Presented by Michael Pignone, MD, MPH, at UCSF's symposium "The Role of Risk Stratification and Biomarkers in Prevention of Cardiovascular Disease" in Jan 2012.

1. Primary Prevention of Cardiovascular Disease: the role of aspirin and statins Michael Pignone, MD, MPH Professor of Medicine UNC Division of General Internal Medicine UCSF CVD prevention symposium Jan 30, 2012

5. Aspirin for CVD prevention Lancet 2009; 373: 1849–60 Overall Men Women Non-fatal MI 0.77 (0.67, 0.89) CHD death 0.95 (0.78, 1.15) Major coronary event 0.82 (0.75, 0.90) 0.77 (0.67,0.89) 0.95 (0.77, 1.17) Stroke 0.95 (0.85, 1.06) Ischemic stroke 0.86 (0.74, 1.00) 1.01 (0.74, 1.39) 0.77 (0.59, 0.99)

6. Trial characteristics * 8831 women ** 2583 women ^ all women Year Duration (yrs) Subjects Dose (mg) BMD 1988 5-6 5,139 500 qd PHS 1989 5 22,071 325 qod TPT 1998 6.8 2,540 75 qd HOT 1998 3.8 18,790* 75 qd PPP 2001 3.6 4495** 100 qd WHS 2005 10.1 39,876^ 100 qod

8. Summarizing aspirin benefits and harms Men Women Non-fatal myocardial infarction Reduces risk No effect Fatal CHD events Small or no reduction No effect Stroke No effect Reduces risk GI bleed Increased risk Increased risk

9. Aspirin modeling studies Cost per QALY for 55 year old patients with 5% CVD risk Cost per QALY for 55 year old patient with 10% CVD risk Earnshaw 2011 Dominant (men) Dominant (men) Greving 2008 111,949 € (men) ------------------------------- Dominated by no Tx (women) 20,298 € (men) ------------------------------ 114,356 € (women) Earnshaw 2007 Dominated by no Tx (women) Not assessed (women)

10. Comparison of inputs *ischemic strokes only Earnshaw 2007 (women) Greving 2008 Earnshaw 2011 (men) RR - MI 1.01 0.68 (men) 1.01 (women) 0.70 RR - stroke 0.76 1.00 (men) 0.76 (women)* 1.06 (total strokes) RR - GI bleed 7 per 10,000 absolute 1.72 (men) 1.68 (women) 2.0 Utility, MI 0.88 0.88 0.87 Utility stroke 0.5 (major) 0.75 (minor) 0.5 (major) 0.75(minor) 0.61 (initial) 0.83 (later) Utility, taking aspirin 1.0 0.999 1.0 Utility, GI bleed 0.94 0.94 0.94 Cost aspirin $5.75 97 € $14 Cost – GI bleed $7538 1625 € $13,342

11. Comparison of inputs *ischemic strokes only Earnshaw 2007 (women) Greving 2008 Earnshaw 2011 (men) Model type Markov Markov Markov Time horizon lifetime 10 years lifetime Year for costs 2005 2005 2009 Discount rate 3% ? (4%) 3% Secondary events modeled? Yes No Yes GI Bleed risk increase with age? No Yes Yes Risk of death from GI bleed? 1/100,000 3% 1/1000

13. Statins

14. Effectiveness of statins for primary prevention Mills et al JACC 2008; 52: 1769-81 RR 95% CI Myocardial infarction 0.77 (0.63, 0.95) Stroke 0.88 (0.78, 1.0) CVD mortality 0.89 (0.81, 0.98) All-cause mortality 0.93 (0.87, 0.99)

15. Trial characteristics Trial Duration (yrs) % female Drug and Dose (mg) ASCOT 3.3 81 Atorva 10 AFCAPS 5.2 15 Lova 20/40 ALLHAT 4.8 51 Prava 20/40 MEGA 5.3 68 Prava 10/20 PROSPER 3.2 58 Prava 40 WOSCOPS 4.9 0 Prava 40

17. Statin modeling studies Cost /QALY for treatment of 55 year old patients with CVD risk of 5% Cost /QALY for treatment of 55 year old patients with CVD risk of 10% Lee 2010 < $50,000 (men) >$50,000 (women) < $50,000 (men) ≈ $50,000 (women) Lazar 2011 Pletcher 2009 Treating all with LDL > 130 dominates “treat none” Greving 2011 125,544 € (men) 167,080 € (women) 34,995 € (men) 41,544 € (women)

18. Comparison of inputs * Based on LDL lowering and age; 22-28% in 45-55 age range Lee 2010 Lazar 2011 Pletcher 2009 Greving 2011 RR MI 0.77 0.66 – 0.92* 0.71 (major coronary events) RR CHD death 0.83 --- RR stroke 0.83 --- 0.81 Statin cost $401 $48 9€ MI cost $17,000 --- 17,342€ Stroke cost $15,000 (acute) $48,000 (Year 1) --- 36K€ initial 21K€ subsequent Utility: taking statin No decrement No decrement 0.999

19. Comparison of inputs * 17.5% stop within 6 months due to muscle symptoms Lee 2010 Lazar 2011 Pletcher 2009 Greving 2011 Model type Markov Markov Markov Discount rate 3% 3% ? Time horizon lifetime 30 years 10 years Adherence 100%* 100% 60% Costing Year 2008 2008 2008

20. Integrating aspirin and statin decision making

21. (Older) analysis: for men, start aspirin at 7.5% risk, add statin above 10% risk Statin cost assumed to be $710 per year Pignone et al; Annals Int Med 2006; 144: 326-36 Low (5%) Moderate (7.5%) Moderate-High (10%) High (15%) ASA alone Aspirin less effective, more costly Aspirin more effective, less costly Aspirin more effective, less costly Aspirin more effective, less costly ASA + statin NA $56,200 $42,500 $33,600

22. Sensitivity of Cost-effectiveness to Cost of Statin Statin cost $710

24. Does aspirin reduce cancer mortality? Rothwell et all Lancet 2011; 377:31-41

26. Stephanie Earnshaw to describe current model