The RE-LY Study: Randomized Evaluation of Long-term anticoagulant therapY

1. The RE-LY Study:Randomized Evaluation of Long-term anticoagulant therapY Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke

2. Atrial Fibrillation and Stroke • AF responsible for 1/6 of all strokes • Warfarin reduces stroke in AF by 64% • significant increase in intracranial and other hemorrhage • Difficult to use • Only 50% of eligible patients receive warfarin • An alternative treatment is needed

3. Dabigatran • Dabigatran Etexilate, a pro-drug, is rapidly converted to dabigatran • 6.5% bioavailability, 80% excreted by kidney • Half-life of 12-17 hours • Phase 2 data identified 220 mg daily and 150 mg BID as viable doses

4. RE-LY: A Non-inferiority Trial Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events. R open Blinded Dabigatran Etexilate 150 mg b.i.d. N=6000 Warfarin (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg b.i.d. N=6000 10 efficacy outcome = stroke or systemic embolism 10 safety outcome = major bleeding Non-inferiority margin 1.46

5. Trial Execution • Performed December 2005-March 2009 • Median Follow up 2.0 years • Follow up 99.9% complete • Mean TTR = 64% (patients on warfarin)

6. Baseline Characteristics

7. # at Risk Year 0.5 1.0 1.5 2.0 2.5 D110 6015 5336 5026 3950 2491 1176 D150 6076 5329 5015 3955 2528 1172 0.4 W 6022 5563 5269 4158 2561 1187 0.3 Dabigatran150 Stopping Rates Dabigatran110 0.2 Warfarin 0.1 0.0 0 0.5 1.0 1.5 2.0 2.5 Years of Follow-up Permanent Discontinuation

8. Non-inferiority Superiority p-value p-value Dabigatran 110 vs. Warfarin <0.001 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Stroke or Systemic Embolism

9. Primary Outcome * These, and all subsequent, p values, are for superiority

10. Stroke Classification

11. No. at Risk 0.05 W 6022 5862 4593 2890 1322 5718 D110 6015 5862 5710 4593 2945 1385 D150 5939 5779 4682 3044 1429 6076 0.04 0.03 Cumulative Hazard Rates Dabigatran110 0.02 Warfarin Dabigatran 150 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 Years Stroke or Systemic Embolism

12. MI, Hospitalization and Death

13. Bleeding and Net Clinical Benefit * stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed

14. Important Sites of Major Bleeding

15. # at Risk Year 0.5 1.0 1.5 2.0 2.5 0.12 D110 6015 5835 5640 4510 2872 1349 D150 6076 5839 5638 4557 2928 1366 W 6022 5801 5600 4474 2797 1269 0.10 Warfarin 0.08 Dabigatran150 Cumulative Hazard Rates 0.06 Dabigatran110 0.04 0.02 0.0 0 0.5 1.0 1.5 2.0 2.5 Years Major Bleeding

16. Dabigatran 150 mg vs. 110 mg

17. 0.04 # at Risk Year 0.5 1.0 1.5 2.0 2.5 D110 6015 5860 5692 4601 2950 1394 D150 6076 5925 5759 4675 3034 1427 W 6022 5858 5708 4592 2906 1331 0.03 Warfarin Cumulative Risk 0.02 Dabigatran110 Dabigatran150 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 Years ALT or AST >3x ULN

18. Common Adverse Events *Occurred more commonly on dabigatran p<0.001

19. Conclusions • Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding • Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding • Both doses markedly reduced intra-cranial and life-threatening hemorrhage • Both doses are free of liver and other major toxicity, although they increase dyspepsia and GI bleeding

20. Conclusions • Both Dabigatran doses offer advantages over warfarin • Dabigatran 150 is more effective and dabigatran 110 has a better safety profile • The availability of two effective doses, with different benefit risk profiles, creates the potential to tailor therapy to individual patient characteristics