Standard Medical TherapyStandard Medical Therapy

TRA40 mg + 2.5 mg/d

TRA40 mg + 2.5 mg/d

PlaceboPlacebo

1 EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.2 EP: CV Death/MI/strokeEP: CV Death/MI/stroke1 EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.EP:CV Death/MI/stroke/hosp for RI/urgent coronary revasc.2 EP: CV Death/MI/strokeEP: CV Death/MI/stroke

Double-blindDouble-blindDouble-blindDouble-blind

Patients with high-risk Non-ST-Segment Elevation Acute Patients with high-risk Non-ST-Segment Elevation Acute Coronary Syndrome Coronary Syndrome <<24h of symptoms24h of symptoms

Patients with high-risk Non-ST-Segment Elevation Acute Patients with high-risk Non-ST-Segment Elevation Acute Coronary Syndrome Coronary Syndrome <<24h of symptoms24h of symptoms

N=10,000N=10,000N=10,000N=10,000

Follow-Up Day 30; 4, 8, 12 Months; Every 6 months after 1st year

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

Duration: >1 year follow-up; >2334 1 EP and >1457 key 2 EP events

1:11:1

TRA•CER Study DesignTRA•CER Study Design

TRA ProgramTRA Program

Primary EP: Composite of CV Death, MI, Stroke, Primary EP: Composite of CV Death, MI, Stroke, Recurrent Ischemia with Rehosp, Recurrent Ischemia with Rehosp,

Urgent Coronary RevascularizationUrgent Coronary Revascularization

Primary EP: Composite of CV Death, MI, Primary EP: Composite of CV Death, MI, Stroke and Urgent RevascularizationStroke and Urgent Revascularization

F/U: 30 Days, 4, 8, 12 months and 6 months thereafter1 yr minimum, event driven

SCH530348 SCH530348Placebo Placebo

TRA ProgramTRA Program29,500 patients29,500 patients

Age Distribution of People With AFAge Distribution of People With AFCompared With U.S. General PopulationCompared With U.S. General Population

Arch Int Med. 1995;155:471.

Age (years)

Population withAtrial Fibrillation

U.S. Population

U.S

. P

op

ula

tio

n (

x 10

00)

5–95–9<5 10–14

15–1920–24

25–2930–34

35–3940–44 50–54 60–64 70–74 80–84 90–94

45–49 55–59 65–69 75–79 85–89 >95

AF

Po

pu

lati

on

(x

10)

0

10.000

20,000

30,000

0

100

200

300

400

500

Warfarin for Atrial FibrillationWarfarin for Atrial FibrillationLimitations Lead to Under-treatmentLimitations Lead to Under-treatment

0

20

40

60

80

<55<55 55-6455-64 65-7465-74 75-8475-84 8585

44%44%

58%58%61%61%

57%57%

35%35%

Age (years)Age (years)

Wa

rfa

rin

Us

e in

Wa

rfa

rin

Us

e in

Elig

ible

Pat

ien

ts (

%)

Elig

ible

Pat

ien

ts (

%) 55% 55%

Overall Overall UseUse

Go A et al. Go A et al. Ann Intern MedAnn Intern Med 1999;131:927. 1999;131:927.

WarfarinWarfarinBattling All Comers for Over a DecadeBattling All Comers for Over a Decade

Warfarin vs placeboWarfarin vs placebo

Warfarin vs ASAWarfarin vs ASA

Warfarin vs ASA + fixed dose wafarinWarfarin vs ASA + fixed dose wafarin

Warfarin vs DTIWarfarin vs DTI

Warfarin vs dual antiplateletWarfarin vs dual antiplatelet

RELYDabigatran for stroke prevention in atrial fibrillation

Non-valvular atrial fibrillation at moderateto high risk of stroke or systemic embolism

(at least one high risk factor)

R

Warfarin1 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

Atrial Fibrillation with At Least One Additional Risk Factor for Stroke

Apixaban placebo twice dailyApixaban placebo twice daily++

Warfarin (target INR 2-3)Warfarin (target INR 2-3)

Apixaban 5 mg oral twice dailyApixaban 5 mg oral twice daily++

Warfarin placeboWarfarin placebo

Primary outcome: stroke and systemic embolismPrimary outcome: stroke and systemic embolism

Other outcomes: Death, MI, bleedingOther outcomes: Death, MI, bleedingStratified by warfarin-naïve statusStratified by warfarin-naïve status

448 events over anticipated 2 year median follow-up; 448 events over anticipated 2 year median follow-up; >90% power to show non-inferiority >90% power to show non-inferiority

(apixaban vs warfarin upper bound of 95% CI <1.38)(apixaban vs warfarin upper bound of 95% CI <1.38)

RandomizeRandomizeDouble blindDouble blind(n = 15,000)(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

ARISTOTLE

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 daily15 mg for Cr Cl 30-

49

Atrial Fibrillation

RandomizeDouble blind / Double Dummy

(n ~ 14,000)

Risk FactorsRisk Factors• CHF CHF • Hypertension Hypertension • Age Age 75 75 • Diabetes Diabetes OROR• Stroke, TIA or Systemic Stroke, TIA or Systemic

embolus embolus

At least 2 At least 2 requiredrequired

Monthly Monitoring and adherence to standard of care guidelines