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

Conflict of Interest StatementDr. 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 hemorrhageDifficult to use

Only 50% of eligible patients receive warfarin

An alternative treatment is neededC. Michael Gibson, M.S., M.D.

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

DabigatranApixabanRivaroxabanEdoxaban(DU-176b)Betrixaban(PRT054021)TargetIIa (thrombin)XaXaXaXaHrs to Cmax21-32-41-2NRCYP MetabolismNone15%32%NRNoneHalf-Life12-14h8-15h9-13h8-10h19-20hRenal Elimination80%25%66%35%

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

RE-LYROCKET-AFARISTOTLEENGAGE AF-TIMI 48DrugDabigatranRivaroxabanApixabanEdoxabanDose (mg)Freq150, 110BID20 (15*)QD5 (2.5*)BID60*, 30*QDN18,11314,26618,206>21,000DesignPROBE2x blind2x blind2x blindAF criteriaAF x 1< 6 mthsAF x 2(>1 in

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; 20113+87%

RE-LYDabigatran 110 mgDabigatran 150 mgWarfarinCHADS2 Mean 0-1 (%) 2 (%) 3+ (%)2.132.634.732.72.232.235.232.62.130.937.032.1

ROCKET AFRivaroxaban WarfarinCHADS2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%)3.51343291323.5134428122

ARISTOTLERivaroxaban WarfarinCHADS2 Mean 0-1 (%) 2 (%) 3+ (%)2.13435.830.22.13435.830.2

Comparison of Trial MetricsC. 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

RE-LYROCKET AFARISTOTLETime in Therapeutic Range (TTR)64%67% warfarin-experienced61% warfarin-naveMean 55%Median 58%62%

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

ROCKET AFRivaroxaban 20mg1.7% per yearWarfarin2.2% per year

ARISTOTLEApixaban 5 mg1.27% per yearWarfarin1.60% per yearPrimary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis p

Hemorrhagic StrokeDabigatran 110 mg 0.12% / yr0.31

Ischemic StrokeDabigatran 110 mg 1.34% / yr1.200.35Dabigatran 150 mg 0.92% / yr0.760.03

Warfarin 1.20% / yrHRITTP-valueRivaroxaban 20 mg1.62% / yr0.990.92*

Warfarin1.64% / yrROCKET AFRE-LYC. Michael Gibson, M.S., M.D.*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.Aoixaban 5 mg0.97% / yr0.920.42

Warfarin1.05% / yrARISTOTLEPatel 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; 2011Dabigatran now has a superiority labeling for stroke in the US

Ischemic/Unspecified StrokeYears of Follow-up Cumulative Hazard Rates0.00.020.040.060.0800.51.01.52.02.5Dabigatran110Dabigatran150WarfarinDabigatran now has a superiority labeling for stroke in the US

D 110 mg vs. WarfarinD 150 mg vs. WarfarinRR =1.1195% CI = 0.89-1.40P = 0.35RR = 0.7695% CI = 0.60-0.98P = 0.03

Revised US LabelThe 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.

PRADAXA150 mg twice dailyWarfarinHazard ratio vs. warfarin(95% CI)Patients randomized60766022Stroke 1221860.64 (0.51, 0.81) Ischemic stroke1031340.75 (0.58, 0.97) Hemorrhagic stroke12450.26 (0.14, 0.49)Systemic embolism13210.61 (0.30, 1,21)

Dabigatran 110 mg 2.71% / yr0.80.003Dabigatran 150 mg3.11% / yr0.930.31

Warfarin3.36% / yr150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.001.34) p = 0.052Major BleedingHRITTP-valueRE-LYRivaroxaban 20 mg3.60% / yr0.920.58*

Warfarin3.45% / yrROCKETC. Michael Gibson, M.S., M.D.*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.On TreatmentP-value

P-valueApixaban 5 mg2.13% / yr0.69

Post Marketing SurveillanceExcess 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 SurveillanceThe 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 medicineOn 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 MortalityDabigatran 110 mg 3.75% / yr0.91 0.35Dabigatran 150 mg 3.64% / yr0.88 0.051

Warfarin 4.13% / yrHRITTp-valueRivaroxaban 20 mg4.52% / yr0.92 0.152*

Warfarin4.91% / yrROCKETRE-LYC. Michael Gibson, M.S., M.D.*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.Apixaban 5 mg3.52% / yr0.89 0.01

Warfarin3.94% / yrARISTOTLEPatel 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; 201195% CI 0.89 (0.80, 0.998)N=448 events planned, 480 in trial

Japanese RE-LY Data: Baseline CharacteristicsHori M, et al: Circ J 75: 800805, 2011Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

CharacteristicOverallJapanRandomized18,113326Mean age (years)71.571.2Male (%)63.676.7CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) 2.131.935.632.52.231.334.034.7Prior stroke / SEE / TIA(%)21.833.1Prior MI (%)16.65.5CHF (%)32.031.0Baseline ASA (%)39.835.9VKA naive (%)50.456.1

Hori M, et al: Circ J 75: 800805, 2011Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009INR control/ Time in Therapeutic Range For Age >=70 in Japan: INR 2.0-2.6

RegionnINR2.0INR2.0-3.0INR3.0Overall5,78922.264.413.5Japan10836.857.65.6

Stroke or Systemic EmbolismOverallJapanRR 0.90 (95% CI: 0.74-1.10)RR 0.65 (95% CI: 0.52-0.81)RR 0.52 (95% CI: 0.10-2.84)RR 0.25 (95% CI: 0.03-2.27)Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009 Connolly SJ, et al: N Engl J Med 363: 1875-1876, 2010Hori M, et al: Circ J 75: 800805, 2011

Bleeding Events in Japanese Subjects* OverallHori M, et al: Circ J 75: 800805, 2011

Event (yearly rate)110 mg bid (N=107)150 mg bid (N=111)Warfarin(N=108)Major bleeding8 (5.53)*(2.87)5 (3.33)*(3.32)5(3.31)*(3.57)Life threatening1 (0.69)3 (2.00)2 (1.33)Gastrointestinal3 (2.11)1 (0.67)1 (0.67)Intracranial1 (0.69)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)

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.Summary / Japanese patientsHori M, et al: Circ J 75: 800805, 2011

Warfarin20022.5 mg2.5 mg1.5mgnose bleeddementiaStrokedementia2.161.541.362.12.150.912.133.531.350.780.810.871.160.81012342004JanFebMarAprMayOctNovDec2005JanFebMarAprPT-INR2.5 mgdementiaaspirinAge 81 FemaleLiving alone, ADLindependent Chronic AFHT(-), No heart disease, DM(-), LAD 43mm

29th 4,200514th 5,2005Age 81 FemaleLiving alone, ADLindependent Chronic AFHT(-), No heart disease, DM(-), LAD 43mm

mRS by subtype of brain infaction HIROSAKI Stroke and Rehabilitation Centern=768 Oct, 2005Jan, 20080 20 40 60 80 100 (%)0123456No symptomsDeadBedriddenAble to carry out all usual activitiesAble to look after own affairs without assistanceRequires some help, but able to walk unassistedUnable to walk unassistedm-Rankinscale31%54%Lacunarn=215Atherothrombotic infarction n=308Cerebral embolism n=245Ken Okumura, Norihumi Metoki, Jyoji HagiiJapanese Journal of Electrocardiology 2011;31:292-296

ECG on admissionPrevalence of AF among Cerebral embolism patients:267 consecutive patients during 2008-2009HIROSAKI Stroke and Rehabilitation CenterKen Okumura, Norihumi Metoki, Jyoji HagiiJapanese Journal of Electrocardiology 2011;31:292-296

Severity of stroke by AF typeSustained AF VS Paroxysmal AF VS Not defined AFSustainedn=120Paroxysmaln=80Not defined AFn=67Percentage of patients with internal carotid artery stenosis PNSPercentage of patients with mRS = 4,5,6PNS0 20 40 60 80 100%0 20 40 60 80 100%*Patients with acute stroke within 3 hours of onset were treated with tPA

CHADS2 Score and Severity of strokeCHADS2=0,1 Scoren=41 VS CHADS2=2-6 Scoren=1590 20 40 60 80 100%CHADS2=0,1n=41 24177386329341250 20 40 60 80 100%CHADS2=2-6n=159 Percentage of patients with internal carotid artery stenosis PNSPercentage of patients with mRS = 4,5,6PNS

CHADS2(%)The Japanese Society of Electrocardiology J-RHYTHM RegistryCHADS2 Score of registered AF patients (n=7,937)

Graph1

15.7

34.04

27.84

14.41

5.68

2

0.34

Sheet1

0123456

15.734.0427.8414.415.6820.34

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 personyearsof observation; 53% of patients were receiving warfarin treatment. 1092 thromboembolic events, 299 intracranial hemorrhagic eventsNetclinical benefit of patients with Prior Stroke= 2.48% per year Net clinical benefit of warfarin = 0.68% per yearNet Clinical Benefit=(TE rateoff warfarin TE rateon warfarin) 1.5 (ICH rateon warfarin ICH rateoff warfarin)

Intracranial hemorrhage rate0Dabigatran150mg BIDn=38/6,076n=90/6,022Warfarin110mg BIDn=27/6,015DabigatranConnolly SJ, et al.: N Engl J Med 361, 1139-1151, 2009Connolly SJ, et al.: N Engl J Med 363, 1875-1876, 2010Intracranial hemorrhage: Hemorrhagic Stroke (Intracerebral hemorrhage), Subdural hematoma and Subarachnoid hemorrhage

CHADS2 ScoreHeart failure 1pointHypertension 1point75 years old 1pointDiabetes 1pointHistory of cerebral infarction or TIA 2pointsMitral stenosisor mechanical valve 1point2pointsOther risk factorsCardiomyopathy65 to 74 years oldFemale patientsCoronary heart diseaseThyrotoxicosisNon-valvular AFWarfarinINR2.03.0RecommendedWarfarinINR2.0 to 3.0 for < 70 years oldINR1.6 to 2.6 for 70 years old RecommendedDabigatranWarfarinINR2.0 to 3.0 for < 70 years oldINR1.6 to 2.6 for 70 years old ConsideredDabigatranWarfarinINR2.0 to 3.0 for < 70 years oldINR1.6 to 2.6 for 70 years old ConsideredDabigatranRecommendedOgawa S, et al: Circ J 75: 27192721, 2011Urgent Statement on Antithrombotic Therapy of Atrial Fibrillation : JCS Guideline Statement (Aug.2011)

*Over all : calculated from NEJM, 2009, 361, 12************0.76 /90/6022150mg2/0.32 /38/6076110mg2/0.23 /27/6015

150mg2/59110mg2/70