The early termination of a study into the cardiovascular outcomes associated with the weight-loss drug rimonabant, due to high suicide rates and other psychiatric side-effects, is detailed in an Article in this week's Cardiology Special Issue of The Lancet, written by Professor Eric J Topol, Scripps Translational Science Institute, La Jolla, CA, USA, and colleagues.
Rimonabant works by blocking the brain's cannabinoid-1 receptors (a reward pathway), reducing appetite, and, ultimately, food consumption and obesity. The drug also helps correct metabolic abnormalities such as abnormal triglycerides, good cholesterol, and fasting blood glucose levels. In the CRESCENDO* study, the authors assessed whether rimonabant improved major vascular event-free survival.
This trial took place in 974 hospitals in 42 countries. involving 18 695 patients with previously manifest or increased risk of vascular disease. Patients were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke.
On November 6, 2008, at a mean follow-up of 13•8 months (the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant, both in clinical trials and among those taking the commercially approved drug for weight loss. In CRESCENDO, suicide rates were in comparison quite low: Four patients in the rimonabant group (0.04%) and one in the placebo group (0.01%) committed suicide. All randomised participants were still analysed, and the researchers found the primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred at similar rates in both groups: 364 (3•9%) patients assigned to rimonabant and375 (4•0%) assigned to placebo. With rimonabant, gastrointestinal (33% vs 22%), neuropsychiatric (32% vs 21%), and serious psychiatric side-effects (2•5% vs 1•3%) were significantly increased compared with placebo.
The authors say: "The findings did not provide evidence of efficacy for rimonabant's prevention of adverse cardiovascular outcomes, but further substantiated its effect of inducing serious neuropsychiatric side-effects."
Putting the findings in context, Professor Topol states:** "We believe our findings will be instructive for future drug development. Genomics could potentially be used to pre-empt use of the drug in individuals with risk of serious adverse events. Also, it is important to recognize how such a large international clinical trial can be placed in jeopardy by not fully addressing side effect issues in an era when regulatory authorities can pull the trigger."
Due to these concerns, the European Medicines Agency recommended doctors no longer prescribe rimonabant from October 2008, while the US FDA never approved it in the first place.
In a linked Comment, Dr S Matthijs Boekholdt and Dr Ron JG Peters, Academic Medical Center, Amsterdam, Netherlands, say: "If CRESCENDO had been completed, a large improvement in cardiovascular outcome could have outweighed a small risk of serious adverse events, in a similar way to, for example, the large cardiovascular benefits of statins outweighing a small risk of rhabdomyolysis. However, any mortality associated with cardiovascular preventive therapy is generally viewed as unacceptable."
They add that in daily practice medical supervision for rimonabant use, including periodic screening for serious neuropsychiatric side-effects, will be unlikely, and conclude: "The story of rimonabant might be tarnished by low public and regulatory acceptance for a drug designed to counteract the consequences of our abundant lifestyle. Focus should now return to motivating patients to control their caloric intake and increase physical activity. Although cumbersome, this approach is causal and safe. New strategies to effectively achieve these lifestyle changes are needed."
Dr S Matthijs Boekholdt and Dr Ron JG Peters, Academic Medical Center, Amsterdam, Netherlands. T) +31 20 566 6952 E) firstname.lastname@example.org
For full Article and Comment see: http://press.thelancet.com/cresc.pdf
Note to editors: *CRESCENDO: The Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes trial
**Quote direct from Prof Topol and cannot be found in text of Article.