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CRESCENDO, rimonabant's (anti-obesity drug) "obituary," published in Lancet
 
 
  August 12, 2010 | Michael O'Riordan Theheart.org
 
La Jolla, CA - The drug was hailed as a breakthrough for the treatment of obesity, as well as for the improvement of other cardiovascular risk factors, but in the end the psychiatric side effects with rimonabant (Sanofi-Aventis) were its undoing. In a paper published in the August 14, 2010 issue of the Lancet [1], investigators report truncated results from rimonabant's large morbidity and mortality study, a report that editorialists' call "the obituary for a wonder drug. [2]"
 
After just 14 months of follow-up for a trial initially designed to go at least 33 months, researchers, led by Dr Eric Topol (Scripps Clinic, La Jolla, CA), presented findings from the Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO) study. After one year of treatment with rimonabant, there was no significant difference in the primary end point of cardiovascular death, MI, or stroke compared with placebo. There were, however, four suicides in the rimonabant arm, while one patient taking the placebo committed suicide.
 
In 2008, the European Medicines Agency (EMA) halted the marketing of rimonabant in Europe because of psychiatric concerns that were emerging from postmarketing registries and ongoing clinical trials. As a result, the drug came off the market, and it was recommended that CRESCENDO be stopped.
 
"We didn't want to stop the study."
 
"This study was stopped by regulatory authorities, which is a new precedent," Topol told heartwire. "I am not aware of any studies that were in midstream—we were only one-third of the way done at 14 months of follow-up—when the plug was pulled. We didn't want to stop the study. In fact, the chair of the data and safety monitoring board [DSMB] (Dr Robert Frye [Mayo Clinic, Rochester, MN]) actually pleaded with the European authorities to not stop the trial, because it was such an important question to sort out the risk/benefit for rimonabant. But when a few countries, and they were high-enrolling countries, stop using the drug, then what are we going to do? Basically, the trial was over at that point."
 
No risk for a preventive therapy?
 
In the editorial accompanying the study, Drs Matthijs Boekholdt and Ron Peters (Academic Medical Center, Amsterdam, the Netherlands) note that if CRESCENDO had been completed and a large cardiovascular benefit observed, this benefit could have outweighed a small risk of adverse events, not unlike how statins' benefit must be balanced with a small risk of rhabdomyolysis. "However," they quickly counter, "any mortality associated with cardiovascular preventive therapy is generally viewed as unacceptable. The preventive approach is fundamentally different from curative therapy for a potentially lethal illness."
 
"Focus should now return to motivating patients to control their caloric intake and increase physical activity."
 
Topol, on the other hand, disagrees with the editorialists on this point. He pointed out that obese individuals, including those with no other cardiovascular risk factors, are undergoing bariatric surgery to lose weight. In CRESCENDO, investigators enrolled patients with vascular disease or those at increased risk of vascular disease, and the average body-mass index of patients in the study was 33 kg/m2.
 
"Bariatric surgery carries a death rate that is not trivial, and that is far greater than what was seen in this study with respect to suicides," said Topol. "Four suicides in the rimonabant group is a very small number. So I disagree with the editorialists in that respect. I think once you have obesity and cardiovascular disease, there may be an acceptable tradeoff. Patients, however, would need to be strongly advised that there is a risk/benefit [tradeoff]. There is also a chance that they might die from their current medical problems, no less the drug, and they have to factor that in as well."
 
"I think once you have obesity and cardiovascular disease, there may be an acceptable tradeoff."
 
In addition to the four suicides with rimonabant, nine patients taking the drug attempted suicide compared with five patients randomized to placebo. Gastrointestinal side effects were also increased with rimonabant, as were psychiatric disorders such as anxiety, depression, and insomnia.
 
To heartwire, Topol said that he felt the decision to stop the trial should have rested with the DSMB and the study's executive committee. He noted, however, that one of the concerns with the drug was that even if the study successfully showed a reduction in cardiovascular events, real-world use of rimonabant would be challenging. While the "stakes are high for obesity and cardiovascular disease," he said, diligent screening of baseline psychiatric conditions, done with neuropsychiatric evaluations, would be necessary, but in the real world, such screening might not be performed. As a result, adverse event rates could be higher.
 
In their editorial, Boekholdt and Peters note that the CRESCENDO investigators never hailed rimonabant as a miracle drug for weight loss, but the public would likely see the drug this way. They also note that medical screening for neuropsychiatric side effects would not be as strict in the real world. And, if used just for weight loss, the drug might be used episodically, rather than for long-term use, as was being tested in CRESCENDO.
 
"On the basis of these arguments, the European Medicines Agency's decision seems appropriate," they write. "Focus should now return to motivating patients to control their caloric intake and increase physical activity. Although cumbersome, this approach is causal and safe."
 
Sanofi-Aventis sponsored the CRESCENDO trial, and all investigators have received research funding and financial support, either through consulting or honoraria fees, from the company. Boekholdt and Peters report no conflicts of interest. Topol is editor in chief of theheart.org.
 
 
 
 
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