1. C-1 Efficacy of the Combination: Meta-Analyses Donald A. Berry, Ph.D. Frank T. McGraw Memorial Chair of Cancer Research University of Texas M.D. Anderson Cancer Center 7asdf

2. C-2 Speakers for This Morning Dr. René Belder Mechanism of action of components PK analysis Safety and tolerability of combination Dose combinations available Efficacy– based on individual trials Dr. Donald Berry Efficacy– based on meta-analyses Efficacy– presence of consistent benefit Dr. Thomas Pearson Medical Need

3. C-3 Patient Group Comparisons PlaceboPravastatin Aspirin Users Aspirin Non-Users Prava+ASA Prava alone Placebo+ASA Placebo alone Randomized Groups Randomized Comparison Observational Comparison

4. C-4 Is the Combination More Effective than Pravastatin Alone? Unadjusted event rates in LIPID and CARE suggest pravastatin + aspirin is more effective than pravastatin alone

5. C-5 Event Rates for Primary Endpoints in LIPID and CARE Aspirin Users Aspirin Non-Users 5.8% 8.8%14.8% 9.3% LIPID CHD Death CARE CHD Death or Non-fatal MI Pravastatin-treated Subjects Only Trial: Primary Endpoint: Observational Comparison

6. C-6 Accounting for Baseline Risk Factors Age Gender Previous MI Smoking status Baseline LDL-C, HDL-C, TG Baseline DBP & SBP Additional analyses also included revascularization, diabetes and obesity

7. C-7 Trial LIPID CARE REGRESS PLAC I PLAC II Totals Number of Subjects*% on Aspirin 82.7 83.7 54.4 67.5 42.7 80.4 Primary Endpoint CHD mortality CHD death & non-fatal MI Atherosclerotic progression (& events) 9014 4159 885 408 151 14,617 Atherosclerotic progression (& events) *99.7% of pravastatin-treated subjects received 40mg dose Meta-Analysis of these Pravastatin Secondary Prevention Trials

8. C-8 Trial Commonalities Similar entry criteria Patient populations with clinically evident CHD Same dose of pravastatin (40mg) Randomized comparison of pravastatin against placebo All trials had durations of  2 years Pre-specified endpoints Covariates recorded Common meta-analysis data management

9. C-9 Meta-Analysis Endpoints Considered Fatal or non-fatal MI Ischemic stroke Composite: CHD death, non-fatal MI, CABG, PTCA or ischemic stroke

10. C-10 Model 1: Multivariate Cox proportional hazards model Patients combined across trials; trial effect is a fixed covariate Meta-Analysis Models

11. C-11 RRR = Relative Risk Reduction Relative Risk (95% CI) RRR Relative Risk Reduction Cox Proportional Hazards – All Trials Prava+ASA vs ASA alone Prava+ASA vs Prava alone Fatal or Non-Fatal MI 0.4000.8001.0000.600 0.4000.8001.0000.600 CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke Prava+ASA vs ASA alone Prava+ASA vs Prava alone 24% 0.76 13% 0.87 31% 0.69 26% 0.74 Prava+ASA vs ASA alone Prava+ASA vs Prava alone 29% 0.71 31% 0.69 Ischemic Stroke 0.4000.8001.0000.600

12. C-12 Relative Risk Reduction Cox Proportional Hazards – LIPID and CARE Ischemic Stroke Prava+ASA vs ASA alone – LIPID Prava+ASA vs ASA alone – CARE 0.4000.8001.0000.600 0.70 0.71 1.2000.200 CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke Prava+ASA vs ASA alone – LIPID Prava+ASA vs ASA alone – CARE 0.4000.8001.0000.600 0.76 1.2000.200 Prava+ASA vs ASA alone – LIPID Prava+ASA vs ASA alone – CARE Fatal or Non-Fatal MI Relative Risk (95% CI) 0.4000.8001.0000.6001.2000.200 0.65 0.79

13. C-13 Relative Risk Reduction Cox Proportional Hazards – LIPID and CARE Ischemic Stroke Prava+ASA vs Prava alone – LIPID Prava+ASA vs Prava alone – CARE 0.4000.8001.0000.600 0.74 0.49 1.2000.200 CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke Prava+ASA vs Prava alone – LIPID Prava+ASA vs Prava alone – CARE 0.4000.8001.0000.600 0.86 0.78 1.2000.200 Prava+ASA vs Prava alone – LIPID Prava+ASA vs Prava alone – CARE Fatal or Non-Fatal MI Relative Risk (95% CI) 0.4000.8001.0000.6001.2000.200 0.72 0.74

14. C-14 Model 1: Multivariate Cox proportional hazards model Patients combined across trials; trial effect is a fixed covariate Model 2: Same as Model 1 except Allows trial heterogeneity: Bayesian hierarchical (random effects) model of trial effect Meta-Analysis Models

15. C-15 0.000 0.025 0.050 0.075 0.100 012345 Year Model 2 – Hierarchical, Random Effects Fatal or Non-Fatal MI Placebo Prava alone ASA alone Prava+ASA Cumulative Proportion of Events

16. C-16 0.000 0.005 0.010 0.015 0.020 0.025 012345 Model 2 – Hierarchical, Random Effects Ischemic Stroke Only ASA alone Prava+ASA Year Cumulative Proportion of Events Prava alone Placebo

17. C-17 0.00 0.05 0.10 0.15 0.20 0.25 012345 Year Model 2 – Hierarchical, Random Effects CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke Prava+ASA ASA alone Prava alone Placebo Cumulative Proportion of Events

18. C-18 Combination is More Effective than Either Agent Alone Pravastatin + aspirin provides benefit for all three endpoints: 24% - 34% RRR compared with aspirin 13% - 31% RRR compared with pravastatin This benefit was similar in Models 1 and 2 This benefit was consistent in both LIPID and CARE trials

19. C-19 Model 2: Fatal or Non-Fatal MI Cumulative Proportion of Events 0.000 0.025 0.050 0.075 0.100 Year 012345 Prava+ASA ASA alone Prava alone Placebo 0.000 0.005 0.010 0.015 0.025 Year 012345 0.020 HazardPrava+ASA ASA alone Prava alone Placebo

20. C-20 Model 1: Multivariate Cox proportional hazards model Patients combined across trials; trial effect is a fixed covariate Model 2: Same as Model 1 except Allows trial heterogeneity: Bayesian hierarchical (random effects) model of trial effect Model 3: Same as Model 2 except Treatment hazard ratios vary over time Meta-Analysis Models

21. C-21 Model 3: Fatal or Non-Fatal MI Cumulative Proportion of Events 0.000 0.025 0.050 0.075 0.100 Year 012345 Prava+ASA ASA alone Prava alone Placebo 0.000 0.005 0.010 0.015 0.030 Year 5 Separate Analyses: One per Year 012345 0.020 Hazard 0.025 Prava+ASA ASA alone Prava alone Placebo

22. C-22 Conclusion of Hazard Analysis over Time Benefit of pravastatin+aspirin over aspirin was present in each year of the 5-year duration of the trials Benefit of pravastatin+aspirin over pravastatin was present in each year of the 5-year duration of the trials Benefits estimated from Model 1 (and confidence intervals) confirmed by more general models and fewer assumptions