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The Carvedilol and ACE-inhibitor Remodeling Mild Heart Failure Evaluation Trial - CARMEN
Description:
Comparison of 1) enalapril monotherapy or 2) combination carvedilol and enalapril and 3) carvedilol monotherapy in patients with mild left ventricular systolic dysfunction
Hypothesis:
Carvedilol would lead to improved left ventricular remodeling and less progression of CHF than enalapril
Study Design
Patients Enrolled: 572
NYHA Class: Class I 7-9%; Class II 62-68% Class III 25-31%)
Mean Follow Up: 18 months
Mean Patient Age: Mean 62 years
Female: 23%
Mean Ejection Fraction: 30%
Patient Populations:
1) >18 years of age 2) Stable (>2 month history) symptoms 3) Mild heart failure symptoms
Exclusions:
1) Taking ACE inhibitor or beta-blocker within previous 2 weeks 2) Uninterpretable echocardiogram 3) Ejection fraction >40% 4) Acute hospitalization within 2 weeks 5) Medical regimen for heart failure modified within 2 weeks
Secondary Endpoints:
1) Changes from baseline to 18 months in left ventricular end systolic volume index within each treatment group 2) Changes in left ventricular end diastolic volume index and left ventricular ejection fraction 3) Mortality 4) Hospitalizations
Drug/Procedures Used:
Uptitration over 2 weeks to 1) Carvedilol 25 mg orally twice per day and placebo or 2) enalapril 10 mg orally twice per day and placebo. Patients assigned to enalapril or carvedilol monotherapy were continued on this medication as well as placebo. Enalapril (10 mg orally twice per day) was then added to those patients in the carvedilol group assigned to combination therapy. Echocardiography was obtained at baseline, 6, 12 and 18 months.
Concomitant Medications:
Diuretics, digoxin, nitrates. >60% of patients were treated with ACE inhibitors and 5% with beta-blockers (discontinued prior to enrollment)
Principal Findings:
Left ventricular systolic volume improved significantly in the group treated with combination therapy compared to those treated with enalapril alone (1 ml/m2 enalapril v. 5.8 ml/m2 combination; p<0.002). Baseline left ventricular end systolic volumes were 62.7 ml/m2 with enalapril monotherapy, 59.2 ml/m2 with combination therapy and 63.7 ml/m2 with carvedilol monotherapy. There was no significant difference between the group treated with carvedilol monotherapy and enalapril monotherapy (p=ns). In those patients treated with carvedilol monotherapy or combination therapy but no enalapril monotherapy, there was a decrease in left ventricular systolic volume index over 18 months follow-up. There was no detected difference in all-cause mortality.
Interpretation:
This study shows that the adjunctive use of carvedilol along with enalapril is associated with improved left ventricular remodeling in mild congestive heart failure. This study uses left ventricular end systolic index a surrogate endpoint for mortality since very large numbers of patients would be required to detect a mortality benefit between the three arms. While this assumption may be correct, the lack of benefit in the enalapril monotherapy arm is puzzling since both enalapril and carvedilol have ample evidence to support a survival benefit in patients with impaired left ventricular systolic function. This finding may be due to the fact that patients in the enalapril monotherapy arm had larger left ventricular end systolic volumes at baseline, and the majority of patients were already being treated with ACE inhibitors prior to enrollment and may have already reaped the benefits of this therapy. This is the first trial to compare beta-blocker monotherapy to monotherapy with ACE inhibitors and sets the stage for larger trials looking at hard endpoints comparing an up front strategy of beta-blocker monotherapy and ACE inhibitor monotherapy in patients with mild and moderate to severe congestive heart failure.
References:
Presented by W.J. Remme at the Annual Meeting of the European Society of Cardiology, September 2, 2002.
Remme WJ, Riegger G, Hildebrandt P, et al. The benefits of early combination treatment of carvedilol and an ACE-inhibitor in mild heart failure and left ventricular systolic dysfunction. The carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN). Cardiovasc Drugs Ther. 2004 Jan;18(1):57-66
Keywords: Enalapril, Carbazoles, Heart Failure, Ventricular Remodeling, Stroke Volume, Propanolamines, Systole, Echocardiography
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