Out of Tune: Rimonabant Fails to Slow Progression of CAD in STRADIVARIUS

Lisa Nainggolan

April 01, 2008

April 1, 2008 (Chicago, IL) – The weight loss drug rimonabant (Acomplia, Sanofi-Aventis) has failed to show any benefit on progression of atherosclerosis in an intravascular ultrasound (IVUS) study in patients with abdominal obesity and coronary artery disease (CAD). In addition, the drug resulted in higher rates of psychiatric and other side effects compared with placebo, Dr Steve Nissen (Cleveland Clinic Foundation, OH) reported during the late-breaking clinical-trials session at the American College of Cardiology (ACC) 57th Annual Scientific Session. The study was also published simultaneously in the Journal of the American Medical Association [1].

Despite not reaching its primary end point, one of the secondary end points--total atheroma volume--was significantly reduced by rimonabant in the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant--the IVUS Study (STRADIVARIUS), leading Nissen to conclude that the drug continues to hold promise. "With respect to the science, I'm encouraged that treating abdominal obesity might have an effect on coronary artery disease--no one's been able to do that before."

But in an editorial accompanying the paper [2], Dr John S Rumsfeld (Denver Veterans Affairs Medical Center, CO) and Dr Brahmajee K Nallamothu (University of Michigan, Ann Arbor) lament the "alarmingly high rate of psychiatric adverse events" seen with rimonabant. "Given the known correlation between obesity and psychiatric comorbidity--as evidenced by the high prevalence of anxiety and depression in the placebo group of STRADIVARIUS--the potential for a medication that targets weight loss to cause depression is a major concern," they say.

Europeans say benefits outweigh risks, others disagree

The US FDA did not approve rimonabant last summer, primarily due to concerns about psychiatric side effects such as anxiety and depression. The European authorities, however, took a different view. The drug was already on the market in a number of countries there at the time it was rejected by the FDA, and the European Medicines Evaluation Agency concluded that the benefits of the drug continue to outweigh the risks, "except in patients with ongoing major depression and/or taking antidepressants."

US experts polled by heartwire disagree, however: Dr James Stein (University of Wisconsin, Madison) said: "The door is closing very quickly on the endocannabinoid [receptor blockers] as a viable pharmacologic method for weight control. Despite some salutary effects on risk factors, rimonabant didn't reduce atherosclerosis in STRADIVARIUS. And the high risk of psychiatric side effects--seen in almost 50% of those on the drug--plus a threefold higher risk of gastrointestinal side effects and a tripling in the risk of erectile dysfunction do not bode well. We need to stop wishing for a magic bullet for people to lose weight. Eat less and exercise more--that's a safe and effective way of reducing heart disease!"

Dr Harlan Krumholz (Yale University, New Haven, CT) said: "There are many issues with this trial. The primary end point was negative, and there was a dramatically high rate of psychiatric side effects that raises huge concerns."

And Dr Tim Gardner (Christiana Care Health Center, Wilmington, DE) told heartwire : "This is another disappointing trial . . . even with improved weight reduction, etc, with the drug, there was no apparent atherosclerosis benefit and possible harmful side effects. Based on these findings, the drug shouldn't be used unless or until the side effects are eliminated and unless further outcomes studies show definite cardiovascular benefit."

Severe psychiatric events "uncommon"

STRADIVARIUS, a double-blind, randomized study conducted at 112 centers in North America, Europe, and Australia, assigned 839 patients with CAD and abdominal obesity to either rimonabant 20 mg daily or placebo. Patients underwent IVUS at baseline and after 18 months (at study completion, n=676).

Consistent with previous studies, those on rimonabant lost more weight--on average 9.5 pounds (4.3 kg) and 1.8 inches (4.5 cm) in waist circumference--than those on placebo, and they had greater improvements in lipid profiles (22.4% increase in HDL-C and a 20.5% reduction in triglycerides), in levels of C-reactive protein (CRP), and glycated hemoglobin (HbA1C) levels.

But there was no significant difference between the groups in the primary end point--change in percent atheroma volume (PAV) by IVUS (+0.25% in the rimonabant group vs +0.51% in the placebo group, p=0.22). The secondary end point of normalized total atheroma volume (TAV) did improve in the rimonabant patients, however (-2.2 mm3 vs +0.88 mm3, p=0.03).

The rate of psychiatric adverse effects was higher in the rimonabant group (43.4% vs 28.4% in the placebo group, p<0.001). One patient in the rimonabant group committed suicide and one in the placebo group attempted suicide. Nissen said they deliberately enrolled patients whether or not they had a history of psychiatric illness--20% of patients were on antidepressants at baseline--and the protocol of the study was amended to include a questionnaire to standardize reporting of these specific adverse effects.

"Severe psychiatric adverse effects, including major depression, suicidal ideation, and attempted or successful suicide were relatively uncommon, occurring with similar frequency in the rimonabant and placebo groups (4.7% vs 3.8% respectively, p=0.52)," he noted. Nausea was seen in 14.9% of patients in the rimonabant group vs 5.5% in the placebo group (p<0.001).

In their editorial, Rumsfeld and Nallamothu say the STRADIVARIUS investigators' decision to enroll patients with prior psychiatric disorders, thereby reflecting the risks of depression and anxiety encountered in routine clinical practice, "should be commended. . . . This is a particular strength of the study."

Nevertheless, the investigators' assertion that the higher rates of depression and anxiety did not translate into significant differences in severe psychiatric side effects such as suicide "warrants caution," they note. "The study was not powered for evaluating these outcomes any more than it was powered for evaluating cardiovascular death or MI and is thus inconclusive in this regard. Of concern, an analysis by the US FDA of all randomized clinical trials evaluating rimonabant . . . suggested that a 20-mg dose was associated with a twofold higher suicide risk," and the psychiatric profile of the drug was the primary concern of the FDA panel that failed to recommend approval of rimonabant last year, they say.

Promise has faded

The "promise" of rimonabant "has faded," Rumsfeld and Nallamothu conclude. The results "reinforce caution about use of IVUS findings as surrogate markers of patient outcomes. [IVUS results] have yet to be definitely linked to lower rates of death or MI," they note, commenting that the findings in STRADIVARIUS "closely mirror those reported for torcetrapib . . . recently found to be associated with worse patient outcomes."

Gardner agrees: "Despite some positive outcomes in laboratory values and clinical features . . . the primary atherosclerosis end point was not affected, suggesting that despite the positive changes, there may be no cardiovascular benefit with rimonabant. This finding is similarto the ENHANCE trial, which showed a reduction in LDL but no change in carotid artery medial thickening. The major difference, however, between rimonabant and ezetimibe is that rimonabant has potentially severe psychiatric side effects, as was seen in STRADIVARIUS."

"The other possibility is that the IVUS technique for determining atherosclerosis disease presence and progression is not reliable or precise enough," Gardner continued, adding: "It is distressing to see so much of the JAMA manuscript devoted to the IVUS technology and the IVUS-related results of this study rather than to the clinical implications of the negative atherosclerosis result and worrisome psychiatric side effects."

Future studies will yield more information

Because STRADIVARIUS failed to achieve a significant effect for the primary end point, additional studies will be needed to further define the role of rimonabant in the treatment of abdominally obese patients with CAD and metabolic risk factors, Nissen said.

Two such placebo-controlled trials are under way: the two-year Atherosclerosis Underlying Development Assessed by Intima-Media Thickness in Patients on Rimonabant (AUDITOR) and the Comprehensive Rimonabant Evaluation Study of Cardiovascular End Points and Outcomes (CRESCENDO), a long-term cardiovascular outcomes trial in 17 000 patients with a high risk for cardiovascular events, he noted.

Stein--whose institution is participating in the AUDITOR trial--says: "We still need the results of AUDITOR before we can pass judgment on the atherosclerotic effects of rimonabant."

Merck's taranabant: Higher doses dropped due to side effects

Another investigational cannabinoid-receptor blocker from Merck has also shown some evidence of psychiatric and gastrointestinal side effects in phase 3 trials for weight loss, resulting in a recommendation by an independent external data and safety monitoring committee (DSMC) to rerandomize patients on the highest dose to the lowest dose. The 52-week results of a two-year study were presented at the ACC meeting on March 31, 2008.

The phase 3 trial of the compound, taranabant, showed that patients experienced significant weight loss with taranabant compared with placebo after a year of therapy, the company says. Patients were initially randomized to taranabant 2 mg (n=414), 4 mg (n=415), or 6 mg (n=1256) or to placebo (n=417), and all were placed on a diet and encouraged to exercise. But during the study, those taking the 6-mg dose were rerandomized to receive placebo or taranabant 2 mg (ratio 1:2) following the DSMC recommendation.

Psychiatric adverse events were greater at higher doses of taranabant: 28% on 2-mg dose, 40% on the 4-mg dose, 38% on the 6-mg dose, and 20% on placebo. Gastrointestinal side effects were experienced by 42% of those on the 2-mg dose, 47% taking the 4-mg dose, 46% on 6 mg, and 29% on placebo.

"Based on the benefit/risk considerations and the lack of a substantial improvement in the efficacy of taranabant at the 4-mg and 6-mg doses seen in our clinical program compared with the 2-mg dose, we have decided to continue to evaluate taranabant in doses up to and including 2 mg in our phase 3 studies," vice president of clinical research, Dr John Amatruda, explains in a company press release.

STRADIVARIUS was funded by Sanofi-Aventis. Nissen reports research support from AstraZeneca, Atherogenics, Lilly, Novartis, Pfizer, Takeda, Daiichi-Sankyo, and Sanofi-Aventis and consults for a number of pharmaceutical companies without financial compensation. Disclosures for the other authors appear in the paper.

  1. Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease. The STRADIVARIUS randomized controlled trial. JAMA 2008; 299: 1547-1560.

  2. Rumsfeld JS and Nallamothu BK. The hope and fear of rimonabant. JAMA 2008; 299:1601-1602.

  3. The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.



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