Why the Antiarrhythmics Versus Implantable Defibrilliator (AVID) Trial Sets the Wrong Precedent

T Antiarrhythmics versus Implantable Defibrillator (AVID) trial was discontinued on April 7, 1997, after a 38% reduction in overall mortality was recognized in patients randomized to the implantable cardioverter defibrillator (ICD).1 The primary purpose of AVID was to assess whether the ICD—which has long been known to prevent sudden death—would also prolong the overall survival of patients with lifethreatening ventricular tachyarrhythmias. Accordingly, patients with such arrhythmias were randomized to therapy either with the ICD or with antiarrhythmic drugs (amiodarone or sotalol). In announcing the termination of the trial, National Heart, Lung, and Blood Institute Director Lenfant, called AVID a ‘‘landmark study’’ that showed for the first time that ICDs ‘‘improve overall survival in patients with serious ventricular arrhythmias.’’1 Although everyone can agree that AVID is a precedent setting study, not all agree that it is a precedent that should be set. Some, in fact, have voiced grave misgivings about this study since before its inception.2–10 To be sure, among those misgivings was a concern that the results of AVID might inappropriately stifle an effective new technology. It is therefore a relief to learn that the results apparently will not do that. The more substantial misgivings expressed about AVID, however, went far beyond the fear that the outcome might not be to one’s liking. In fact, now that the results seem to validate the efficacy of the ICD, and since it is likely that a majority of our peers will ‘‘like’’ the results of AVID, there is even more reason to be concerned about the long-term ramifications of this study. I will argue in this editorial that AVID was based on 3 false premises, premises that demonstrate how economic imperatives can distort the principles of science, logic, and ethics upon which clinical research is founded; and that further, if AVID becomes a precedent for how one may—or even must—design randomized trials in a new era of economic constraint, then the principles that were violated in its design may be lost forever. False premise 1: only a randomized trial yields acceptable data: The notion that only randomized data are acceptable data (and conversely, that all nonrandomized data are unacceptable), is dogma masquerading as science. The most that can be gained from any clinical trial, randomized or not, is a statistical inference, such is the nature of clinical medicine. To design a randomized trial is to strive to draw a more accurate inference than might be inferred with an observational study; however, it is still merely making a statistical inference, it does not distinguish truth from falsity. Most pertinent in this regard is the issue of statistical bias. Despite commonly held misconceptions to the contrary, the act of randomizing does not eliminate bias. In fact, it can be argued that the major benefit of a randomized trial (and also the major threat) is that it systematizes bias, thus presenting the designers of the trial an opportunity to minimize and otherwise control it. Accordingly, decisions made when designing a randomized trial ultimately determine the direction of that statistical bias. Perhaps the most fundamental decision that must be made when designing a randomized trial is whether the trial is to be a fastidious or a pragmatic one, a decision that always affects the direction of statistical bias. A fastidious trial enrolls only a narrowly defined subset of patients. Fastidious trials are therefore inherently more ‘‘scientific’’ because the intervention being tested is nearly the only variable among treatment groups. Fastidious trials also allow the designers of a randomized trial to maximally challenge the null hypothesis. By including only those patients who seem most likely to respond favorably to a new therapy, for instance, investigators have a better chance of demonstrating that the therapy can be beneficial in at least some patients. The disadvantage with a fastidious trial is that the results can be applied only to patients who are identical to the specific subset enrolled in the trial; results cannot be extrapolated. This limitation is not merely a rule (because rules can be changed); it is a law of nature. Because all other subsets of patients are systematically excluded from a fastidious study, it is fundamentally invalid to generalize the results. Another occupational hazard in designing fastidious trials is that the typically long list of inclusion and exclusion criteria that make the study fastidious also provides a built-in means of criticizing the study after the fact. One who disagrees with the results of such a study can find a ready-made list of excuses for discounting those results. Such a technique is illustrated by recent criticisms of the Multicenter Automatic Defibrillator Implantation Trial.11 On the other hand, a pragmatic study can be designed. Pragmatic trials make eligible for enrollment From the Allegheny University of Health Sciences and Allegheny General Hospital, Pittsburgh, Pennsylvania. Manuscript received and accepted April 30, 1997. Address for reprints: Richard N. Fogoros, MD, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, Pennsylvania 15212.