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

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 (Boehringer Ingelheim) C. Michael Gibson, M.S., M.D.

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.

PK/PD of 5 Novel Oral Agents Dabigatran Apixaban Rivaroxaban Edoxaban (DU-176b) Betrixaban (PRT054021) Target IIa (thrombin) Xa Hrs to Cmax 2 1-3 2-4 1-2 NR CYP Metabolism None 15% 32% Half-Life 12-14h 8-15h 9-13h 8-10h 19-20h Renal Elimination 80% 25% 66% 35% <5% 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

Phase III AF trials RE-LY ROCKET AF ARISTOTLE ENGAGE AF-TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban Dose (mg) Freq 150, 110 BID 20 (15*) QD 5 (2.5*) 60*, 30* N 18,113 14,266 18,206 >21,000 Design PROBE 2 x blind AF criteria AF x 1 <6 mths AF x 2 (≥ 1 in <30d) AF or AFI x 2 <12 mths % VKA naive 50% 38% 43% 40% goal *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

RE-LY ROCKET AF ARISTOTLE Dabigatran 110 mg 150 mg Warfarin CHADS2 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 ROCKET AF Rivaroxaban Warfarin CHADS2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.5 13 43 29 2 44 28 12 3+ 87% ARISTOTLE Rivaroxaban Warfarin CHADS2 Mean 0-1 (%) 2 (%) 3+ (%) 2.1 34 35.8 30.2 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

Comparison of Trial Metrics 67% warfarin-experienced RE-LY ROCKET AF ARISTOTLE Time in Therapeutic Range (TTR) 64% 67% warfarin-experienced 61% warfarin-naïve Mean 55% Median 58% 62% 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

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis p vs warfarin HR RE-LY 　Dabigatran 110 mg 1.53% / yr 0.91 <0.001 　Dabigatran 150 mg 1.11% / yr 0.66 <0.001 　Warfarin 1.69% / yr (ITT) ROCKET AF 　Rivaroxaban 20 mg 1.7% / yr 0.79 <0.001 　Warfarin 2.2% / yr (Modified ITT) ARISTOTLE 　Apixaban 5 mg 1.27% / yr 0.79 <0.001 　Warfarin 1.60% / yr (ITT) No ITT analysis is available for non-inferiority in ROCKET AF. 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

Hemorrhagic Stroke RE-LY Dabigatran 110 mg 0.12% / yr 0.31 <0.001 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 ROCKET AF 　Rivaroxaban 20 mg 0.26% / yr 0.59 0.012* 　Warfarin 0.44% / yr ARISTOTLE 　Apixaban 5 mg 0.24% / yr 0.51 <0.001 　Warfarin 0.47% / 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

Ischemic Stroke RE-LY Dabigatran 110 mg 1.34% / yr 1.20 0.35 ITT p vs warfarin HR RE-LY 　Dabigatran 110 mg 1.34% / yr 1.20 0.35 　Dabigatran 150 mg 0.92% / yr 0.76 0.03 　Warfarin 1.20% / yr Dabigatran now has a superiority labeling for stroke in the US ROCKET AF 　Rivaroxaban 20 mg 1.62% / yr 0.99 0.92* 　Warfarin 1.64% / yr ARISTOTLE 　Apixaban 5 mg 0.97% / yr 0.92 0.42 　Warfarin 1.05% / 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

Ischemic/Unspecified Stroke Cumulative Hazard Rates 0.08 Dabigatran 110 mg vs. Warfarin Dabigatran 150 mg RR =1.11 95% CI = 0.89-1.40 P = 0.35 RR = 0.76 95% CI = 0.60-0.98 P = 0.03 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 0.5 1.0 1.5 2.0 2.5 Years of Follow-up

Hazard ratio vs. warfarin 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. PRADAXA　 150 mg twice daily Warfarin Hazard ratio vs. warfarin (95% CI) Patients randomized 6076 6022 Stroke 122 186 0.64 (0.51, 0.81) Ischemic stroke 103 134 0.75 (0.58, 0.97) Hemorrhagic stroke 12 45 0.26 (0.14, 0.49) Systemic embolism 13 21 0.61 (0.30, 1,21)

Dabigatran 150 mg BID preferable to dose- adjusted VKA* for: 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

2012 ACCP guidelines for antithrombotic therapy in patients with AF Patient features Recommended antithrombotic therapy Low risk of stroke (e.g. CHADS2 = 0) None (rather than antithrombotic therapy) Intermediate risk of stroke (e.g. CHADS2 = 1) Oral anticoagulation (rather than no therapy, Aspirin, or Aspirin + clopidogrel) Dabigatran 150 mg BID (rather than dose-adjusted VKA*) High risk of stroke (e.g. CHADS2 = 2) Previous stroke/TIA 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

Major Bleeding RE-LY Dabigatran 110 mg 2.71% / yr 0.8 0.003 ITT p vs warfarin HR RE-LY 　Dabigatran 110 mg 2.71% / yr 0.8 0.003 　Dabigatran 150 mg 3.11% / yr 0.93 0.31 　Warfarin 3.36% / yr 150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052 ROCKET AF 　Rivaroxaban 20 mg 3.60% / yr 0.92 0.58* 　Warfarin 3.45% / yr (On Treatment) 2 g drop *There is no ITT analysis of safety in ROCKET AF. There is no on treatment analysis of safety from RE-LY. ARISTOTLE 　Apixaban 5 mg 2.13% / yr 0.69 <0.001 　Warfarin 3.09% / 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

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.

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

All Cause Mortality RE-LY Dabigatran 110 mg 3.75% / yr 0.91 0.35 ITT p vs warfarin HR RE-LY 　Dabigatran 110 mg 3.75% / yr 0.91 0.35 　Dabigatran 150 mg 3.64% / yr 0.88 0.051 　Warfarin 4.13% / yr ROCKET AF 　Rivaroxaban 20 mg 4.52% / yr 0.92 0.152* 　Warfarin 4.91% / yr ARISTOTLE 　Apixaban 5 mg 3.52% / yr 0.89 0.01 　Warfarin 3.94% / 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

Japanese RE-LY Data: Baseline Characteristics Overall Japan Randomized 18,113 326 Mean age (years) 71.5 71.2 Male (%) 63.6 76.7 CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) 2.1 31.9 35.6 32.5 2.2 31.3 34.0 34.7 Prior stroke / SEE / TIA(%) 21.8 33.1 Prior MI (%) 16.6 5.5 CHF (%) 32.0 31.0 Baseline ASA (%) 39.8 35.9 VKA naive (%) 50.4 56.1 Over all : calculated from NEJM, 2009, 361, 12 Hori M, et al: Circ J 75: 800–805, 2011 Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

INR control / Time in Therapeutic Range Region n INR＜2.0 INR2.0-3.0 INR＞3.0 Overall 5,789 22.2％ 64.4％ 13.5％ Japan 108 36.8％ 57.6％ 5.6％ 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

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 1.11 1.0 0.67 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

Bleeding Events in Japanese Subjects Event (yearly rate) 110 mg bid (N=107) 150 mg bid (N=111) Warfarin (N=108) Major bleeding 8 (5.53) *(2.87) 5 (3.33) *(3.32) 5(3.31) *(3.57) Life threatening 1 (0.69) 3 (2.00) 2 (1.33) Gastrointestinal 3 (2.11) 1 (0.67) Intracranial 1 ( 0.67) 1 (0.66) Minor bleeding 35 (24.19) *(13.16) 50 (33.26) *(14.85) 50 (33.14) *(16.37) Any bleeding (major or minor) 40 (27.64) *(14.74) 52 (34.59) *(16.56) 51 (33.81) *(18.37) * Overall Hori M, et al: Circ J 75: 800–805, 2011

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