Sudden Death after Myocardial Infarction ― Who Needs Prophylaxis, and When?
【关键词】 Myocardial,
Although the age-adjusted mortality from cardiovascular disease has declined in recent years, the number of sudden deaths has risen.1 According to data from the Centers for Disease Control and Prevention, 63 percent of deaths from cardiovascular causes in the United States, or more than 450,000 events, in 1998 were sudden and unexpected, most being attributable to coronary disease. Sudden death is the end result of multiple processes, usually manifested electrocardiographically as ventricular fibrillation or ventricular tachycardia.
The type of arrhythmia observed depends on the temporal relation to myocardial infarction. In the acute phase of myocardial infarction, the metabolic consequences of severe ischemia may trigger ventricular fibrillation, even though ventricular function was often normal before the event. Such cases may account for half of sudden deaths.2 Scar formation after myocardial infarction may lead to the development of the substrate for intramyocardial reentry, resulting in ventricular tachycardia, which, in turn, may precipitate cardiac arrest in the absence of active ischemia. This type of ventricular tachycardia (usually monomorphic) may develop days or years after the index infarction. Finally, some patients have gradual, extensive ventricular remodeling after myocardial infarction, and the remodeling leads to the syndrome of heart failure. The development of heart failure, with its attendant neurohormonal abnormalities, sets the stage for other mechanisms that may cause ventricular tachycardia (usually the polymorphic type). Thus, the mechanisms responsible for sudden death vary according to their temporal relation to myocardial infarction and multiple other factors, including the presence or severity of left ventricular dysfunction.
In the prethrombolytic era, multiple variables were shown to influence the risk of both sudden and nonsudden death after myocardial infarction. In a substudy of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) reported in this issue of the Journal, Solomon and colleagues3 extend and reinforce our understanding of factors influencing the risk of death after acute myocardial infarction. VALIANT compared the effect of valsartan, captopril, or both on the risk of death in more than 14,000 patients with acute myocardial infarction complicated by left ventricular dysfunction (defined as a left ventricular ejection fraction of 40 percent or less), heart failure, or both between 1998 and 2001.4 Several characteristics of the patients enrolled in the trial are noteworthy. The mean left ventricular ejection fraction was 35 percent, 28 percent had had a prior myocardial infarction, and approximately three fourths were in Killip class II, III, or IV at the time of enrollment.4 During a median follow-up of 24.7 months, 7.3 percent of the patients died suddenly or were resuscitated after cardiac arrest.3 Solomon et al. emphasize two major points: the temporal occurrence of sudden death after myocardial infarction and the importance and limitations of the left ventricular ejection fraction as a risk factor for sudden death.
Clustering of sudden deaths in the early period after myocardial infarction was noted in the prethrombolytic era.5 The time course of sudden death in the modern era has been explored less extensively, but some work in unselected populations of survivors of acute myocardial infarction suggests a delay in sudden death to 18 months after the acute event.6 This issue is clarified in the current study. Solomon et al. clearly demonstrate the period of highest risk to be the first month after myocardial infarction (event rate, 1.4 percent), with a dramatic drop to a fairly constant rate of 0.14 to 0.18 percent per month thereafter.
The association between a reduced left ventricular ejection fraction and an increased risk of death after myocardial infarction has been recognized for years. In both the prethrombolytic era and the post-thrombolytic era, the risk of death increases markedly if the left ventricular ejection fraction is 40 percent or less.7 At first glance, it may seem surprising that Solomon et al. found the risk of sudden death to be similar among patients with a left ventricular ejection fraction of more than 40 percent and those with an ejection fraction of 30 to 40 percent. This finding is most likely explained by the fact that in order to enter VALIANT, any patient with a left ventricular ejection fraction of more than 40 percent would have had to have heart failure, reaffirming the importance of heart failure as a risk factor for sudden death.
Although Solomon et al. note a number of significant differences between survivors and patients who died, there were no clinically useful factors distinguishing those who died suddenly from those who had a nonsudden death. In other words, a reduced left ventricular ejection fraction and evidence of advanced heart failure carried an equally increased risk of sudden and of nonsudden death and did not have a cause-and-effect relation to arrhythmic events. The importance of this limitation has implications for preventive therapy. If we are to use efficacious treatments, such as implantable cardioverter defibrillators (ICDs), in a cost-effective manner, we need risk-stratification tests that identify patients whose risk of sudden death significantly exceeds their risk of nonsudden death. To date, there is only one such test ― the electrophysiological test.8
What is the importance of the current study? It reinforces findings in earlier studies that the risk of sudden death is greatest in the early period after infarction among patients with clinically significant ventricular dysfunction or heart failure. This point raises several questions. Should patients with high-risk characteristics undergo prolonged hospitalization after myocardial infarction? An alternative solution, given the observation of Solomon et al. that risk drops dramatically within six months after acute myocardial infarction, might be to provide noninvasive vest defibrillators or automatic external defibrillators to high-risk patients for limited periods. The latter approach is the subject of an ongoing trial sponsored by the National Heart, Lung, and Blood Institute in selected patients with a recent anterior myocardial infarction. These noninvasive approaches to prophylactic defibrillation are attractive in light of the results of the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which demonstrated the failure of ICDs to reduce the risk of death among high-risk patients with clinically significant left ventricular dysfunction after a recent myocardial infarction.9
How do the results of this large, multicenter trial by Solomon et al. relate to studies demonstrating the ability of ICDs to prevent sudden death in patients with chronic coronary heart disease?10,11,12 These trials ― the Multicenter Automatic Defibrillator Implantation Trial (MADIT), the Multicenter Unsustained Tachycardia Trial (MUSTT), and MADIT-II ― were predicated on earlier observations, similar to those of Solomon et al., that patients with spontaneous ventricular arrhythmias and clinically significant ventricular dysfunction after a recent myocardial infarction have a substantial risk of death. However, a minority of patients in these trials had a myocardial infarction within 2 years before enrollment: the average times from myocardial infarction to enrollment were 39 months in MUSTT and 81 months in MADIT-II. The total mortality rate in VALIANT after the first year was approximately 5 percent per year. The rate of sudden death or resuscitation after cardiac arrest was approximately 2.5 percent per year among patients with a left ventricular ejection fraction of 30 percent or less. After the first year, the total mortality rates and the rate of sudden death were fairly constant and low. These figures contrast with the total mortality rates of 11 percent per year in the control patients with a left ventricular ejection fraction of less than 30 percent in both MUSTT and MADIT-II. Thus, event rates in the ICD trials were double those in VALIANT.
What is the explanation for this difference? In part, it may be due to the fact that two thirds of the patients enrolled in MADIT and MUSTT had symptomatic heart failure, as reflected by a New York Heart Association class of at least II, in addition to a reduced left ventricular ejection fraction. I suspect that another reason for the higher rates of events in the ICD trials is enrollment bias, resulting in the recruitment of patients at very high risk. Why is this important? Because it suggests that the results of the ICD trials may not be generalizable to all patients meeting the entry criteria for those studies. The mortality risks observed in the ICD trials may have been exaggerated because of the manner in which patients were recruited. Thus, when performing such studies, we must strive to enroll broad-based, representative populations, unencumbered by referral bias.
In summary, the analysis by Solomon et al. is a useful reality check on the problem of sudden death among survivors of acute myocardial infarction. This study documents the natural history of sudden death and some of the risk factors for it with contemporary treatment of myocardial infarction. The challenge going forward is to translate these observations into cost-effective preventive therapy.
Source Information
From the Cardiology Division, Department of Medicine, Brown Medical School, Lifespan Academic Medical Center, Providence, R.I.
References
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