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Steven E. Nissen MD

STRADIVARIUS Effect of Rimonabant on Progression of Atherosclerosis in Patients with Abdominal Obesity and Coronary Artery Disease. Steven E. Nissen MD.

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Steven E. Nissen MD

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  1. STRADIVARIUSEffect of Rimonabant on Progressionof Atherosclerosis in Patients with Abdominal Obesity and Coronary Artery Disease 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 JP 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, and E. Murat Tuzcu MD for The STRADIVARIUS Investigators

  2. Background and Objectives • Obesity is increasing at an alarming rate in developed countries; 34% in the US population have BMI >30. • Abdominal obesity is associated with specific metabolic abnormalities that increase the risk of CAD. • Rimonabant, a cannabinoid receptor (CB1) antagonist, enhances weight loss and improves obesity-related metabolic abnormalities. • We sought to determine if rimonabant could reduce progression of coronary atherosclerosis measuredby IVUS in abdominally-obese CAD patients.

  3. Methods • Patients selected with abdominal obesity (definedas waist >102 cm for men or >88 cm for women) undergoing angiography for clinical indications. • Inclusion criteria required two additional risk factors of the metabolic syndrome or current smoking. • Intravascular ultrasound (IVUS) was performed to assess atheroma volume in 839 patients randomized to placebo or rimonabant 20 mg. • After 18 months, repeat IVUS was performed in the 676 patients who remained in the trial, regardlessof whether they were still taking study drug.

  4. Changein PercentAtheromaVolume AtheromaCSA AtheromaCSA    = – LumenArea EEMCSA EEMCSA (baseline) (Month 18) Atheroma Area  EEM Area  n n n n n Change in Atheroma Volume Atheroma Volume Atheroma Volume – = (Month 18) (baseline) Intravascular Ultrasound Endpoint Calculations  Median numberof slices inall pullbacks EEMCSA TotalAtheroma Volume LumenCSA – n = x Number of slices in patient’s pullback

  5. Baseline Patient Characteristics (n=839)

  6. Medications at Randomization (n=839)

  7. Baseline Lab Values & Blood Pressure (n=676) *median values

  8. Weight and Waist Circumference Changes Body Weight (kg) Waist Circumference (cm) -0.5 kg -1.0 cm P < 0.001 P < 0.001 Change in Body Weight (kg) Change in Waist Circumference (cm) -4.5 cm -4.3 kg Months after Randomization

  9. Percent Changes in Biochemical Parameters HDL-cholesterol HbA1c in Diabetics (n=248) 0.42% 22.4% P=0.001 P<0.001 6.9% -0.13% hs C-reactive Protein Triglycerides -6.2% P<0.001 -30.9% P<0.001 -20.5% -50.3%

  10. Primary and Secondary IVUS Endpoints PAV: Primary Endpoint TAV: Secondary Endpoint P = 0.37 P < 0.001 0.88 0.51 P=0.22 P=0.03 P =0.09 0.25 -2.2 P=0.03 Placebo Rimonabant

  11. Additional Exploratory IVUS Endpoints TAV in Most Diseased Segment Maximum Atheroma Thickness P < 0.001 0.01 P = 0.37 P =0.01 -0.89 P = 0.05 -0.0006 -1.47 P = 0.88 P = 0.001 Placebo Rimonabant

  12. Primary Endpoint in Selected Subgroups ≥ 58 years < 58 years Age Male Female Gender ≥ median < median BMI (34.3) BaselineHDL-C ≥ median < median (38.6) } Statinuse Yes (560)no (116) P = 0.03 } Triglyc-erides ≥ median < median P = 0.03 (140.0) ≥ median < median hsCRP (3.5) 2 1 0 2 1 Favors Placebo Favors Rimonabant

  13. Major Adverse Cardiovascular Events *P = 0.06

  14. Psychiatric Adverse Effects * Major depression, suicidal ideation, attempted or successful suicide

  15. Other Treatment-Emergent Adverse Effects *n = 545 male patients

  16. Conclusions • Treatment of abdominally-obese coronary disease patients for 18 months with rimonabant: • Reduced body weight 4.3 kg and waist circumference4.5 cm, increased HDL-C 22.4%, reduced triglycerides 20.5%, hsCRP 50.3%, and favorably affected HbA1c. • The study did not demonstrate an effect for rimonabant on the primary endpoint, PAV (P = 0.22), but a favorable effect for the secondary endpoint, TAV (P = 0.03). • Psychiatric and GI adverse effects were more common with rimonabant, which resulted in a higher rate of drug discontinuation.

  17. Some Final Thoughts Development of effective and durable treatment strategies for management obesity has provena daunting challenge. New approaches are greatly needed to reduce the burdens of this global epidemic and its metabolic consequences. We believe CB1 inhibition shows promise for treatment of obesity-related atherosclerotic disease, but its benefits will need to be confirmed in additional trials, which are currently underway.

  18. Back Up Slides

  19. Changes: Lab Values and Obesity Measures

  20. Changes in HbA1c: All Patients and Diabetics Diabetic Patients (N= 248) All Patients (N = 676) 0.42% 0.40% P <0.001 P <0.001 Change in HbA1c (%) Change in HbA1c (%) 0.11% -0.13% Months after Randomization

  21. Time to Permanent Drug Discontinuation HR = 2.75 Log rank P < 0.001 Placebo Rimonabant

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