1. PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22) Disclosure Statement: Dr. Cannon currently receives research grant support from Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He serves as a consultant to AstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and Vertex

2. Background Statin therapy is highly effective vs. placebo in long- term treatment of CHD l Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? l Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than “standard” LDL-C lowering to an average of 95 mg/dL?

3. 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke PROVE IT - TIMI 22: Study Design 2x2 Factorial: Gatifloxacin vs. placebo Double-blind

4. Patient Population Inclusion Criteria: l Hospitalization for acute MI or high-risk unstable angina < 10 d l Total cholesterol < 240 mg/dL (< 200 mg/dL if on Lipid  Rx) l Stabilized (i.e., without ischemia, CHF, post PCI if performed) Major Exclusion Criteria: l Co-morbidity: patient survival < 2 years l Current therapy with simvastatin or atorvastatin 80 mg l Need for, or anticipated use of fibrates or niacin l CABG for treatment of qualifying ACS l Liver disease or unexplained CK elevations l Strong inhibitors of CYP450 3A4 (2 o atorvastatin metabolism)

5. Patient Enrollment by Country Australia A. Tonkin, I. Meridith 18266 Canada J. Rouleau 20349 France A. Castaigne 20132 GermanyH. Darius 2193 Italy G. DeFerrari 1586 SpainJ. Velasco 14102 United Kingdom G. Jackson 20186 United StatesC. Cannon 2212948 Total 3494162 # Sites # Pts # Sites # Pts

6. Top Ten Enrolling Clinical Centers Huntsville Hospital, Huntsville ALW. Haught K. Griffin Fremantle Hospital, Fremantle WAR. Hendriks D. Greenwell Detar Hospital, Victoria, TXH. Chandna D. Holly St. Francis Hospital, Tulsa, OKJ. M. CassidyN. Ritchie Advanced Health Institute, Galax, VAJ. Puma E. Jones Michigan Heart, Ypsilanti, MI J. Bengtson C. Carulli N. Mississippi Medical Center, Tupelo, MSB. BertoletM. Jones Wilford Hall Med Center, Lackland AFB, TXR. Krasuski U. Ward Queen Elizabeth Hospital, Woodville, Sa J. Horowitz R. Prideaux Moses H. Cone Hospital, Greensboro, NCT. Kelly K. Cochran PrincipalResearch Hospital InvestigatorCoordinator

7. TIMI Study Group Eugene Braunwald, MD Brigham and Women’s Hosp. Christopher Cannon, MD Carolyn McCabe, BS Carolyn McCabe, BS Data Coordinating Center Allan Skene PhD. Nottingham Karen Hill Sponsors: Rene Belder, MD Bristol-Myers Squibb Steven Joyal, MD and Sankyo Co. LTD Gabriella Cucinotta Chen-Sheng Lin, PhD Chen-Sheng Lin, PhD Clinical Events Committee: Marc Pfeffer, MD, PhD Trial Organization

8. Baseline Characteristics Atorvastatin 80mgPravastatin 40mg (2099)(2063) Mean Age (years)5858 Male/Female (%)78 / 2278 / 22 History of HTN (%)5149 Current Smoker (%)3637 History of Diabetes (%)1918 History of CHD (%)3739 STEMI / NSTEMI / UA (%)36 / 36 / 2933 / 37 / 30 Prior Statin Use (%)2625 Atorvastatin 80mgPravastatin 40mg (2099)(2063) Mean Age (years)5858 Male/Female (%)78 / 2278 / 22 History of HTN (%)5149 Current Smoker (%)3637 History of Diabetes (%)1918 History of CHD (%)3739 STEMI / NSTEMI / UA (%)36 / 36 / 2933 / 37 / 30 Prior Statin Use (%)2625

9. Concomitant Therapies PCI for initial ACS pre-Rand 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14% PCI for initial ACS pre-Rand 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14%

10. Changes from (Post-ACS) Baseline in Median LDL-C Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline LDL-C (mg/dL) 20 40 60 80 100 120 Rand.30 Days4 Mos.8 Mos.16 Mos.Final Pravastatin 40mg Atorvastatin 80mg 49%  21%  P<0.001 Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) <24h

11. All-Cause Death or Major CV Events in All Randomized Subjects031821242730691215 % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005) 30 25 20 15 10 5 0

12. Events Rates RR Atorva 80 Prava 40 17%1.9% 2.2% 18%6.3% 7.7% 14%12.2% 14.1% 16%22.4%* 26.3%* 30 Days 90 Days 180 Days End of Follow-up Primary Endpoint Over Time Atorvastatin 80mg Better 0.5 0.75 1.0 1.25 1.5 Pravastatin 40mg Better *2-year event rates

13. Reductions in Major Cardiac Endpoints 2 Year Event Rates RR Atorva 80 Prava 40 28%2.2%3.2% 30%1.1%1.4% 13%6.6%7.4% 18% 8.3% 10.0% 14%16.3% 18.8% 29%3.8%5.1% 25% 12.9% 16.7% 0.51.01.5 All-Cause Mortality Death or MI Death/MI/Urg.Revasc MI Revasc > 30 d UA Req Hosp 0.751.25 Atorvastatin 80 mg BetterPravastatin 40 mg Better CHD Death

14. % with Event 031821242730691215 20 15 10 5 0 Months of Follow-up All-Cause Death, Non-Fatal MI, or Urgent Revascularization Pravastatin 40mg 16.7% Atorvastatin 80mg 12.9% 25% RR P = 0.0004

15. Subgroups: Reduction in All-Cause Mortality or Major CV Events All p interaction = NS except as noted Age > 65 Age < 65 Male Female 0.50.751.01.251.5 Diabetes No Diabetes 2 Year Event Rates Atorva 80 Prava 40 23.0%26.2% 20.3%27.0% 28.8%34.6% 21.0%24.6% 28.1%29.5% 20.1%25.0% 27.5%28.9% 20.6%25.5% 21.7% 26.7% 23.1% 26.0% 20.1% 28.2% 23.5% 25.6% Prior Statin No Prior Statin Atorvastatin 80 mg BetterPravastatin 40 mg Better LDL-C < 125 LDL-C > 125 p i = 0.02 HDL-C < 40 HDL-C > 40 % of Pts 78 22 18 82 30 70 25 75 44 56 27 73

16. Liver and Muscle Effects Atorvastatin 80mg Pravastatin 40mg P-value ALT > 3 ULN 3.3% 1.1% <0.001 CK > 3 ULN 1.5% 1.1% 0.24 D/C for Myalgia/CK elevations 3.3% 2.7% 0.23 Atorvastatin 80mg Pravastatin 40mg P-value ALT > 3 ULN 3.3% 1.1% <0.001 CK > 3 ULN 1.5% 1.1% 0.24 D/C for Myalgia/CK elevations 3.3% 2.7% 0.23

17. Summary In patients recently hospitalized within 10 days for an acute coronary syndrome:  “Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005)  Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up  Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

18. PROVE-IT Conclusion Our findings indicate that patients recently hospitalized for an acute coronary syndrome benefit from early and continued lowering of LDL-C to levels substantially below current target levels. Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:15 www.nejm.org M ARCH 8, 2004