STRADIVARIUS: Rimonabant fails to slow atherosclerosis progression

Rimonabant has failed to show any benefit on progression of atherosclerosis in STRADVIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant-The Intravascular Ultrasound Study) in patients with abdominal obesity and coronary artery disease (CAD). The study was presented by Dr Steve Nissen, Cleveland Clinic, Ohio during the American College of Cardiology 2008 Scientific Sessions, and published simultaneously in the Journal of the American Medical Association

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;299:1547-60.

In STRADIVARIUS, 839 patients with abdominal obesity and metabolic syndrome were randomized to treatment with rimonabant (20 mg daily) (n=422) or matching placebo (n=417), in addition to dietary counselling. The duration of treatment was 18 months. Coronary intravascular ultrasonography was performed at baseline and at the end of the treatment period. A total of 676 patients completed the study. The primary endpoint was the change in percent atheroma volume (PAV), and the secondary endpoint was the change in normalized total atheroma volume (TAV).

The two groups were similar in terms of baseline characteristics. Patients were aged less than 60 years (overall mean age 57 years), and two-thirds were men. Mean waist circumference was 103.5 cm (40.7 inches) and mean body mass index was 35 kg/m2.

At 18 months, while there was a lower rate of atherosclerosis progression in the rimonabant group (increase in PAV by 0.25% vs. 0.51% on placebo), this was not statistically significant (p=0.22). There was, however, a significant difference in TAV in favour of rimonabant treatment; TAV decreased by 2.2 mm3 in the rimonabant group but increased by 0.88 mm3 in the placebo group (p=0.03). Dr Nissen commented that the relatively short duration of treatment may have been a factor contributing to the lack of a significant effect on the primary endpoint.

Consistent with previous reports, treatment with rimonabant was also associated with greater weight loss (on average, 4.3 kg), and greater reduction in waist circumference. As well, there was greater improvement in lipid profiles, notably a 22.4% increase in HDL cholesterol and 20.5% decrease in triglycerides (p<0.001 versus placebo) (Figure 1). Glycated haemoglobin (HbA1c) and C-reactive protein also showed greater improvement on rimonabant than placebo (Table 1).

Table 1. Change from baseline (%) in laboratory variables in STRADIVARIUS


 Placebo
(N=341)		Rimonabant
(N=335)
Body weight, kg-0.5-4.3*
Waist circumference, cm-1-4.5*
HDL cholesterol, mg/dL+1.8 (6.9%)+5.8 (22.4%)*
Triglycerides, mg/dL-8.9 (-6.2%)-24.8 (-20.5%)*
LDL cholesterol, mg/dL-3.2 (1.7%)-3.8 (0.44%)
CRP, mg/L-0.9 (-30.9%)-1.3 (-50.3%)*
HbA1c, %0.40.11*
Fasting insulin, pmol/L7.8 (7.9%)-13.7 (-10.6%)

Psychiatric adverse events were more frequently reported in the rimonabant group (43.4% vs. 28.4% with placebo, p<0.001). These were primarily anxiety (16.0% vs. 11.8% with placebo, p=0.01) and depression (16.8% vs. 11.3% with placebo, p=0.02). However, Dr Nissen reported that patients were enrolled irrespective of psychiatric disorders at baseline, in fact 20% were on antidepressants at the time of study entry. This decision reflects a particular strength of the study, as commented in an accompanying editorial.2

Dr Nissen concluded that the potential for treating abdominal obesity to slow coronary disease still holds promise, but further trial data are needed. In this context, the ongoing AUDITOR (Atherosclerosis Underlying Development Assessed by Intima-Media Thickness in Patients on Rimonabant) trial and the CRESCENDO (Comprehensive Rimonabant Evaluation Study on Cardiovascular ENDpoints and Outcomes) trial may help to resolve this issue. In particular, data are awaited from CRESCENDO which is investigating the effect of rimonabant on mortality and morbidity in more than 17,000 patients.

References

1. Hollander P. Endocannabinoid blockade for improving glycemic control and lipids in patients with type 2 diabetes mellitus. Am J Med 2007;120(2 suppl 1): S18-28.
2. Rumsfeld JS, Nallamothu BK. The hope and fear of rimonabant. JAMA 2008;299:1601-2.

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