Treatment with beta-blockers such as carvedilol, metoprolol and bisoprolol significantly reduces mortality in patients with congestive heart failure. Results of the Carvedilol or Metoprolol European Trial (COMET) showed that carvedilol was superior to metoprolol. For example, investigators found a significantly greater risk reduction in cardiovascular mortality versus metoprolol (20% risk reduction) and death due to stroke (67% risk reduction).

One possible reason for this advantage is that carvedilol blocks multiple adrenoreceptors. In contrast, metoprolol is selective for the beta-1 adrenoreceptor. Others have suggested that carvedilol has ancillary properties, such as an antioxidant effect.

Another possible explanation is that carvedilol has atypical binding kinetics. Researchers have reported that the binding of this beta-blocker to myocardial membranes is nearly irreversible. This raises the possibility that the beta-blocking effect of carvedilol may persist even after plasma elimination.

To test this hypothesis, Dr. Kindermann and colleagues compared catecholamine response in the heart during carvedilol or metoprolol administration, and after abrupt withdrawal of either beta-blocker. They performed in vitro investigations on isolated and electrically stimulated human atrial muscle strips. They also performed in vivo experiments in 7 healthy volunteers.

In Vitro Experiments

Investigators measured the contractility of isolated, electrically stimulated human atrial muscle strips in response to isoproterenol. They measured contractility before applying beta-blockers, during incubation with beta-blockers, and after withdrawal.

During beta-blocker application, there was significant reduction in the potency of isoproterenol compared with control conditions. This occurred for both carvedilol and metoprolol.

However, there was a striking difference between beta-blockers when investigators removed atrial muscle strips from the beta-blocker solution. After washout of beta-blockers, isoproterenol potency returned to baseline levels for metoprolol. In contrast, the potency of isoproterenol remained lower. This difference was highly significant, Dr. Kindermann said.

In Vivo Experiments

Seven healthy volunteers received 50 mg of carvedilol and 190 mg of metoprolol for 10 days in a randomized, crossover study. They all underwent dobutamine stress echocardiography before, during and 44 hours after receiving study medication.

Plasma concentrations of carvedilol and metoprolol during treatment were within the therapeutic range; at the 44-hour measurement, plasma concentrations were below detectable levels in both groups.

Heart rate response during therapy was comparable between beta-blockers. Both metoprolol and carvedilol resulted in a significant reduction of heart rate response during dobutamine stimulation in all volunteers. However, after withdrawal of medication, the heart rate response returned to baseline levels for metoprolol. On the other hand, there was still a beta-blocking effect for carvedilol.

Similarly, cardiac output in response to dobutamine was different between beta-blockers. Cardiac output returned to baseline levels 44 hours after withdrawal of metoprolol. In contrast, cardiac output remained depressed after withdrawal of carvedilol.

Investigators made similar observations for heart rate-corrected velocity of circumferential fiber shortening (VCFc). After withdrawal of metoprolol, this parameter returned to baseline values, whereas it remained significantly reduced in carvedilol-treated volunteers.

These results show that the beta-blocking effect of carvedilol continues long after its selimination from plasma. This may occur because of persistent receptor binding.

These findings show that carvedilol prevents a beta-blocker rebound phenomenon. Even after withdrawal of medication, the beta-blocking effect remains for at least 44 hours. Compliance to carvedilol therapy may not be as critical as in other beta-blocker therapy. The beta-blocking effect may remain even if patients occasionally miss a dose.