New Aspects in the Diagnosis and Treatment of Atrial Fibrillation: Antithrombotic Therapy

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1 New Aspects in the Diagnosis and Treatment of Atrial Fibrillation: Antithrombotic Therapy Hans-Christoph Diener Department of Neurology and Stroke Center University Hospital Essen Germany

2 Conflict of Interest Statement The speaker or his institution received financial support from the following bodies or companies: German Research Council German Ministry of Health German Ministry of Science and Technology European Union MSD Astra-Zeneca GlaxoSmithKline Pfizer Bayer Wyeth Knoll Servier Paion Solvay Yamaguchi Novo Nordisk Novartis Neurobiological Technologies MindFrame Fresenius CoAxia Abbott Novartis Schering Aventis Janssen-Cilag SanofiAventis Boehringer Ingelheim D-Pharm BMS

3 Stroke Prevention in Atrial Fibrillation Vitamin-K antagonists Combination of warfarin plus aspirin Antiplatelet combination therapy New antithrombotic drugs

4 Stroke Prevention in Atrial Fibrillation Vitamin-K antagonists Combination of warfarin plus aspirin Antiplatelet combination therapy New antithrombotic drugs

5 Morley J, et al. Am J Cardiol 1996;77:38A-44A; Hart RG, et al. Ann Intern Med 2007;146: RRR: relative risk reduction Warfarin is more effective than aspirin for primary stroke prevention in AF -71% Risk reduction compared to placebo -67% -26% -79% 39% RRR of stroke with adjusted-dose warfarin compared to antiplatelets (meta-analysis of 12 RCTs in AF; n=12,963)

6 Combination of oral anticoagulation and aspirin in patients with atrial fibrillation (AF) Akins et al, SPORTIF Pooled Analysis, Stroke 2007

7 Odds ratio Need for intense monitoring with OAC Ischaemic stroke Intracranial bleeding International Normalized Ratio Narrow therapeutic index: INR < 2.0 = higher risk of stroke INR > 3.0 = higher risk of bleeding Unpredictable INR (food/drug interactions, low specificity) Fuster V, et al. Eur Heart J 2006;27:

8 Stroke Prevention in Atrial Fibrillation Vitamin-K antagonists Combination of warfarin plus aspirin Antiplatelet combination therapy New antithrombotic drugs

9 ACTIVE W: preventive superiority of OACs Stopped early after median follow-up 1.28 years -30% p= % p=0.005 (Primary outcome+major bleed) ACTIVE Writing Group of the ACTIVE Investigators Lancet 2006;367:

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11 ACTIVE A: benefit in stroke reduction when adding clopidogrel to aspirin RR -28% p<0.001 RR -3% p=0.69 Significant reduction by clopidogrel + aspirin versus aspirin alone is primarily due to reduction in stroke (no or only weak differential treatment effects for subgroups) after median follow-up of 3.6 years Connolly SJ, et al. N Engl J Med 2009;360:

12 Panel B shows the cumulative incidence of stroke. The relative risk for aspirin plus clopidogrel, as compared with aspirin alone, was 0.72 (95% CI, 0.62 to 0.83; P<0.001)

13 Conclusions 1 Patients with TIA or stroke and cardiac source of embolism who are not willing to take oral anticoagulation have only a small benefit from aspirin The combination of aspirin and clopidogrel is inferior to warfarin and carries a similar bleeding risk The combination of aspirin plus clopidogrel is superior to aspirin mono-therapy but carries a higher bleeding risk The combination of warfarin plus aspirin carries a higher bleeding risk and offers no additional benefit K4

14 Stroke Prevention in Atrial Fibrillation Vitamin-K antagonists Combination of warfarin plus aspirin Antiplatelet combination therapy New antithrombotic drugs

15 Targets for novel antithrombotic agents in the coagulation cascade 1 Tissue factor/viia Vitamin K antagonist: Tecarfarin (Ph II completed) 2 X IX Direct factor Xa inhibitors: Apixaban (Ph III ongoing) 5,6 Rivaroxaban (Ph III ongoing) 7 Edoxaban (Ph III ongoing) 8 Betrixaban (Ph II ongoing) 9 II Va Xa VIIIa IXa AT Thrombin Indirect factor Xa inhibitors: Idraparinux (Ph III terminated) 3 SSR (withdrawn 2009) 4 Direct thrombin inhibitors: Dabigatran etexilate (Ph III completed) 10 Ximelagatran (withdrawn 2006) 11,12 AZD0837 (Ph II completed) 13 Fibrinogen Fibrin AT= antithrombin; Ph = Phase 1. Adapted from Turpie AG. Eur Heart J 2008;29:155 65; 2. Ellis DJ et al. Circulation 2009;22:120: ; 3. Bousser MG et al. Lancet 2008;371:315 21; 4. NCT ; available at accessed Sept 09; 5. Lopes RD et al. Am Heart J 2010;159:331 9; 6. Eikelboom JW et al. Am Heart J 2010;159:348 53; 7. ROCKET-AF Study Investigators. Am Heart J 2010;159:340 47; 8. NCT ; available at accessed Sept 09; 9. NCT ; available at accessed Sept 09; 10. Connolly SJ et al. N Engl J Med 2009;361: ; 11. Olsson SB et al. Lancet 2003;362:1691 8; 12. Albers GW et al. JAMA 2005;293:690 8; 13. Lip GY et al. Eur Heart J 2009;30:

16 Potential advantages of new anticoagulants High specificity Good efficacy-safety balance No monitoring / dose adjustment requirement (fixed dose) Quick onset of action Less drug interactions No food interaction

17 Study design of SPORTIF III and V trials Stroke Prevention using an ORal direct Thrombin Inhibitor in atrial Fibrillation Patients with non-valvular AF and risk factors for stroke N=7329 Adjusted-dose warfarin (target INR 2 3) Fixed-dose ximelagatran (36 mg BID) SPORTIF III: 1 23 nations Open-label (n=3407) SPORTIF V: 2 US, Canada Double-blind (n=3922) BID = twice daily; INR = international normalized ratio 1. Olsson SB et al. Lancet 2003;362:1691 8; 2. Albers GW et al. JAMA 2005;293:

18 Non-inferiority of ximelagatran compared with warfarin in patients with AF Stroke and systemic embolism Ximelagatran better Warfarin better SPORTIF III 1 P= SPORTIF V 2 P= Pooled 3 P= Non-inferiority Difference in absolute event rates (ximelagatran warfarin) 4 1. Olsson SB et al. Lancet 2003;362:1691 8; 2. Albers GW et al. JAMA 2005;293:690 8; 3. Albers GW. Am J Manag Care 2004;10(14 Suppl):S462 9; discussion S

19 Modified from Turpie AGG. Eur Heart J 2007;29:155-65; Clinical trials for stroke prevention in AF (2) Drug class OAC Phase II Phase III (comparison with warfarin unless*) VKAs tecarfarin (ATI-5923) 1 completed EmbraceAC almost finished FXa inhibitors rivaroxaban 1 completed (Japanese) ROCKET-AF in follow-up 1 ongoing Direct thrombin inhibitors YM150 1 completed - DU-176b apixaban 1 completed 2 ongoing 1 (effect on bleeding) recruiting betrixaban EXPLORE-Xa recruiting - dabigatran PETRO completed, PETRO-Ex terminated EngageAFTIMI48 recruiting ARISTOTLE and AVERROES (*comparison to aspirin in AVERROES) RE-LY completed RELY-ABLE recruiting

20 THE MEDICAL NEWS from News-Medical.Net - Latest Medical News and Research from Around the World Phase 3 AVERROES clinical trial of apixaban for atrial fibrillation closes early due to clear evidence of efficacy 11. June :09

21 RE-LY study design Atrial fibrillation with 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6000 Dabigatran etexilate 110 mg bid N=6000 Dabigatran etexilate 150 mg bid N=6000 Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up Ezekowitz MD, et al. Am Heart J 2009;157: Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

22 Cumulative hazard rates Time to first stroke / SSE Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR 0.91 (95% CI: ) p<0.001 (NI) p=0.34 (Sup) RRR 34% RR 0.66 (95% CI: ) p<0.001 (NI) p<0.001 (Sup) Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

23 RE-LY in perspective Category W vs placebo W vs W low dose W vs ASA vs ASA + clopidogrel Meta-analysis of ischaemic stroke or systemic embolism W vs ximelagatran W vs dabigatran 150 Camm J.: Oral presentation at ESC on Aug 30th Favours warfarin Favours other treatment Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

24 OAC is more effective than aspirin for secondary stroke prevention in AF EAFT: European, multi-centre RCT 1,007 patients with non-rheumatic AF and recent TIA or minor ischaemic stroke (mean follow-up 2.3 years) p<0.001 p=0.31 EAFT Study Group. Lancet 1993;342:

25 % per year Stroke/SSE in patients with prior stroke or TIA 3 2,5 RR 0.85 (95% CI: ) P=0.37 RR 0.76 (95% CI: ) P=0.14 2,74 2 1,5 2,32 2,07 1 0,5 RRR 15% RRR 24% 0 D110 mg bid D150 mg bid Warfarin 55 / / / 1195 Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

26 Number of events Haemorrhagic stroke: all patients RR 0.31 (95% CI: ) p<0.001 (sup) RRR 69% RR 0.26 (95% CI: ) p<0.001 (sup) RRR 74% D110 mg bid D150 mg bid Warfarin Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

27 Number of events Intra-cranial bleeding rates in patients with prior stroke or TIA RR 0.20 (95% CI: ) p<0.001 RR 0.41 (95% CI: ) 30 P= RRR 80% RRR 59% D110 mg bid D150 mg bid Warfarin Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with

28 Strengths of RE-LY Large study with two doses of dabigatran Rigorous adjudication of events Subgroup of patients with prior TIA or ischemic stroke 50% of patients VKS naive

29 Conclusions Dabigatran etexilate has shown to concurrently reduce both thrombotic and hemorrhagic events Both doses of dabigatran provide different and complimentary advantages over warfarin 150 mg BID has superior efficacy with similar bleeding 110 mg BID has significantly less bleedings with similar efficacy Similar net clinical benefit was seen between the two dabigatran doses Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

30 Stroke Prevention in Atrial Fibrillation Vitamin-K antagonists Combination of warfarin plus aspirin Antiplatelet combination therapy New antithrombotic drugs Difficult to handle, poor compliance Not recommended (exception: stent) Not superior to warfarin, bleeding Superior or equivalent to warfarin or aspirin

31 Thank you for your attention