In this report, Dr. Remme described subgroup analyses of the Carvedilol Ace-inhibitor Remodeling in Mild heart failure EvaluatioN (CARMEN) study. Investigators undertook the CARMEN study to evaluate the effect of the beta blocker carvedilol with or without ACE inhibitor in patients with CHF.

One rationale for the study is that beta blockade may be able to replace ACE inhibition with respect to effect on cardiac remodeling. Previously, effect of beta blockade on cardiac remodeling had always been evaluated in conjunction with an ACE inhibitor. However, it is not clear whether the combination is mandatory to achieve this effect. Furthermore, beta blockade may have a similar or better effect than ACE inhibition.

To study these issues, investigators in 13 countries enrolled 572 patients with stable mild heart failure in the CARMEN study. The mean age of the patients was 62 years and 81% were male. This parallel-group randomized study included three arms: carvedilol and enalapril, carvedilol alone and enalapril alone. Patients had to stop all existing beta-blockers and ACE inhibitors before entering the study. About 65% had been taking ACE inhibitors prior to the start of the study, and only 6% were on beta-blockers. Treatment lasted for 18 months.

Investigators uptitrated carvedilol to a target dose of 25 mg twice daily. They uptitrated enalapril to a target dose of 10 mg twice daily. In the combination arm, they first uptitrated carvedilol before starting enalapril.

The primary endpoint was change in left ventricular end systolic volume index over 18 months. Dr. Remme presented a subgroup analysis of this primary endpoint for the 320 patients who had been taking ACE inhibitors. There was a reduction of 4.7 ml/m2 in left ventricular end systolic volume index in the carvedilol group, and a reduction of in the group receiving carvedilol and enalapril. There was a slight increase in the enalapril only group.

For the 159 patients who had not been taking ACE inhibitors, there was a significant decrease in left ventricular end systolic volume index for the patients who received combination treatment with carvedilol and enalapril.

Left ventricular ejection fraction improved in the subgroup of patients formerly taking ACE inhibitors who received carvedilol or carvedilol plus enalapril. In the subgroup of patients who were not on ACE inhibitors and then received combination treatment on study, there was a significant improvement in left ventricular ejection fraction.

Overall safety and tolerability profiles were similar. Adverse events occurred in about three-quarters of patients in each group. At least 70% of patients completed treatment in each group.

Dr. Remme said combination therapy with carvedilol and an ACE inhibitor can have a favorable impact on left ventricular remodeling and function in patients with mild CHF, regardless of whether or not they had been taking an ACE inhibitor beforehand.

Replacing an ACE inhibitor with carvedilol also produced significant reversal of cardiac remodeling in contrast to ongoing ACE inhibition alone. These patients did not have more side effects despite changing therapy.

Current guidelines recommend using an angiotensin recepter blocker when a CHF patient must stop an ACE inhibitor due to intolerance or some other reason. According to Dr. Remme, these results suggest that carvedilol is also a reasonable alternative for patients who discontinue ACE inhibitor use.

Guidelines also suggest that these patients should receive ACE inhibitors first and only start beta-blockers later if the patient remains symptomatic. However, Dr. Remme argued against this delay in therapy. The CARMEN results suggest that it may be feasible, effective and safe to give the ACE inhibitor and carvedilol as closely together as possible.