B-1 Pravastatin-Aspirin Combination René Belder, M.D. Executive Director Clinical Design and Evaluation, Metabolics Pharmaceutical Research Institute Bristol-Myers Squibb 7asdf

B-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

B-3 Different Mechanisms of Action of Components Aspirin Reduces platelet aggregation by inhibiting cyclo-oxygenase Pravastatin Reduces cholesterol levels by inhibiting HMG CoA reductase

B-4 *Ratio of Geometric Least Square Means (90%CI) No Pharmacokinetic Interaction in Single Dose Cross-Over Study µg/mLµgh/mL C max AUC 95% (85-105%)* 92% (82-103%)* 102% (99-105%)* 102% (95-108%)* Prava +ASA PravaASA Pravastatin level Salicylate level Prava +ASA PravaASA Pravastatin level Salicylate level Prava +ASA Product Administered

B-5 Changes in Mean Lipid Levels by Month 3 in CARE Percent Change from Baseline

B-6 Pravastatin Atherosclerosis Intervention Program (1) Prevention Program Secondary prevention –Long-term Intervention with Pravastatin in Ischemic Disease study (LIPID) –Cholesterol and Recurrent Events (CARE) Primary prevention –West of Scotland Coronary Prevention Study (WOSCOPS) No. of Subjects 9,014 4,159 6,595

B-7 Pravastatin Atherosclerosis Intervention Program (2) No. of Subjects Regression Program Regression Growth Evaluation Statin Study (REGRESS) Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Pravastatin Limitation of Atherosclerosis in the Carotid Arteries (PLAC II) Kuopio Atherosclerosis Intervention Study (KAPS)

B-8 Contribution of Trials to Total CHD Patient-Years of Exposure Total Exposure = 73,900 Patient-Years LIPID 68% CARE 28% REGRESS 2% PLAC-I 1% PLAC-II 1%

B-9 Reassuring Safety of the Combination CK abnormalities –no signal Liver Function Test abnormalities –no signal Gastrointestinal bleeds –no signal Hemorrhagic stroke –no signal

B-10 Appropriate Dosing of Pravastatin 40mg approved as the starting dose All prevention studies used the same pravastatin dose: 40mg This dose was extremely well tolerated and safe In these trials, no titration occurred for safety No need for lower doses in elderly Lower dose of pravastatin only indicated in patients requiring complex management: –renal or hepatic impairment –post transplant

B-11 Appropriate Dosing of Aspirin For secondary prevention the aspirin label advises: mg once daily and indefinite continuation of therapy Aspirin dose available in combination product: 81 or 325mg –81mg: most widely used for secondary prevention in U.S. –325mg: upper end of approved dose range

B-12 Is Pravastatin + Aspirin More Effective than Aspirin Alone? Investigation of efficacy of pravastatin in aspirin-users –LIPID –CARE

B-13 Aspirin Usage in Secondary Prevention Trials ‘Aspirin-users’ defined as those using aspirin at baseline Dose level of aspirin not collected 97% of baseline aspirin-users were still using it at the end of the trials

B-14 Evaluated Endpoints For individual trials: primary endpoints –LIPID: CHD death –CARE: CHD death or non-fatal MI In addition, the following endpoints*, based on the overlap of the pravastatin and aspirin labels, were evaluated –Fatal or non-fatal MI –Ischemic stroke –CHD death, non-fatal MI, CABG, PTCA or ischemic stroke *These endpoints were also prospectively defined in the individual trials

B-15 LIPID Trial Details 9,014 post-MI or unstable angina patients Mean follow-up of 6.1 years Primary endpoint of CHD death Randomized to pravastatin 40mg or placebo 83% also taking aspirin All Patients Prava 4512 Placebo 4502 Aspirin Users

B-16 LIPID Trial Results: LIPID Trial Results: Superiority of Combination vs Aspirin Alone * Relative risk reduction based on Cox Proportional Hazards model CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke 23.5%29.7%23.9%<0.001 Fatal or Non-fatal MI7.1%10.4%34.7% Ischemic Stroke2.6%3.6%29.7% < All PatientsN = 4512N = 4502 PlaceboPravaRRR*p value CHD Death6.4%8.3%24.0%<0.001 Aspirin UsersN = 3730N = 3698 CHD Death5.8%8.1%28.3%<0.001 Placebo (+ASA) Prava (+ASA) RRR*p value All PatientsN = 4512N = 4502 PlaceboPravaRRR*p value CHD Death6.4%8.3%24.0%<0.001

B-17 CARE Trial Details 4,159 post-MI subjects Mean follow-up of 5 years Normal cholesterol Primary endpoint – CHD death or non-fatal MI Randomized to pravastatin 40mg or placebo 83.7% also taking aspirin All Patients Prava 2081 Placebo 2078 Aspirin Users

B-18 CARE Trial Results: CARE Trial Results: Superiority of Combination vs Aspirin Alone * Relative risk reduction based on Cox Proportional Hazards model CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke 21.6%27.4%23.6% Fatal or Non-fatal MI10.1%12.5%20.6% Ischemic Stroke2.0%2.7%28.9% All PatientsN = 2081N = 2078 PlaceboPravaRRR*p value CHD Death or Non-fatal MI10.2%13.2%24.0%0.003 Aspirin UsersN = 1742N = 1735 CHD Death or Non-fatal MI9.3%12.6%28.2%0.001 Placebo (+ASA) Prava (+ASA) RRR*p value All PatientsN = 2081N = 2078 PlaceboPravaRRR*p value CHD Death or Non-fatal MI10.2%13.2%24.0%0.003

B-19 The combination of pravastatin and aspirin is significantly more effective than aspirin alone, as evidenced by randomized comparisons from the secondary prevention trials: LIPID CARE

B-20 Is Pravastatin+Aspirin More Effective than Pravastatin Alone? Aspirin studies were conducted before statins were widely used Placebo-controlled trial with aspirin is not feasible Investigation of pravastatin database to explore this question