Update in ESC: Dabigatran among OAC Department of Cardiology, Hirosaki University Graduate School of Medicine, Japan Professor, Ken Okumura 1

Age 81 Female (Living alone, ADL: independent ) Chronic AF　HT(-), No heart disease, DM(-), LAD 43mm dementia nose bleed dementia dementia Stroke Warfarin (2002~) 2.5mg 2.5mg aspirin 2.5mg 1.5mg 4 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 0.78 0.81 0.87 0.81 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) n=768 (Oct, 2005~Jan, 2008) m-Rankin scale 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 20 40 60 80 100 (%) Ken Okumura, Norihumi Metoki, Jyoji Hagii　Japanese Journal of Electrocardiology 2011;31:292-296 4

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 AF(-) n=67 (25%) AF(-) n=128 (48%) AF(+) n=139 (52%) Sustained AF n=120 (45%) paroxysmal AF n=80 (30%) Ken Okumura, Norihumi Metoki, Jyoji Hagii　Japanese Journal of Electrocardiology 2011;31:292-296 5

Severity of stroke by AF type Sustained AF vs Paroxysmal AF vs Not defined AF (HIROSAKI Stroke and Rehabilitation Center) Percentage of patients with internal carotid artery stenosis (P＝NS) Percentage of patients with mRS = 4,5,6 (P＝NS) Sustained (n=120) 23 97 57 63 Paroxysmal (n=80) 12 68 33 47 Not defined AF (n=67) 9 58 25 42 20 40 60 80 100 (%) 20 40 60 80 100 (%) *Patients with acute stroke within 3 hours of onset were treated with tPA 6

CHADS2 Score and Severity of stroke CHADS2=0,1 Score (n=41) vs CHADS2=2-6 Score (n=159) (HIROSAKI Stroke and Rehabilitation Center) 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 20 40 60 80 100 (%) 20 40 60 80 100 (%) 7

J-RHYTHM Registry J-RHYTHM Registry The Japanese Society of Electrocardiology J-RHYTHM Registry CHADS2 Score of registered AF patients (n=7,937) J-RHYTHM Registry J-RHYTHM Registry (%) 35 30 20 40 60 80 100 (cases) 25 20 1.9% 2.8% 4.0% 5.9% 8.5% 12.5% 18.2% Incidence for stroke National Registry of AF 15 10 5 1 2 3 4 5 6 CHADS2 Score

Net Clinical Benefit in ATRIA Study (Singer DE, et al. Ann Intern Med 2009;151:297-305) 13,559 adults with non-valvular atrial fibrillation at Kaiser Permanente Northern California (73 years median age; Male 57%; more than 66,000 person-years of observation; 53% of patients were receiving warfarin treatment.) → 1,092 thromboembolic events, 299 intracranial hemorrhagic events 2.22 4-6 0.58 3.75 2.07 3 1.21 2.79 0.97 CHADS2 score 2 0.43 1.41 0.19 Net clinical benefit of warfarin = 0.68%/yr Net clinical benefit of patients with Prior Stroke = 2.48%/yr 1 -0.27 0.45 -0.11 -0.44 0.20 -1 -0.5 0.5 1 1.5 2 2.5 3 3.5 Worse with Warfarin Better with Warfarin Net Clinical Benefit ＝(TE rate off warfarin −TE rate on warfarin) − 1.5 x (ICH rate on 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 RR 0.30 (95% CI: 0.19–0.45) P<0.001 1.0 Event rate (% per year) 0.8 0.76 0.6 RRR 59% 0.4 RRR 70% 0.32 0.2 0.23 Dabigatran 150mg bid (n=38/6,076) Dabigatran 110mg bid (n=27/6,015) Warfarin (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

INR2.0 to 3.0 for < 70 years old Urgent Statement on Antithrombotic Therapy of Atrial Fibrillation : JCS Guideline Statement (Aug.2011) CHADS2 Score Heart failure 1point Hypertension 1point ≥75 years old 1point Diabetes 1point History of cerebral infarction or TIA 2points Mitral stenosis or mechanical valve 1point ≥2points Other risk factors 　Cardiomyopathy 　65 to 74 years old 　Female patients 　Coronary heart disease 　Thyrotoxicosis Non-valvular AF Warfarin INR2.0~3.0 Recommended INR2.0 to 3.0 for < 70 years old INR1.6 to 2.6 for ≥ 70 years old Dabigatran Considered JCS: Urgent Statement 2011　http://www.j-circ.or.jp/guideline/pdf/statement.pdf