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 1

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

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

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 Warfarin (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 10 efficacy outcome = stroke or systemic embolism 10 safety outcome = major bleeding Non-inferiority margin 1.46

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

Baseline Characteristics Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized 6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 30.9 37.0 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Naïve (%) 49.9 49.8 51.4

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

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

Primary Outcome D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Number rate/yr RR 95% CI P* Stroke or systemic Embolism 182 1.5 %/yr 134 1.1 %/yr 199 1.7 %/yr 0.91 0.74-1.11 0.34 0.66 0.53-0.82 <0.001 Stroke 171 1.4 %/yr 122 1.0 %/yr 185 1.6 %/yr 0.92 0.74-1.13 0.41 0.64 0.51-0.81 Systemic Embolism 14 0.1 %/yr 13 19 0.2 %/yr 0.73 0.37-1.46 0.38 0.67 0.33-1.36 0.27 * These, and all subsequent, p values, are for superiority

Stroke Classification D 110mg D 150mg warfarin D 110 mg vs. Warfarin D 150 mg vs. Warfarin Number rate/yr RR 95% CI p Ischemic/ Unspecified 159 1.3 %/yr 111 0.9 %/yr 142 1.2 %/yr 1.11 0.89-1.40 0.35 0.76 0.60-0.98 0.03 Hemorrhagic 14 0.1 %/yr 12 45 0.4 %/yr 0.31 0.17-0.56 <0.001 0.26 0.14-0.49

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

All Intracranial Bleeding Years Cumulative Hazard Rates 0.0 0.01 0.02 0.03 0.04 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150 Warfarin # at Risk Year 0.5 D110 D150 W 6015 5900 5771 4666 3006 1420 6076 5958 5817 4735 3080 1451 6022 5887 5759 4632 2933 1343

Cumulative Hazard Rates Hemorrhagic Stroke Years Cumulative Hazard Rates 0.0 0.01 0.02 0.03 0.04 0.5 1.0 1.5 2.0 2.5 Dabigatran110 Dabigatran150 Warfarin # at Risk Year 0.5 D110 D150 W 6015 5901 5775 4669 3010 1423 6076 5963 5827 4743 3088 1457 6022 5899 5772 4652 2952 1351

MI, Hospitalization and Death D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate RR 95% CI p Myocardial Infarction 0.7% 0.7 % 0.5 % 1.35 0.98-1.87 0.07 1.38 1.00-1.91 0.048 Hospitalization 19.4 % 20.2% 20.8 % 0.92 0.87-0.97 0.003 0.97 0.92-1.03 0.34 Vascular Death 2.4 % 2.3 % 2.7 % 0.90 0.77-1.06 0.21 0.85 0.72-0.99 0.04 Death 3.8 % 3.6 % 4.1 % 0.91 0.80-1.03 0.13 0.88 0.77-1.00 0.05

Bleeding and Net Clinical Benefit 110mg 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate RR 95% CI p Major Bleeding 2.7 % 3.1 % 3.4 % 0.80 0.69-0.93 0.003 0.93 0.81-1.07 0.31 Life-Threatening major 1.2 % 1.5 % 1.8 % 0.68 0.55-0.83 <0.001 0.81 0.66-0.99 0.04 Minor Bleeding 13.2 % 14.8 % 16.4% 0.79 0.74-0.84 0.91 0.85-0.97 0.005 Total Bleeding (Major+Minor) 14.6 16.4 18.2 0.78 0.74-0.83 0.86-0.97 0.002 Net Clinical Benefit* 7.1 % 6.9 % 7.6 % 0.92 0.84-1.02 0.10 0.82-1.00 * stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed

Important Sites of Major Bleeding D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate RR 95% CI p Gastro-intestinal (GI) 1.1 % 1.5 % 1.0 % 1.10 0.86-1.41 0.43 1.50 1.19-1.89 <0.001 Intracranial (ICH) 0.2 % 0.3 % 0.7 % 0.31 0.20-0.47 0.40 0.27-0.60 Major Bleed (non-GI, non-ICH) 1.8 % 0.85 0.70-1.04 0.11 0.87 0.71-1.06 0.16

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

Dabigatran 150 mg vs. 110 mg Dabigatran 110mg Dabigatran 150mg D 150mg vs. D 110 mg Number rate/yr Relative Risk 95% CI p Stroke and systemic embolism 1.5% 1.1 % 0.73 0.58-0.91 0.005 Ischemic/unspecified stroke 1.3 % 0.9 % 0.69 0.54-0.88 0.002 Hemorrhagic stroke 0.1% 0.1 % 0.85 0.39-1.83 0.67 Major Hemorrhage 2.7 % 3.1 % 1.16 1.00-1.34 0.05 GI Major Hemorrhage 1.5 % 1.36 1.09-1.70 0.007 Net Clinical Benefit 7.1 % 6.9 % 0.98 0.89-1.08 0.66

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

Common Adverse Events Adverse events occurring in >5% of any group Dabigatran 110 mg % Dabigatran 150 mg Warfarin Dyspepsia * 11.8 11.3 5.8 Dyspnea 9.3 9.5 9.7 Dizziness 8.1 8.3 9.4 Peripheral edema 7.9 7.8 Fatigue 6.6 6.2 Cough 5.7 6.0 Chest pain 5.2 5.9 Arthralgia 4.5 5.5 Back pain 5.3 5.6 Nasopharyngitis 5.4 Diarrhea 6.3 6.5 Atrial fibrillation Urinary tract infection 4.8 Upper respiratory tract infection 4.7 *Occurred more commonly on dabigatran p<0.001

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

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