1. Ashfaq Shuaib, MD Professor of Neurology and Medicine Director University of Alberta Stroke Program University of Alberta New Oral Anticoagulants in Stroke Prevention in Atrial Fibrillation

2. Competing Interests Declaration Competing interests –chair the steering committee of the SENTIS trial and FastFlo Trial and am an advisor to CoAxia. I am also on the steering committee of the DIAS III & DIAS IV trials, Impact-24 trial and the MASCI trial. In the past 5 years, I have received speaker fees from: Sanofi-Aventis/BMS, BI, Pfizer, Merck, Roche, Servier, AstraZeneca, Bayer In the past 5 years, I have served on national and international advisory boards for: AstraZeneca, BI, Lundbeck, Bayer, Sanofi-Aventis/BMS, Roche, Pfizer

3. Key questions addressed today Stroke and AF a Case History Warfarin and stroke prevention in AF NOACs and stroke prevention in AF “Flawed” comparison

4. Case History (three days ago) 76 years old male AF for 10 years. Initially on warfarin but switched to Dabigatran 110 twice daily due to difficulty maintaining INRs therapeutic Hypertension, DM, CHF Lower GI bleed. Dabi reduced to once/d Presents with L face weekness/dysarthria Imaging

5. Course in hospital Hold anticoagulation? Further imaging? Prevention of recurrent stroke (in-hospital) –ASA ? –iv anticoagulation ? When to start oral anticoagulation What is the best medication for long term prophylaxis

6. Key questions addressed today Stroke and AF a Case History Warfarin and stroke prevention in AF NOACs and stroke prevention in AF “Flawed” comparison

7. Atrial Fibrillation is a Major Preventable Cause of Stroke AF accounts for 1 in 6 ischemic strokes (1 in 4 in the elderly) –More than 14,000 AF related strokes a year in Canada –Many times more ‘silent’ strokes Strokes caused by atrial fibrillation are generally severe; 1-year mortality is 50%

8. Also remember…. AF paroxysmal in up to one third of patients The presence of a non-AF identifiable cause does not rule out cardio-embolic stroke secondary to AF Many “cryptogenic strokes” may be seconday to AF

11. Stroke Prevention in AF Stroke-risk dependent on presence of “risk factors”. CHAD2 and CHAD-VASc scores ASA reduces risk but not significant in patients with previous TIAs or stroke ASA+ clopidogrel better than ASA; however increased bleeding risk Warfarin very effective in stroke prevention: however TTR problematic

13. Hart Ann Int Med 1999;131:492 RRR = 64%

16. Key questions addressed today Stroke and AF a Case History Warfarin and stroke prevention in AF New Oral Anticoagulants and stroke prevention in AF “Flawed” comparison

17. World Stroke Congress 2010 Seoul, South Korea

18. Advantages of New Oral Anticoagulants Over Warfarin FeatureWarfarinNew Orals OnsetSlowRapid DosingVariableFixed Food effectYesNo InteractionsManyFew MonitoringYesNo OffsetLongShort

19. Disadvantages of New Oral Anticoagulants Over Warfarin FeaturesWarfarinNew Agents FrequencyOnce daily Once or twice daily MonitoringINRUncertain ClearanceNon-renalRenal 25-80% AntidoteVit K, FFP, PCCNone FamiliarityExtensiveLimited

20. Comparative Pharmacology CharacteristicRivaroxabanApixabanDabigatran TargetFactor Xa Thrombin ProdrugNo Yes Bioavailability80%60%6% Dosingo.d. (b.i.d.)b.i.d.b.i.d. (o.d.) Half life7-11 h12 h12-17 h Renal33% (66%)25%80% MonitoringNo Interactions3A4/P-gp P-gp

21. Dabigatran and stroke prevention RE-LY: probe design (110 and 150 mg Dabigatran vs Warfarin) 18,118 patients Both doses of Dabi non-inferior to Warfarin Higher dose superior to Warfarin Significantly less bleeding, especially ICH Higher dose associated with significantly fewer ischemic strokes

22. Nov 2012 The Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE ® ) study Stuart J Connolly, Lars Wallentin, Michael Ezekowitz, John Eikelboom, Jonas Oldgren, Janice Pogue, Paul Reilly, Martina Brueckmann, Salim Yusuf; on behalf of the RELY-ABLE ® Steering Committee and Investigators November 2012 Nov 2012 Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los Angeles, CA, 7 Nov 2012 Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of products outside the Canadian approved Product Monograph The content of this slide may contain information not reviewed by Health Canada Note that there may be discrepancies between the information in this presentation and the final publication

23. Stroke and ischaemic events: RELY-ABLE ® 23 Event D150 (%/yr) D110 (%/yr) HR95% CI Stroke or SEE1.461.600.910.69–1.20 All stroke1.241.380.890.66–1.21 Ischaemic1.15 1.240.920.67–1.27 Haemorrhagic0.130.140.890.34–2.30 Myocardial infarction0.690.720.960.63–1.45 Pulmonary embolism0.130.111.140.41–3.15 5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio SEE = systemic embolic event Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los Angeles, CA, 7 Nov 2012 Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of products outside the Canadian approved Product Monograph The content of this slide may contain information not reviewed by Health Canada Note that there may be discrepancies between the information in this presentation and the final publication

24. Mortality and net benefit: RELY-ABLE ® Event RELY-ABLE ® D150 (%/yr) D110 (%/yr) HR95% CI Total mortality3.023.100.97 0.80 – 1.19 Vascular mortality1.671.621.03 0.78 – 1.35 Disabling stroke, life- threatening bleed or death 4.534.451.02 0.86 – 1.20 Stroke, systemic embolism, myocardial infarction, pulmonary embolism, major bleed or death 7.366.891.070.94 – 1.22 24 5851 patients followed for mean of 2.25 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los Angeles, CA, 7 Nov 2012 Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of products outside the Canadian approved Product Monograph The content of this slide may contain information not reviewed by Health Canada Note that there may be discrepancies between the information in this presentation and the final publication

25. Conclusions During 2.3 years of additional treatment after RE-LY ® (total mean follow-up 4.3 years), rates of stroke and major bleeding remain low on dabigatran and are consistent with those seen during RE-LY ® Dabigatran 150 vs dabigatran 110 –Both doses have very low rates of hemorrhagic stroke over 4+ years –With dabigatran 150, there is a lower rate of ischemic stroke but a higher rate of major bleeding –Both doses have similar mortality 25 Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los Angeles, CA, 7 Nov 2012 Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of products outside the Canadian approved Product Monograph The content of this slide may contain information not reviewed by Health Canada Note that there may be discrepancies between the information in this presentation and the final publication

26. Study limitations Study medication blinded but warfarin open label More MIs in treatment arms (initial publication) GI intolerance GI bleeding rates similar to warfarin in elderly Renal disease increased risk of complications, especially with higher dose of Dabigatran

27. Rivaroxaban and stroke prevention ROCKET-AF: 20 mg daily vs Warfarin 14,264 patients, double blind CHAD2 scores higher than other trials 55 % of patients with previous TIA or stroke Major bleeding, especially ICH lower with Rivaroxiban Rivaroxaban non-inferior to Warfarin

28. Study limitations Non-inferior but NOT superior to Warfarin on ‘intention to treat” analysis Once a day dose of Rivaroxaban Higher rates of GI bleeding with study drug Study end and switch to Warfarin –Time to therapeutic INR (13 vs 3 days) –Higher events in the patients previously on Rivaroxaban

29. Apixaban and stroke prevention AVERROES (5,599) and ARISTOTLE (18,201) trials AVERROES stopped early because of significantly fewer events (stroke and ICH) in apixaban group ARISTOTLE: Apixaban superior to Warfarin Significantly fewer hemorrhages (ICH and systemic) Lower mortality

31. Study limitations Patient selection (unable to tolerate warfarin !!!) in AVERROES Short follow up period in AVERROES –bleeding risk underestimated ? Low stroke risk in AVERROES Issues with FDA for AF indication

32. Key questions addressed today Stroke and AF a Case History Warfarin and stroke prevention in AF NOACs and stroke prevention in AF Specific stroke prevention sub-groups “Flawed” comparison

33. For patients with atrial fibrillation, anticoagulation effectively reduces the risk of stroke. Circulation 2012;125:159-164

34. Stroke risk in patients with previous TIAs and Stroke

35. Risk of hemorrhage in patients with previous TIAs and Stroke

36. Limitations with NOACs When to start treatment after acute stroke Reversal of anticoagulation Treatment of ICH Thrombolysis in acute stroke Combination with ASA or dual antiplatelets Long-term experience lacking Compliance cannot be monitored

37. Antithrombotic guidelines for stroke prevention in AF trial fibrillation ACCP 2012 “…we suggest dabigatran 150 mg bid rather than adjusted-dose VKA therapy…”. AHA 2012 “….newer agents superior to VKA therapy…” CCS 2012 “…we suggest…that…most patients should receive dabigatran, rivaroxaban or apixaban in preference to warfarin...” You JJ, et al. Chest 2012; 141: e531S-575S Skanes AC, et al. Can J Cardiol 2012; 28: 125-136

38. CharacteristicChoiceRationale Mechanical valve or valvular a.fibWarfarinNew agents not studied Poor complianceWarfarin or nothingMissed doses of greater consequence with shorter-acting new agents Stable on WarfarinWarfarinPatient preference might mean switching CrCl < 30 mL/minWarfarinSuch patients were excluded from trials with new agents CrCl of 30-50 mL/minRivaroxaban or Apixaban Oral factor Xa inhibitors are less affected by impaired renal function than dabigatran Dyspepsia or upper GI complaintsRivaroxaban or Apixaban Dyspepsia in up to 10% given dabigatran Recent GI bleed and ongoing riskApixabanMore gastrointestinal bleeding with dabigatran (150 mg BID) or rivaroxaban than with warfarin Recent Acute Coronary SyndromeRivaroxaban or Apixaban Small myocardial infarction signal with dabigatran Poor compliance with BID regimen or desire for once daily RivaroxabanOnly agent that is once a day Liver dysfunction with elevated INRWarfarinNew agents require hepatic metabolism Atrial Fibrillation treatment choices