Selective versus nonselective beta-blockade for heart failure therapy: are there lessons to be learned from the COMET trial?

The recently reported COMET trial found that the beta1/beta2/alpha1 receptor blocking agent carvedilol given in a relatively high beta1-receptor blocking dose regimen was superior in mortality reduction to immediate release metoprolol given in a relatively low beta1-receptor blocking dose schedule. We analyze the problems with the trial design of COMET from the standpoint of comparing 2 therapeutic agents at different positions on a common dose-response curve, and discuss the theoretical reasons why postjunctional adrenergic receptor blockade that is in addition to beta1-receptor antagonism will likely produce only minimal or no incremental benefit in chronic heart failure.