1. HPS: Heart Protection Study Purpose To determine whether simvastatin reduces mortality and vascular events in patients with and without coronary disease, but all at high risk, and with a broad range of baseline cholesterol levels Reference HPS Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.

2. HPS: Heart Protection Study - TRIAL DESIGN - Design Multicenter, randomized, double-blind, placebo-controlled Patients 20,536 patients aged 40–80 years, with and without coronary heart disease, but all at high risk, and with broad range of baseline total cholesterol: all >135mg/dL (>3.5mmol/L), mean 230 mg/dL (5.9 mmol/L) Follow up and primary endpoint Primary endpoint: all-cause mortality. Mean 5 years follow up. Treatment Placebo or simvastatin 40 mg daily

3. HPS: Heart Protection Study - TRIAL DESIGN continued- All patients Men Women History of coronary disease Previous MI Other Other risk factors in absence of coronary disease a Baseline characteristics 20,536 15,454 5082 8510 4876 7150 No. 75 25 41 24 35 Cerebrovascular disease Peripheral arterial disease Diabetes mellitus 1820 2701 3982 9 13 19 % of total a Some patients had more than one of these conditions. HPS Collaborative Group.Lancet 2002;360:7Ð22.

4. HPS: Heart Protection Study - RESULTS - All-cause mortality in simvastatin group significantly reduced compared with placebo (12.9 vs. 14.7%, P<0.0003); reduction was attributed largely to significant reduction in coronary death: —Other vascular death reduced but with marginal significance —Nonvascular death reduced but not significantly First major vascular event rate significantly reduced, as were the individual event rates (fatal/nonfatal MI, fatal/nonfatal stroke, and revascularization) No difference in new cancers (7.9 vs 7.8%, rate ratio 1.0, P=0.9) except nonmelanoma skin cancer (2.4 vs 2.0%) No difference in withdrawal due to myopathy (0.5% in both groups)

5. HPS: Heart Protection Study - RESULTS continued - Vascular causes Coronary Other vascular Subtotal: any vascular Non-vascular causes Neoplastic Respiratory Other medical Nonmedical Subtotal: any nonvascular ANY DEATH 587 194 781 359 90 82 16 547 1328 (5.7) (1.9) (7.6) (3.5) (0.9) (0.8) (0.2) (5.3) (12.9) Cause of death Death rate ratio (95% CI)Simvastatin (n=10,269) No.(%) 707 230 937 345 114 90 21 570 1507 (6.9) (2.2) (9.1) (3.4) (1.1) (0.9) (0.2) (5.6) (14.7) RR=0.83 (0.75–0.91) P<0.0001 RR=0.95(0.85–1.07) P=0.4 RR=0.87(0.81–0.94) P<0.0003 No.(%) Placebo (n=10,267) HPS Collaborative Group. Lancet 2002;360:7–22. Dashed line indicates overall RR for a subtotal 1.01.21.40.80.60.4 Simvastatin betterPlacebo better Cause-specific mortality

6. HPS: Heart Protection Study - RESULTS continued - P Nonfatal MI or coronary death0.73 (0.67–0. 79)<0.0001 First major vascular event 898 No. (8.7) (%) Simvastatin (n=10,269) 1212 No. (11.8) Fatal or nonfatal stroke0.75 (0.66–0.85)<0.0001444(4.3)585(5.7) Revascularization0.76 (0.70–0.83)<0.0001939(9.1)1205(11.7) Any major vascular event a 0.76 (0.72–0.81)<0.00012033(19.8)2585(25.2) (%) Placebo (n=10,267) Event rate ratio (95% CI) HPS Collaborative Group. Lancet 2002;360:7–22. a Data are for patients having first event of each type, hence non-additivity

7. HPS: Heart Protection Study - SUMMARY - In high-risk patients with a broad range of baseline cholesterol values, simvastatin reduced: All-cause mortality Coronary deaths Major vascular events