1. The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels Frank M. Sacks, M.D., Marc A. Pfeffer, M.D., Ph.D., Lemuel A. Moye, M.D., Ph.D., Jean L. Rouleau, M.D., J. Malcolm O. Arnold, M.D., Chuan-Chuan Wun, Ph.D., Barry Davis, M.D., Ph.D., Eugene Braunwald, M.D., for the Cholesterol and Recurrent Events Trial Investigators N Engl J Med 1996; 335:1001-9

2. CARE - Study Design Secondary prevention of CHDSecondary prevention of CHD 80 centers in the US and Canada80 centers in the US and Canada 4159 men and women aged 21 to 75 enrolled4159 men and women aged 21 to 75 enrolled 3 to 20 months post-MI3 to 20 months post-MI Total-C < 240; LDL-C between 115 and 174; Triglycerides < 350 mg/dLTotal-C < 240; LDL-C between 115 and 174; Triglycerides < 350 mg/dL 5 yr Treatment with Pravastatin 40 mg vs. placebo5 yr Treatment with Pravastatin 40 mg vs. placebo Sacks, F. et al, N Engl J Med 1996; 335:1001-9

3. CARE - Study Endpoints Primary:Primary: –CHD death or nonfatal MI Secondary:Secondary: –CHD death Tertiary:Tertiary: –Total Mortality Others:Others: –Fatal MI, nonfatal MI, PTCA, CABG, Stroke Sacks, F. et al, N Engl J Med 1996; 335:1001-9

4. CARE - Baseline Characteristics 86% male; 14% female86% male; 14% female Mean age 59 ± 9 yearsMean age 59 ± 9 years 93% white93% white 21% current smoker21% current smoker 42% hypertensive42% hypertensive 14% diabetic14% diabetic Sacks, F. et al, N Engl J Med 1996; 335:1001-9

5. CARE - Baseline Characteristics Mean 10 ± 5 months post-MIMean 10 ± 5 months post-MI 54% had prior PTCA / CABG54% had prior PTCA / CABG 83% taking aspirin83% taking aspirin 41% taking -blockers41% taking -blockers 40% taking calcium antagonists40% taking calcium antagonists 15% taking ACEIs15% taking ACEIs Sacks, F. et al, N Engl J Med 1996; 335:1001-9

6. Lipids at Baseline Sacks, F. et al, N Engl J Med 1996; 335:1001-9 Plasma LipidPlaceboPravastatin (n=2078)(n=2081) Cholesterol (mg/dL) Total209 209 Total209 209 VLDL2727 VLDL2727 LDL139139 LDL139139 HDL3939 HDL3939 Triglycerides (mg/dL)155156

7. Percent LDL Reduction on Treatment P < 0.001 for all comparisons Sacks, F. et al, N Engl J Med 1996; 335:1001-9

8. Fatal CHD or Nonfatal Myocardial Infarction (Primary Endpoint) Sacks, F. et al, N Engl J Med 1996; 335:1001-9 24% Risk Reduction p = 0.003

9. Coronary Bypass Surgery or Angioplasty 27% Risk Reduction p<0.001 Sacks, F. et al, N Engl J Med 1996; 335:1001-9

10. CARE - Achievement of Endpoints Primary: CHD death or nonfatal MIPrimary: CHD death or nonfatal MI –24% reductionp = 0.003 Secondary: CHD deathSecondary: CHD death –20% trend to reductionp = 0.10 (ns) Tertiary: Total MortalityTertiary: Total Mortality –9% trend to reductionp = 0.37 (ns) Sacks, F. et al, N Engl J Med 1996; 335:1001-9

11. CARE - Achievement of Endpoints Fatal MIFatal MI –37% reduction (p=0.07) Nonfatal MINonfatal MI –23% reduction (p=0.02) Combined MI endpointsCombined MI endpoints –25% reduction (p=0.002) Sacks, F. et al, N Engl J Med 1996; 335:1001-9 CABG/PTCA/CombinedCABG/PTCA/Combined –26% reduction (p=0.005) PTCAPTCA –23% reduction (p=0.01) Combined CABG/PTCACombined CABG/PTCA –27% risk reduction (p<0.001) Other: StrokeOther: Stroke –31% reduction (p=0.03)

12. CARE - Observations Fatal CHD + nonfatal MI + CABG + PTCAFatal CHD + nonfatal MI + CABG + PTCA –Women vs. Men: 46% vs. 20% –Current smokers vs. other: 33% vs. 22% – 60 yr: 20% vs. 27% –EF 40%: 28% vs. 23% –Hypertension, yes vs. no: 23% vs. 24% –Diabetes, yes vs. no: 25% vs. 23% –Prior PTCA/CABG, yes vs. no: 22% vs. 25% p values for all subgroups were statistically significant Sacks, F. et al, N Engl J Med 1996; 335:1001-9

13. CARE - Observations Baseline LDL influence on Events*Baseline LDL influence on Events* –LDL 125-150 26% p < 0.001 –LDL < 125 3%p = 0.85 –LDL > 150-175 p = 0.008 Sacks, F. et al, N Engl J Med 1996; 335:1001-9 *Events included; fatal CHD, nonfatal MI, CABG or Angioplasty

14. CARE - Safety No difference in fatal and nonfatal primary cancers... exceptNo difference in fatal and nonfatal primary cancers... except Breast Cancer:Breast Cancer: –Placebo (n=1) –Pravastatin (n=12), p=0.002* Sacks, F. et al, N Engl J Med 1996; 335:1001-9 Of the 12 breast cancer cases in the pravastatin group, all were nonfatal; 3 occurred in patients who had previously had breast cancer, 1 was ductal carcinoma in situ, and 1 occurred in a patient who took pravastatin for only six weeks.

15. Summary Cholesterol lowering with pravastatin in patients with MI and TC < 240 mg/dL Fatal CHD or nonfatal MI24% Fatal MI37% Nonfatal MI23% All MI, fatal or nonfatal25% Coronary artery bypass surgery26% Coronary angioplasty23% Stroke31% Reduced Sacks, F. et al, N Engl J Med 1996; 335:1001-9

16. Expected Number of Cardiovascular Events Preventable by Treating 1000 Patients with Pravastatin for Five Years Number of Events Number of Events Events Total Group Age > 60 Women Fatal CHD112710 Nonfatal Ml264683 CABG253234 PTCA372066 Strokes TIA132528 Other Cardiovascular38577 All Cardiovascular Events 150207228 Patients with 1 event pre-517197 vented Sacks, F. et al, N Engl J Med 1996; 335:1001-9

17. Conclusion These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levelsThese results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels Sacks, F. et al, N Engl J Med 1996; 335:1001-9