A-1 Pravastatin-Aspirin Introduction Todd Baumgartner, MD, MPH Vice President Regulatory Sciences Pharmaceutical Research Institute Bristol-Myers Squibb

A-2 June 2001 Original application filed January 18 Initial Cardio-Renal Drugs Advisory Committee Meeting February - May Discussions with FDA on remaining issues May 8 Revised application filed Pravastatin-Aspirin Chronology

A-3 Contents of Original Pravastatin-Aspirin NDA Meta-analysis of 5 secondary prevention trials demonstrating efficacy, safety and independent contribution of individual components Pharmacokinetic study demonstrating no PK interactions

A-4 Pravastatin-Aspirin Advisory Committee – Jan 18, 2002 General agreement …a population could be identified for which the combination product would be indicated …meta-analysis demonstrated individual contribution to the beneficial cardiovascular outcomes in the secondary prevention population …choice of the two doses of aspirin (81mg and 325mg)

A-5 Issues To Be Discussed Today Choice of pravastatin doses to be offered Potential for excessive bleeding should pravastatin- aspirin not be discontinued prior to surgery Potential for inappropriate discontinuation of pravastatin Concern over inappropriate use in a non-indicated population

A-6 Pravastatin-Aspirin Proposed Secondary Prevention Indication Long-term management to reduce the risk of the following cardiovascular events in patients with clinically evident coronary heart disease: Death Non-fatal myocardial infarction Myocardial revascularization procedures Ischemic stroke

A-7 Experts Available to Committee Jerome L. Avorn, MD –Associate Professor of Pharmacoepidemiology, Harvard Medical School Donald A. Berry, PhD –Professor and Chair of Biostatistics, University of Texas, M.D. Anderson Cancer Center Bernard R. Chaitman, MD –Professor of Medicine, St. Louis University Lawrence J. Dacey, MD –Associate Professor of Surgery, Dartmouth – Hitchcock Medical Center, NH

A-8 Experts Available to Committee Charles H. Hennekens, MD, DrPH –Professor of Medicine, Epidemiology and Public Health, University of Miami School of Medicine, FL Thomas A. Pearson, MD, PhD, MPH –Professor and Chair of Community Medicine, University of Rochester, NY Marc A. Pfeffer, MD, PhD –Professor of Medicine, Brigham & Women’s, Boston Eric J. Topol, MD –Chair of Cardiovascular Medicine, Cleveland Clinic

A-9 Agenda Todd Baumgartner, MD, MPH –Introductory remarks Rene Belder, MD –Pravastatin doses and rationale –Aspirin safety considerations –Temporary discontinuation of statin therapy Fred Fiedorek, MD –Pravastatin-aspirin: Context and rationale