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Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial
Eric J Topol1, Marie-Germaine Bousser, Keith A A Fox
1Scripps Translational Science Institute, La Jolla, CA 92037, USA. etopol@scripps.edu
Insights
Rimonabant, a cannabinoid receptor blocker, did not improve major vascular event-free survival in patients at risk. The trial was stopped early due to unacceptable neuropsychiatric side effects, including suicide concerns.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Metabolic Disorders
Background:
- Endocannabinoid receptor blockade shows promise in reducing obesity and improving metabolic parameters.
- Previous research indicated potential benefits for triglycerides, HDL cholesterol, and fasting blood glucose.
- The study aimed to evaluate rimonabant's impact on major vascular event-free survival.
Purpose of the Study:
- To assess the efficacy of rimonabant in improving major vascular event-free survival.
- To determine if rimonabant reduces cardiovascular death, myocardial infarction, or stroke in high-risk patients.
- To investigate the safety profile of rimonabant concerning cardiovascular and psychiatric adverse events.
Main Methods:
- A double-blind, placebo-controlled trial involving 18,695 patients across 974 hospitals in 42 countries.
- Patients were randomly assigned to receive either rimonabant 20 mg or a matching placebo.
- The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke, with intention-to-treat analysis.
Main Results:
- The trial was prematurely discontinued due to regulatory concerns regarding suicide in the rimonabant group.
- No significant difference was observed in the primary endpoint between the rimonabant and placebo groups (3.9% vs 4.0%).
- Rimonabant significantly increased gastrointestinal, neuropsychiatric, and serious psychiatric side-effects compared to placebo, including four suicides in the rimonabant group.
Conclusions:
- The trial highlights critical lessons for drug development, particularly concerning neuropsychiatric safety.
- Rimonabant, intended for weight loss and tested for cardiovascular outcomes, exhibited unacceptable serious neuropsychiatric effects.
- Regulatory authorities led to the abrupt termination of both the drug and the clinical trial.
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.
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