Pearls and perils of an implantable defibrillator trial using a common control: implications for the design of future studies

Common control trials compare several intervention groups to a single rather than separate control groups. Though potentially requiring fewer patients than trials using separate controls, variation in the common control group will influence all comparisons and creates correlations between findings. During subgroup analyses, this dependency of outcomes may increase belief in the presence of a real subgroup effect when, in fact, it should increase skepticism. For example, a high (r = 0.92), statistically unlikely (p = 0.052) correlation between comparisons was observed across the subgroups reported in SCD-HeFT. Such concordance between amiodarone and a defibrillator across subgroups was unexpected, given how much the effects of these treatments significantly differed from one another in the main study. This suggests the study's subgroup findings (specifically the absence of benefit from defibrillators in advanced CHF) were not necessarily a consequence of treatment; more likely, they resulted from variation in what the treatments were compared against, the common control.Common control trials can be more efficient than other designs, but induce dependence between treatment comparisons and require cautious interpretation.Implantation of a cardioverter defibrillator is considered life-saving therapy in patients with moderate to severe symptoms of congestive heart failure (CHF) and diminished ventricular function. In most defibrillator trials, patients with "sicker" hearts derived the largest survival benefit from such treatment [1-4]. Surprisingly, a recent randomized trial, Sudden Cardiac Death in Heart Failure (SCD-HeFT), reached an opposing conclusion [5]. The so-called "SCD-HeFT paradox" was the puzzling finding that survival in the subgroup of patients with New York Heart Association (NYHA) Class III CHF was not improved by receipt of an implantable defibrillator. This apparent contradiction may not, however, represent a true clinical phenomenon, but rather a conse