Cardiovascular Outcome Trials for New Obesity Drugs

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.