Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant: The Intravascular Ultrasound Study - STRADIVARIUS

Apr 01, 2008
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi-aventis
Date Presented:
01/01/2008
Date Published:
01/01/2008
Date Updated:
04/01/2008
Original Posted Date:
04/01/2008
References

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.

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

Patient Populations:

• 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

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

Drug/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.

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;299:1547-1560.

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.

Keywords: Depression, Follow-Up Studies, Plaque, Atherosclerotic, Cholesterol, LDL, Counseling, Pyrazoles, Glycated Hemoglobin A, Metabolic Syndrome, Waist Circumference, Piperidines, C-Reactive Protein, Obesity, Cholesterol, HDL, Cannabinoids, Diabetes Mellitus, Suicide


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