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

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

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

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  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 (Boehringer Ingelheim) 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 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

  9. 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

  10. ITT P-value Ischemic Stroke 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

  11. Ischemic/Unspecified Stroke 0.08 0.06 Dabigatran now has a superiority labeling for stroke in the US Dabigatran110 Cumulative Hazard Rates 0.04 Warfarin 0.02 Dabigatran150 0.0 0 0.5 1.0 1.5 2.0 2.5 Years of Follow-up

  12. Revised US Label Thecontributions 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. Major Bleeding 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 Dabigatranvs 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

  14. 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

  15. 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

  16. All Cause Mortality ITT p-value 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 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

  17. 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

  18. 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

  19. Stroke or Systemic Embolism Overall Japan 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) % per year % per year 150mg bid 110mg bid (n=134/6,076) (n=183/6,015) (n=202/6,022) 150mg bid 110mg bid (n=1/111) (n=12/107) (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

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

  21. 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

  22. Age 81 Female（Living alone, ADL：independent ） Chronic AFHT(-),No heart disease, DM(-), LAD 43mm dementia nose bleed dementia dementia Stroke Warfarin（2002～） aspirin 2.5 mg 2.5 mg 2.5 mg 4 1.5mg 3.53 3 2.16 2.15 2.1 2.13 PT-INR 2 1.35 1.54 1.16 1.36 1 0.91 0.87 0.81 0.81 0.78 0 2004 Jan 2005 Jan Feb Mar Apr May Oct Nov Dec Feb Mar Apr

  23. Age 81 Female（Living alone, ADL：independent ） Chronic AFHT(-),No heart disease, DM(-), LAD 43mm） 29th4,2005 14th 5,2005

  24. mRS by subtype of brain infaction（HIROSAKI Stroke and Rehabilitation Center） m-Rankin scale n=768 （Oct, 2005～Jan, 2008） No symptoms 0 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 4 31% 54% Cerebral embolism （n=245） Bedridden 5 Dead 6 020406080100 (%) Ken Okumura, NorihumiMetoki, JyojiHagiiJapanese Journal of Electrocardiology2011;31:292-296

  25. 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 ECG on admission Sustained AF n=120（45%） paroxysmal AF n=80（30%） Ken Okumura, NorihumiMetoki, JyojiHagiiJapanese Journal of Electrocardiology2011;31:292-296

  26. Severity of stroke by AF type Sustained AF VS Paroxysmal AF VS Not defined AF Percentage ofpatients 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

  27. CHADS2Score and Severity of stroke CHADS2=0,1 Score（n=41） VS CHADS2=2-6 Score（n=159） Percentage ofpatients 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%

  28. The Japanese Society of Electrocardiology J-RHYTHM Registry CHADS2 Score of registered AF patients (n=7,937) J-RHYTHM Registry (%) (cases) 100 80 18.2% 60 12.5% Incidence fo stroke National Registry of AF 40 8.5% 5.9% 20 4.0% 2.8% 1.9% 0 CHADS2スコア

  29. Net Clinical Benefit in ATRIA Study (Singer DE, et al. Ann Intern Med 2009;151:297-305) 13559 adults with non-valvularatrial 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 rateoffwarfarin− TE rateonwarfarin) − 1.5 × (ICH rateonwarfarin− ICH rateoffwarfarin)

  30. 0.76 0.32 0.23 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 RR 0.30 （95％ CI: 0.19–0.45） P＜0.001 1.0 0.8 Event rate （% per year） 0.6 RRR 59％ RRR 70％ 0.4 0.2 0 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

  31. Urgent Statement on Antithrombotic Therapyof Atrial Fibrillation : JCS Guideline Statement(Aug.2011) Mitral stenosis or mechanical valve Non-valvular AF Other risk factors Cardiomyopathy 65 to 74 years old Female patients Coronary heart disease Thyrotoxicosis CHADS2Score Heart failure 1point Hypertension 1point ≥75years old 1point Diabetes 1point History of cerebral infarction or TIA 2points ≥2points 1point Recommended Recommended Considered Considered Warfarin INR2.0to 3.0 for < 70 years old INR1.6to 2.6 for ≥ 70 years old Warfarin INR2.0～3.0 Warfarin INR2.0to 3.0 for < 70 years old INR1.6to 2.6 for ≥ 70 years old Warfarin INR2.0to 3.0 for < 70 years old INR1.6to 2.6 for ≥ 70 years old Dabigatran Recommended Dabigatran Dabigatran Ogawa S, et al: Circ J 75: 2719–2721, 2011

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