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.

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% LDL-C  28% LDL-C  25% LDL-C  35% LDL-C  34%

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 LDL-C (3-3.5 mmol) 37% LDL-C < 116 (<3 mmol) 35% LDL-C  35% LDL-C  35% LDL-C  37%

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)

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.

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 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: ; Crit Path Cardio 2003;2:150-7.

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 Possible PROVE-IT Outcomes Uncertain No clinical equivalence (& inferior) Secondary Analysis

PatientsDurationEndpointsPower* COMPASS days 19280% ASSENT % REPLACE days 57492% TARGET % * 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 = hazard ratio of Cox proportional model PROVE-IT years 92587% Upper 95%CI ** Is PROVE-IT Powered Appropriately to Detect Non-Inferiority?

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%)

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

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