Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial.
Publication/Presentation Date
8-14-2010
Abstract
BACKGROUND: Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether rimonabant would improve major vascular event-free survival.
METHODS: This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18,695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00263042.
FINDINGS: At a mean follow-up of 13.8 months (95% CI 13.6-14.0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3.9%) patients assigned to rimonabant and 375 (4.0%) assigned to placebo (hazard ratio 0.97, 95% CI 0.84-1.12, p=0.68). With rimonabant, gastrointestinal (3038 [33%] vs 2084 [22%]), neuropsychiatric (3028 [32%] vs 1989 [21%]), and serious psychiatric side-effects (232 [2.5%] vs 120 [1.3%]) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide.
INTERPRETATION: The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated.
FUNDING: Sanofi-Aventis.
Volume
376
Issue
9740
First Page
517
Last Page
523
ISSN
1474-547X
Published In/Presented At
Topol, E. J., Bousser, M. G., Fox, K. A., Creager, M. A., Despres, J. P., Easton, J. D., Hamm, C. W., Montalescot, G., Steg, P. G., Pearson, T. A., Cohen, E., Gaudin, C., Job, B., Murphy, J. H., Bhatt, D. L., & CRESCENDO Investigators (2010). Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet (London, England), 376(9740), 517–523. https://doi.org/10.1016/S0140-6736(10)60935-X
Disciplines
Medicine and Health Sciences
PubMedID
20709233
Department(s)
Department of Medicine
Document Type
Article