Cardiovascular Outcome Trials for New Obesity Drugs
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Cardiovascular Outcome Trials for Anti-Obesity Medicines
ASBP Annual Symposium
Orlando, October 26, 2012
Ed J. Hendricks, MD, FASBP
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Obesity and Cardiovascular Disease
Obesity – increases risks for:• Stroke and ischemic heart disease• New onset Atrial Fibrillation– Framingham – if BMI > 30, 45-50% increase– Incidence by 4% for each 1 unit BMI increase
• Sudden Cardiac Death – 325,000/year in U.S.– 5% of all SCD, 16,250 deaths/year in U.S.
• Congestive Heart Failure
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Cardiovascular Outcome Trials
• EMDAC recommended statistical analysis using Relative Risk (RR)
• Relative Risk = difference in probability of an event between treated subjects and control subjects
• Recommended Hard Endpoints: MACE = MI, Stroke, CV Death.
• Rejected MACE+
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CVOT
• Trial Hypotheses • • Risk Improvement: CV risk of active is statistically better
than the CV risk of control (similar to a superiority comparison) • H0: ρ ?≥ ?1 • H1: ρ ?< 1 • • Non-Excessive Risk: CV risk of active is statistically no
worse than CV risk of control by some value (define as risk margin; notated as Δ*)
• H0: ρ ?≥Δ* • H1: ρ ?< Δ*
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I0.5
I1.5
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SCOUT Trial
• Sibutramine Cardiovascular OUTcomes Study • ~10,000 obese with known CVD, T2DM• 1st Look: Morbidity 16 % Rx cohort; no
difference in mortality • 1st Look: analysis ignored weight loss• 2nd Look: analysis stratified by weight loss• Mortality AND Morbidity if weight loss
occurred
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New Implications of SCOUT
① Pharmacotherapy-assisted long-term weight loss and maintenance in the obese with cardiovascular disease and/or T2DM reduces both CVD mortality and CVD morbidity.
② Long-term morbidity & mortality incidences are important criteria of drug effectiveness.
③ CV Outcome trials for new obesity drugs
④ Sibutramine withdrawal not necessary.
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Contrave CVOT (LIGHT Study)
• Primary ITT analysis of MACE• MACE (CV death, MI, stroke)• Exclude a doubling of MACE at interim to
obtain approval• Exclude a 40% increase in MACE at final to
remain on market. i.e. RR < 1.4• Enroll patient population targeting a
background MACE rate of 1.5% per year
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Contrave CVOT (LIGHT Study)
Inclusion Criteria1. Age ≥50 years (women) or ≥45 (men)
2. BMI ≥27 kg/m2 and ≤50 kg/m2
3. WC ≥88 cm (women) or ≥102 cm (men)
4. At increased risk of adverse cardiovascular outcomes…….
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At Risk for Adverse CV Outcomes
• Prior MI >3 months prior to screening• Prior coronary revascularization• Prior carotid or peripheral revascularization• Angina + Ischemic EKG changes• Positive Exercise test or Cardiac Imaging • Ankle brachial index <0.9 (by simple palpation)• ≥50% stenosis of a coronary, carotid, or lower
extremity artery
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At Risk for Adverse CV Outcomes
AND/OR T2DM with at least 2 of
1. Hypertension (<145/95 mm Hg)
2. Dyslipidemia requiring Rx
3. HDL <50 mg/dL (women), <40 mg/dL (men)
4. Current tobacco smoker
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Qysmia Planned CVOT
• 15,000 subjects• 5-Year duration• Designed to identify cardiovascular benefit • Vivus & FDA still negotiating as of 10/7/12.
Final details to be determined.• Estimated cost $250 million
Source: Conversation with Vivus executive, October 7, 2012
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0 1 2 3 4 8 12 26 40 1 2 3 4 5 6 7
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0P Rx HTN Patients
% Wt LossDelta SBPDelta DBPDelta HR
Weeks/Years
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Mortality: IHD & BP
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BP ➔ Mortality
Whelton, JAMA, 2002; 288:1882-8
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1 2 3 4 5 6 7
-15.0
-10.0
-5.0
0.0
5.0
10.0Delta SBP vs Years
NBP
PreHTN
HTN
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No Q Rx
All Q HTN Q No P Rx
All P HTN P
-20-18-16-14-12-10
-8-6-4-20
Qnexa vs Phentermine
SBPDBPWt Loss
One Year Data
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P Rx Study Suggests
1 Long-term P Rx, by improving maintenance, lowers BP and retards the natural progression from NBP to PreHTN to HTN in the obese.
2 Wt Loss, sustained by P Rx, may reduce mortality from MI and stroke in hypertensive obese patients.
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Evidence: CV Effects
• Amphetamine therapy for ADD/ADHD does not increase risk for CVD in children or adults.• Phentermine Clinical Trials• Qnexa Clinical Trials (2 years)• Long-term phentermine treatment
study
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CV Outcomes in Treated HTN
• 37,348 subjects. Mean study follow-up duration ranged from 1.6 to 12.2 y.
RR 95% CI P
Major CV Event
0.89 0.79-0.99 0.036
MI 0.87 0.75-1.00 0.049
Stroke 0.76 0.63-0.92 0.004
CV Death 1.00 0.82-1.22 0.979
Lv, PLOS Med 2012;9(8):e1001293
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Summary
• FDA expects some obesity drugs may increase CV morbidity and mortality.
• CVOTs will be required to reassure that the RR of adverse CV events is less than 1.3.
• Design and analysis of CVOTs critical.• Recently published evidence suggests that
CVOTs will show CV Benefit, not harm.