1. HYPERLIPIDAEMIA

2. 4S 4444 patients –Hx angina or MI –Cholesterol 5.5-8.0 Simvastatin 20mg (10-40) vs. placebo FU 5 years  total cholesterol 25%;  LDL 35%;  HDL 8% 30% reduction in overall mortality (p=0.0003) 42% reduction in CV mortality No difference in non-cardiovascular death Scandinavian Simvastatin Survival Study. Lancet 1994;344:1383-9

3. CARE 4159 patients with history of MI –total cholesterol <6.2 –LDL 3-4.5 –no history of diabetes Pravastatin 40mg od vs. placebo FU 5 years  total cholesterol 20%;  LDL 28%;  HDL 5% No difference in: –overall mortality –cardiovascular death –non-cardiovascular death MI  23% (p=0.02) CVA  31% (p=0.03) NEJM 1996; 335:1001-9

4. WOSCOPS 6595 men –LDL cholesterol >6.5 –and LDL cholesterol >4 after dietary modification –5% angina; 0% MI –78% smokers or ex-smokers Pravastatin 40mg od vs. placebo FU 5 years  total cholesterol 20%;  LDL 26% 31% reduction in coronary events 32% reduction in cardiovascular death No increase in non-cardiovascular death NEJM 1995; 333:1301-7

5. LIPID Long-term intervention with pravastatin in ischaemic disease SECONDARY PREVENTION > 9000 pts in Australia /New Zealand Baseline cholesterol 4-7 Pravastatin 40mg od vs. placebo FU 6 years –  cholesterol by 1mmol/l –  overall & CHD mortality (22%, 24%) –  MI (29%) –  hospitalisation for unstable angina (12%) –  CABG, PTCA (22%,19%) NEJM 1998; Nov 05;339:1349-57

6. Baseline Lipid Values PlaceboPravastatin Baseline Characteristics n = 4502n = 4512 Median (25%, 75%) Total Cholesterol5.65 (5.08, 6.20)5.65 (5.07, 6.22) LDL Cholesterol HDL Cholesterol0.92 (0.79, 1.09)0.92 (0.79, 1.07) Triglycerides1.56 (1.18, 2.12)1.60 (1.17, 2.21) TC/HDL Ratio6.07 (5.12, 7.14)6.11 (5.13, 7.15) 3.88 (3.38, 4.40)3.88 (3.36, 4.39) (mmol/L)

7. Effects on Lipids* Intention-to-Treat Comparison Averaged Over 5 Years of Treatment LDLTotalHDLTriglycerides * Mean differences between pravastatin and placebo % Change -18% -25% 5% -11% -30% -20% -10% 0% 10%

8. Major Cardiovascular Events Reduction in Relative Risk p = 0.048p <0.001 24 CHD Death 22 Total Mortality* 24 CHD Events** 19 Stroke 30 20 10 0 % Reduction in Relative Risk *Not currently a licenced indication for pravastatin **CHD death or non-fatal MI

9. CHD Events % Reduction in Relative Risk 40 30 20 10 p = 0.005p = 0.024p < 0.001 12 Unstable Angina 19 PTCA 22 CABG 29 MI 0

10. CHD Mortality Years Since Randomisation 01234567 0% 5% 10% Cumulative Risk p <0.001 Placebo Pravastatin 24% reduction

11. Total Mortality* 01234567 Years Since Randomisation 0% 5% 15% Cumulative Risk p < 0.001 Placebo Pravastatin 22% reduction 10%

12. Continuum of Risk* High Risk CHD Patients Majority of CHD Patients Patients at High Risk of CHD Relevance to Clinical Practice 4S (simvastatin) CARE (pravastatin) WOSCOPS (pravastatin) LIPID (pravastatin) *Annual risk of cardiovascular mortality

13. 4S Total Cholesterol Range CARE LIPID mmol/L876543 Major Secondary Prevention Trials with Statins

14. Illustration of overlap between active and placebo treated populations Overlap On Treatment LDL Cholesterol placebopravastatin patient numbers

15. WOSCOPS - Investigators’ Overlap Analysis Comparison of 4.5 Yr event rates in patients with on-treatment LDL-C values of 3.6-4.6 mmol/l On-treatment Placebo mean LDL-C = 4.4mmol/l n = 1120 On-treatment Pravastatin mean LDL-C = 4.1 mmol/l n = 1071 n = 1071 4.5 Yr CHD Event Rate (%) 9.6% 6.3% 0 4 8 10 6 2 Relative risk reduction* = 36% (p=0.014) *Cox Analysis of risk reduction for CHD death or non-fatal MI adjusting for baseline differences in risk factors for CHD. (Packard et al. in press)

16. CARE - Overlap Analysis Comparison of 4.5 Yr event rates in patients with on-treatment LDL-C values of 2.6-3.4 mmol/l On-treatment Placebo LDL-C = 2.9 mmol/l n = 652 On-treatment Pravastatin LDL-C = 3.1 mmol/l n = 643 n = 643 4.5 Yr CHD Event Rate (%) 19.5% 13.8% 0 10 20 15 5 *Cox Analysis of risk reduction for CHD death, non-fatal MI, CABG or PTCA adjusting for baseline differences in HDL, diabetes and use of nitrates. Relative risk reduction* = 28% (P=0.01)

17. Framingham CHD Risk Model Age, Sex, Smoking, Blood Pressure, Total Cholesterol, HDL-C, Diabetes Regression Model Predicted 4.5 Year Risk of Coronary Event Anderson et al, 1990 Am Heart J 121:293-298.

18. WOSCOPS Investigators’ Framingham Analysis Packard et al. in press -40 -30 -20 -10 0 24% 35% Predicted*Actual % Risk Reduction p= 0.026

19. WOSCOPS Investigators’ Quintile Analysis (intention to treat) 4.4 yr Event Rate (per 100) Percent Change in LDL Cholesterol Quintile 1 2 3 4 5 0.51.01.5 Risk Relative to Placebo 1.09 0.72 0.53 0.69 0.51 051015 -39 -31 -24 -12 0 p=0.54 p=0.03 p= 0.007 p=0.018 p=0.0001 Comparison to Placebo by Cox Hazard MethodPackard et al. in press

20. Plaque stabilisation Reduced thrombus formation Fibrinogen Potential Ancillary Mechanisms for Coronary Event Reduction Libby. Circulation. 1995;91:2844-50. Falk et al. Circulation. 1995;92:657-71. Brown. Circulation. 1993;87:1781-1.