1. The Prospective Pravastatin Pooling Project L I P I D CARECARE PPP Project Investigators Am J Cardiol 1995; 76:899–905

2. WOSCOPS Study Design Males aged 45–64 years with total-C  252 mg/dl and no prior MI Diet therapy x 4 weeks LDL-C  155 mg/dl on visits 2 and 3 and  174  232 mg/dl on 1 of these visits 5 years Placebo (n = 3293) Pravastatin 40 mg QD (n = 3302) Shepherd et al. N Engl J Med. 1995;333:1301–07.

3. WOSCOPS: Baseline Characteristics Age at visit 1 (years)55 55 History of MI (%)0 0 Mean LDL-C at baseline (mg/dl)192 192 History of hypertension (%)15 16 Current cigarette smoker (%)35 35 Shepherd et al. N Engl J Med. 1995;333:1301–07. Placebo Pravastatin (n = 3293) (n = 3302)

4. Early Benefit with Pravastatin in WOSCOPS: Myocardial Infarction* Shepherd et al. N Engl J Med. 1995;333:1301–07. 0 1 2 4 6 Percent with Event 8 10 12 23 Years 456 Pravastatin (n = 3302) Placebo (n = 3293) 31% risk reduction P < 0.001 * Primary endpoint: Non-fatal MI and CHD death

5. Early Benefit with Pravastatin in WOSCOPS: Cardiovascular Mortality Shepherd et al. N Engl J Med. 1995;333:1301–07. 0.0 0123 Years 456 0.5 1.0 1.5 2.0 Percent with Event 2.5 3.0 3.5 32% risk reduction P = 0.033 Pravastatin (n = 3302) Placebo (n = 3293)

6. Benefit with Pravastatin in WOSCOPS: Total Mortality Shepherd et al. N Engl J Med. 1995;333:1301-7. 0 1 1 2 3 Percent with Event 4 5 6 23 Years 456 22% risk reduction P = 0.051 Pravastatin (n = 3302) Placebo (n = 3293)

7. CARE: Study Design Sacks et al. N Engl J Med. 1996;335:1001–9. 4159 Males and Females, 21–75 years of age Post-MI 3–20 months, LVEF >25% Total-C < 240 mg/dL, LDL-C 115-174 mg/dL and TG < 350 mg/dL Step II diet if LDL-C > 174 mg/dL 5 years Placebo (n = 2078) Pravastatin 40 mg QD (n = 2081) Primary Endpoint: Fatal CHD or confirmed non-fatal MI Secondary endpoints: Revascularizations, combined coronary events, stroke

8. CARE: Baseline Characteristics Sacks et al. N Engl J Med. 1996;335:1001–09. Placebo Pravastatin Characteristic n = 2078 n = 2081 Other Medications Age (years) Women/Men (%) History of HTN (%) Diabetes (%) Total Chol. mg/dL (mean) LDL mg/dL (mean) Aspirin (%) 43 15 14/86 59 209 139 8383 139 209 14 42 14/86 59 Antihypertensives (%) 8282 Current Cig. Smoker (%) 21

9. CARE: Cardiovascular Events: Reduction of Relative Risk Sacks et al. N Engl J Med. 1996;335:1001–09. % Risk Reduction CHD Death or Non-fatal MI * CHD Death Fatal MI Non-fatal MI * CABG * PTCA * Unstable Angina Stroke * -10 -20 -30 -40 0 * p < 0.05 -24% -20% -37% -23% -26% -23% -13% -31%

10. CARE: Stroke and Stroke/TIA -40 -30 -20 -10 0 StrokeStroke/TIA Relative Risk RiskReduction p = 0.029 p = 0.03 -31% -26% Sacks et al. N Engl J Med. 1996;335:1001–09. Revised Pravastatin Package Insert. Indications and Usage. March 1998. 83% Aspirin Use 82% Use of Antihypertensives

11. Long-term Intervention with Pravastatin Ischemic Disease (LIPID) Trial Design Males & females aged 31–75 years with average cholesterol and a prior history of acute MI or unstable angina Diet therapy x 8 weeks Total cholesterol between 155–271 mg/dl,Triglycerides < 445 mg/dl, stratified by Diagnosis 6.0 years Placebo (n = 4502) Pravastatin 40 mg QD (n = 4512) The LIPID Study Group. Am J Cardiol. 1995;76:474–79. Primary : Coronary mortality Primary endpoint: Coronary mortality Secondary endpoints: Total mortality, nonfatal MI & CHD death, stroke etc.

12. LIPID: Baseline Characteristics The LIPID Study Group. Am J Cardiol. 1995;76:474–79. PlaceboPravastatin Characteristic n = 4502 n = 4512 Other Medication Use Age (years) Women/Men (%) History of HTN (%) Current Cig. Smoker (%) Diabetes (%) Total Chol. mg/dL (mean) LDL mg/dL (mean) Aspirin (%) 42 9 10 17/83 62 218 150 8283 150 218 9 9 41 17/83 62

13. Years Since Randomization 01234567 0% 5% 10% Cumulative Risk p = 0.0004 Placebo Pravastatin 24% reduction CHD Mortality LIPID: Total & CHD LIPID: Total & CHD Mortality Total Mortality Years Since Randomization 01234567 0% 5% 15% Cumulative Risk p = 0.00002 Placebo Pravastatin 23% reduction 10% The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

14. LIPID: Total Stroke 01234567 Years since randomization 0% 2% 4% 6% Cumulative Risk Placebo (n = 4502) Pravastatin (n = 4512) 19% risk reduction p = 0.048 The LIPID Study Group. N Engl J Med. 1998;339:1349–57.

15. Benefit of Pravastatin in Reducing Stroke -40 -30 -20 -10 0CARELIPIDRelative Risk RiskReduction p = 0.048 p = 0.03 In both trials, stroke was a pre-specified endpoint and 83% of all pravastatin patients received aspirin. -31% -19% Sacks et al. N Engl J Med. 1996;335:1001–09. Tonkin et al. ACC, March 1998.

16. CARE(U.S./Canada) 4159 M&F Age: 21–75 100% MI WOSCOPS(Scotland) 6595 Males Age: 45–64 5% Angina 0% MI LIPID (Australia /N. Zealand) 9014 M&F Age: 31–75 64% MI 36% Unstable Angina Pectoris The PPP Investigators. Am J Cardiol. 1995;76:899–905. Pravastatin Pooling Project (PPP) Over 110,000 patient-years of follow-up

17. Prospective Pravastatin Pooling Project: Baseline Characteristics CHD statusNo CHDMI WOSCOPS (n = 6595) CARE (n = 4159) MI, unstable angina LIPID (N=9014) LIPID (n = 9014) Age (years) Mean Upper limit 55 64 59 75 61 75 Men100%86%83% Diabetes1%14%9% Hypertension16%43%42% Smokers35%16%10%

18. Prospective Pravastatin Pooling Project: Baseline Lipids Lipids (mg/dL) WOSCOPS (n = 6595) CARE (n = 4159) LIPID (N=9014) LIPID (n = 9014) Total cholesterol Limits Mean > 252 272 < 240 209 155–271 219 LDL cholesterol Limits Mean 174–232 192 115–174 139 None 150 HDL cholesterol Mean 44 3937 Triglycerides Limits Mean < 533 162 < 350 156 < 445 159

19. 0 10 20 30 24% (P<0.001) 12% (P=0.1) 17% (P=0.25) Relative Risk Reduction (%) CHD Mortality Other Vascular Mortality Non-CVD Mortality Prospective Pravastatin Pooling Project: Mortality Simes et al. Eur Heart J. 2002;23:207–15. 20% (P<0.001) Total Mortality CARE, LIPID, & WOSCOPS (n = 19,768)

20. Prospective Pravastatin Pooling Project: Population Subgroups (Expanded End Points) Age <55 (6637) Age 55–64 (8288) Age 65–75 (4843) Men (17,676) Women (2092) Diabetic (1444) Non-diabetic (18,324) -30 -25 -20 -15 -10 -5 0 22% (P<0.001) 22% (P<0.001) 26% (P<0.001) 23% (P<0.001) 27% (P<0.001) 26% (P<0.002) 23% (P<0.001) EventRate (%) * (%) * * CHD death and non-fatal MI, PTCA, CABG, stroke; 4131 patients with events Sacks et al. Circulation. 1999;100:I–238.

21. The Prospective Pravastatin Pooling Project Extent of Exposure to Study Medication Number of subjects receiving at least 1 dose of study medication Pravastatin 40 mg n = 9809 Placebo n = 9783 Extent of Exposure to Study Medication (Years) Mean + SD Median Min (days) Max Mean + SD Median Min (days) Max 4.6 + 1.7 5.017.1 4.6 + 1.7 5.017.1 4.5 + 1.8 5.017.1 5.017.1

22. Number of Subjects Years of Exposure The Prospective Pravastatin Pooling Project Extent of Exposure to Study Medication Pfeffer MA et al. European Heart J 2001;22:271. PravastatinPlacebo

23. The Prospective Pravastatin Pooling Project Common Serious Adverse Events (Non-CV) Modified from Pfeffer et al. Circulation 2002;105:r95–r100. 5% 10% 15%20%UrologicProc. MuscularPain Inv. GI Proc. Ortho.SurgProstateDisorderAbd.Surg Hernia DermNeopl.DermProc.PulmInfect. Gall Bl Disorder EyeSurgLensOpacity Musculo- Skel Abn. PUD Reprod.NeoplasmBoneFx Gall Bl. SurgPlaceboPravastatin

24. The Prospective Pravastatin Pooling Project Incidence of Cancer by Treatment Group Pfeffer MA Data on File Treatment Group PlaceboPravastatinTotal Fatal Cancer 221 (2.3%) 234 (2.4%) 455 (2.3%) Any Cancer 946 (9.6%) 946 (9.6%) 914 (9.3%) 914 (9.3%) 1860 (9.5%)

25. The Prospective Pravastatin Pooling Project Site Specific Incidence of Primary Cancer Pfeffer MA et al. European Heart J 2001;22:271. PlaceboPravastatin HematDermGIEndoHep Musc - Skel RenalResp General Neuro Special Senses Any Ca Pravastatin 9.3% Placebo 9.6% 0 5% 3% 4% 2% 1%

26. The Prospective Pravastatin Pooling Project Total Number of AST and ALT Measurements Taken at Baseline and Post Baseline Total Number of Measurements Number of Subjects with Laboratory Measurements Mean Number of Measurements per Subject AST 154,431 Overall 11,70413.2 77,685 Pravastatin 585213.3 76,746 Placebo 585213.1 ALT 243,506 Overall 18,63713.1 123,193 Pravastatin 933813.2 120,313 Placebo 929912.9 Pfeffer MA et al. European Heart J 2001;22:271.

27. Pravastatin Placebo 95% CI Pravastatin Placebo 95% CI Any Elevated ALT 804 / 9185 (8.8%) 746 / 9152 (8.2%) -0.21, 1.42 > 1.5 - 1.5 - < 3 X ULN 676 (7.4%) 615 (6.7%) -0.11, 1.39 > 3 - 3 - < 5 X ULN 84 (0.9%)90 (1.0%) -0.36, 1.39 > 5 - 5 - < 7 X ULN 24 (0.3%)19 (0.2%) -0.10, 0.21 > 7 - 7 - < 9 X ULN6 (<0.1) 9 (<0.1%) -0.13, 0.06 > 9 X ULN 14 (0.2%)13 (0.1%) -0.11, 0.13 Any Elevated ALT 804 / 9185 (8.8%) 746 / 9152 (8.2%) -0.21, 1.42 > 1.5 - 1.5 - < 3 X ULN 676 (7.4%) 615 (6.7%) -0.11, 1.39 > 3 - 3 - < 5 X ULN 84 (0.9%)90 (1.0%) -0.36, 1.39 > 5 - 5 - < 7 X ULN 24 (0.3%)19 (0.2%) -0.10, 0.21 > 7 - 7 - < 9 X ULN6 (<0.1) 9 (<0.1%) -0.13, 0.06 > 9 X ULN 14 (0.2%)13 (0.1%) -0.11, 0.13 The Prospective Pravastatin Pooling Project Post Baseline Elevations in ALT Pfeffer MA et al. European Heart J 2001;22:271.

28. The Prospective Pravastatin Pooling Project: Incidence of Post-baseline ALT Abnormalities In 579 Subjects With Abnormal Baseline ALTALT > 1.5 X ULN > 3 X ULN Pravastatin 127 / 317 (40.1%) 16 / 317 (5.0%) Placebo 101 / 262 (38.5%) 19 / 262 (7.3%) Pfeffer MA et al. European Heart J ;22:271. Pfeffer MA et al. European Heart J 2001;22:271.

29. The Prospective Pravastatin Pooling Project: Total Number of CPK Measurements Taken at Baseline and Post Baseline Total Number of Measurements Number of Subjects with Laboratory Measurements Mean Number of Measurements per Subject CPK 1 126,370Overall10,57611.9 63,452Pravastatin 529512.0 62,918Placebo 528111.9 LIPID does not include CORE Lab CPK Pfeffer MA et al. European Heart J 2001;22:271.

30. Pravastatin Placebo 95% CI Pravastatin Placebo 95% CI Any Elevated CPK 587 / 5245 (11.2%) 563 / 5233 (10.8%)-0.78, 1.65 > 1.5 - 1.5 - < 3 X ULN 480 (9.2%) 460 (8.8%)-0.75, 1.48 > 3 - 3 - < 5 X ULN 84 (1.6%) 79 (1.5%)-0.40, 0.59 > 5 - 5 - < 7 X ULN 8 (0.2%) 16 (0.3%)-0.36, 0.05 > 7 - 7 - < 9 X ULN 6 (0.1) 6 (0.1%)-0.15, 0.15 > 9 X ULN 9 (0.2%)2 ( 9 X ULN 9 (0.2%)2 (<0.1%)-0.02, 0.28 Any Elevated CPK 587 / 5245 (11.2%) 563 / 5233 (10.8%)-0.78, 1.65 > 1.5 - 1.5 - < 3 X ULN 480 (9.2%) 460 (8.8%)-0.75, 1.48 > 3 - 3 - < 5 X ULN 84 (1.6%) 79 (1.5%)-0.40, 0.59 > 5 - 5 - < 7 X ULN 8 (0.2%) 16 (0.3%)-0.36, 0.05 > 7 - 7 - < 9 X ULN 6 (0.1) 6 (0.1%)-0.15, 0.15 > 9 X ULN 9 (0.2%)2 ( 9 X ULN 9 (0.2%)2 (<0.1%)-0.02, 0.28 The Prospective Pravastatin Pooling Project: Post Baseline Elevations in CPK Pfeffer MA et al. European Heart J 2001;22:271.

31. Myotoxicity In Major Statin Trials Trial Pravastatin Pooling Project [CARE, LIPID, WOSCOPS] (n = 19,592) 4S (n = 4444) AFCAPS/TexCAPS (n = 5605) Total (n = 30,641) Farmer JA Lancet. 2001;358:1383–85. Myositis Myositis Statin Control 3 7 3 7 6 1 6 1 21 21 21 21 30 39 30 39Rhabdomyolysis Statin Control 0 0 0 0 1 0 1 0 1 2 1 2 2 2 2 2

32. Proportion of Subjects Still On Meds 2345671 Years of Follow-up Time to Discontinuation of Study Medication Excluding Discontinuation Due to CV AEs Pravastatin ( n = 9809) Placebo (n = 9783) Pfeffer MA et al. European Heart J 2001;22:271. Placebo Pravastatin 538 431 439 339 755 826 710 579 2465 2527 3322 3488 1473 1690 Number of Subjects < 1 Yr 1 - <2 yr 2 - <3 yr 3 - <4 yr 4 - <5 yr > 6 yr

33. The Prospective Pravastatin Pooling Project: Predicting Medication Discontinuation A Multivariate Cox Model Parameter Hazard Ratio p-value Treatment Group (Pravastatin)0.690.0001 History of Diabetes1.340.0001 Presence of CV SAE0.760.0001 Current Smoker1.250.0001 Gender (males)0.830.0001 Primary/Secondary Prevention1.150.0042 Age1.000.4718 Pfeffer MA et al. European Heart J 2001;22:271.