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The STRADIVARIUS Randomized Controlled Trial

Steven E. Nissen, MD; Stephen J. Nicholls, MBBS, PhD; Kathy Wolski, MPH; Josep Rodés-Cabau, MD; Christopher P. Cannon, MD; John E. Deanfield, MD; Jean-Pierre Després, PhD; John J. P. Kastelein, MD, PhD; Steven R. Steinhubl, MD; Samir Kapadia, MD; Muhammad Yasin, MD; Witold Ruzyllo, MD; Christophe Gaudin, MD; Bernard Job, MD; Bo Hu, PhD; Deepak L. Bhatt, MD; A. Michael Lincoff, MD; E. Murat Tuzcu, MD; for the STRADIVARIUS Investigators

JAMA. 2008;299(13):1547-1560. Published online April 1, 2008 (doi:10.1001/jama.299.13.1547).

Context  Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease.

Objective  To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome.

Design, Setting, and Patients  Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia.

Interventions  Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676).

Main Outcome Measures  The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV).

Results  In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (–0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm³ (–4.09 to –0.24) vs an increase of 0.88 mm³ (–1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (–0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm³ (–3.8 to –0.10) vs an increase of 1.19 mm³ (–0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [–5.1 to –3.5] vs 0.5 kg [–1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [–5.4 to –3.7] vs 1.0 cm [–1.9 to –0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (–35.4 to –17.3) (20.5%) vs 8.9 mg/dL (–14.2 to –1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [–1.7 to –1.2] [50.3%] vs 0.9 mg/dL [–1.4 to –0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001).

Conclusions  After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way.

Trial Registration  clinicaltrials.gov Identifier: NCT00124332

Author Affiliations: Department of Cardiovascular Medicine and Cleveland Clinic Lerner School of Medicine (Drs Nissen, Nicholls, Kapadia, Bhatt, Lincoff, and Tuzcu and Ms Wolski) and Department of Quantitative Health Sciences, Cleveland Clinic (Dr Hu), Cleveland, Ohio; Laval Hospital and Quebec Heart Institute, Quebec City, Canada (Drs Rodés-Cabau and Després); TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Cannon); University College, London, England (Dr Deanfield); Academic Medical Center, Amsterdam, the Netherlands (Dr Kastelein); University of Kentucky, Lexington (Dr Steinhubl); Southwest Cardiology, Oklahoma City, Oklahoma (Dr Yasin); Instytut Kardiologii I Klinika Warsaw, Warsaw, Poland (Dr Ruzyllo); and sanofi-aventis, Paris, France (Drs Gaudin and Job).

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Rimonabant and Progression of Atherosclerosis in Obese Persons
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JAMA. 2008;300(3):280.
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Rimonabant and Progression of Atherosclerosis in Obese Persons—Reply
Steven E. Nissen, Stephen J. Nicholls, and Kathy Wolski
JAMA. 2008;300(3):280-281.
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