Volume 346:931-933 March 21, 2002 Number 12

Almost 250,000 out-of-hospital cardiac arrests occur annually in the United States; the majority are attributed to coronary artery disease. About half of these episodes appear to be caused by ventricular tachyarrhythmias in the absence of acute myocardial infarction. With occasional exceptions, secondary prevention in the form of implantable cardiac defibrillators is chosen for survivors of cardiac arrest. More than 95 percent of victims of out-of-hospital cardiac arrest die during the episode, but the few who are quickly resuscitated usually live many additional years if they receive a defibrillator. The extremely low survival rate after out-of-hospital cardiac arrest is the motivating factor behind the prophylactic implantation of a defibrillator as a means of primary prevention.

In this issue of the Journal, Moss et al.1 report the results of the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II), a randomized clinical trial that used simple criteria to identify patients with coronary heart disease who would benefit from the prophylactic implantation of a defibrillator. Among 1232 patients with a previous myocardial infarction and a left ventricular ejection fraction of 0.30 or less, 742 were randomly assigned to receive an implantable defibrillator and 490 were assigned to receive conventional medical therapy. During 20 months of follow-up, there was a 31 percent reduction in the relative risk of death from any cause (absolute reduction in risk, 6 percent) among patients in the defibrillator group as compared with those in the conventional-therapy group.

The first MADIT2 and the Multicenter Unsustained Tachycardia Trial (MUSTT),3 both of which were primary-prevention trials, showed that patients with coronary heart disease, a reduced left ventricular ejection fraction (0.35 or less and 0.40 or less, respectively), and inducible sustained ventricular tachyarrhythmias benefited from the prophylactic implantation of a defibrillator. The Coronary Artery Bypass Graft Patch Trial, another primary-prevention trial, studied 900 patients who were scheduled to undergo elective coronary-artery bypass grafting and who had had a myocardial infarction, had a left ventricular ejection fraction of less than 0.36, and had abnormalities on signal-averaged electrocardiograms.4 This trial found that the prophylactic implantation of a defibrillator had no benefit whatsoever, showing that this approach is not advantageous in every high-risk coronary subgroup.

The MADIT II study reports only a portion of the data, and we await additional results. Neither spontaneous nor inducible sustained ventricular arrhythmia was used as a criterion to identify survivors of myocardial infarction who would benefit from the prophylactic implantation of a defibrillator. Only a previous myocardial infarction and a left ventricular ejection fraction of 0.30 or less (a cutoff point chosen to provide the number of end points needed for adequate statistical power) were necessary to qualify for the trial. Some experts thought that selecting a high-risk group of patients on the basis of the left ventricular ejection fraction alone (without an indicator of the presence of arrhythmia) not only would increase the total mortality rate, but also would decrease the fraction of deaths from arrhythmia and thereby reduce the benefit of a defibrillator. MUSTT showed that untreated patients who had inducible sustained ventricular tachycardia at base line and who did not receive antiarrhythmic therapy during follow-up had rates of cardiac arrest and death from arrhythmia that were 50 percent higher during two years of follow-up than the rates among patients who did not have inducible tachycardia.5 In MADIT II, the benefit of the prophylactic implantation of a defibrillator was somewhat smaller than in previous trials that used inducible sustained ventricular tachyarrhythmias as a selection criterion, but the benefit was still substantial.

MADIT II showed that defibrillator therapy was beneficial when it was added to effective drug therapy for heart failure, including angiotensin-converting–enzyme inhibitors (taken by 68 percent of the patients in the defibrillator group) and beta-blockers (taken by 70 percent), and lipid-lowering statins (67 percent), all of which were used by similar percentages of patients in the two groups. The study also achieved its goal of minimizing the use of drugs that have class I antiarrhythmic action (used by 3 percent of patients in the defibrillator group). It is gratifying to see that the implantation of a defibrillator made a significant difference in outcome among patients who had a remarkable degree of compliance with current drug-treatment guidelines.

Defibrillator therapy was associated with the expected rates of device-related complications (1.8 percent) and late complications (0.7 percent), but this approach was also associated with a higher rate of new or worsened heart failure than was conventional therapy — a worrisome finding. The Coronary Artery Bypass Graft Patch Trial also found that defibrillator therapy was associated with a higher rate of death from heart failure and hospitalization for heart failure.6 The MADIT II investigators speculate that effective treatment of potentially lethal arrhythmias leads to longer survival, thus allowing time for heart failure to develop. Also, something about defibrillator therapy itself (e.g., asynchronous pacing) may aggravate left ventricular dysfunction. If we can identify the cause, we should be able to modify it in order to reduce heart-failure events. For example, resynchronization through the use of left ventricular pacing might decrease the symptoms of heart failure and improve outcomes.7

Another puzzling finding is the timing of the benefit of defibrillator therapy. Kaplan–Meier curves revealed a different pattern of survival in MADIT: benefit was evident within the first few months after implantation. In MADIT II, there was no evidence of benefit for almost a year. The reason for this striking difference is not apparent.

A key question raised by the trial is whether the results indicate that all patients with a previous myocardial infarction and a left ventricular ejection fraction of 0.30 or less should receive a defibrillator. Maybe, but maybe not. Future analyses will determine whether the benefit was substantially greater in, or even confined largely to, participants who had inducible sustained ventricular arrhythmias. The investigators planned from the outset to use the results of electrophysiological testing performed during implantation of the defibrillator to address this issue (along with an analysis of the cumulative rates of discharge of the defibrillator and the evaluation of intracardiac electrograms recorded by the defibrillators during follow-up to determine the causes of defibrillator shocks). If all, or nearly all, of the patients who had sustained ventricular tachyarrhythmias during follow-up had inducible arrhythmia during implantation of the defibrillator, then electrophysiological testing would remain a desirable (even essential) part of the strategy to identify patients who would benefit from the prophylactic implantation of a defibrillator. Other markers of arrhythmia may also be valuable in the selection of patients. MUSTT showed that the finding of abnormalities on signal-averaged electrocardiograms is as good as or better than the results of programmed ventricular stimulation for identifying high-risk patients and is better than the presence of a left ventricular ejection fraction of less than 0.30 alone.8 Several ongoing trials of the prophylactic implantation of a defibrillator are using the presence of unsustained ventricular arrhythmias or variability in the RR interval as eligibility criteria.9 The attempt to optimize the selection process is likely to continue for some time. The cutoff point for left ventricular ejection fraction used by MADIT II may be too low if a marker of arrhythmia is also used to identify suitable candidates.

Additional important information should be provided by the ongoing Sudden Cardiac Death in Heart Failure Trial. This large defibrillator trial randomly assigned patients with heart failure as a result of either coronary heart disease or noncoronary dilated cardiomyopathy who had a left ventricular ejection fraction of less than 0.36 to receive placebo, amiodarone, or a defibrillator.10 Like MADIT II, this study did not use any markers of arrhythmia to identify high-risk patients. Although amiodarone has been shown to be significantly inferior to defibrillator therapy in several secondary-prevention trials,11,12,13 the results might differ if amiodarone is used for primary prevention in patients with severe left ventricular dysfunction and heart failure.

The cost effectiveness of defibrillator prophylaxis remains in question and looms as a barrier to the wider use of this approach.14 The MADIT II investigators hope that market forces (e.g., decreased margins on the sales of defibrillators, an increased volume of sales, and the manufacture of lower-cost defibrillators made especially for prophylactic use) will make this approach more cost effective. The expense of defibrillator therapy could be offset by a decrease in the rate of hospitalization for arrhythmic events, but this decrease was smaller than expected in MADIT II because the rate of hospitalization for heart failure was higher in the defibrillator group than in the conventional-therapy group. A corollary is that a more precise screening method will help optimize the cost effectiveness of the approach. The ideal candidate is at high risk for death from arrhythmia but not for death from other causes.

A key determinant of the cost effectiveness of a treatment is the increase in life expectancy that it yields. The initial report from MADIT II suggests that defibrillator therapy lengthened survival only moderately. However, the average follow-up was only 20 months — far shorter than the 4-to-5-year service life of the defibrillator. Accordingly, the full benefit of defibrillator therapy in MADIT II has not yet accrued, and continued follow-up should lead to a more precise estimate.

The findings of MADIT II represent a substantial advance in the prophylactic use of defibrillators but do not in themselves confirm that this approach should be used in all patients with coronary heart disease and severe left ventricular dysfunction. It is possible that more careful screening of potential candidates for the prophylactic implantation of a defibrillator would decrease the risk of complications, inconvenience, and expense yet save almost as many lives as did the criteria used by MADIT II.

J. Thomas Bigger, M.D.

Columbia University College of Physicians and Surgeons

New York, NY 10032

References

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2.Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933-1940.[Abstract/Full Text]

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