Reducing CVD globally through combination approaches to prevention: the polypill. Salim Yusuf

Reducing CVD globally through combination approaches to prevention: the polypill. Salim Yusuf

Disclosure None

Polypill & CVD Prevention 1. Why do we need a polypill? 2. What components in the polypill? 3. What are the data re polypill? 4. In whom can the polypill be used? -now -potentially in the future 5. The polypill as part of a strategy for cost efficient prevention & treatment

High Prevalence of Multiple Risk Factors Among Canadian Adults 90 80 80.2% Adults 20-59 (%) 70 60 50 40 30 41.1% 20 10 0 11.1% 3 2 1 Number of risk factors Includes smoking, physical inactivity, overweight, high BP, diabetes Heart and Stroke Foundation 2003, Source: Statistics Canada, Canadian Community Health Survey.

Risk of AMI associated with Risk Factors in the Overall Population Risk factor % Cont % Cases PAR 1 (99% CI) ApoB/ApoA-1(5 v 1) 20.0 33.5 54.1 (49.6, 58.6) Curr smoking 26.8 45.2 36.4(33.9,39.0) Diabetes 7.5 18.5 12.3 (11.2, 13.5) Hypertension 21.9 39.0 23.4 (21.7, 25.1) Abd Obesity (3 v 1) 33.3 46.3 33.7 (30.2, 37.4) Psychosocial - - 28.8 (22.6, 35.8) Veg & fruits daily 42.4 35.8 12.9 (10.0, 16.6) Exercise 19.3 14.3 25.5 (20.1, 31.8) Alcohol 24.5 24.0 13.9 (9.3, 20.2) Combined - - 90.4 (88.1, 92.4)

Drugs Antiplatelet Agents Beta Blockers % ACE Inhibitors or ARBs Statins

% receiving proven medications in CAD (154,000 people from 17 countries:pure) 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 0 Overall HIC UMIC LMIC LIC 5593 671 1338 2879 705

What is the early evidence showing the effectiveness of global risk management strategies?

Steno-2: Effects on Combined CV Outcomes 60 50 40 30 p=0.007 Conventional therapy Intensive therapy 53% relative risk reduction Number needed to treat (NNT) = 5 20 10 Hazard ratio (HR) = 0.47 (95% confidence interval [CI] = 0.24-0.73) No. at risk 0 0 12 24 36 48 60 72 84 96 Months of follow-up Conventional therapy 80 72 70 63 59 50 44 41 13 Intensive therapy 80 78 74 71 66 63 61 59 19 Gaede P, et al, N Engl J Med 2003;348:383-93.

Effect of long-term modest reductions in CV risk factors 10% Reduction in BP + 10% Reduction in Total-C = 45% Reduction in CVD Emberson et al. Eur Heart J. 2004;25:484-491.

Combination Pill / Polypill Yusuf /Peto: Propose combination pill of ACEI, BB, ASA and statin in secondary prevention to reduce risk by 75%. Wald /Law: 3 BP lowering drugs at half doses + statin + ASA+ folate: Could reduce CVD by 80 to 90%! Give it to all over 55 yrs without measuring anything else! Excellent tolerability

TIPS: Components of each Groups vs Low dose Polycap Antiplatelet ASA 100 mg/d Statin Simvastatin 20 mg/d ACE-Inhibitors Ramipril 5 mg/d Beta-blocker Atenolol 50 mg/d Diuretic Hydrochlorothiazide 12.5 mg/d Polycap All of the above

Percent TIPS: Reasons for Permanent Discontinuation of Study Drug Polycap: Reasons f or Permanent Discontinuation 30 25 20 15 10 Other Reasons Specific Reasons Social Reasons/Refusals 5 0 As,S,T TR,Tat,RAt TRAt TRAtAs Polycap

Estimated reductions in CHD/Stroke of a low dose Polycap in Those With Average Risk Factor Levels Reduction in Risk Factors % Relative Reduction CHD Stroke LDL-C (mmol/l) Est (Simv 20) 0.80 27% 8% DBP (mmhg) Est (3, ½ dose) 5.7 24% 33% Platelet function Est (ASA 100 mg) Similar 32%* 16% Combined Est - 62% 48% *RCTs suggest a smaller benefit

Changes in BP with Full dose vs low dose Polycap: TIPS-2 Systolic BP Diastolic BP SBP 125 130 135 140 145 Low Dose Full Dose p=0.076 DBP 75 80 85 90 Low Dose Full Dose p=0.005 Systolic BP Diastolic BP V1 V2 Rand W 2 W4 W 8 W 12 Visit V1 V2 Rand W 2 W4 W 8 W 12 Visit Change in SBP -6-4 -2 0 2 4 Low Dose Full Dose p=0.003 Chang in DBP -4-2 0 2 4 Low Dose Full Dose p=0.001 Rand W 2 W4 W 8 W 12 Rand W 2 W4 W 8 W 12 Visit Visit

Changes in lipids with full dose vs low dose Polycap: TIPS-2 Cholesterol 3.0 3.5 4.0 4.5 p=0.014 LDL 1.6 1.8 2.0 2.2 2.4 p=0.006 V1 Rand W 8 V1 Rand W 8 Visit Visit Low Dose Full Dose HDL 0.90 1.00 1.10 p=0.680 Triglycerides 1.5 1.7 1.9 p=0.733 V1 Rand W 8 V1 Rand W 8 Visit Visit

Estimated reductions in CHD/Stroke of a Full dose Polycap in Those With Average Risk Factor Levels Reduction in Risk Factors % Relative Reduction CHD Stroke LDL-C (mmol/l) Est (Simv 40) 1.1 35% 15% DBP (mmhg) Est (3, full dose) 10.0 40% 50% Platelet function Est (ASA 100 mg) Similar 32%* 16% Combined Est - 70 to 80% 65 to 75% *RCTs suggest a smaller benefit

Trials with the Polypill Authors Components No BP LDL Proj RRR in CVD 1. TIPS-1 (Lancet 2009) 2. TIPS-2 (unpublished) (dose in mg) (mmhg) (mmol/l) ASA (100), Ram (5), HTZ (12.5), AT (50), Simv (20) 2053-7.4/-5.6 0.80 ~55% Double of above 510 (?) -12/-7.5* 1.0* ~65%* 3. PILL Collab (PLOS One 2011) ASA (75), Lis (10, HCTZ (12.5), Simv (20) 378-9.9/5.3 0.8 ~50% 4. Malekzadeh (Int J Clin Pract 2010) ASA (81), Enal (2.5), HCTZ (12.5), Atorv (20) 475 (348 completed) -4.5/-1.6 0.46 ~25%

Who should get the polypill? ON CURRENT EVIDENCE: Those with established vascular disease (v high risk). Those without vascular disease, but at hi risk( >2% /yr) eg. hi risk hypertension, diabetes or multiple RF. POTENTIAL: Moderate risk individuals eg >55 yrs + additional RF (trials underway: HOPE-3 and TIPS- 3). FUTURE: All >55 yrs(????!!!)

The Polycap to revolutionize prevention Low cost(<$ 5 to 10/mo), simple (little dose titration), safe, well tolerated (so no monitoring). Can the polycap be used by NPHW (using algorithms and phys mentorship) for secondary and hi risk prim prev (diabetes, hypertension)? Physician involved only with complex patients, resistant risk factors or side-effects?