Stroke Prevention in Atrial Fibrillation Trial Data are Supported by Clinical Experience

2. PUSAT JANTUNG Regional Stroke Prevention in AtrialFibrillation Trial Data are Supported by Clinical Experience Dr. MUHAMMAD SYUKRI, Sp JP BAGIAN KARDIOLOGI DAN KEDOKTERAN VASKULAR FKUA/PUSAT JANTUNG RS. DR. M DJAMIL, PADANG

3. Topics of Discussion • Burden and Management of AF • Challenges and limitation of ASA and VKA • New Oral Anti Coagulants ( NOACs) • Results of the studies with NOACs, RELY and RELY-ABLE • Results of RELY among Asian population • What the Guideline Says • The goal of OAC therapy • Summary

4. Burden and Management of AF Sinus Rhytm Affectedportion of the brain Atrial Fibriillation Thrombus (clot) Atrial fibrillation is a supraventricular arrhythmia characterized by chaotic and uncoordinated contraction of the atrium Chowdhury P, et al. Cleve Clin J Med. 2009;76:543–550

5. Burden and Management of AF David Bloom's silent killer. David Bloom was an American television journalist covering Iraq warwho died suddenly in 2003 after a pulmonary embolism. The Stroke Association: www.stroke.org.uk. Base on: Office of National Statistics Health Statistics Quarterly, Winter 2001 "Stroke incidence and risk factors in a population based cohort study“. The Stroke Association estimate that 5,000 people per year have a stroke in Northern Ireland Scottish Stroke Care Audit 2005/2006.

6. Burden and Management of AF Prevention of complications, including thromboembolism (particularly ischaemic stroke) and heart failure Relief of symptoms Choice of antithrombotic therapy should be tailored to the patient based on: Risk of thromboembolism Risk of bleeding ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429; ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am CollCardiol 2011;57:e101–9

7. Burden and Management of AF Superior Efficacy Profile of OAC vs ASAto Prevent Stroke in Patients With Non Valvuler AF Hart et al, Ann Intern Med 2007;146:857–867

8. Burden and Management of AF Similar safety profile of OAC and ASAin intracranial bleeding and major bleeding Friberg, Rosenqvist & Lip Eur Heart J 2012

9. Challenges and limitations of ASA and VKA CammAJ et al. Eur Heart J 2012;33:2719–47; Aspirin Tablets BP 300 mg: SmPC, 2013; Ansell J et al. Chest 2008;133;160S–198S; Nutescu EA et al. CardiolClin 2008;26:169–87; UmerUshman MH et al. J Interv Card Electrophysiol 2008;22:129–37

10. Fast onset and offset of action At least as effective as warfarin Predictable response Low incidence and severity of adverse effects Long term safety profile No need for routine anticoagulation monitoring Is there any NEW,Better & Ideal Antithrombotic Agent? Wide therapeutic window ? Requirements Oral fixed dose ? ? Low potential for food or drug interactions ? ? ? ? ? ? ? Guidelines ? 13 Lip GY et al. EHJ Suppl. 2005;7:E21–25

11. NOACs approved for prevention of systemic embolism or stroke in patients with non-valvular AF

14. RRR 24% RRR 69% RRR 74% Result of New OAC Clinical Studies RE-LY® Results: Primary Endpoint • Dabigatran ® 150 mg twice daily is proven to provide superior Ischaemic Stroke prevention vs. Warfarin1 • 24% risk reduction in • Ischaemic Stroke Haemorrhagic Stroke Both dosages of Dabigatran®dramatically reduced the risk of haemorrhagic stroke compared with warfarin:1 17

15. RRR 33% RRR 20% RRR 70% RRR 59% RE-LY ® Results: Secondary Endpoint Life-Threatening Bleeding Rates Both doses of Dabigatran ® Significantly reduced the risk of life threatening bleeding compared with warfarin1 Intracranial Bleeding Both doses of Dabigatran ® substantially reduced the risk of intracranial bleeding compared with warfarin1 18

16. Result of New OAC Clinical Studies(stroke ischemic) The objective is to reduce Ischemic Stroke… 25

17. Result of New OAC Clinical Studies(Intracranial Hemorrhage) … and minimizing the risk of Intracranial Haemorrhage 27

18. Results of the studies with NOACs(CV Mortality) RE-LY® ROCKET-AF ARISTOTLE c Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011 Not head-to-head comparison – for illustrative purposes only

19. Results of RELY among Asian populationEfficacy outcomes (Asia vs. non-Asia) Rate (%/year) Dabigatran 110mg bid vs. Warfarin Dabigatran 150mg bid vs. Warfarin Dabigatran Warfarin Interaction pvalue Interaction pvalue HR (95%CI) HR (95%CI) 150mgbid 110mgbid 1.39 1.06 1.12 0.81 0.17 0.09 0.50 0.86 4.01 3.57 2.50 1.37 2.05 1.14 0.11 0.12 0.51 0.88 5.01 3.53 3.06 1.48 2.02 0.98 0.75 0.32 0.58 0.65 5.09 3.96 Stroke or SEE Asia Non-Asia Ischemic stroke Asia Non-Asia Hemorrhagic stroke Asia Non-Asia Myocardial infarction Asia Non-Asia Death from any cause Asia Non-Asia 0.0853 0.1977 0.7590 0.3782 0.4244 0.5597 0.5959 0.2729 0.3761 0.5929 0 1.0 2.0 0 1.0 2.0 Dabigatranbetter Warfarin better Dabigatranbetter Warfarin better RE-LY® Asia

20. Results of RELY among Asian populationSafety outcomes (Asia vs. non-Asia) Rate (%/year) Dabigatran 150mg bid vs. Warfarin Dabigatran 110mg bid vs. Warfarin Dabigatran Warfarin Interaction pvalue Interaction pvalue HR (95%CI) HR (95%CI) 150mgbid 110mgbid 2.17 3.52 0.96 1.69 1.28 1.52 0.45 0.29 12.43 15.27 13.99 17.02 2.22 2.99 1.15 1.14 0.91 1.29 0.23 0.23 10.12 13.69 11.72 15.27 3.82 3.53 1.41 1.01 2.20 1.79 1.10 0.71 19.66 15.81 22.03 17.74 Major bleeding Asia Non-Asia GI major bleeding Asia Non-Asia Life threatening bleeding Asia Non-Asia Intracranial bleeding Asia Non-Asia Minor bleeding Asia Non-Asia Major or minor bleeding Asia Non-Asia 0.0079 0.0089 0.1749 0.9509 <0.0001 <0.0001 0.0705 0.3379 0.0738 0.4561 <0.0001 <0.0001 0 1.0 2.0 0 1.0 2.0 Dabigatranbetter Warfarin better Dabigatranbetter Warfarin better RE-LY® Asia

21. RELY-ABLE® The RELY-ABLE® study: Long-term multi-centre extension of dabigatran treatment in patients with atrial fibrillation Study design 20

22. AF and ≥1 additional risk factor for stroke Absence of contraindications OBJECTIVE: Evaluate long-term safety of dabigatranetexilate (two doses) in patients with AF R Warfarin (INR 2.0–3.0) n=6022 Dabigatran etexilate 110 mg BID n=6015 Dabigatran etexilate 150 mg BID n=6076 Dabigatran etexilate 150 mg BID N=2937 Dabigatran etexilate 110 mg BID N=2914 RELY-ABLE®: Extension of RE-LY® • BID = twice daily RE-LY® RELY-ABLE®

23. RELY-ABLE® goals, design and summary • Goals • To describe the long-term efficacy and safety of ongoing dabigatran therapy following RE-LY® • Methods • Patients eligible at completion of RE-LY® study if: • Alive and still receiving study dabigatran • Being followed at centre participating in RELY-ABLE® • Dabigatran blinded dose continued in RELY-ABLE® for 2.3 years • Analysis • Two follow-up periods described • RELY-ABLE® (post-RE-LY®) • RE-LY® + RELY-ABLE® (beginning of RE-LY® to end of RELY-ABLE®)

24. RELY-ABLE® goals, design and summary • In patients who continued treatment on dabigatran after RE-LY®, the rates of stroke and major bleeding remain low • There were no new safety signal observed during this extended follow up period • The results from RELY-ABLE® are highly consistent with those observed in RE-LY®

25. What the Guideline Says: ESC 2012 Atrial fibrillation Yes Valvular AF* No (i.e. nonvalvular) <65 years and lone AF (including females) Yes No Assess risk of strokeCHA2DS2-VASc score No room for Antiplatelet 0 1 ≥2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences  to choose right dose No antithrombotictherapy NOAC VKA Recommended Optional Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253

26. What the Guideline Says: ESC 2012(Risk of stroke) • Updatestrongly recommends a practice shift towards identification of ‘truly low risk’ patients with AF (i.e. age <65 years and lone AF) who do not need antithrombotic therapy • CHADS2 does not reliably identify ‘truly low risk’ patients • CHA2DS2-VASc: • inclusive of the most common stroke risk factors • validated in multiplecohorts • better than CHADS2 at identifying ‘truly low risk’ patients • As good as CHADS2 in identifying patients who develop stroke and thromboembolism Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253

27. What the Guideline Says: ESC 2012(Risk of bleeding) HAS-BLED score: • allows clinicians to make informed assessment of bleeding risk • makes clinicians think of the correctable risk factors for bleeding • has been validated in several independent cohorts • correlates well with ICH risk High HAS-BLED score per se should not be used to exclude patients from OAC therapy Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253

28. 2012 28

29. ESC Guidelines 2012for the management of AF • *Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist • Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253 29

30. THE GOAL of OAC therapy “I need to maximize risk reduction at the same time as minimizing harm to the patient… “ - PCPCPA Study 1. Circulation. 2008; 118 : 2029-2037. 2. Connoly SJ et al. N Engl J Med 2009; 361(12): 1139-1151

31. Fast onset and offset of action At least as effective as warfarin Predictable response Low incidence and severity of adverse effects Long term safety profile No need for routine anticoagulation monitoring Is there any NEW,Better & Ideal Antithrombotic Agent? Wide therapeutic window Dabigatran Requirements SUPERIOR Oral fixed dose YES YES Low potential for food or drug interactions YES YES YES YES YES ACCP, ESC, AHA/ASA, NICE, CCS, PERDOSSI Guidelines RELY-ABLE, PMS (FDA and EMA) 34 Lip GY et al. EHJ Suppl. 2005;7:E21–25

32. Summary • AF confers an increased risk of stroke, which is dependant upon the presence of various stroke risk factors • All NVAF patient with ≥ 1 risk of stroke should receive anticoagulation - ASA is not an alternative, availability of NOACs has led to revisions in treatment guidelines • The net clinical benefit balancing ischaemic stroke vs intracranial bleeding favors Dabigatranfrom RE-LY® • Net clinical benefit was consistently in favor of DE for both doses compared with warfarin, in both Asians and non-Asians • Give right dose for the right patient (150mg or 110mg): Age, HASBLED, renal function and drug interactions • Dabigatranprovides long-term safety data in this setting (RELY-ABLE, PMS EMA and FDA)

33. Terima Kasih