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STRADIVARIUS trial fails to show effect of rimonabant in primary IVUS endpoint, but secondary endpoint data suggest drug might reduce atherosclerosis progression

Thursday, April 03 2008 | Comments
Evidence Grade 0 What's This?
By Courtneay Parsons

Results of the STRADIVARIUS trial failed to show a significant effect of the cannabinoid receptor (CB1) antagonist rimonabant on the percent change in atheroma volume, the study's primary endpoint. However, additional findings from the trial suggest the drug might slow the progression of atherosclerosis in patients with abdominal obesity and other metabolic syndrome risk factors.

The trial included 839 adults (mean age, approximately 58 years) who were randomized to receive treatment with rimonabant 20 mg or placebo for 18 months. In addition to abdominal obesity, all participants had 2 other risk factors for the metabolic syndrome or they were current smokers, and all were undergoing angiography for a clinical indication.

Intravascular ultrasound (IVUS) was performed in all patients at baseline, and again at endpoint in the 676 patients who remained in the trial (regardless of whether they were still taking the study drug).

Among those who completed the trial, rimonabant was associated with significant reductions in body weight (-4.3 kg vs -0.5 kg; P<.001), waist circumference (-4.5 cm vs -1.0 cm; P<.001), high sensitivity C-reactive protein (-50.3% vs -30.9%; P<.001), and triglycerides (-20.5% vs -6.2%; P<.001) relative to placebo. The rimonabant group also exhibited significantly greater increases in HDL cholesterol (22.4% vs 6.9%; P<.001). Among individuals with diabetes (n=248), rimonabant was associated with a 0.13% decrease in hemoglobin A1C compared with an increase of 0.42% with placebo (P<.001).

With respect to the primary endpoint, the least-square mean change in percent atheroma volume was 0.25% with rimonabant compared with 0.51% with placebo (P=.22).

Although this group difference failed to reach statistical significance, subgroup analyses revealed statistical heterogeneity when patients were stratified by both statin use at baseline and triglyceride levels, suggesting statin-naive patients and those with triglyceride levels greater than the median at baseline benefited more from the use of rimonabant.

In addition, there was a significant between-group difference in the change in total atheroma volume, the trial's secondary endpoint. Specifically, the least-square mean change in total atheroma volume was -2.2 mm3 in the rimonabant group compared with +0.88 mm3 in the placebo group (P=.03).

In an analysis of exploratory IVUS endpoints, researchers observed a significant group difference favoring rimonabant for the change in maximum atheroma thickness (P=.01), but not for the change in total atheroma volume of the most diseased segment (P=.37).

Rates of major adverse cardiovascular events were similar in the 2 groups, except for all-cause mortality, which was higher in the placebo group (1.9% vs 0.5%; P=.06). Rates of depression, anxiety, nausea, diarrhea, vomiting, erectile dysfunction, and fatigue were all significantly higher in the rimonabant group as compared with the placebo group.

Dr. Steven Nissen, lead investigator of the trial, concluded that "CB1 inhibition shows promise for treatment of atherosclerotic disease in patients with abdominal obesity, but these potential benefits will need to be confirmed in additional trials, which are currently under way." (Presentation 412-5.)

This information concerns a use that has not been approved by the Food and Drug Administration.

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