Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled 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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Sanofi-Aventis.
Topol
Eric J
EJ
Scripps Translational Science Institute, La Jolla, CA 92037, USA. etopol@scripps.edu
Bousser
Marie-Germaine
MG
Fox
Keith A A
KA
Creager
Mark A
MA
Despres
Jean-Pierre
JP
Easton
J Donald
JD
Hamm
Christian W
CW
Montalescot
Gilles
G
Steg
P Gabriel
PG
Pearson
Thomas A
TA
Cohen
Eric
E
Gaudin
Christophe
C
Job
Bernard
B
Murphy
Judith H
JH
Bhatt
Deepak L
DL
D000368:Aged; D000369:Aged, 80 and over; D063387:Cannabinoid Receptor Antagonists; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D004311:Double-Blind Method; D017277:Drug Approval; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced; D009765:Obesity / Q000188:drug therapy*; D010880:Piperidines / Q000009:adverse effects* / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D000077285:Rimonabant; D013405:Suicide
D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant