of atherosclerosis in patients with abdominal obesity an

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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
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Background and objectives

• Obesity is increasing at an alarming rate in
  developed countries 34 in the US population
  have BMI gt30.
• Abdominal obesity is associated with specific
  metabolic abnormalities that increase the risk
  for 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.

Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
3
Methods

• Patients selected with abdominal obesity (defined
  as waist gt 102 cm for men or gt 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 completed the trial, regardless
  of whether they were still taking study drug

Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
4
Intravascular ultrasound endpoint calculations
?
Median numberof slices inall pullbacks
Totalatheroma volume
EEMCSA
LumenCSA

x
n

Number of slices in patients pullback
Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
5
Baseline patient characteristics (N839)
Adapted from Nissen SE, Nicholls SJ, et al.
JAMA. 20082991547-1560.
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Medications at randomization (N839)
Adapted from Nissen SE, Nicholls SJ, et al.
JAMA. 20082991547-1560.
7
Baseline lab values blood pressure (N676)
median values
Adapted from Nissen SE, Nicholls SJ, et al.
JAMA. 20082991547-1560.
8
Changes lab values and obesity measures
Adapted from Nissen SE, Nicholls SJ, et al. JAMA
20082991547-1560.
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Weight and waist circumference changes
Body weight (kg)
Waist circumference (cm)
-0.5 kg
-1.0 cm
P lt 0.001
P lt 0.001
Change in waist circumference (cm)
Change in body weight (kg)
-4.3 kg
-4.5 cm
Months after randomization
Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
10
Percent changes in biochemical parameters
HDL-cholesterol
HbA1c in diabetics (n248)
0.42
22.4
P 0.001
P lt 0.001
-0.13
6.9
Triglycerides
hs C-reactive protein
-6.2
P lt 0.001
P lt 0.001
-30.9
-20.5
-50.3
Adapted from Nissen SE, Nicholls SJ, et al.
JAMA. 20082991547-1560.
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Changes in HbA1c all patients and diabetics
Diabetic patients (n248)
All patients (N676)
0.40
0.42
P lt 0.001
P lt 0.001
0.11
Change in HbA1c ()
Change in HbA1c ()
-0.13
Months after randomization
Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Primary and secondary IVUS endpoints
PAV primary endpoint
TAV secondary endpoint
P lt 0.001
P 0.37
0.51
0.88
P 0.22
P 0.09
P 0.03
0.25
-2.2
P 0.03
Adapted from Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Additional exploratory IVUS endpoints
TAV in most diseased segment
Maximum atheroma thickness
P lt 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
Adapted from Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Primary endpoint in selected subgroups
58 years lt 58 years
Age
Male Female
Gender
median lt median
BMI
(34.3)
BaselineHDL-C
median lt median
(38.6)
Statinuse
Yes (560)no (116)

P 0.03
Triglyc-erides
median lt median
(140.0)

P 0.03
median lt median
hsCRP
(3.5)
0
2
2
1
1
Favors placebo
Favors rimonabant
Adapted from Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Major adverse cardiovascular events
P 0.06
Adapted from Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Psychiatric adverse effects
Major depression, suicidal ideation, attempted
or successful suicide
Adapted from Nissen SE, Nicholls SJ, et al. JAMA
20082991547-1560.
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Other treatment-emergent adverse effects
n 545 male patients
Adapted from Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Time to permanent drug discontinuation
HR 2.75 Log rank P lt 0.001
Nissen SE, Nicholls SJ, et al. JAMA. 2008 299
1547-1560.
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Conclusions

• Treatment of abdominally-obese coronary disease
  patients for 18 months with rimonabant
• Reduced body weight 4.3 kg and waist
  circumference 4.5 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.

Nissen SE, Nicholls SJ, et al. JAMA.
20082991547-1560.
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Nissen SE, Nicholls SJ, et al. JAMA
20082991547-1560.
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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 atherosclerotic disease in patients
with abdominal obesity, but these benefits will
need to be confirmed in additional trials,
currently underway.