Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure

doi:10.1016/S0140-6736(96)10488-8

The Lancet

Volume 349, Issue 9057, 5 April 1997, Pages 971-977

https://doi.org/10.1016/S0140-6736(96)10488-8 Get rights and content

Summary

Background

Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival. Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation; the drug improves symptoms of heart failure. We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre, randomised placebo-controlled study.

Methods

Patients with advanced severe heart failure (New York Heart Association classes III and IV) and evidence of severe left-ventricular disease, who were already receiving optimum treatment for heart failure, were randomly allocated oral ibopamine 100 mg three times daily or placebo. The primary endpoint was all-cause mortality. The study was designed to recruit 2200 patients, and the minimum duration of treatment would be 6 months. We did intention-to-treat and on-treatment analyses; a post-hoc subgroup analysis was also done.

Findings

After we had recruited 1906 patients the trial was stopped early, because of an excess of deaths among patients in the ibopamine group. 232 (25%) of 953 patients in the ibopamine group died, compared with 193 (20%) of 953 patients in the placebo group (relative risk 1·26 [95% Cl 1·04–1·53], p=0·017). The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group. In multivariate analysis, only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients.

Interpretation

Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy, but the reasons for this increase are not clear. Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.

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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There are more references available in the full text version of this article.

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ArticlesRandomised study of effect of ibopamine on survival in patients with advanced severe heart failure

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

Effect of oral milrinone on mortality in severe chronic heart failure

N Engl J Med

Treatment of severe heart failure: quantity or quality of life? A trial of enoximone

Heart

Articles
Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure