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HYPERLIPIDAEMIA

HYPERLIPIDAEMIA. 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.

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HYPERLIPIDAEMIA

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  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. LIPIDLong-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 Characteristics Placebo Pravastatin Baseline Lipid Values (mmol/L) n = 4502 n = 4512 Median (25%, 75%) Median (25%, 75%) Total Cholesterol 5.65 (5.08, 6.20) 5.65 (5.07, 6.22) LDL Cholesterol 3.88 (3.38, 4.40) 3.88 (3.36, 4.39) HDL Cholesterol 0.92 (0.79, 1.09) 0.92 (0.79, 1.07) Triglycerides 1.56 (1.18, 2.12) 1.60 (1.17, 2.21) TC/HDL Ratio 6.07 (5.12, 7.14) 6.11 (5.13, 7.15)

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

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

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

  10. CHD Mortality 24% reduction 10% p <0.001 Placebo Cumulative Risk 5% Pravastatin 0% 0 1 2 3 4 5 6 7 Years Since Randomisation

  11. Total Mortality* 15% 22% reduction Placebo p < 0.001 10% Cumulative Risk Pravastatin 5% 0% 0 1 2 3 4 5 6 7 Years Since Randomisation

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

  13. Major Secondary Prevention Trials with Statins Total Cholesterol Range 3 4 5 6 7 8 mmol/L LIPID CARE 4S

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

  15. WOSCOPS - Investigators’ Overlap AnalysisComparison of 4.5 Yr event rates in patients with on-treatment LDL-C values of 3.6-4.6 mmol/l 9.6% Relative risk reduction* = 36% (p=0.014) 10 8 6.3% 4.5 YrCHDEventRate (%) 6 4 2 0 On-treatment Placebo mean LDL-C = 4.4mmol/l n = 1120 On-treatment Pravastatin mean LDL-C = 4.1 mmol/l n = 1071 *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 AnalysisComparison of 4.5 Yr event rates in patients with on-treatment LDL-C values of 2.6-3.4 mmol/l Relative risk reduction* = 28% (P=0.01) 19.5% 20 13.8% 15 4.5 YrCHDEventRate (%) 10 5 0 On-treatment Placebo LDL-C = 2.9 mmol/l n = 652 On-treatment Pravastatin LDL-C = 3.1 mmol/l n = 643 *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.

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

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

  19. Risk Relative to Placebo 0.5 1.0 1.5 Quintile 1.09 1 0.72 2 0.53 3 0.69 4 0.51 5 WOSCOPS Investigators’ Quintile Analysis (intention to treat) 4.4 yr Event Rate (per 100) 0 5 10 15 0 p=0.54 -12 p=0.03 Percent Changein LDL Cholesterol -24 p= 0.007 -31 p=0.018 -39 p=0.0001 Comparison to Placebo by Cox Hazard Method Packard et al. in press

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

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