Clinical Trial Result Information

Protocol number
MF4455

Title of Study
A multicenter randomized double-blind, controlled study to compare the effect on mortality and morbidity over 46–74 months of carvedilol (Dilatrend) (oral titrated administration of 6.25 mg bid to 25 mg bid, with a preceding dose of 3.125 mg bid) and metoprolol (oral titrated administration of 12.5 mg bid to 50 mg bid with a preceding dose of 5 mg bid) in patients with chronic heart failure (NYHA II-IV).

Sponsor
F. Hoffmann-La Roche Ltd.

Company division
Pharmaceutical

Product name
Dilatrend

Generic name
carvedilol

Therapeutic area
Heart Failure

Clinical study summary
This was a double-blind, randomized, active-controlled, multicenter study of Dilatrend and metoprolol. Patients were given oral Dilatrend or metoprolol twice daily, and the dose was up-titrated every 2 weeks to the maximum tolerated dose/target dose for 46–74 months.

Study center(s)
This was a multicenter study conducted in 15 European countries at 317 centers: Austria, Belgium, Denmark, Finland, France, Germany, Great Britain, Hungary, Italy, Netherlands, Norway, Portugal, Spain, Sweden, and Switzerland.

Phase of development
III

Objectives
To determine the effect of Dilatrend compared with metoprolol on mortality and morbidity in patients with chronic heart failure.

Methodology
Patients were randomly assigned to treatment with either Dilatrend or metoprolol, and monitored over a period of 46 to 74 months. The primary endpoint variable was time to event, defined as the number of days from the date of randomization to the date of event or to the date of the cut-off, if the patient did not have an event during the course of the study.

Number of patients (planned/analyzed)
3000 were planned, and 3029 were randomized.

Diagnosis and main criteria for inclusion
Chronic Heart Failure (New York Heart Association Classification II-IV) remaining symptomatic despite standard treatment with diuretics and angiotensin-converting enzyme inhibitors.

Test product, dose and mode of administration or test procedure
Dilatrend 3.125 mg, 6.25 mg, 12.5 mg, and 25 mg/bid/po; up-titrated every 2 weeks to the maximum tolerated dose/target dose of 25 mg/bid.

Duration of treatment
46–74 months.

Reference therapy, dose and mode of administration or reference procedure
Metoprolol tartrate, 5 mg, 12.5 mg, 25 mg, and 50 mg/bid/po; up-titrated every 2 weeks to the maximum tolerated dose/ target dose of 50 mg bid.

Criteria for evaluation (efficacy, safety)
Efficacy parameters: (1) All-cause mortality; and (2) All-cause mortality or all-cause hospitalization. Safety parameters: (1) Spontaneously reported adverse events; and (2) Laboratory test results.

Statistical methods
It was determined that 1020 fatal events would be required to detect a risk reduction of 20% with ≥80% power. With respect to the composite endpoint, approximately 2400 events were expected, giving 80% power to detect a 15% reduction in risk at a significance level of 0.01. The comparative effects of the study treatments were examined initially using a log-rank test without covariates. A Cox proportional hazards model was fitted with treatment as the only independent variable to obtain an estimate of the hazard ratio and a 95% confidence interval (CI) for this parameter. Kaplan-Meier estimates of the survival functions were displayed to characterize treatment effects. All patients who received ≥1 dose of study drug were included in the analyses according to the intent-to-treat principle.

Summary (efficacy, safety, other results)
For all-cause mortality, there were 512 (33.9%) deaths in the Dilatrend group compared with 600 (39.5%) in the metoprolol group (hazard ratio 0.83; 95% CI 0.74, 0.93; P=0.0017 in favor of Dilatrend). The median survival (assuming constant hazards) was estimated to be 8.0 years for Dilatrend and 6.6 years for metoprolol, a difference of 1.4 years (95% CI: 0.5–2.3 years). For the combined endpoint of all-cause mortality or all-cause hospitalization, there were 1116 (73.9%) reports in the Dilatrend group compared with 1160 (76.4%) in the metoprolol group (hazard ratio 0.94; 95% CI 0.86, 1.02; P=0.12, not statistically significant).

Safety – Of 1511 patients allocated to Dilatrend, 93.6% experienced an adverse event and 73.7% a cardiovascular adverse event. Of 1518 patients allocated to metoprolol, the percentages were 95.7% and 75.6%. Adverse event reports of sudden death (8.7% vs 12.0%), myocardial infarction (4.6% vs 6.3%), unstable angina (3.7% vs 5.1 %) and stroke (3.5% vs 4.3%) were less common with Dilatrend. Heart failure (42.2% vs 44.9%), dyspnea (9.5% vs 11.0%), and peripheral edema (2.5% vs 3.6%) occurred more frequently with metoprolol. No consistent differences were seen with regard to bradycardia or heart block. Hypotension (14.2% vs 10.4%), dizziness (12.2% vs 11.3%), and syncope (8.1% vs 6.1%) were more common with Dilatrend, while diabetes (11.0% vs 12.5%) and hypokalemia (2.0% vs 3.2%) were less common. The incidences of bronchospasm (0.7% vs 0.4%) and asthma (0.3% vs 0.3%) were very low in both groups.

Conclusions
No previous comparisons of beta-blocking drugs with different properties on long-term mortality and morbidity have been made in patients with chronic heart failure optimally treated with diuretics and ACE inhibitors. In these patients, Dilatrend had a significantly greater mortality benefit than metoprolol. No statistically significant difference in the composite endpoint, all-cause mortality or all-cause hospitalization was evident. Sudden death, myocardial infarction, unstable angina, stroke, peripheral edema, diabetes and hypokalemia occurred less requently with Dilatrend, while hypotension, dizziness and syncope occurred more frequently. Metabolic and hemodynamic adverse events are compatible with the known different properties of these two beta-blockers.

Publications (references, if available)
Poole-Wilson PA, Cleland JG, Di Lenarda A, et al. Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Eur J Heart Fail 2002;4:321-329. Poole Wilson PA, Swedberg K, Cleland JGF et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure. Results of the Carvedilol Or Metoprolol European Trial (COMET). Lancet 2003:362:7-13.

Date of report
12/19/2003