CARMEN: Carvedilol prevents progression of mild heart failure

Julia Rommelfanger

September 03, 2002

Berlin, Germany - Left ventricular remodeling in patients with mild chronic heart failure (HF) can be significantly improved by the early administration of carvedilol (Dilatrend® - Roche) in combination with an ACE inhibitor, data from the CARMEN trial indicate. This outcome confirms current HF treatment guidelines, which mandate not to delay combination treatment of beta-blockage plus ACE inhibition, said lead investigator Dr Willem Remme (STICARES Cardiovascular Research Foundation, Rhoon, the Netherlands) here at the European Society of Cardiology Congress 2002.

"Early addition of carvedilol to ACE-inhibitor therapy in mild heart failure can reverse the effects of left ventricular remodeling," he said.

Dr Willem Remme

His study, the Carvedilol ACE Inhibitor Remodelling Mild CHF Evaluation (CARMEN) trial, is the first large-scale study directly comparing the effects of a beta blocker with an ACE inhibitor in this condition. In 65 institutions in 13 European countries, a total of 572 patients with mild HF (ejection fraction [EF] < 39%) were randomized in a double-blind design into 3 study arms, receiving 18 months of treatment on top of their current HF therapy (diuretics, digoxin, nitrates):

  • Carvedilol in combination with enalapril (n=191)

  • Carvedilol alone (n=191)

  • Enalapril alone (n=190)

The objective of the trial was to evaluate the efficacy of carvedilol alone or a combination of carvedilol with enalapril vs enalapril alone, in terms of left ventricular remodeling, tolerability, and safety. The primary study end point, the change in LV-end-systolic-volume index, was assessed by echocardiogram at the initiation of treatment and at 6 and 18 months of follow-up.

Historic practice challenged
The results are a challenge to the historical practice of initiating ACE inhibition before beta-blocker therapy.

In patients receiving carvedilol plus ACE inhibitor and in those taking carvedilol alone the researchers found a highly significant improvement of LV-remodeling and a significant reduction in heart size. Patients on enalapril only, in contrast, did not show a benefit. All 3 treatment arms had similar safety and tolerability profiles and no significant difference in mortality and morbidity. "The outcome is important, because the use of beta blockers has long been contraindicated in heart failure," said Remme. "The results are a challenge to the historical practice of initiating ACE inhibition before beta-blocker therapy."

He pointed out, however, that "this is not an effect you may see with other beta blockers as well. Carvedilol was the exception."

Questions remain

Dr PA Poole-Wilson (Imperial College School of Medicine, London, UK) was less enthusiastic about the trial outcome, although he did consider it "a study that matters, because it has got important clinical implications," being the first large study comparing these agents.

One problem, he explained, was that previous studies in HF, such as the SOLVD trial, did show an effect of enalapril. He suspected the lack of benefit in the enalapril group in CARMEN to be due to the high number of patients (65%) being on ACE inhibitors at baseline. Because LV-remodeling had already occurred before the initiation of study treatment in those patients, no further benefit could be shown, Poole-Wilson said. The best way to demonstrate a real benefit, he suggested, would be to study a beta blocker vs current best treatment of a beta blocker plus ACE inhibitor. "But who's going to do that study and who will pay for it?"

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