1. OVERALL SURVIVAL Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389. % of patients alive 100 95 90 85 0 Simvastatin (n=2221) 01 2345 6 Years since randomization 30% risk reduction P=0.0003 Placebo (n=2223)

2. CORONARY MORTALITY Adapted from Kjekshus J et al Am J Cardiol 1995;76(9):64C-68C. No. of deaths 200 150 100 50 0 Placebo (n=2223) 42% risk reduction P=0.00001 Simvastatin (n=2221) 189 111

3. CAUSES OF MORTALITY Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389. Placebo (n=2223) Simvastatin (n=2221) 11.5% 8.2% Coronary Other cardiovascular Cancer Other

4. 100 90 80 70 0 MAJOR CORONARY EVENTS Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389. Coronary Death or Nonfatal MI % of patients without events Simvastatin (n=2221) 01 2345 6 Years since randomization 34% risk reduction P <0.00001 Placebo (n=2223)

5. CORONARY EVENTS VS. BASELINE LDL Coronary Deaths or Nonfatal MIs by Baseline LDL-C Quartiles Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1995;345(8960):1274-1275. 40 35 30 25 20 15 10 5 0 % risk reduction <4.39 mmol/L (170 mg/dl) 35 % 4.40–4.84 mmol/L (170–187 mg/dl) 4.85–5.34 mmol/L (188–207 mg/dl) >5.35 mmol/L (207 mg/dl) 33 % 32 % 36 % Baseline LDL-C

6. SUBGROUP COMPARISON – MAJOR CORONARY EVENTS Adapted from Miettinen TA et al Circulation 1997;96:4211-4218. Coronary Death and Nonfatal MI % of patients Men 34 % risk reduction 29.5 20.5 21.7 14.7 26.4 18.1 33.4 23.6 Women 34 % risk reduction Age <65 34 % risk reduction Age >65 34 % risk reduction Placebo Simvastatin 35 30 25 20 15 10 5 0

7. CORONARY EVENT REDUCTION Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389; Kjekshus J et al Am J Cardiol 1995; 76(9):64C-68C; Data on file, MSD. Simvastatin better Placebo better Age Gender Smoking Hypertension Diabetes <60 yrs 60–70 yrs Men Women Yes No Yes No Yes No 0.20.40.6 0.8 1.01.2 P <0.0001 P <0.00001 P=0.01 P=0.00105 P=0.00009 P=0.00006 P <0.00001 P <0.00169 P <0.000001 Relative risk (95% Cl)

8. MI REDUCTION Myocardial Infarction Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389; Data on file, MSD. No. of patients 600 500 400 300 200 100 0 Placebo (n=2223) 37% risk reduction P <0.00001 Simvastatin (n=2221) 369 562

9. NEED FOR PTCA/CABG PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graft Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389. 100 90 80 0 % of patients without PTCA or CABG Simvastatin (n=2221) 01 2345 6 Years since randomization 37% risk reduction P <0.00001 Placebo (n=2223)

10. HOSPITAL DAYS Adapted from Pedersen TR et al Circulation 1996;93(10):1796-1802. Cardiovascular Hospital Days No. of cardiovascular hospital days 16,000 12,000 8000 4000 0 Placebo (n=2223) 34% reduction P <0.0001 Simvastatin (n=2221) 15,089 9951

11. ATHEROSCLEROSIS Coronary arteries Carotid arteries Femoral arteries Atherosclerosis is a widespread disease affecting all vascular beds including

12. STROKE/TIA Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335. 28% risk reduction P=0.033 65432106543210 % of patients Simvastatin (n=2221) Placebo (n=2223) Years 0 1 2 34 5 6

13. 48% risk reduction P=0.009 CAROTID BRUITS* *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335. 2.5 2.0 1.5 1.0 0.5 0 % of patients Simvastatin (n=2221) Placebo (n=2223) Years 0 1 2 34 5 6

14. INTERMITTENT CLAUDICATION* *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335. New or Worsening Intermittent Claudication 38% risk reduction P=0.008 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 % of patients Simvastatin (n=2221) Placebo (n=2223) Years

15. ANGINA PECTORIS* *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335. New or Worsening Angina Pectoris 0 1 2 34 5 6 26% risk reduction P<0.0001 40 35 30 25 20 15 10 5 0 % of patients Simvastatin (n=2221) Placebo (n=2223) Years

16. DEVELOPMENT OF HEART FAILURE Adapted from Kjekshus J et al J Card Fail 1997;3(4):249-254. 100 98 96 94 92 90 0 % without CHF Simvastatin (n=2221) 61218243036424854606672 21% risk reduction P <0.015 Placebo (n=2223) Months since randomization

17. CHOLESTEROL PARAMETERS Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389; Data on file, MSD. Simvastatin 20 mg, Week 6 20 10 0 –10 –20 –30 –40 Mean % change LDL-CTotal CHDL-CTriglycerides P <0.0001 –38 % +8 % –28 % –15 %

18. PATIENT FOLLOW-UP PlaceboSimvastatin (n=2223)(n=2221) Lost to follow-up 0% 0% Treatment discontinuations13%10% Adverse effects 6% 6% Personal reasons/other 7% 5% Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389.

19. TRANSAMINASES AND CK AST = aspartate aminotransferase; ALT = alanine aminotransferase; CK = creatine kinase; ULN = upper limit of normal Adapted from Pedersen TR et al Arch Intern Med 1996;156:2085-2092. Elevations Occurring More than Once during 5.4 Years of Therapy PlaceboSimvastatin No. (%) No. (%) AST >3  ULN 7 (0.3) 5 (0.2) ALT >3  ULN 12 (0.6)14 (0.7) CK >10  ULN0 0

20. CONCOMITANT CARDIOVASCULAR THERAPY – BASELINE Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383-1389. Simvastatin Placebo 20–40 mg Drug Class/Therapy No.No. Aspirin 815 822 Beta blockers 1266 1258 Calcium antagonists 668 712 Isosorbide mono/dinitrate 727 684 Thiazides 138 151

21. LONG-TERM SAFETY Simvastatin had an excellent five-year safety profile Adverse experiences similar to placebo Only one reversible case of myopathy reported Incidence of liver enzyme elevations similar to that of placebo No interactions reported with beta blockers, calcium-channel blockers, aspirin, and thiazides No increase in cancer overall or at any particular site No previously unrecognized adverse effects observed Adapted from Pedersen TR et al Arch Intern Med 1996;156:2085-2092. 4S provided the largest and longest follow-up of patients treated with simvastatin (5.4 median years)