Title: Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant: The Intravascular Ultrasound Study (STRADIVARIUS — Presented at SCAI-ACC i2 Summit/ACC 2008)
Trial Sponsor: Sanofi-aventis
Year Presented: 2008
Year Published 2008
Topic(s): General Cardiology
Summary Posted: 4/1/2008
Writer: Anthony A. Bavry, M.D., M.P.H.
Author Disclosure: Consulting Fees/Honoraria: Boston Scientific, Modest (< $10,000); Consulting Fees/Honoraria: Access Closure, Modest (< $10,000)
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000)
Description
The goal of this trial was to evaluate treatment with the cannabinoid type 1 receptor inhibitor rimonabant compared with placebo in obese patients with the metabolic syndrome.
Hypothesis
The cannabinoid type 1 receptor inhibitor rimonabant would be more effective at reducing coronary artery progression, as assessed by intravascular ultrasound.
Drugs/Procedures Used
Obese patients with the metabolic syndrome, who were already receiving dietary counseling, were randomized to rimonabant 20 mg daily (n = 422) or placebo (n = 417).
Concomitant Medications
Medication use at baseline: aspirin 91%, clopidogrel or ticlopidine 60%, beta-blocker 70%, and statins 82%
Principal Findings
Percent atheroma volume increased 0.25% in the rimonabant group and 0.51% in the control group (p = 0.22). Total atheroma volume decreased 2.2 mm2 with rimonabant versus an increase of 0.88 mm2 with control (p = 0.03). Major adverse cardiac events occurred in 10% with rimonabant and 11% with control (p = 0.79).

Reduction in total body weight was 4.3 kg versus 0.5 kg (p < 0.001) and reduction in waist circumference was 4.5 cm versus 1.0 cm (p < 0.001), respectively, for rimonabant versus control.

High-density lipoprotein cholesterol increased 5.8 mg/dl versus 1.8 mg/dl (p < 0.001), high-sensitivity C-reactive protein decreased 1.3 mg/dl versus 0.9 mg/dl (p < 0.001), and glycated hemoglobin increased 0.11% versus 0.40% (p < 0.001), respectively, for rimonabant versus control. There was no change in low-density lipoprotein cholesterol: 1.7% versus 0.44% (p = 0.78), respectively.

Psychiatric symptoms were 43% in the rimonabant group versus 28% in the control group (p < 0.001) and gastrointestinal track disorders were 34% versus 18% (p < 0.001), respectively.
Interpretation
Among obese patients with the metabolic syndrome, rimonabant failed to show a difference in the primary outcome, percent atheroma volume at 18 months of follow-up; however, there was a reduction in total atheroma volume. This therapy did demonstrate favorable reductions in body weight, waist circumference, high-sensitivity C-reactive protein, and less increase in glycated hemoglobin.

Rimonabant resulted in more psychiatric symptoms and gastrointestinal disorders compared with control. The increased psychiatric symptoms were characterized primarily by anxiety and depression; however, the incidence of major depression and suicide was similar. The gastrointestinal symptoms were more likely to result in medication discontinuation in the rimonabant group.

The clinical significance of discrepant findings in percent atheroma volume and total atheroma volume are unknown and will require longer-term clinical follow-up. Additionally, the finding of increased psychiatric symptoms requires careful monitoring. The ongoing CRESCENDO trial will provide data about clinical outcomes.
Conditions
• Diabetes mellitus
• Coronary heart disease
• Arteriosclerosis

Therapies
• Medical

Study Design
Placebo controlled. Randomized. Blinded.

Patients Screened: 1,949
Patients Enrolled: 839
Mean Follow-Up: 18 months
Mean Patient Age: 58 years
% Female: 35

Primary Endpoints
Change in coronary percent atheroma volume from baseline to follow-up
Secondary Endpoints
• Change in normalized coronary atheroma volume from baseline to follow-up
• Change in body weight
• Change in waist circumference
• Change in serum lipids
• Change in adverse events
• Secondary endpoints also included a neurological and psychiatric questionnaire
Patient Population
• Adult obese patients with metabolic syndrome

Metabolic syndrome was defined by the presence of at least two of the following risk factors:
• Triglyceride level >150 mg/dl
• High-density lipoprotein <40 mg/dl in men or <50 mg/dl in women
• Fasting glucose more than 110 mg/dl
• Blood pressure more than 140/90 mm Hg or currently taking antihypertensives
References: 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.

Effect of Rimonabant on Progression of Atherosclerosis in Patients With Abdominal Obesity and Coronary Artery Disease. Presented by Dr. Steven Nissen at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Source
Content provided by the American College of Cardiology Foundation