Dr. MUHAMMAD SYUKRI, Sp JP PUSAT JANTUNG Regional Stroke Prevention in Atrial Fibrillation 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

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

Burden and Management of AF Affected portion of the brain Sinus Rhytm 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

Burden and Management of AF David Bloom's silent killer. David Bloom was an American television journalist covering Iraq war who 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.

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 Coll Cardiol 2011;57:e101–9

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

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

Challenges and limitations of ASA and VKA Camm AJ 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. Cardiol Clin 2008;26:169–87; Umer Ushman MH et al. J Interv Card Electrophysiol 2008;22:129–37

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

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

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 RRR 24% Haemorrhagic Stroke AF is the most common heart rhythm disturbance1 It is estimated that 1 in 4 individuals aged 40 years or older will develop AF1 In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain, France and the UK were living with diagnosed AF2 Due to the aging population, this number is expected to double within 30 years3 1. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046. 2. Decision Resources. Atrial Fibrillation Report. Dec 2008. 3. Go AS, et al. JAMA 2001;285:2370-2375. RRR 74% RRR 69% Both dosages of Dabigatran® dramatically reduced the risk of haemorrhagic stroke compared with warfarin:1 17

RE-LY ® Results: Secondary Endpoint Life-Threatening Bleeding Rates RRR 20% RRR 33% Both doses of Dabigatran ® Significantly reduced the risk of life threatening bleeding compared with warfarin1 Intracranial Bleeding AF is the most common heart rhythm disturbance1 It is estimated that 1 in 4 individuals aged 40 years or older will develop AF1 In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain, France and the UK were living with diagnosed AF2 Due to the aging population, this number is expected to double within 30 years3 1. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046. 2. Decision Resources. Atrial Fibrillation Report. Dec 2008. 3. Go AS, et al. JAMA 2001;285:2370-2375. RRR 59% RRR 70% Both doses of Dabigatran ® substantially reduced the risk of intracranial bleeding compared with warfarin1 18

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

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

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

Results of RELY among Asian population Efficacy outcomes (Asia vs Results of RELY among Asian population Efficacy outcomes (Asia vs. non-Asia) Rate (%/year) Dabigatran 150mg bid vs. Warfarin Dabigatran 110mg bid vs. Warfarin Dabigatran Warfarin Interaction p value Interaction p value 150mg bid 110mg bid HR (95%CI) HR (95%CI) Stroke or SEE Asia Non-Asia Ischemic stroke Hemorrhagic stroke Myocardial infarction Death from any cause 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 0.0853 0.1977 0.7590 0.3782 0.4244 0.5597 0.5959 0.2729 0.3761 0.5929 1.0 2.0 1.0 2.0 Dabigatran better Warfarin better Dabigatran better Warfarin better RE-LY® Asia

Results of RELY among Asian population Safety outcomes (Asia vs Results of RELY among Asian population Safety outcomes (Asia vs. non-Asia) Rate (%/year) Dabigatran 150mg bid vs. Warfarin Dabigatran 110mg bid vs. Warfarin Dabigatran Warfarin Interaction p value Interaction p value HR (95%CI) HR (95%CI) 150mg bid 110mg bid Major bleeding Asia Non-Asia GI major bleeding Life threatening bleeding Intracranial bleeding Minor bleeding Major or minor bleeding 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 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 0.0079 0.0089 0.1749 0.9509 <0.0001 0.0705 0.3379 0.0738 0.4561 <0.0001 1.0 2.0 1.0 2.0 Dabigatran better Warfarin better Dabigatran better Warfarin better RE-LY® Asia

RELY-ABLE® The RELY-ABLE® study: Long-term multi-centre extension of dabigatran treatment in patients with atrial fibrillation Study design RE-LY® – Trial conduct The RE-LY® study was conducted to very high standards. Follow-up was completed for 99.9% of the patients who participated in the study, with only 20 of the 18,113 patients lost to follow-up.1 The quality of INR control for patients in the warfarin treatment arm was also high.1 The time-in-therapeutic-range (TTR) in RE-LY® was 67% for VKA-experienced and 61% for VKA-naïve patients.1 The higher TTR in VKA-experienced patients is not surprising given they had previous experience with dealing with the challenges of VKA treatment and so would be expected to achieve better INR control. The quality of INR control achieved in RE-LY® was considerably better than is typically achieved in routine clinical practice. In the meta-analysis of studies of INR control in the community setting presented earlier, the average TTR was only 51%.2 Therefore, warfarin is likely to have performed better in RE-LY® than is typical of routine clinical practice and any benefits demonstrated with dabigatran etexilate compared with warfarin in RE-LY® might be enhanced in the real-life as compared with the clinical trial setting. References Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009;15:244–252. 20

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

RELY-ABLE® goals, design and summary 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®)

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®

What the Guideline Says: ESC 2012 Atrial fibrillation Valvular AF* Assess risk of stroke CHA2DS2-VASc score No antithrombotic therapy NOAC VKA 1 No (i.e. nonvalvular) Yes ≥2 Oral anticoagulant therapy <65 years and lone AF (including females) Assess bleeding risk (HAS-BLED score) Consider patient values and preferences  to choose right dose Yes No No room for Antiplatelet AHA/ ASA 5 points: CHADS2  CHA2DS2-VASc No room for ASA NOAC = VKA Ablation Future research for CHA2DS2-VASc 0-1 Recommended Optional Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253

What the Guideline Says: ESC 2012 (Risk of stroke) Update strongly 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 multiple cohorts 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

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

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ESC Guidelines 2012 for the management of AF Recommendation Class Level In patients with CHA2DS2-VASc score ≥2, OAC therapy with: a dose-adjusted VKA (INR 2–3); or a direct thrombin inhibitor (dabigatran); or an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*) … is recommended unless contraindicated I A In patients with CHA2DS2-VASc score 1, OAC therapy with: … should be considered, based upon an assessment of the risk of bleeding complications and patient preferences IIa 29 *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

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

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

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 Dabigatran from 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 Dabigatran provides long-term safety data in this setting (RELY-ABLE, PMS EMA and FDA)

Terima Kasih