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Second Prospective Randomized Study of Ibopamine on Mortality and Efficacy in Heart Failure - PRIME-2
Description:
PRIME-2 sought to investigate the effect of ibopamine on mortality and safety in patients with severe CHF.
Hypothesis:
Ibopamine added to standard medical therapy results in mortality equivalent to standard medical therapy alone for severe CHF.
Study Design
Study Design:
Patients Screened: Not reported
Patients Enrolled: 1,906
NYHA Class: Baseline Class III, 60%; Class III/IV, 32%; Class IV, 8%
Mean Follow Up: up to 3 years
Mean Patient Age: Not reported
Female: 20
Mean Ejection Fraction: Baseline EF in ibopamine arm = 26.0 +/- 8.5; in placebo arm = 26.4 +/- 9.6
Patient Populations:
NYHA functional class III-IV; Hospital admission for advanced congestive cardiac failure, or symptoms of congestive heart failure at rest despite optimal therapy, within the 2 months before randomization; Evidence of severe left-ventricular disease; Age 18–80 years.
Exclusions:
Hospitalized patients who were not realistically expected to be discharged. Obstructive valve disease; obstructive or restrictive cardiomyopathy; any potentially transient cause of heart failure; a myocardial infarction during the previous 3 months; unstable angina; uncontrolled arrhythmias; current need for intravenous inotropic support; intolerance of dopamine or ibopamine; concomitant use of medication known to interact with these drugs (eg, metoclopramide, levodopa); pregnancy or lactation; inadequate contraception in women of childbearing age; and administration of another investigational drug within the previous 30 days.
Primary Endpoints:
All cause mortality
Secondary Endpoints:
Cause of death, the need for cardiac transplantation, the number of and reason for hospital admissions, quality of life, symptom scores, and reasons for withdrawal from trial medication.
Drug/Procedures Used:
Ibopamine, 100 mg three times daily for a minimum of 6 months.
Concomitant Medications:
Optimum treatment for heart failure, which was defined as ACE inhibitors, diuretics (furosemide 80 mg or more daily, if ACE inhibitors were not prescribed, or at least 40 mg daily in combination with an ACE inhibitor), and, if indicated, digoxin and other vasodilators.
Principal Findings:
Increased mortality in ibopamine patients (25% vs 20%, p=0.017) prompted study to be stopped early by Safety/Monitoring Committee.
No differences from placebo were found in symptoms or quality of life scores.
Post hoc analysis noted increased deaths in ibopamine group in patients on antiarrhythmic drugs (28.2% vs 16.0%).
Increased deaths occurred in NYHA class III/IV and class IV patients on ibopamine (34.7% vs 26.1%) but not in class III patients (17.2% vs 16.4%, p=NS).
Interpretation:
Ibopamine increased mortality in patients with advanced heart failure already receiving optimum therapy. The adverse effect of ibopamine on survival was unexpected, given the properties of ibopamine which were expected to confer benefit to patients with heart failure (vasodilatation, an appropriate effect on neurohormones). At the time of the study, ibopamine was approved in several European countries for the treatment of heart failure, and no previous study suggested the possibility that ibopamine might increase fatality. As a result of the study, restrictions were placed on the use of ibopamine in patients with severe heart failure in those European countries where the drug was previously licensed.
References:
Lancet 1997;349:971–977
Keywords: Vasodilation, Deoxyepinephrine, Quality of Life, Diuretics, Heart Failure, Neurotransmitter Agents, Vasodilator Agents, Cardiotonic Agents
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