cardiovascular outcome trials for new obesity drugs
DESCRIPTION
The FDA has decided to require Cardiovascular Outcome Trials (CVOT) for new obesity drugs. Trails may be required either before or after approval and marketing. This 2012 presentation discusses the rationales for such trials and points out that some believe one such previous trial was misinterpreted.TRANSCRIPT
Cardiovascular Outcome Trials for Anti-Obesity Medicines
ASBP Annual Symposium
Orlando, October 26, 2012
Ed J. Hendricks, MD, FASBP
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
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+
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*
I0.5
I1.5
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
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.
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
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…….
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
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
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
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
Mortality: IHD & BP
BP ➔ Mortality
Whelton, JAMA, 2002; 288:1882-8
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
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
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.
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
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
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.