The Polypill Protocol

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The Polypill Protocol
Prevention of Cardiovascular Complications
CPCRA Group Meeting May 2005
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CVD on cART Update from the DAD Study
Incidence of MI by cART exposure

• n23,441 11 cohorts
• 76,577 pt-years follow-up
• Mean ARV exposure 4.5 years
• 24 women
• At baseline 42 dyslipidemic, 47 smokers, 16
  ex-smokers
• 277 first MI 3.6/1000 pt-years
• 28.5 fatal
• RR 1.17/year cART (95 CI 1.081.26)

plt0.0001
El-Sadr W, et al. 12th CROI, Boston 2005, 42
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CVD on cART Update from the DAD Study
Additional risk factors in DAD
Relative ratio of myocardial infarction (95
CI) Multivariable Poisson Regression model Also
adjusted for all factors in previous slide
El-Sadr W, et al. 12th CROI, Boston 2005, 42
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Reduction of Stroke with Combination Blood
Pressure Lowering Therapy in PROGRESS, by
Baseline Blood Pressure
Lancet. 2001 Sep 29 358(9287)
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Reduction of Cardiovascular Events with
Cholesterol Lowering in the Heart Protection
Study, by Baseline Cholesterol
Lancet. 2002 Jul 6360(9326
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Joint Effects of Blood Pressure, Cholesterol, and
Smoking on Coronary Heart Disease Mortality for
Men Screened in the MRFIT
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The Polypill
12.5 mg of hydrochlorthiazide
40 mg of pravastatin
75 mg of aspirin
10 mg of lisinopril
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Polypill Study Design
8,000 HIV-infected patients (400 in a vanguard
study) with CD4 gt 50, and with 5-year risk of
CVD gt 7.5
Polypill nutritional advice 40 mg
pravastatin 75 mg aspirin 12.5 mg
hydrochlorothiazide 10 mg lisinopril
Placebo nutritional advice
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Calculation of Framingham Risk
Age Cholesterol HDL
LDL Blood Pressure Diabetes Smoking
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Framingham Risk Score
Cholesterol Risk Score for Men
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Risk over 7.5

• Easy to get there
• Male over 40 smoker systolic BP over 130 or
  HDL between 35-44
• Woman over 50 and smoker or smoker and HDL
  between 35 -44

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Nutritional Advice
Weight Loss Limiting Alcohol Physical
Activity Decreasing salt intake Healthy Diet
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Vanguard StudyPill vs. Placebo

• Primary Objective
• Change in 5 year Framingham risk Score
• Change in LDL cholesterol
• Change in systolic blood pressure
• Duration 1 year
• N 400

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Vanguard StudyPill vs. Placebo

• Secondary Objectives
• Adherence to blinded medication
• Addition of lipid lowering or blood pressure
  medication

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Polypill Study Design
8,000 HIV-infected patients (400 in a vanguard
study) with CD4 gt 50, and with 5-year risk of
CVD gt 7.5
Polypill nutritional advice 40 mg
pravastatin 75 mg aspirin 12.5 mg
hydrochlorothiazide 10 mg lisinopril
Placebo nutritional advice
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Clinical Endpoint studyPolypill vs. Placebo
Secondary Objectives

• coronary heart disease (fatal or non-fatal
  myocardial infarction and other deaths from
  coronary heart disease death)
• fatal or non-fatal stroke
• cardiovascular mortality
• all cardiovascular events, defined as an expanded
  composite of total coronary events, total stroke
  events, revascularization procedures (coronary
  artery bypass, percutaneous coronary angioplasty,
  peripheral revascularization), hospitalization
  for heart failure, transient ischemic attack or
  cardiovascular death
• all-cause mortality
• new onset diabetes
• development of hypertension or hypercholesterolemi
  a requiring drug treatment according to national
  guidelines

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Clinical Endpoint StudyPrimary endpoint

• Major cardiovascular events defined composite of
  non-fatal myocardial infarction, stroke or
  cardiovascular mortality

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Inclusion Criteria

• Patients with gt 7.5 Absolute Risk based on
  Framingham Risk Function (irrespective of ART)
• Participants with Framingham risk between 4-7.4
  who are currently on ART and have had more than 7
  years on ART

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Exclusion Criteria

• Indication for any component of polypill
• CAD, diabetes
• Hepatitis or cirrhosis
• AST/ALT gt 2x ULN
• Creatinine gt 2 mg/dl
• Recent gastrointestinal hemorrhage
• CD4 lt 50 cells

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Concomitant Medications

• Need ASA? Add open-label ASA 75 mg
• Need a BP med? Beta-blockergt Ca channel blocker
  gt ACE
• Need diuretic or ACE? Add open-label diuretic or
  ACE
• Need a statin? Add 10-20 mg of pravastatin. OK
  for fibrates

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Five Years Later
POLYPILL