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Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure - PRECISE
Description:
The goal of this trial was to assess the efficacy of carvedilol in patients with moderate to severe congestive heart failure (CHF).
Hypothesis:
Exercise tolerance will be higher in patients receiving carvedilol, than in patients not receiving carvedilol.
Study Design
Study Design:
Patients Screened: 301
Patients Enrolled: 278
NYHA Class: II to IV; majority - class III
Mean Follow Up: Six months
Female: 27
Mean Ejection Fraction: Mean: 22% in both groups
Patient Populations:
NYHA class II-IV heart failure despite conventional therapy, heart failure regimen unchanged in the preceding month, and left ventricular ejection fraction <35%
Exclusions:
Uncorrected primary valvular disease; active myocarditis; restrictive cardiomyopathy; myocardial infarction, stroke, unstable angina, or coronary artery bypass graft surgery within three months; symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or an implantable defibrillator; sick sinus syndrome or advanced heart block (unless treated by a pacemaker); any condition other than heart failure that could limit exercise; systolic blood pressure >160 or <85 mm Hg or diastolic blood pressure >100 mm Hg; heart rate <68 bpm; significant hepatic, renal, or endocrine disease; drug or alcohol abuse; or therapy with calcium channel blockers, alpha- or beta-adrenergic agonist or antagonist drugs, or specific antiarrhythmic drugs (disopyramide, flecainide, encainide, moricizine, amiodarone, propafenone, or sotalol)
Primary Endpoints:
Exercise tolerance, as assessed by the six-minute corridor walk and the nine-minute treadmill test
Secondary Endpoints:
NYHA functional class, left ventricular ejection fraction, quality-of-life scores, and frequency of hospitalization for cardiovascular causes
Drug/Procedures Used:
All patients were enrolled in a two-week open-label run-in period, during which they received carvedilol 6.25 mg twice daily. Patients who were able to tolerate that dose were randomly assigned in a 1:1 fashion to receive long-term therapy with carvedilol or placebo. Carvedilol dosage was increased gradually, to a target dose of 25 mg twice daily in patients weighing ≤85 kg, and 50 mg twice daily in patients >85 kg. Double-blind therapy was then continued for six months.
Concomitant Medications:
Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and digoxin
Principal Findings:
Of the 301 patients enrolled in the open-label run-in period, 278 were able to tolerate the baseline dose of carvedilol, and were enrolled in the randomized portion of the trial. At six months, patients received an average dosage of 28 ± 13 mg daily of carvedilol and the equivalent of 32 ± 13 mg daily of placebo, with 87% receiving their target dosages of carvedilol.
After six months of follow-up, therapy with carvedilol was associated with small changes in exercise tolerance. The six-minute walk distance increased by 9 m in the carvedilol group, but decreased by 3 m in the placebo group (p=0.048). Differences between the two groups on the nine-minute treadmill test were not significant. New York Heart Association (NYHA) functional class was significantly improved in the carvedilol group. The proportion of patients in class III or IV CHF decreased in the carvedilol group (from 64% to 41%, p=0.014), but not in the placebo group (from 58% to 51%).
Additional benefits associated with carvedilol in this study included an increase in ejection fraction (8% vs. 3% for placebo, p<0.001) and decrease in cardiovascular hospitalizations (14.5% vs. 24.5%, p=0.029). Although mortality was not significantly different between the groups, the overall probability of a major fatal or nonfatal event was lower in the carvedilol group (31.0% vs. 19.6%, p=0.029).
Interpretation:
When added to a conventional therapy with ACE inhibitors, diuretics, and digoxin, treatment of patients with moderate to severe CHF with carvedilol was associated with significant improvements in hemodynamic and clinical events compared with conventional therapy plus placebo.
References:
Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation 1996;94:2793-9.
Keywords: Exercise Tolerance, Follow-Up Studies, Digoxin, Diuretics, Propanolamines, Vasodilator Agents, Carbazoles, Adrenergic alpha-1 Receptor Antagonists, Heart Failure, Stroke Volume, Probability
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