function.
In the retrospective studies just cited, almost all the deaths were sudden, suggesting that the patients had died from an arrhythmia. Subsequent analyses showed that patients with a persistently occluded infarct-related artery after myocardial infarction were more likely than those with a patent artery to have late potentials, an indicator of an increased likelihood of subsequent ventricular tachycardia and fibrillation, on signal-averaged electrocardiography.8 Other studies9 showed that patients with a patent infarct-related artery after infarction were unlikely to have ventricular tachyarrhythmia that was inducible during invasive programmed electrical stimulation, whereas the absence of antegrade flow was often accompanied by inducible ventricular tachycardia or fibrillation. On the basis of these data, we and others hypothesized that antegrade perfusion of the infarct-related artery reduced electrical instability in the periinfarction region (the so-called border zone), where viable myocytes are interspersed with irreversibly damaged myocytes.
In our original study,5 in which 21 of 115 patients with persistently occluded infarct-related arteries died during follow-up, only 1 of those who died had been taking a beta-adrenergic blocker; a beta-blocker was thought to be contraindicated for the other 20 patients. In the 1980s, when these patients were being treated and followed, the use of beta-adrenergic blockers in general, and after myocardial infarction in particular, was not nearly as ubiquitous as it is today. Many patients had coexisting conditions (i.e., left ventricular systolic dysfunction, symptoms of heart failure, peripheral vascular disease, or insulin-dependent diabetes mellitus) that were thought to contraindicate the use of a beta-adrenergic blocker. Nowadays, patients with these conditions routinely receive one. In a subsequent analysis,10 we showed that survivors of myocardial infarction with a persistently occluded infarct-related artery had an excellent long-term prognosis, provided that treatment with a beta-adrenergic blocker was maintained: among 46 such patients treated with a beta-adrenergic blocker, only 1 died during an average follow-up of 54 months, whereas 20 of 67 patients who were not receiving a beta-adrenergic blocker died during a follow-up of similar duration (P=0.007). In essence, the prognosis among patients with a persistently occluded infarct-related artery who were treated with a beta-adrenergic blocker was as good as that among those whose infarct-related artery was patent. Thus, the prevention of lethal arrhythmias, accomplished by restoring antegrade flow in the occluded infarct-related artery or simply by giving a beta-adrenergic blocker, resulted in markedly improved survival.
The open-artery hypothesis, although not previously validated in a prospective, randomized study, has nonetheless been embraced by many practicing physicians. As a result, many patients whose infarct-related artery is shown to be occluded after myocardial infarction are referred for percutaneous coronary intervention (PCI) days or weeks after the acute event, in the belief that the restoration of antegrade flow will reduce morbidity and mortality.11 In this issue of the Journal, Hochman and colleagues12 report the results of a large randomized, prospective study assessing the open-artery hypothesis. Their study unequivocally shows that the restoration of antegrade flow reduces neither disease progression nor the rate of death: patients whose infarct-related artery was opened mechanically fared no better than those whose infarct-related artery remained occluded. The late restoration of antegrade flow did not reduce the incidence of death, reinfarction, or heart failure.
Why are the results of this study disparate from the previously published data? First, almost all the studies cited here were retrospective and not randomized; as a consequence, the analyses may have been confounded by unrecognized variables or selection bias. Second, the almost universal use of beta-adrenergic blockers in the study by Hochman et al. (in 86% of patients undergoing mechanical restoration of antegrade flow in the occluded infarct-related artery and in 89% of those not undergoing PCI) may have obscured the potential advantage of restoring antegrade flow in the occluded infarct-related artery for reducing rates of disease progression and death. In our studies, beta-adrenergic blockers were as effective as mechanical restoration of antegrade flow in improving survival among patients with a persistently occluded infarct-related artery after myocardial infarction. Unfortunately, Hochman et al. do not provide data on the minority of patients (146 who underwent PCI and 117 who did not) who were not given beta-adrenergic blockers; information about their long-term follow-up would be of great interest. For survivors of myocardial infarction in whom a beta-adrenergic blocker is contraindicated or cannot be tolerated, it is conceivable that the restoration of antegrade flow in a persistently occluded infarct-related artery may be beneficial.
How should the results of the study by Hochman et al. be incorporated into the care of patients after myocardial infarction? First, for most such patients without spontaneous or inducible myocardial ischemia in whom left ventricular systolic function is not depressed, routine coronary angiography, often performed previously to identify a persistently occluded infarct-related artery, is not warranted. Second, all survivors of myocardial infarction should receive a beta-adrenergic blocker indefinitely, unless, of course, they cannot tolerate it or there is a contraindication to its use. As the results of the study by Hochman et al. show, nowadays only a relatively small minority of such patients (10 to 15%) cannot be treated with beta-adrenergic blockers. This small minority may benefit from the mechanical restoration of antegrade flow in the occluded infarct-related artery days, weeks, or even several months after myocardial infarction.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Medicine (Cardiovascular Division), University of Texas Southwestern Medical Center, Dallas (L.D.H.); and the Department of Medicine (Cardiovascular Division), Johns Hopkins Medical Institutions, Baltimore (R.A.L.).
This article was published at www.nejm.org on November 14, 2006.
References
Gruppo Italiano per lo Studio della Streptochinasi Nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402.
Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673-679.
Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983;309:1477-1482.
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-360.
Cigarroa RG, Lange RA, Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J Cardiol 1989;64:155-160.
Lange RA, Cigarroa RG, Hillis LD. Influence of residual antegrade coronary blood flow on survival after myocardial infarction in patients with multivessel coronary artery disease. Coron Artery Dis 1990;1:59-63.
Lamas GA, Flaker GC, Mitchell G, et al. Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation 1995;92:1101-1109.
Lange RA, Cigarroa RG, Wells PJ, Kremers MS, Hillis LD. Influence of anterograde flow in the infarct artery on the incidence of late potentials after acute myocardial infarction. Am J Cardiol 1990;65:554-558.
Kersschot IE, Brugada P, Ramentol M, et al. Effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation: a prospective, randomized study. J Am Coll Cardiol 1986;7:1234-1242.
Glamann DB, Lange RA, Hillis LD. Beneficial effect of long-term beta blockade after acute myocardial infarction in patients without anterograde flow in the infarct artery. Am J Cardiol 1991;68:150-154.
Berger AK, Edris DW, Breall JA, Oetgen WJ, Marciniak TA, Molinari GF. Resource use and quality of care for Medicare patients with acute myocardial infarction in Maryland and the District of Columbia: analysis of data from the Cooperative Cardiovascular Project. Am Heart J 1998;135:349-356.
Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006;355:2395-2407.(L. David Hillis, M.D., an)