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

Implantable defibrillators are considered life-saving therapy in heart failure (CHF) patients. Surprisingly, the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) reached an opposing conclusion from that of numerous other trials about their survival benefit in patients with advanced CHF. A critical analysis of common control trial design may explain this paradoxical finding, with important implications for 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.