Stroke Prevention in AF : Old and New. Disclosure

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1 Stroke revention in AF : Old and New Michael D. Ezekowitz, MBChB, Dhil, FACC, FAHA, FRC, MA rofessor, Thomas Jefferson Medical School Director Atrial Fibrillation Research and Education The Cardiovascular Research Foundation NY Lankenau Medical Center Disclosure Michael D. Ezekowitz, MBChB, Dhil, FACC, FAHA, FRC, MA Consultant: ARYx Therapeutics, AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Medtronic, ortola, sanofiaventis, Merck, fizer, J&J, Coherex Gilead, St Jude Medical Grants: ARYx Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, ortola, sanofi-aventis CO-I etro and RELY : Executive committee Engage AF: CO-I Explore Xa :Co- I Evert : I Hestia and ascal Left atrial appendage thrombus migration captured by TEE (arekh Ezekowitz Circ 6 ) A modified Model D Olympus fiberoptic gastroscope. =attachment to Varian 2-dimensional echocardiograph; 2=mechanism for up and down and lateral movement of gastroscope tip; = gastroscope tip to which is attached a.5 m Hz transducer. Maximum width of tip is.2 cm. Michael D. Ezekowitz, et al. Left atrial mass: Diagnostic of transesophageal 2-dimensional echocardiography and indium- platelet scintigraphy Am J Cardiol 98;5:56-6

2 Bottom Line : Which Drug to use when? All Clinical trials involving Novel agents superseded expectations None were stopped prematurely Head to head comparisons only method of true comparison Stroke Risk Stratification in AF WARFARIN ERA Completed Studies: vs. lacebo CHADS 2 Risk Factor Score Cardiac failure HTN Age 75 years Diabetes Stroke 2 CHA 2 DS 2 -VASc Risk Factor Score Cardiac failure HTN Age 75 years 2 Diabetes Stroke 2 Vascular disease (MI, peripheral arterial disease, aortic atherosclerosis) Age 65-7 years Sex category (female) HTN = hypertension; MI = myocardial infarction Annual Risk of Stroke (%) CHADS 2 CHA 2 DS 2 -VASc Total Score AFASAK: eterson et al Lancet 989;:75 BAATAF: Investigators NEJM 99;2;55 SAF: Investigators Stroke 99;2:58 SINAF: Ezekowitz et al NEJM 992;27:6 % 5% % -5% -% worse # Events t-yrs Lip GY, et al. Am J Med. 2;2(6):8-88. Camm AJ, et al. Eur Heart J. 2:;

3 Country-Based Variation in TTR Mean % time in therapeutic INR range hysicians more influenced by events induced (bleeds) than those prevented (strokes) The decision to use warfarin in NVAF is driven by perceived risks (intracerebral bleeds) Gross C, Vogel EW, Dhond, AJ, Marple CB, Edwards RA, Hauch O, Demers EA, Ezekowitz MD. Factors Influencing hysician Use of Anticoagulation in Atrial Fibrillation. Submitted to Clinical Therapeutics 2;25: No 6. 9 New Agents for Stroke revention in Non valvular AF Stroke revention in AF : Less Antiplatelet agents and VKAs Anticoagulants Antiplatelet agents Non-antithrombotic drugs VKAs Novel anticoagulants Aspirin ± Clopidogrel AntiHTN Statins Antiarrhythmic Non-warfarin VKAs Tecarfarin Direct thrombin s Ximelagatran Dabigatran Factor X s Apixaban Betrixaban Edoxaban Rivaroxaban 2

4 Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban Mechanism of action Thrombin Factor Xa Factor Xa Factor Xa Factor Xa T /2-7 hours 5- hours 2 hours 9-2 hours 6-2 hours Regimen BID QD, BID BID QD QD eak to trough 2 2 (QD) -5 ~ ~ Renal excretion of absorbed drug otential for drug interactions ~8% 6%-5% 25%-% ~5% 5% -glycoprotein CYA = cytochrome 5 A. Characteristics of New Oral Anticoagulants CYA substrate and -glycoprotein CYA substrate and -glycoprotein Not substrate for major CYs CYA substrate and -glycoprotein Usman MH.. Ezekowitz : Curr Treat Cardiovasc Med. 28;(5): iccini J, et al. Curr Opin Cardiol. 2;25():2-2. Stroke Risk Stratification in AF CHADS 2 Risk Factor Score Cardiac failure HTN Age 75 years Diabetes Stroke 2 CHA 2 DS 2 -VASc Risk Factor Score Cardiac failure HTN Age 75 years 2 Diabetes Stroke 2 Vascular disease (MI, peripheral arterial disease, aortic atherosclerosis) Age 65-7 years Sex category (female) HTN = hypertension; MI = myocardial infarction. Lip GY, et al. Am J Med. 2;2(6):8-88. Camm AJ, et al. Eur Heart J. 2:; Annual Risk of Stroke (%) CHADS 2 CHA 2 DS 2 -VASc Total Score Dabigatran 5 mg (no monitoring ) vs TTR 6% (Event Rate, %/year) Efficacy Outcomes Dabigatran Stroke/Systemic Embolism..69 Stroke..57 Ischemic Stroke.92.2 Hemorrhagic Stroke..8 MI.7.5 All-Cause Mortality.6. Safety Outcomes Major Bleeding..6 ICH..7 Major GI Bleeding.5.2 Dabigatran mg vs TTR 6% (Event Rate, %/year) Efficacy Outcomes Dabigatran Stroke/Systemic Embolism.5.69 Stroke..57 Ischemic Stroke..2 Hemorrhagic Stroke.2.8 MI.72.5 All-Cause Mortality.75. Safety Outcomes Major Bleeding ICH.2.7 Major GI Bleeding Dabigatran Connolly SJ,Ezekowitz MD et al. N Engl J Med. 29;6(2): Dabigatran Connolly SJ,Ezekowitz MD et al. N Engl J Med. 29;6(2):9-5.

5 Adverse Events 5% of atients Safety Set MedDRA preferred term DE N (%) DE 5 N (%) N (%) atients, N Total with AEs 7 (78.6) 76 (78.) 55 (75.9) Dizziness 57 (7.6) 58 (7.6) 55 (9.2) Atrial fibrillation (5.) (5.2) 27 (5.5) Dyspnea 98 (8.) 526 (8.7) 55 (9.2) Edema 6 (7.5) 2 (7.) 5 (7.6) Dyspepsia 68 (6.2) 5 (5.7) 8 (.) Fatigue 7 (6.2) 67 (6.) 5 (5.9) Diarrhea 55 (5.9) 67 (6.) 28 (5.5) Chest ain 287 (.8) 55 (5.9) 2 (5.7) Cough 2 (5.) (5.) 6 (5.8) Nasopharyngitis 5 (5.) 9 (5.) 27 (5.5) Arthralgia 28 (.) (5.2) 29 (5.5) Back pain 295 (.9) 289 (.8) (5.5) Urinary tract infection 22 (.) 252 (.2) 6 (5.) Upper respiratory tract inf 266 (.) 262 (.) 297 (5.) 7 ROCKET AF Trial: Rivaroxaban Nonvalvular AF, history of stroke, TIA, or embolism or at least 2 of the following: HF, HTN, age 75 years, or diabetes mellitus R Day Treatment period 2-2 months Rivaroxaban 2 mg QD Rivaroxaban 5 mg QD (creatinine clearance -9 ml/min at entry) N =,26 target INR, 2.5 (INR range, 2.-.) End of treatment Follow-up Day after last dose rimary study endpoint: composite of all-cause stroke and non- CNS systemic embolism rimary safety endpoint: composite of major and clinically relevant nonmajor bleeding events ROCKET = Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted- Dose Oral for the revention of Stroke in Subjects with Non-Valvular Atrial Fibrillation; CNS = central nervous system. ROCKET AF Study Investigators. Am Heart J. 2;59():-7.e. ROCKET AF: Rivaroxaban (no monitoring )vs TTR 55% Efficacy Outcomes Stroke/Systemic Embolism Stroke Ischemic Stroke Hemorrhagic Stroke Myocardial Infarction All-Cause Mortality Safety Outcomes ICH Major Bleeding Major GI Bleeding Major + CRNM Bleeding Courtesy of MD Ezekowitz. Mahaffey KW. resented at AHA, November 2. atel M et al. N Engl J Med. 2;65: Rivaroxaban Hazard Ratio Mean CHADS 2 score =.5.5% vs 2.6%, <. AF or atrial flutter patients with risk factor 8,26 ARISTOTLE Trial: Apixaban E R Double-blind INR, 2.-. Apixaban (5 mg BID; 2.5 mg BID in selected patients*) Noninferior trial º efficacy endpoint: confirmed ischemic or hemorrhagic stroke, or systemic embolism º safety endpoint: time to first occurrence of confirmed major bleeding Follow-up: up to years Stratified by warfarin-naïve status *At least 2 of the following: age 8 years, weight 6 kg, or serum creatinine.5 mg/dl. ARISTOTLE = Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation. Lopes RD, et al. Am Heart J. 2;59():-9. 5

6 Apixaban (no monitoring ) vs TTR 62% ENGAGE AF TIMI 8: Edoxaban (Event Rate, %/year) Efficacy Outcomes Apixaban Stroke/Systemic Embolism.27.6 Stroke.9.5 Ischemic Stroke.97.5 Hemorrhagic Stroke.2.7 MI.5.6 All-Cause Mortality.52.9 Safety Outcomes ISTH Major Bleeding 2..9 ICH..8 Major GI Bleeding AF patients with CHADS 2 score 2, >2, E Noninferior trial Double-blind º efficacy endpoint: composite primary endpoint of stroke and systemic embolic events 2º efficacy endpoints: composite clinical outcome of stroke, systemic embolic events, and all-cause mortality; also major bleeding events Treatment period: up to 2 years R INR, 2.-. treatment arms Edoxaban (6 mg vs mg QD) ISTH = International Society of Thrombosis and Haemostasis. Granger CB, et al. N Engl J Med. 2;65(): Apixaban ENGAGE AF-TIMI = Global Study to Assess the Safety and Effectiveness of DU-76b vs Standard ractice of Dosing With in atients with Atrial Fibrillation. ClinicalTrials.gov identifier NCT789. RE-LY Subgroup Analysis: Dabigatran in Cardioversion Nagakaranti, Ezekowitz et al Circ 2 Rate (%) Stroke and systemic embolism.5 p = p = D mg BID D5 mg BID 6

7 2 Stroke and SE with/without TEE Timing of thromboembolic events after cardioversion.5 Rate (%).5.5 D mg BID D5 mg BID With TEE prior to cardioversion.5.62 D mg BID. D5 mg BID.5 Without TEE prior to cardioversion eri-procedural clinical outcomes subgroup analysis Healey... Ezekowitz Circ 22 Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. lease check local prescribing information for further details eri-procedural outcome Analysis Aim: To assess outcomes in patients undergoing surgery/invasive procedure during RE-LY Approach: Bleeding and thromboembolic events assessed rimary analysis limited to the first surgery/procedure per patient eri-procedural period: 7 days before to day post-procedure 59 patients included in the subanalysis Even distribution of patients and surgery types across treatment arms Common surgeries/procedures included dental, pacemaker/icd, cataract removal (all ~%) ICD = implantable cardioverter defibrillator; Healey JS et al. Circulation 22 doi:.6/ CIRCULATIONAHA..96 7

8 eriprocedural anticoagulation management managed according to local practice Dabigatran withheld prior to procedure: Dec 25 Aug 28: 2 hours for all patients Aug 28 Mar 29: 2 5 days (based on CrCl) for high-risk procedures Dabigatran restarted post-procedure after achieving adequate haemostasis Time from last anticoagulant dose to procedure: Dabigatran: 9 (5 85) hours : (87 ) hours eri-procedural bridging with heparin used in 5.% (D), 7.% (D5), and 28.5% (warfarin) of patients (<.) CrCl = creatinine clearance; D = dabigatran mg twice daily; D5 = dabigatran 5 twice daily Healey JS et al. Circulation 22 doi:.6/ CIRCULATIONAHA..96 eri-procedural bleeding outcomes No significant difference in risk of bleeding for either dose vs warfarin Major bleeding Fatal bleeding D n=87 % patients D vs warfarin D5 vs warfarin D5 n=56 n= (.59.7) ( ) Re-operation (.26.) RBC transfusion Minor bleeding (.56.8) (.8.) D = dabigatran mg twice daily; D5 = dabigatran 5 mg twice daily; RBC = red blood cell; = relative risk Healey JS et al. Circulation 22 doi:.6/ CIRCULATIONAHA (.8.9).62. (. 7.5).2.9 (.7 2.6) (.6.2).8.5 (.9.5) eri-procedural thromboembolic events Low incidence of thromboembolic events across all treatment groups Ischaemic stroke or SE Stroke (all cause) D n=87 % patients D vs warfarin D5 vs warfarin D5 n=56 n= (.55 2.) (.28.92) SE....5 (.7 6.7) CV death (.5.6).89. ( ).5.7 (.27.85).97. (.6 6.).55. ( ) eri-procedural outcomes subgroup analysis: major bleeding by timing of anticoagulation interruption Significantly lower rate of bleeding with dabigatran (both doses) for patients undergoing surgery within 8 hours of anticoagulation interruption <2 hrs 2.8 (5/8) 2 8 hrs.2 (6/55) 8 72 hrs.5 (/) >72 hrs.7 (2/5) % patients (n/n) D vs warfarin D5 vs warfarin D D5 6.8 (/92). (7/52).5 (/9) 6.2 (29/68) 5. (2/78) 9. (8/89) 5.7 (7/22).6 (5/27).8 (.7.5).5 (.6.8).79 (..9).28 ( ) <.. (.2.92)..6 (.6.82).6.79 (..9)..7 ( ) -Trend CV cardiovascular; D = dabigatran mg twice daily; D5 = dabigatran 5 mg twice daily; = relative risk; SE =systemic embolism Healey JS et al. Circulation 22 doi:.6/ CIRCULATIONAHA..96 D = dabigatran mg twice daily; D5 = dabigatran 5 mg twice daily; = relative risk Healey JS et al. Circulation 22 doi:.6/ CIRCULATIONAHA..96 8

9 Stroke and systemic embolism (SE) Major bleeding D BID vs. warfarin D5 BID vs. warfarin D BID vs. warfarin D5 BID vs. warfarin CHA 2DS 2-VASc Annual rate, % D D Annual rate, % CHA 2DS 2-VASc D D p(inter)=.8 p(inter)=.6 p(inter)=.6 p(inter)= Dabigatran.5..5 Dabigatran.5..5 Dabigatran.5..5 Dabigatran Intracranial bleeding Interventional Devices WATCHMAN Device D BID vs. warfarin D5 BID vs. warfarin ROTECT-AF trial: 6 pts randomized to WATCHMAN Annual rate, % CHA 2DS 2-VASc D D p(inter)=.77 p(inter)=.9 2 to warfarin At 65 patient-years of follow-up: efficacy event (stroke, CV death, & systemic embolism) Relative risk ()=.62 with WATCHMAN vs. warfarin robability of noninferiority >99.9% Right atrium Aorta Transseptal catheterization Left atrium Watchman device placed in left atrial appendage.5..5 Dabigatran.5..5 Dabigatran safety events =.69 with WATCHMAN vs. warfarin Figure reprinted from Maisel WH. N Engl J Med. 29. Holmes et al. Lancet. 29. Flexible catheter inserted through right femoral vein and up the inferior vena cava Watchman device placed in the left atrial appendage to reduce stroke risk in AF 9