Atrial Fibrillation Management Past, Present and Future C. Michael Gibson, M.S., M.D. Atrial Fibrillation Management Past, Present and Future 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 ARISTO TLE 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 2x blind AF criteria AF x 1 < 6 mths AF x 2 (>1 in <30d) AF or AFl x 2 <12 mths < 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 Dabigatran 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 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 Non Inferiorirty p vs warfarin RE-LY Dabigatran 110 mg 1.53% per year Dabigatran 150 mg 1.11% per year Warfarin 1.69% per year ROCKET AF Rivaroxaban 20mg 1.7% per year Warfarin 2.2% per year ARISTOTLE Apixaban 5 mg 1.27% per year Warfarin 1.60% per year ITT Analysis HR = 0.91 p<0.001 HR = 0.66 p<0.001 Modified ITT HR = 0.79 p<0.001 ITT Analysis HR = 0.79 p<0.001 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 ITT P-value RE-LY HR 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 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 ITT P-value 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 Aoixaban 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 0.08 D 110 mg vs. Warfarin D 150 mg vs. Warfarin 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 Dabigatran110 0.04 Warfarin 0.02 Dabigatran150 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)

Major Bleeding RE-LY HR Dabigatran 110 mg 2.71% / yr 0.8 0.003 ITT P-value RE-LY HR 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 On Treatment P-value ROCKET Rivaroxaban 20 mg 3.60% / yr 0.92 0.58* Warfarin 3.45% / yr 2 g drop *There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY. P-value 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 ITT p-value RE-LY HR 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 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 % per year 150mg bid 110mg bid (n=134/6,076) (n=183/6,015) (n=202/6,022) % per year 150mg bid 110mg bid (n=1/111) (n=12/107) (n=4/108) RR 0.65 (95% CI: 0.52-0.81) RR 0.25 (95% CI: 0.03-2.27) RR 0.90 (95% CI: 0.74-1.10) RR 0.52 (95% CI: 0.10-2.84) 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

Age 81 Female（Living alone, ADL：independent ） Chronic AF　HT(-), No heart disease, DM(-), LAD 43mm dementia nose bleed dementia dementia Stroke Warfarin（2002～） 4 2.5 mg 2.5 mg aspirin 1.5mg 2.5 mg 3.53 3 2.16 2.1 2.15 2.13 PT-INR 2 1.35 1.54 1.16 1.36 1 0.91 0.81 0.87 0.81 0.78 2004 Jan 2005 Jan Feb Mar Apr May Oct Nov Dec Feb Mar Apr

Age 81 Female（Living alone, ADL：independent ） Chronic AF　HT(-), No heart disease, DM(-), LAD 43mm） 29th 4,2005 14th 5,2005

mRS by subtype of brain infaction （HIROSAKI Stroke and Rehabilitation Center） m-Rankin scale n=768 （Oct, 2005～Jan, 2008） No symptoms Lacunar （n=215） Able to carry out all usual activities 1 Able to look after own affairs without assistance 2 Atherothrombotic infarction （n=308） Requires some help, but able to walk unassisted 3 Unable to walk unassisted 31% 54% 4 Cerebral embolism （n=245） 5 Bedridden 6 Dead 0　　　 20　　 　40　　 60　　 　80　　 100 (%) Ken Okumura, Norihumi Metoki, Jyoji Hagii　Japanese Journal of Electrocardiology 2011;31:292-296 24

Prevalence of AF among Cerebral embolism patients: 267 consecutive patients during 2008-2009 （HIROSAKI Stroke and Rehabilitation Center） Data from previous Dr & ECG during hospitalization Sustained AF （45%） paroxysmal AF （30%） ECG on admission Ken Okumura, Norihumi Metoki, Jyoji Hagii　Japanese Journal of Electrocardiology 2011;31:292-296 25

Severity of stroke by AF type Sustained AF VS Paroxysmal AF VS Not defined AF Percentage of patients with internal carotid artery stenosis （P＝NS） Percentage of patients with mRS = 4,5,6 （P＝NS） Sustained （n=120） Paroxysmal （n=80） Not defined AF （n=67） 0 20 40 60 80 100% 0 20 40 60 80 100% *Patients with acute stroke within 3 hours of onset were treated with tPA 26

CHADS2 Score and Severity of stroke CHADS2=0,1 Score（n=41） VS CHADS2=2-6 Score（n=159） Percentage of patients with internal carotid artery stenosis （P＝NS） Percentage of patients with mRS = 4,5,6 （P＝NS） CHADS2=0,1（n=41） 9 32 17 24 CHADS2=2-6（n=159） 34 125 73 86 0 20 40 60 80 100% 0 20 40 60 80 100% 27

J-RHYTHM Registry CHADS2スコア J-RHYTHM Registry The Japanese Society of Electrocardiology J-RHYTHM Registry CHADS2 Score of registered AF patients (n=7,937) J-RHYTHM Registry (%) 20 40 60 80 100 (cases) 1.9% 2.8% 4.0% 5.9% 8.5% 12.5% 18.2% Incidence fo stroke National Registry of AF CHADS2スコア

→ 1092 thromboembolic events, 299 intracranial hemorrhagic events Net Clinical Benefit in ATRIA Study (Singer DE, et al. Ann Intern Med 2009;151:297-305) 13559 adults with non-valvular atrial fibrillation at Kaiser Permanente Northern California （ 73 years median age; Male 57%; more than 66000 personyears of observation; 53% of patients were receiving warfarin treatment. ） → 1092 thromboembolic events, 299 intracranial hemorrhagic events Net clinical benefit of warfarin = 0.68% per year Netclinical benefit of patients with Prior Stroke= 2.48% per year Net Clinical Benefit=(TE rateoff warfarin − TE rateon warfarin) − 1.5 × (ICH rateon warfarin − ICH rateoff warfarin)

Intracranial hemorrhage rate Intracranial hemorrhage: Hemorrhagic Stroke (Intracerebral hemorrhage), Subdural hematoma and Subarachnoid hemorrhage RR 0.41 （95％ CI: 0.28–0.60） P＜0.001 0.8 0.6 0.4 0.2 RR 0.30 （95％ CI: 0.19–0.45） 1.0 0.32 0.23 0.76 RRR 59％ 70％ Event rate （% per year） 頭蓋内出血の発現率は、ワルファリン群で0.76％ /年（90/6，022例）であったのに対し、ダビガトラン150mg×2/日群で0.32％ /年（38/6，076例）、ダビガトラン110mg×2/日群で0.23％ /年（27/6，015例）であり、ダビガトランの両群ともにワルファリン群に比べ有意な低下が認められました。 ダビガトラン150mg×2/日群でのリスク低下率は59％、ダビガトラン110mg×2/日群でのリスク低下率は70％でした。 有効性でワルファリンと同等かそれ以上の成績を残した薬剤において、抗凝固薬投与中に最も注意しなくてはならない頭蓋内出血の発現率が減少するという結果は意外であったし、それによりこの薬剤への期待は一層高まったのではないでしょうか。 （参考） 頭蓋内出血の定義： 出血性脳卒中（脳内出血）、クモ膜下出血および硬膜下出血 Dabigatran Dabigatran Warfarin 150mg BID （n=38/6,076） 110mg BID （n=27/6,015） （n=90/6,022） Connolly SJ, et al.: N Engl J Med 361, 1139-1151, 2009 Connolly SJ, et al.: N Engl J Med 363, 1875-1876, 2010

Urgent Statement on Antithrombotic Therapy of Atrial Fibrillation : JCS Guideline Statement (Aug.2011) Mitral stenosis or mechanical valve Non-valvular AF CHADS2 Score Heart failure 1point Hypertension 1point ≥75 years old 1point Diabetes 1point History of cerebral infarction or TIA 2points Other risk factors 　Cardiomyopathy 　65 to 74 years old 　Female patients 　Coronary heart disease 　Thyrotoxicosis ≥2points 1point Recommended Recommended Considered Considered Warfarin INR2.0～3.0 Warfarin INR2.0 to 3.0 for < 70 years old INR1.6 to 2.6 for ≥ 70 years old Warfarin INR2.0 to 3.0 for < 70 years old INR1.6 to 2.6 for ≥ 70 years old Warfarin INR2.0 to 3.0 for < 70 years old INR1.6 to 2.6 for ≥ 70 years old Dabigatran Recommended Dabigatran Dabigatran Ogawa S, et al: Circ J 75: 2719–2721, 2011