Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial.
BACKGROUND
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.


METHODS
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.


METHODS
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).


METHODS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00124332.
Nissen
Steven E
SE
Department of Cardiovascular Medicine and Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio, USA. nissens@ccf.org
Nicholls
Stephen J
SJ
Wolski
Kathy
K
Rodés-Cabau
Josep
J
Cannon
Christopher P
CP
Deanfield
John E
JE
Després
Jean-Pierre
JP
Kastelein
John J P
JJ
Steinhubl
Steven R
SR
Kapadia
Samir
S
Yasin
Muhammad
M
Ruzyllo
Witold
W
Gaudin
Christophe
C
Job
Bernard
B
Hu
Bo
B
Bhatt
Deepak L
DL
Lincoff
A Michael
AM
Tuzcu
E Murat
EM
D000368:Aged; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000517:prevention & control*; D003324:Coronary Artery Disease / Q000150:complications* / Q000188:drug therapy; D003331:Coronary Vessels / Q000000981:diagnostic imaging; D004038:Diet, Reducing; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000503:physiopathology / Q000628:therapy*; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000178:diet therapy; D010880:Piperidines / Q000627:therapeutic use*; D011446:Prospective Studies; D011720:Pyrazoles / Q000627:therapeutic use*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D018084:Ultrasonography, Interventional
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant