1. Double-blind, randomized trial in 4,162 patients with Acute Coronary Syndrome <10 days and Total Cholesterol < 240 mg/dL ASA + Standard Medical Therapy Pravastatin 40 mg qhs Atorvastatin 80 mg qhs Gatifloxacin * Placebo Duration: Mean 2 year follow-up (925 events) Primary Endpoint: Death, MI, Stroke, UA requiring hosp., or revascularization (> 30 days after randomization) Primary Endpoint: Death, MI, Stroke, UA requiring hosp., or revascularization (> 30 days after randomization) PROVE IT (TIMI 22): Study Design * Gatifloxacin 400mg qd X 10 days/month Cannon et al. Am J Card 2002;89:860–861.

2. 200 LDL-C(mg/dL) Placebo LDL-C levels Statin LDL-C levels 4S LIPID CARE Secondary Prevention Trials 31%24%24% HPS 26% PROSPER * 24% Relative Risk Reduction (CHD Death/NFMI): Overview of Degree of LDL-C Lowering, Achieved LDL-C Levels, and Reduction in Clinical Events from Randomized Trials * Only secondary prevention patients included LDL-C  35% 75 100 125 150 175 LDL-C  28% LDL-C  25% LDL-C  35% LDL-C  34%

3. 175 LDL-C(mg/dL) LDL-C >135 (>3.5 mmol) HPS LDL-C Subgroup Analysis 39% Relative Risk Reduction (Major vascular events): HPS: Effects of Fixed Dose Statin by LDL-C Subgroups Placebo LDL-C levels Simvastatin LDL-C levels 50 75 100 125 150 LDL-C 116-135 (3-3.5 mmol) 37% LDL-C < 116 (<3 mmol) 35% LDL-C  35% LDL-C  35% LDL-C  37%

4. 175 150 125 100 75 LDL-C(mg/dL) Baseline LDL-C levels On Statin LDL-C levels Standard Dose Statin Therapy (Pravastatin 40mg) ??? Event Reduction: Is Aggressive LDL-C Lowering More Effective in Reducing Clinical Events?  25-35%  50% Aggressive Statin Therapy (Atorvastatin 80mg)

5. PROVE IT: PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22) Primary Objectives: l To determine if there is clinical equivalence between pravastatin and atorvastatin in reducing major cardiovascular events in patients with ACS AND AND l To determine if the antimicrobial agent gatifloxacin is superior to placebo in reducing major cardiovascular events in patients with ACS Cannon et al. Am J Card 2002;89:860–1.

6. Primary Statin Non-inferiority Comparison: PROVE-IT is designed to determine whether the 2 year CV event rate of pravastatin is ‘clinically equivalent’ to atorvastatin – –‘Clinical equivalence’ declared if the upper 95% CI of relative risk of event rates at 2 years is < 1.17 – –Using Cox proportional Hazard model, hazard ratio (over the entire period of follow-up) of 1.197 leads to a relative risk of 1.17 for events at 2 years. – –Assuming 22% event rate in atorvastatin arm, the greatest absolute difference between pravastatin and atorvastatin that would meet the pre-spcified definition would be 1.2% (eg. atorva 22% vs. prava 23.2%). Cannon et al. Am J Card 2002;89:860-861; Crit Path Cardio 2003;2:150-7.

7. Relative Risk Pravastatin BetterAtorvastatin Better Upper 95% confidence limit of the relative risk between pravastatin and atorvastatin can be no worse than 1.17 at 2 years (1.198 hazard ratio) to demonstrate equivalence Clinical equivalence (& superior) Clinical equivalence 1.01.17 Possible PROVE-IT Outcomes Uncertain No clinical equivalence (& inferior) Secondary Analysis

8. PatientsDurationEndpointsPower* COMPASS 3089 30 days 19280% ASSENT-2 16949 104480% REPLACE 2 6010 30 days 57492% TARGET 5308 32788% * Power calculations are based on number of endpoints and are function of number of patients and trial duration ** relative risk of 1.17 at 2 years = 1.198 hazard ratio of Cox proportional model PROVE-IT4160 2 years 92587% Upper 95%CI 1.50 1.14 1.18 1.47 1.17** Is PROVE-IT Powered Appropriately to Detect Non-Inferiority?

9. PROVE-IT (TIMI 22): What Will it Tell Us? PROVE-IT designed to evaluate ACS patients and determine the 2 year impact of: l Different degrees of LDL-C lowering l Different statins (pravastatin vs atorvastatin) on safety l Continual pulsed antibiotic therapy in patients following an acute coronary syndrome (ACS) l will directly compare efficacy and safety of two statins l strictly defines clinical equivalence l follows 4162 patients for 2 years l is endpoint driven l is adequately powered (>87%)

10. Equivalence Trials l More common in current era of multiple effective therapies l Used to test hypothesis of equivalence between 2 drugs or devices l Must have pre-defined criteria for “non-inferiority”, based on confidence intervals, to ensure adequate power l Definition of equivalence limit is 1) preserves benefit over placebo, or 2) is clinically based difference

11. CME Evaluation form Please go to either: www.clincaltrialresults.org Or directly to: http://www.medmeetings.org/webcasts/eval_091903_CB.php To complete the CME evaluation form and to receive your CME credit.