Should we prescribe aspirin and statins to all subjects over 65? (Or even all over 55?) Terje R.Pedersen Oslo University Hospital Oslo, Norway

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1 Should we prescribe aspirin and statins to all subjects over 65? (Or even all over 55?) Terje R.Pedersen Oslo University Hospital Oslo, Norway

2 The Polypill A strategy to reduce cardiovascular disease by more than 80 % NJ Wald & MR Law Wolfson Institute of Preventive Medicine, London BMJ 2003;326:1419.

3 The Polypill 1. suggestion Statin: atorvastatin 10 mg or simvastatin 40 mg 3 antihypertensive drugs at half standard dose: thiazide, β-blocker, ACE-inhibitor Folic acid 0.8 mg Aspirin 75 mg BMJ 2003;326:1419.

4 The Polypill To be taken by everyone aged 55 years Everyone with cardiovascular disease Risk factors need not be measured Risk reduction: > 80 % Gain in 1/3 of people: 11 years of life free from IHD or stroke BMJ 2003;326:1419.

5 BMJ 2003;326:1419. The Polypill: Risk reductions Risk factor Agent Reduction % IHD risk reduction % Stroke risk reduction LDL chol. Statin 70 mg/dl 61 * 17 * BP 3 drugs 11 mmhg diast. 46 * 63 * Homocystein Folic acid 3 µmol/l 16 * 24 * Platelet func. Aspirin Combined All 88 (95% CI:84-91) 80 (95% CI: 71-87) atorvastatin 10 mg or simvastatin 40 mg in the evening or 80 mg in the morning * Estimated from cohort studies

6 The Polypill: Expected benefits per 100 who start taking the pill at age 55 Men Women Age No. who benefit Years gained No. who benefit Up to Up to Up to Up to any age Years gained BMJ 2003;326:1419

7 The Polypill: Expected adverse effects: Aspirin per 100 people Data from 15 trials with patients Adverse event Aspirin (n) Placebo (n) Excess risk/100 Extracranial bleed Fatal bleed Non-fatal, major Hematemesis Melena Any bleed Heartburn Any adverse effect Stopped medication BMJ 2003;326:1419

8 The Polypill components: symptoms % of patients with symptoms * Drug or vitamin Any symptom Stop treatment Statin 0.1 < 0.1 Thiazide A- II receptor antagonist < 0.1 < 0.1 Ca blocker Folic acid <<0.1 <<0.1 Aspirin * % in treated group minus % in placebo group BMJ 2003;326:1419

9 Relative distributions of risk factors in men who subsequently died of ischaemic heart disease or stroke and in men who did not. Gaussian distribution fitted to data from a cohort of men followed prospectively for 10 years (the BUPA study) IHD Cholesterol IHD Diastolic BP IHD Homocystein Stroke Diastolic BP Wald, N J et al. BMJ 2003;326:1419

10 TIPS: The Indian Polycap Study 2053 individuals at 50 centres Testing components of the Polycap vs The Polycap Double blind, 12 weeks treatment Lancet 2009:373;

11 Polycap: an Indian Polypill Hydrochlorothiazide 12.5 mg Atenolol 50 mg Ramipril 5 mg Simvastatin 20 mg Aspirin 100 mg Manufactured by Cadila Pharmaceuticals, Ahmedabad, India

12 TIPS: Main questions asked Effect on blood pressure? Effect on LDL-C? Tolerance? Interactions? Aspirin: reduction in BP-lowering? Lancet 2009:373;

13 TIPS: Individuals No previous CVD Age: years One risk factor: Type 2 diabetes SBP > 140, DBP >90, but < 160/100 mmhg Waist/hip ratio: women > 0.85, men > 0.90 LDL-C > 120 mg/dl HDL-C < 40 mg/dl Lancet 2009:373;

14 Lancet 2009:373; TIPS: Design No. Drug(s) 205 aspirin 205 thiazide 209 thiazide + ramipril 207 thiazide + atenolol 205 ramipril + atenolol 204 thiazide + ramipril + atenolol 204 thiazide + ramipril + atenolol + aspirin 202 simvastatin 412 Polycap

15 TIPS: Discontinuation rate As = Aspirin S = Simvastatin T = Thiazid At = Atenolol R = Ramipril Lancet 2009:373;

16 TIPS: Change in BP over time Systolic Diastolic Lancet 2009:373;

17 TIPS: Change in Lipoproteins Total cholesterol LDL-cholesterol HDL-cholesterol Apo B Lancet 2009:373;

18 Projected and estimated effects of Polypill LDL-C Agent Risk factor red. CHD Stroke Wald & Law Simvastatin mg/dl -61% -17% Polycap Simvastatin mg/dl -27% -8% DBP Wald & Law 3 drugs -11 mmhg -46% -63% Polycap 3 drugs -5.7 mmhg -24% -33% Combined +aspirin Wald & Law 6 drugs -88% -80% Polycap 5 drugs -62% -48% Lancet 2009:373;

19 First main question: Aspirin to everyone > 55 years?

20 U.S. Preventive Services Task Force Recommendation Aspirin for men when: Age 10-year CHD risk years > 4 % years > 9 % years > 12 % U.S. Preventive Services Task Force. Annals Intern Med 2009;150:

21 U.S. Preventive Services Task Force Recommendation Aspirin for women when: Age 10-year CHD risk years > 3 % years > 8 % years > 11 % U.S. Preventive Services Task Force. Annals Intern Med 2009;150:

22 Antithrombotic Trialist (ATT) Collaboration 6 primary prevention trials individuals person-years 3554 serious vascular events Serious vascular event rates: Control group: 0.57% per year Aspirin group: 0.51% per year Absolute benefit: 0.06% per year Lancet 2009;373:

23 Antithrombotic Trialists (ATT) Collaboration Lancet 2009;373:

24 ATT Strokes and extracranial bleed Event Control (n) Aspirin (n) Rate ratio Yearly absolute difference Stroke, total % Haemorrhagic % Ischemic % Unknown cause % Major excranial bleed % Lancet 2009;373:

25 Lancet 2009;373: ATT: Mortality by cause

26 Second main question: Statins for everyone > 55 years?

27 Brugts, J J et al. BMJ 2009;338:b2376 Primary Prevention Trials with Statins

28 Primary Prevention Trials with Statins Endpoint Statin Placebo Odds ratio (95% CI) All cause mortality / / ( ) Major Coronary Events / / ( ) Major Cerebrovsc. E / / ( ) Cancer / / ( ) Brugts, J J et al. BMJ 2009;338:b2376

29 Cumulative Incidence (%) Primary End Point: Nonfatal MI and Fatal CHD 4 Atorvastatin 10 mg Number of events 100 Placebo Number of events % reduction 2 1 HR = 0.64 ( ) p= ,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Years

30 Cumulative Incidence (%) 3 2 Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 Placebo Number of events % reduction 1 HR = 0.73 ( ) p= ,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Years

31 JUPITER - Patient Flow 89,890 subjects screened 17,802 randomized Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Lost to follow up n=37 Completed study n=8,857 Completed study n=8,864 Ridker P et al. N Eng J Med 2008;359:

32 JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Cumulative Incidence Number at Risk Rosuvastatin Placebo Hazard Ratio 0.56 (95% CI ) P< Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1, Placebo Rosuvastatin 20 mg NNT for 2y = 95 5y* = 25 *Extrapolated figure based on Altman and Andersen method Ridker P et al. N Eng J Med 2008;359:

33 JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Cumulative Incidence Number at Risk Rosuvastatin Placebo *Extrapolated figure based on Altman and Andersen method Projected Incidence Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1, Placebo Rosuvastatin 20 mg

34 Conclusion Statins for everyone is a good idea Aspirin is not Antihypertensive drugs for those with hypertension.