(Circulation. 1995;91:2115-2117.)
© 1995 American Heart Association, Inc.
Articles |
Are Implantable Cardioverter-Defibrillators Better Than Conventional Antiarrhythmic Drugs for Survivors of Cardiac Arrest?
From Krannert Institute of Cardiology and Indiana University School of Medicine, Indianapolis, Ind.
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46202-4800.
Key Words: Editorials • antiarrhythmia agents • tachyarrhythmias
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Numerous studies have shown that the implantable cardioverter-defibrillator (ICD) accurately detects and successfully terminates ventricular tachyarrhythmias. In a recent report of 2834 epicardial and endocardial ICD implants in 2807 patients followed for a mean of 11.7 months, more than half of the patients had a combined total of almost 50 000 spontaneous episodes of ventricular tachyarrhythmias that were recognized and terminated by the ICD, with a success rate of about 98%. At 1 year, sudden cardiac death mortality was 1.4% in the epicardial ICD group and 0.6% in the endocardial group. The overall mortality at 1 year was 12.2% and 6.9% for the two groups, respectively, reflecting in part the greater surgical implant mortality for the epicardial (4.1%) compared with the endocardial (0.74%) systems. Complications requiring an invasive intervention totaled 18.9% for the endocardial implants and 9.2% for the epicardial implants.1 Thus, it becomes amply clear that the ICD effectively performs the functions for which it was created. Data such as these have encouraged many physicians to proceed rapidly to implantation of an ICD in the cardiac arrest survivor rather than spend time searching for a potentially more elusive therapeutic goal, that of an effective antiarrhythmic drug.
Despite these facts (and the "logical" extension that ICDs must save lives if they effectively terminate ventricular tachyarrhythmias), several reports2 3 4 have cautioned against a precipitous embrace of ICDs because the ICD effect on total mortality, particularly when compared against antiarrhythmic agents, has not been established in a rigorous fashion, that is, in a prospective, randomized clinical trial. In fact, as I stated in a recent editorial, "Until we directly randomize the ICD against the best medical management, we will not know which therapy is best in general or for a specific patient group."5 Randomization eliminates the risk of differences due to bias and if sufficient numbers are enrolled the chance differences between the treatment groups. Three large trials now in progress are attempting to answer the question of superiority between device and drug for the patient with a life-threatening ventricular tachyarrhythmia and include the Cardiac Arrest Study Hamburg (CASH),6 the Canadian Implantable Defibrillator Study (CIDS),7 and the Antiarrhythmics Versus Implantable Defibrillators (AVID) investigation,8 supported by the National Heart, Lung, and Blood Institute. A total of more than 2000 patients will be randomized in these three trials, and they should be able to answer the question of which is the better treatment.
Preliminary data from these trials are interesting. The CASH study began with four arms, randomizing patients among propafenone, amiodarone, metoprolol, and an ICD. The propafenone arm was stopped because of excess mortality, but the other therapies continue because there appear to be no significant differences in total mortality among the three groups.6 There are fewer sudden deaths in the ICD group, but the overall mortality is the same as in the other two groups. CIDS randomizes between amiodarone and an ICD and has increased the size of the study from 400 to 500 patients and has extended the completion date from January 1, 1996, to January 1, 1997. The data safety and monitoring board has found no reason to stop the study, and the investigators may increase the enrollment still further to 650 patients. Interestingly, addition of amiodarone to ICD therapy has occurred in 18% of patients, while crossover from amiodarone to an ICD is 9.0% (Stuart J. Connolly, personal communication). In AVID, the preliminary feasibility study that randomized 200 patients to amiodarone (a small number received sotalol) or an ICD has been completed, and another 150 patients have been randomized into the main portion of the study. To date, the number of crossovers between amiodarone and an ICD have been small and equal in both directions.8
Thus, these preliminary data from three large randomized trials raise the possibility that while the ICD may reduce sudden death mortality, there may be no difference in total mortality between amiodarone (and metoprolol in CASH) and an ICD. If true, one could explain the minimal impact of an ICD on total mortality by the operative mortality incurred with thoracotomy systems, now avoided with the use of transvenous systems, or the possibility that prevention of sudden death only slightly delays death from other causes. However, before making any conclusions, it must be emphasized that these studies are ongoing and that preliminary mortality data are available only for CASH.
Now we come to the present study,9 the first to be published in which survivors of cardiac arrest due to late postinfarction ventricular tachycardia or fibrillation were randomized to an ICD or antiarrhythmic agent. Conventional antiarrhythmic drugs were used, and only two patients ended up receiving amiodarone. Drug efficacy was established by the results of electrophysiological testing. Although the study was intended to be a test of cost-effectiveness, the authors analyzed the results for outcome and concluded that early defibrillator implantation was associated with a significantly lower number of main outcome events including death, prolonged syncope with cardiac arrest, and end-stage pump failure necessitating cardiac transplantation. Furthermore, they found better exercise tolerance, shorter hospitalization, lower number of invasive procedures, and less antiarrhythmic therapy changes in the early ICD group. Drug-treated patients were likely to end up with an ICD, and those who remained on drugs as sole therapy had a high risk of death regardless of efficacy assessment.
These conclusions were based on the fact that, of the 29 patients who received an ICD, there were only 4 deaths. Twenty of 31 patients randomized to drugs failed tests of drug efficacy (arrhythmia inducibility at electrophysiological study) and received map-guided surgery (6 patients, of whom 1 died, 1 had cardiac transplantation, and 1 had an ICD implantation) or ICD implantation (14). Of the remaining 11 who received drugs alone, 2 died in the hospital before being retested, 5 subsequently died, and 1 survived cardiac arrest. Therefore, 16 patients who initially received conventional drugs ended up with an ICD, and 3 subsequently died to give a mortality of 11 (35%) in the drug group versus 13% for the ICD group.
These appear to be quite impressive differences, leading the authors to conclude that the ICD is to be preferred over conventional drugs for survivors of cardiac arrest due to old myocardial infarction. We need to ask whether this conclusion is valid, and if so, whether it can be extrapolated to all antiarrhythmic drugs.
This is a well-performed study, but there are some problems with it, as acknowledged by the authors. First, the number of patients (60) is very small and was limited by the size of the grant the authors received to do the study. Thus, regardless of the statistical outcomes, even with the appropriate caution by the authors that confidence limits rather than P values be used as the best estimate of outcome, one must accept the data cautiously. Second, class I (Vaughan Williams) antiarrhythmic drugs or sotalol was used to treat all except 2 patients who were randomized to the drug arm. One of these 2 patients received amiodarone and the other received amiodarone plus quinidine. Leaving amiodarone as the last drug is understandable when using an electrophysiologically guided approach and considering the fact that the study began in April 1989. Even so, most of these patients did not receive a trial with amiodarone before being switched to other therapy. Today, sufficient data exist from controlled and noncontrolled studies10 11 12 13 14 15 to make a good case for using empiric amiodarone, noting that it is not particularly effective in preventing electrically induced arrhythmias but does appear to have a favorable impact on spontaneous arrhythmias and death. The class I drugs the authors chose to use are known to have either an adverse effect on mortality or no proven benefit for patients with ventricular arrhythmias after myocardial infarction.16 17 18 That is the reason amiodarone was selected for use in CASH, CIDS, and AVID. Also, given the low success rate of any antiarrhythmic drug in preventing arrhythmia inducibility by electrophysiological testing,19 the study from the beginning stacks the deck against drugs compared with ICDs, either in improving outcome, based on an intention-to-treat analysis, or reducing cost. Finally, 8 of the 29 patients who had an ICD implanted also had coronary revascularization, compared with only 3 of the conventionally treated group.
What can we conclude from this report? First, the authors are to be complimented for leading the way with a randomized investigation of this type. It took courage and foresight to start this project in 1989. Second, despite the deficiencies, I think we can say that the ICD is superior to class I antiarrhythmic drugs for patients with an old myocardial infarction who have survived a cardiac arrest. I make that conclusion based on data from the present study9 and the impressive survival statistics from the transvenous ICD lead system1 (albeit not a randomized trial) versus no published data showing an improvement in mortality with class I drugs.16 17 18 The results are too lopsided not to believe. However, it is important to stress that, as far as I am concerned, it still has not been shown whether an ICD is better than amiodarone. That conclusion awaits completion of CASH, CIDS, and AVID.
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Acknowledgments |
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Dr Zipes is supported in part by the Herman C. Krannert Fund, by grant 1P50-HL-52323 from the National Heart, Lung, and Blood Institutes of the National Institutes of Health, and by the US Public Health Service. The author thanks Alfred P. Hallstrom, PhD, for helpful comments.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Received February 1, 1995; accepted February 1, 1995.
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References |
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TopIntroductionReferences |
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1. Zipes DP, Roberts D, PCD Investigators. Results of the world-wide study of the implantable pacemaker, cardioverter-defibrillator: a comparison of epicardial and endocardial lead systems. Circulation. In press.
2. Connolly SJ, Yusuf S. Evaluation of the implantable cardioverter defibrillator in survivors of cardiac arrest: the need for randomized trials. Am J Cardiol. 1992;69:959-962. [Medline] [Order article via Infotrieve]
3. Epstein AE. AVID necessity. PACE Pacing Clin Electrophysiol. 1993;16:1773-1775. [Medline] [Order article via Infotrieve]
4. Green HL. Antiarrhythmic drugs versus implantable defibrillators: the need for a randomized controlled study. Am Heart J. 1994; 127:1171-1178.
5.
Zipes DP. Implantable cardioverter-defibrillator: lifesaver
or a device looking for a disease? Circulation. 1994;89:2934-2936.
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7. Connolly SJ, Jent M, Roberts RS, Dorian P, Green MS, Klein GJ, Mitchell LB, Sheldon RS, Roy D. Canadian Implantation Defibrillator Study (CIDS): study design and organization. Am J Cardiol. 1993;72:103F-108F. [Medline] [Order article via Infotrieve]
8. AVID Investigators. Antiarrhythmics Versus Implantable Defibrillators (AVID): rationale, design and methods. Am J Cardiol. In press.
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