1. Standard Medical Therapy TRA 40 mg + 2.5 mg/d TRA 40 mg + 2.5 mg/d Placebo EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc. 1  EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc. EP: CV Death/MI/stroke 2  EP: CV Death/MI/stroke EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc. 1  EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc. EP: CV Death/MI/stroke 2  EP: CV Death/MI/stroke Double-blindDouble-blind Patients with high-risk Non-ST-Segment Elevation Acute Coronary Syndrome <24h of symptoms N=10,000N=10,000 Follow-Up Day 30; 4, 8, 12 Months; Every 6 months after 1st year Duration: >1 year follow-up; >2334 1  EP and >1457 key 2  EP events 1:1 TRACER Study Design

2. TRA Program Primary EP: Composite of CV Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revascularization Primary EP: Composite of CV Death, MI, Stroke and Urgent Revascularization F/U: 30 Days, 4, 8, 12 months and 6 months thereafter 1 yr minimum, event driven SCH530348 Placebo TRA Program 29,500 patients

4. Age Distribution of People With AF Compared With U.S. General Population Arch Int Med. 1995;155:471. Age (years) Population with Atrial Fibrillation U.S. Population U.S. Population (x 1000) 5–9 <5 10–14 15–19 20–24 25–29 30–34 35–39 40–4450–5460–6470–7480–8490–94 45–4955–5965–6975–7985–89>95 AF Population (x 10) 0 10.000 20,000 30,000 0 100 200 300 400 500

5. Warfarin for Atrial Fibrillation Limitations Lead to Under-treatment <5555-6465-7475-84  85 44% 58% 61% 57% 35% Age (years) Warfarin Use in Eligible Patients (%) 55% Overall Use Go A et al. Ann Intern Med 1999;131:927.

6. Warfarin Battling All Comers for Over a Decade  Warfarin vs placebo  Warfarin vs ASA  Warfarin vs ASA + fixed dose wafarin  Warfarin vs DTI  Warfarin vs dual antiplatelet

7. RELY Dabigatran for stroke prevention in atrial fibrillation Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism (at least one high risk factor) R Warfarin 1 mg, 3mg, 5 mg (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg b.i.d. N=6000 Dabigatran Etexilate 150 mg b.i.d. N=6000 Primary objective: Noninferiority to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up. Primary end point: Stroke + systemic embolism

8. Atrial Fibrillation with At Least One Additional Risk Factor for Stroke Apixaban placebo twice daily + Warfarin (target INR 2-3) Apixaban 5 mg oral twice daily + Warfarin placebo Primary outcome: stroke and systemic embolism Other outcomes: Death, MI, bleeding Stratified by warfarin-naïve status 448 events over anticipated 2 year median follow-up; >90% power to show non-inferiority (apixaban vs warfarin upper bound of 95% CI <1.38) Randomize Double blind (n = 15,000)  Age ≥ 75 years  Prior stroke, TIA or SE  CHF or LVEF ≤ 40%  Diabetes mellitus  Hypertension  Age ≥ 75 years  Prior stroke, TIA or SE  CHF or LVEF ≤ 40%  Diabetes mellitus  Hypertension Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device ARISTOTLE

9. 9 Rivaroxaban Warfarin Primary Endpoint: Stroke or non-CNS Systemic Embolism Statistics : non-inferiority, >95% power, 2.3% warfarin event rate INR target - 2.5 (2.0-3.0 inclusive) 20 mg daily 15 mg for Cr Cl 30-49 Atrial Fibrillation Randomize Double blind / Double Dummy (n ~ 14,000) Risk Factors CHF CHF Hypertension Hypertension Age  75 Age  75 Diabetes DiabetesOR Stroke, TIA or Systemic embolus Stroke, TIA or Systemic embolus At least 2 required Monthly Monitoring and adherence to standard of care guidelines