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.

1. Cardiovascular Outcome Trials
for Anti-Obesity Medicines
ASBP Annual Symposium
Orlando, October 26, 2012
Ed J. Hendricks, MD, FASBP

2. 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

4. 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+

5. 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*

6. I
0.5
I
1.5

18. 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

19. New Implications of SCOUT
①Pharmacotherapy-assisted long-term weight
loss and maintenance in the obese with
cardiovascular disease and/or T2DM reduces
both CVD mortality and CVD morbidity.
②Long-term morbidity & mortality incidences
are important criteria of drug effectiveness.
③ CV Outcome trials for new obesity drugs
④Sibutramine withdrawal not necessary.

20. 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

21. Contrave CVOT (LIGHT Study)
Inclusion Criteria
1. 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…….

22. 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

23. 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

27. 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

28. -25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
0 1 2 3 4 8 12 26 40 1 2 3 4 5 6 7
Weeks/Years
P Rx HTN Patients
% Wt Loss
Delta SBP
Delta DBP
Delta HR

29. Mortality: IHD & BP

30.  BP ➔  Mortality
Whelton, JAMA, 2002; 288:1882-8

31. -15.0
-10.0
-5.0
0.0
5.0
10.0
1 2 3 4 5 6 7
Delta SBP vs Years
NBP
PreHTN
HTN

32. -20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
No Q
Rx
All Q HTN Q No P Rx All P HTN P
Qnexa vs Phentermine
SBP
DBP
Wt Loss
One Year Data

33. 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.

34. 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

35. 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

36. 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.