ArticlesRandomised study of effect of ibopamine on survival in patients with advanced severe heart failure
Introduction
In patients with advanced heart failure, the relief of symptoms is important. However, drugs such as milrinone, enoximone, and flosequinan have been shown to improve symptoms at the expense of an increase in fatality1, 3. Thus, evidence that a new drug improves the symptoms of heart failure is necessary but not sufficient for its acceptance into clinical use. Ideally, a new drug would increase survival and improve symptoms; at the least, it should have no effect on survival.
Dopamine agonists have properties that make them potentially useful for the treatment of heart failure. Ibopamine is an orally active compound hydrolysed in vivo to epinine (N-methyldopamine)4. The active metabolite stimulates DA-1 and DA-2 receptors and causes renal and peripheral vasodilatation, and does not seem to have an inotropic effect5. Previous studies showed that in patients with heart failure, ibopamine reduced plasma concentrations of noradrenaline, renin activity, and aldosterone6, 7, 8. Clinical studies have reported that ibopamine improves symptoms and has an effect similar to captopril on exercise tolerance in patients with mild-to-moderate heart failure9, 10. Ibopamine seemed to be a new class of drug that might make an important contribution to the management of patients with heart failure.
The Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II Study) was set up to investigate the effect of ibopamine on mortality and to collect sufficient data to show whether or not ibopamine treatment was safe.
Fatality rates among patients with severe heart failure are high, even if they receive optimum treatment. The PRIME II study was specifically designed to investigate the efficacy and safety of ibopamine in patients with advanced heart failure.
Section snippets
Methods
This multicentre, randomised study compared the effect of ibopamine 100 mg three times daily or placebo on all-cause mortality in patients with advanced heart failure. Secondary endpoints were 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.
Patients were randomly allocated ibopamine or placebo by means of a numbered pack system within each centre. Duration of
Results
The first patient was randomly assigned study medication in September, 1992. In August, 1995, the safety committee, at its regular meeting to review data then available, found a significantly higher fatality rate among ibopamine-treated patients than among placebo-treated patients. Thus, the safety committee advised the steering committee to terminate the study. All patients were subsequently withdrawn from treatment.
By August, 1995, we had recruited 1906 patients rather than the projected
Discussion
This is the fourth major study to report an association between active treatment and increased fatality in patients with heart failure1, 2, 3. Nevertheless, the adverse effect of ibopamine on survival reported here was unexpected. Ibopamine has properties expected to confer benefit to patients with heart failure, particularly vasodilatation and an appropriate effect on neurohormones, and is also thought not to have inotropic effects. The drug is well established in several European countries
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Members of PRIME II are listed at end of paper