Commentary

Thanks to the remarkable successes in drug development, a variety of effective treatments are available for most medical conditions. The new challenge is often how to select the optimal therapy. For approval purposes, regulatory agencies require placebo controlled rather than active comparison trials. The federally funded ALLHAT represents an important comparative trial of antihypertensives.¹ A recently introduced congressional bill calls for more ALLHAT-like comparative trials.² The financial implications are enormous.

The treatment of CHF is a crowded field with multiple choices, both between and within drug classes. In placebo controlled trials in heart failure patients, carvedilol and metoprolol CR/XL reduce mortality to a similar extent. Thus, an indirect comparison suggests little or no difference between drugs.

The findings of COMET, sponsored by the manufacturer of carvedilol, contradict this expectation, and the investigators conclude that carvedilol extends survival more so than metoprolol. Alternative explanations are possible. The target dose for carvedilol in COMET was the Food and Drug Administration recommended dose of 25 mg twice daily. The investigators used metoprolol tartrate 50 mg twice daily, which is not approved for heart failure. The metoprolol dose in COMET was also less than the approved long acting formulation, metoprolol CR/XL 200 mg daily (equivalent to 130 mg metoprolol tartrate). Mean reductions in heart rate and systolic blood pressure in COMET support the view that the β blocking effect of the metoprolol dose was less pronounced than that of the carvedilol dose. An editorial by Dargie³ raised the issue of comparable β blockade. These and other inconsistencies suggest that the results of COMET are not definitive.

Proper trial design is essential to interpretation of comparative trials. Independence from pharmaceutical sponsors may be important to avoid suboptimal comparators, suboptimal doses, or suboptimal formulations.