C. Michael Gibson, M.S., M.D.

1. Atrial Fibrillation Management Past, Present and Future C. Michael Gibson, M.S., M.D. Harvard Medical School

2. Conflict of Interest Statement Dr. Gibson has received research grant support and consulting monies from all major manufacturers of antithrombin and antiplatelet agents including all sponsors of Factor Xa inhibitors (BMS, Pfizer, Johnson and Johnson, Portola, DSI) and Factor II inhibitors (BoehringerIngelheim) C. Michael Gibson, M.S., M.D.

3. 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 C. Michael Gibson, M.S., M.D.

4. PK/PD of 5 Novel Oral Agents CYP = cytochrome P450; NR = not reported Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010; 4: 7-14 Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22 Ruff CR et al. Am Heart J 2010; 160: 635-41

5. Phase III AF trials *Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

6. 3+ 87% C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

7. Comparison of Trial Metrics C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

8. Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis Non Inferiority p vs warfarin HR RE-LY Dabigatran 110 mg 1.53% / yr0.91<0.001 Dabigatran 150 mg 1.11% / yr 0.66<0.001 Warfarin 1.69% / yr (ITT) ROCKETAF Rivaroxaban 20 mg 1.7% / yr 0.79<0.001 Warfarin 2.2% / yr (Modified ITT) ARISTOTLE Apixaban5 mg 1.27% / yr 0.79<0.001 Warfarin1.60% / yr (ITT) No ITT analysis is available for non-inferiority in ROCKETAF. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

9. Hemorrhagic Stroke ITT p vs warfarin HR RE-LY Dabigatran 110 mg 0.12% / yr 0.31<0.001 Dabigatran 150 mg 0.10% / yr 0.26<0.001 Warfarin 0.38% / yr ROCKETAF Rivaroxaban 20 mg 0.26% / yr 0.590.012* Warfarin 0.44% / yr ARISTOTLE Apixaban5 mg 0.24% / yr 0.51<0.001 Warfarin0.47% / yr *In an on treatment analysis in ROCKET AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

10. Ischemic Stroke ITT p vs warfarin HR RE-LY Dabigatran 110 mg 1.34% / yr 1.200.35 Dabigatran 150 mg 0.92% / yr 0.760.03 Warfarin 1.20% / yr Dabigatran now has a superiority labeling for stroke in the US ROCKETAF Rivaroxaban 20 mg 1.62% / yr 0.990.92* Warfarin 1.64% / yr ARISTOTLE Apixaban5 mg 0.97% / yr 0.920.42 Warfarin1.05% / yr *In an on treatment analysis in ROCKET AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

11. Ischemic/Unspecified Stroke 0.08 0.06 Dabigatran now has a superiority labeling for stroke in the US Cumulative Hazard Rates 0.04 Dabigatran110mg Warfarin 0.02 Dabigatran150mg 0.0 0 0.5 1.0 1.5 2.0 2.5 Years of Follow-up

12. Revised US Label The contributions of components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily was superior in reducing ischemic and hemorrhagic stroked relative to warfarin.

13. 2012 ACCP guidelines for antithrombotic therapy in AF: recommendations for dabigatran • Dabigatran 150 mg BID preferable to dose-adjusted VKA* for: • patients at intermediate or high risk of stroke (CHADS2 ≥1) • secondary prevention of cardioembolic stroke • Dabigatran as an alternative to dose-adjusted VKA or LMWH in patients undergoing elective cardioversion *Target range for international normalized ratio: 2.0–3.0 LMWH = low-molecular-weight heparin; VKA = vitamin K antagonist You JY et al. Chest 2012;141;e531S–e575S

14. 2012 ACCP guidelines for antithrombotic therapy in patients with AF BID = twice daily; TIA = transient ischaemic attack; VKA = vitamin K antagonist *Target range for international normalized ratio: 2.0–3.0 You JY et al. Chest 2012;141;e531S–e575S

15. Major Bleeding ITT p vs warfarin HR RE-LY Dabigatran 110 mg 2.71% / yr 0.80.003 Dabigatran 150 mg 3.11% / yr 0.930.31 Warfarin 3.36% / yr 150 mg Dabigatranvs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052 ROCKETAF Rivaroxaban 20 mg 3.60% / yr 0.920.58* Warfarin 3.45% / yr (On Treatment) 2 g drop *There is no ITT analysis of safety in ROCKETAF. There is no on treatment analysis of safety from RE-LY. ARISTOTLE Apixaban5 mg 2.13% / yr 0.69<0.001 Warfarin3.09% / yr 2 g drop in 24 hours C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

16. Post Marketing Surveillance • Excess bleeding reported in some countries for Dabigatran compared to coumadin. • Most likely this is due to the fact that bleeding with warfarin was expected, and it was not expected with Dabigatran.

17. Post Marketing Surveillance • The EMA found that “the frequency of occurrence of fatal bleedings with Pradaxa seen in post-marketing data was significantly lower than what was observed in the clinical trials that supported the authorisation of the medicine” • “On the basis of the available evidence, the Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of Pradaxa continue to outweigh its risks and that it remains an important alternative to other blood-thinning agents.” http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1

18. All Cause Mortality ITT p vs warfarin HR RE-LY Dabigatran 110 mg 3.75% / yr 0.910.35 Dabigatran 150 mg 3.64% / yr 0.880.051 Warfarin 4.13% / yr ROCKETAF Rivaroxaban 20 mg 4.52% / yr 0.920.152* Warfarin 4.91% / yr ARISTOTLE Apixaban5 mg 3.52% / yr 0.890.01 Warfarin3.94% / yr 95% CI 0.89 (0.80, 0.998) N=448 events planned, 480 in trial *In an on treatment analysis in ROCKET AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

19. Japanese RE-LY Data: Baseline Characteristics Hori M, et al: Circ J 75: 800–805, 2011 Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

20. INR control/ Time in Therapeutic Range For Age >=70 in Japan: INR 2.0-2.6 Hori M, et al: Circ J 75: 800–805, 2011 Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

21. Stroke or Systemic Embolism Overall Japan 5.0 5.0 RR 0.65 (95％ CI: 0.52-0.81) RR 0.25 (95% CI: 0.03-2.27) 4.0 4.0 RR 0.90 (95％ CI: 0.74-1.10) RR 0.52 (95% CI: 0.10-2.84) 3.0 3.0 % per year % per year 2.65 2.0 2.0 1.71 1.54 1.38 1.0 1.0 1.11 0.67 0 0 Dabigatran 150mg bid (n=134/6,076) Dabigatran 110mg bid (n=183/6,015) Warfarin (n=202/6,022) Dabigatran 150mg bid (n=1/111) Dabigatran 110mg bid (n=2/107) Warfarin (n=4/108) Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009 Connolly SJ, et al: N Engl J Med 363: 1875-1876, 2010 Hori M, et al: Circ J 75: 800–805, 2011

22. Bleeding Events in Japanese Subjects * Overall Hori M, et al: Circ J 75: 800–805, 2011

23. Summary / Japanese patients • The demographics of the Japanese subgroup differ from the overall population in prior stroke and MI of RE-LY but the overall risk score is similar. • The stroke and systemic embolism frequencies in the Japanese subgroup are comparable with the overall RE-LY results. • The major bleeding rates of 150mg bid in the Japanese subgroups, are generally consistent with the overall population. • The minor bleeding rates of Japanese subgroups, are higher than the overall population. Hori M, et al: Circ J 75: 800–805, 2011