OVERALL SURVIVAL Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344: % of patients alive Simvastatin (n=2221) Years since randomization 30% risk reduction P= Placebo (n=2223)

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

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

MAJOR CORONARY EVENTS Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344: Coronary Death or Nonfatal MI % of patients without events Simvastatin (n=2221) Years since randomization 34% risk reduction P < Placebo (n=2223)

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): % 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

SUBGROUP COMPARISON – MAJOR CORONARY EVENTS Adapted from Miettinen TA et al Circulation 1997;96: Coronary Death and Nonfatal MI % of patients Men 34 % risk reduction Women 34 % risk reduction Age <65 34 % risk reduction Age >65 34 % risk reduction Placebo Simvastatin

CORONARY EVENT REDUCTION Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344: ; 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 P < P < P=0.01 P= P= P= P < P < P < Relative risk (95% Cl)

MI REDUCTION Myocardial Infarction Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344: ; Data on file, MSD. No. of patients Placebo (n=2223) 37% risk reduction P < Simvastatin (n=2221)

NEED FOR PTCA/CABG PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graft Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344: % of patients without PTCA or CABG Simvastatin (n=2221) Years since randomization 37% risk reduction P < Placebo (n=2223)

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

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

STROKE/TIA Adapted from Pedersen TR et al Am J Cardiol 1998;81: % risk reduction P= % of patients Simvastatin (n=2221) Placebo (n=2223) Years

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: % of patients Simvastatin (n=2221) Placebo (n=2223) Years

INTERMITTENT CLAUDICATION* *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81: New or Worsening Intermittent Claudication 38% risk reduction P= % of patients Simvastatin (n=2221) Placebo (n=2223) Years

ANGINA PECTORIS* *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81: New or Worsening Angina Pectoris % risk reduction P< % of patients Simvastatin (n=2221) Placebo (n=2223) Years

DEVELOPMENT OF HEART FAILURE Adapted from Kjekshus J et al J Card Fail 1997;3(4): % without CHF Simvastatin (n=2221) % risk reduction P <0.015 Placebo (n=2223) Months since randomization

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

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:

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: 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

CONCOMITANT CARDIOVASCULAR THERAPY – BASELINE Adapted from Scandinavian Simvastatin Survival Study Group Lancet 1994;344: Simvastatin Placebo 20–40 mg Drug Class/Therapy No.No. Aspirin Beta blockers Calcium antagonists Isosorbide mono/dinitrate Thiazides

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: S provided the largest and longest follow-up of patients treated with simvastatin (5.4 median years)