1. Primary Care Education Progam

2. FAMILY PRACTITIONERS: Dr. Carl Fournier, Montreal, QC Dr. Peter Lin, Toronto, ON Dr. Vinod Patel, St. John’s, NFLD Dr. Kevin Saunders, Winnipeg, MB Dr. Richard Ward, Calgary, AB SPECIALISTS: Dr. Paul Dorian, Toronto, ON Dr. Victor Huckell, Vancouver, BC Dr. Mukul Sharma, Ottawa, ON Dr. Jeffrey Weitz, Hamilton, ON Steering Committee

3. Incidence of AF: Expected to Increase as Population Ages Age- and Sex-Adjusted Incidence of AF in 1995-2000 Projected Number of Persons With AF in the US: 2000- 2050 Millions Year Circulation 2006;114:119

4. About 80% of all strokes are ischemic 1 Effect of first ischemic stroke in patients with AF: 60% are disabling, 20% are fatal 2 ICH has a 30-day mortality rate of 35% to 52% 3 Severe strokes are viewed by many patients as equal to or worse than death 4,5 Perspectives on Stroke 1 Heart and Stroke Foundation; 2 Gladstone Stroke 2009;40:235; 3 AHA Stroke 1999;30:905-15; 4 Gage Arch Intern Med 1996;156:1829; 5 Solomon Stroke 1994;25:1721

5. Embolic Stroke Noncontrast CT brain scan showing two discrete areas of infarction (arrows) within the right middle cerebral artery Kelley RE & Minagar A. Southern Medical Journal 2003;96(4):343-349

6. Gladstone DJ et al. Stroke 2009; 40:235-240 Effect of first ischemic stroke in patients with AF (n=597) Stroke Severity in Patients with AF % of patients Disabling Fatal 60% 40% 0% 50% 30% 20% 10% AF=atrial fibrillation

7. Warfarin reduces stroke in non-valvular AF by 64%  Significant increase in intracranial and other hemorrhage Registries show 50-60% of eligible patients receive warfarin In clinical trials, time in therapeutic range (TTR) is 60-68% In general practice, TTR is typically <50% Warfarin in Atrial Fibrillation: 1 Hart Ann Int Med 2007;146:857; 2 Hylek Stroke 2006;37:1075; 3 Singer Chest 2008;13;3:546S 4 Gladstone Stroke 2009;40:235; 5 Matchar Am J Med 2002;113:42; 6 Bungard Pharmacotherapy 2000;20:1060

8. CCS 2012 Update to AF Guidelines CHADS 2 = 0 *Aspirin is a reasonable alternative in some as indicated by risk/benefit CHADS 2 = 1 CHADS 2 ≥ 2 No anti- thrombotic Assess Thromboembolic Risk (CHADS 2 ) No additional risk factors for stroke Increasing stroke risk ASA OAC* OAC Either female sex or vascular disease Age ≥ 65 yrs or combination of female sex and vascular disease Age ≥ 65 yrs or combination of female sex and vascular disease OAC = Oral anticoagulant ASA = Aspirin Consider stroke risk vs. bleeding risk Only when the stroke risk is low and bleeding risk is high does the risk/benefit ratio favour no antithrombotic therapy 1.Skanes AC, et al. Can J Cardiol 2012;28:125-136.

9. CCS 2012 Update to AF Guidelines When oral anticoagulant therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban*, in preference to warfarin Dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention Dabigatran and rivaroxaban have no more major bleeding and apixaban has less All three new oral anticoagulants have less intracranial hemorrhage and are much simpler to use *Not yet approved in Canada 1.Skanes AC, et al. Can J Cardiol 2012;28:125-136.

10. Prevention of Stroke Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981 0.500.751.001.251.50 Dabigatran 110 mg BID Dabigatran 150 mg BID HR (95% CI) Warfarin betterComparator better Rivaroxaban 20 mg QD Apixaban 5 mg BID Stroke or Systemic Embolism Ischemic Stroke Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Superiority p-value Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph. 0.29 <0.001 0.12 0.01 0.35 0.03 0.59 0.42 0.90 0.65 1.11 0.76 0.88 0.79 0.94 0.92 Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.

11. Reducing the Bleeding Risk HR (95% CI) Warfarin betterComparator better 0.500.751.001.25 0.25 Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Intracranial Hemorrhage ISTH Major Bleeding Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Superiority p-value <0.001 0.02 <0.001 0.003 0.31 0.58 <0.001 Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981 Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph. 0.80 0.93 0.30 0.41 0.67 0.42 1.04 0.69 Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.

12. New OAC vs. warfarin in moderate CKD (eGFR <50 ml/min) RR (95% CI) Dabigatran 110 mg BID 0.77 (0.51-1.18) Dabigatran 150 mg BID 0.55 (0.40-0.81) Rivaroxaban 15 mg QD 0.86 (0.63-1.17) Apixaban 2.5/5 mg BID 0.79 (0.57-1.20) 0.50 0.75 1.00 1.25 1.50 HR (95% CI) New Agent BetterWarfarin Better Hart RG, et al. Nat Rev Nephrol 2012 (on line) Connolly SJ, et al. N Engl J Med. 2009; 361:1139 Fox KAA et al. Euro Heart J 2011; 32: 2387 Granger C, et al. N Engl J Med. 2011; 365: 981 Stroke or Systemic Embolism

13. New OAC vs. warfarin in moderate CKD (eGFR <50 ml/min) RR (95% CI) Dabigatran 110 mg BID 0.99 (0.76-1.28) Dabigatran 150 mg BID 1.03 (0.80-1.34) Rivaroxaban 15 mg QD 0.95 (0.72-1.26) Apixaban 2.5/5 mg BID 0.50 (0.38-0.66) 0.50 0.75 1.00 1.25 1.50 HR (95% CI) New Agent BetterWarfarin Better Major bleeding Hart RG, et al. Nat Rev Nephrol 2012 (on line) Connolly SJ, et al. N Engl J Med. 2009; 361:1139 Fox KAA et al. Euro Heart J 2011; 32: 2387 Granger C, et al. N Engl J Med. 2011; 365: 981

14. Safety Outcomes: RELY D 110mg Annual rate D 150mg Annual rate W Annual rate D 110 mg vs. W RR 95% CI P D 150 mg vs. W RR 95% CI P Major or Minor Bleeding 14.62%16.42%18.15% 0.78 0.73-0.83 <0.001 0.91 0.85-0.96 0.002 Intracranial Bleeding 0.23 %0.32 %0.76 % 0.30 0.19-0.45 <0.001 0.41 0.28-0.60 <0.001 Major Bleeding2.87 %3.32 %3.57% 0.80 0.70-0.93 0.003 0.93 0.81-1.07 0.32 Life-Threatening Major Bleed 1.24 %1.49 %1.85 % 0.67 0.54-0.82 <0.001 0.80 0.66-0.98 0.03 Fatal Bleed*0.19 %0.23 %0.33 % 0.58 0.35-0.97 0.039 0.70 0.43-1.14 0.15 GI Major Bleed1.15 %1.56 %1.07 % 1.08 0.85-1.38 0.52 1.48 1.18-1.85 0.001 Connolly NEJM 2010;363:1876; *Eikelboom Circulation 2011;123:2363

15. Rivaroxaban Event Rate (per 100 patient/years) Warfarin Event Rate (per 100 patient/years) HR (95% CI)P-value Primary: Major and Non-Major Clinically Relevant Bleeding 14.914.51.03 (0.96, 1.11)0.44 Major: >2 g/dL Hgb drop Transfusion (> 2 units) Critical Bleeding Fatal Bleeding 3.6 2.8 1.6 0.8 0.2 3.4 2.3 1.3 1.2 0.5 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) 0.58 0.02 0.04 0.007 0.003 Intracranial Hemorrhage0.50.70.67 (0.47, 0.93)0.02 Major GI Bleeding3.2 % of pts2.2% of ptsNot reported<0.001 Non-Major Clinically Relevant Bleeding 11.811.41.04 (0.96, 1.13)0.35 Epistaxis10.1% of pts8.6 % of ptsNot reported<0.05 Safety Outcomes*: ROCKET AF *Based on Safety On-Treatment Population Patel N Engl J Med 2011;365:883

16. Apixaban Event Rate (per 100 patient/years) Warfarin Event Rate (per 100 patient/years) HR (95% CI) P- value Primary: Major Bleeding 2.133.090.69 (0.60, 0.80) <0.001 Intracranial Hemorrhage 0.330.800.42 (0.30, 0.58) <0.001 Other Location1.792.27 0.79 (0.68, 0.93) 0.004 Major GI Bleeding0.760.86 0.89 (0.70, 1.15) 0.37 Major or Clinically Relevant Non-Major 4.076.01 0.68 (0.61, 0.75) <0.001 Net Clinical Outcome*6.137.20 0.85 (0.78, 0.92) <0.001 Bleeding and Net Clinical Outcomes: ARISTOTLE *Net Clinical Outcome: Stroke, systemic embolism, death, or major hemorrhage Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph.

17. Similarities Across the 3 Novel Oral Anticoagulants: Comparing Dabigatran 150 mg, Rivaroxaban, and Apixaban Vs. Warfarin Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981 All 3 agents were non-inferior to warfarin in reducing the risk of stroke / systemic embolism All 3 agents reduced ICH The 3 agents seem to demonstrate a consistent trend towards mortality reduction Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph. Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.

18. Differences: Comparing Dabigatran 150 mg, Rivaroxaban, and Apixaban Vs. Warfarin Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981 Dabigatran and apixaban demonstrated superiority over warfarin in reducing stroke/systemic embolism Dabigatran reduced ischemic stroke Apixaban reduced major bleeding Rivaroxaban is dosed once daily Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph. Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.

19. AF patients not recommended for therapy with new anticoagulant agents approved for stroke prevention include: Patients with valvular heart disease Patients with mechanical valves Patients with advanced renal impairment (CrCl<30 mL/min) Patients with active bleeding Patients unsuitable for new anticoagulants 1. Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd. 2. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc.

20. Case: Patient with hypertension, diabetes, prior TIA

21. Patient Profile: Jack Jack is a 64-year old Caucasian man Married, lives with wife Works from home but frequently travels to the US for work Goes to the gym twice/week He is 5’ 11” tall (180 cm) Weighs 187 lb (85 kg), BMI is 26.1 “I’m here only because of my wife … she thinks I had a stroke” Jack

22. Jack’s medical conditions are as follows:  Diagnosed with atrial fibrillation 3 years ago - on warfarin  His INR has been stable although he admits this is difficult because of his lifestyle and work-related activities  Hypertension – on ramipril and thiazide  Diabetes – on metformin Jack smokes 5-6 cigarettes/day, especially when he is travelling Jack also drinks 1-2 glasses of wine or beer/day  This increases to 2-3 glasses of wine or beer/day when he is travelling (about once/month) Medical History

23. About 3 weeks ago Jack had a “spell”  While eating dinner he suddenly stopped speaking  The right side of his mouth drooped  The fork fell from his hand  It lasted 20 min Jack did not go the emergency department  “I felt fine and was about to go on a trip” His INR one week ago was 1.5 Medical History

24. Discussion Questions 1. What was the “spell”? - Do you need any other clinical information or investigations? 2. What are the options for management?

25. Important Points The episode was focal, abrupt in onset and brief  It meets the clinical diagnosis of TIA  New criteria require the exclusion of tissue damage with brain imaging The physical examination is directed toward excluding a deficit which would suggest stroke  Speech, motor function, facial strength, visual fields  BP ( correlates with risk of hemorrhage) Investigations are directed toward exclusion of other causes of TIA and excluding rare mimics  CT head, carotid Doppler or CTA/MRA 1. Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010) Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010

26. Jack wants to know when he can travel  “They really need me in Peoria next week” What if his Doppler shows:  < 50% carotid artery stenosis?  50-69% carotid artery stenosis? What if Jack’s CT report reads:  Small area of hypodensity in the right centrum semiovale consistent with infarction What-if Scenarios

27. Most recent guidelines for stroke prevention in patients with AF (CCS, 2012) TIA / minor disabling ischemic stroke is associated with a high early risk of recurrent stroke. TIA is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal or retinal ischemia without infarction while ischemic stroke is defined as an infarction [tissue injury] of central nervous system tissue. Key Evidence 1. Skanes AC, et al. Can J Cardiol 2012;28:125-136. 2. Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010) Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010

28. A clinical syndrome characterized by the sudden onset of a focal neurological deficit presumed to be on a vascular basis The Definition of Stroke/TIA 1. Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010) Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010 2. Johnston et al. Ann Neurol 2006; 60: 301–313.

29. Tissue Based TIA Definition Albers GW et al. N Engl J Med 2002;347:1713-1716. Brief episode (typically <1h) caused by focal brain or retinal ischemia without evidence of infarction Indicates risk Encourages neurodiagnostic tests Facilitates rapid intervention

30. Early risk of stroke after discharge from the emergency department among patients with a first-ever TIA 1. Gladstone D et al. CMAJ. 2004 Mar 30;170(7):1099-104.

31. CHA2DS2- Vasc performed better when patients were categorized as low [score = 0] moderate [score=1] or high [score = >2] risk principally because of more precise estimates of thromboembolic risk in patients with CHADS 2 score of 0 or 1. 2 points for age >75 yrs and 1 point for age 65-74 yrs. 1 point each for vascular disease [prior MI, peripheral arterial disease or aortic plaque] or female sex Key Evidence 1. Lip GY et al. Chest 2010;137:263-272. 2. Skanes AC, et al. Can J Cardiol 2012;28:125-136.

32. 1 point for Congestive Heart Failure 1 point for Hypertension 1 point for Age ≥ 75 years 1 point for Diabetes Mellitus 2 points for Prior Stroke or TIA CHADS 2 Score* Stroke Rate, %/yr (95 %CI) 01.9 (1.2 – 3.0) 12.8 (2.0 – 3.8) 24.0 (3.1 – 5.1) 35.9 (4.6 – 7.3) 48.5 (6.3 – 11.1) 512.5 (8.2 – 17.5) 618.2 (10.5 – 27.4) *Score 0: Patients can be administered aspirin *Score 1: Patients can be administered aspirin or anticoagulant therapy *Score ≥2: Patients should be administered anticoagulant therapy CHADS 2 Score (Simple prediction tool for assessing stroke risk ) 1.Gage BF, et al. JAMA. 2001;285:2864-2870.

33. CHA 2 DS 2 -VASc Score 1 point for Congestive Heart Failure/ LV Dysfunction 1 point for Hypertension 2 points for Age ≥ 75 years 1 point for Diabetes Mellitus 2 points for Prior Stroke or TIA 1 or TE 2 1 point for Vascular Disease 3 1 point for Age 65-74 years 1 point for Sex category (female gender) CHA 2 DS 2 -VASc Score* One year event rate (95% CI) of hospital admission and death due to thromboembolism † per 100 person year 00.78 (0.78 – 1.04) 12.01 (1.70 – 2.36) 23.71 (3.36 – 4.09) 35.92 (5.53 – 6.34) 49.27 (8.71 – 9.86) 515.26 (14.35 – 16.24) 619.74 (18.21 – 21.41) 721.5 (18.75 – 24.64) 822.38 (16.29 – 30.76) 923.64 (10.62 – 52.61) *Score 0: Patients can be administered aspirin *Score 1: Patients can be administered aspirin or anticoagulant therapy *Score ≥2: Patients should be administered anticoagulant therapy † Includes peripheral artery embolism, ischemic stroke, and pulmonary embolism 1 TIA = Transient ischemic attack; 2 TE = Thromboembolism 3 Prior myocardial infarction, peripheral artery disease, aortic plaque 1.Lip GY et al. Chest 2010;137:263-272 2.Olesen JB, et al. BMJ 2011;342:d124 3.Task Force or the Management of Atrial Fibrillation of the ESC. Eur Heart J 2010;31:236902429

34. What if this patient has experienced a TIA more recently, e.g., this morning?  What investigations should be conducted; what are any differences between these investigations and those done if the TIA was experienced 3 weeks ago?  EKG, Blood work (including INR), renal function and lipid profile. Brain/neurovascular imaging to exclude a bleed or a large infarct What-if Scenarios

35. Switch to a newer OAC if INR and eGFR are within normal limits Antithrombotic therapy in CKD patients depends on eGFR  If eGFR >30 such patients should receive antithrombotic therapy according to CHADS2 score as outlined in recommendation for patients with normal renal function Expert Recommendations

36. Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulant Reversal Dowlatshahi D, et al. Stroke 2012. DOI: 10.1161/STROKEAHA.112.652065

37. Anticoagulant-associated ICH (aaICH) presents with large hematoma volumes, high risk of expansion, worse outcomes than spontaneous hemorrhage Prothrombin complex connectrates (PCC) indicated for urgent reversal of anticoagulation Background Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

38. Determined outcomes in patients (N=141) with aaICH treated with PCC Prospective inpatient registry of inpatients with aaICH treated with Octaplex at stroke centres:  Calgary, Edmonton, Ottawa Primary outcomes:  INR correction  Thrombotic events  In-hospital mortality CanPro Registry Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

39. Low Rate of Thrombotic Events 30 day thrombotic event rate was 5% Only 3 events within 7d of therapy (2%) Thrombotic Event Type Time from PCC infusion Warfarin Indication Ischemic stroke21 daysAtrial fibrillation Ischemic stroke5 daysAtrial fibrillation Ischemic stroke1 dayAtrial fibrillation Deep vein thrombosis30 daysAtrial fibrillation Deep vein thrombosis21 daysDeep vein thrombosis Myocardial infarction28 daysAtrial fibrillation Myocardial infarction7 daysPulmonary embolism Thrombotic events associated with prothrombin complex concentrates (PCC) therapy Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

40. Hematoma Growth Significant hematoma growth despite INR correction with PCC. This patient was treated with 1000 U of PCC and 10 mg vitamin K 98 minutes after baseline CT scan. Repeat INR was 1.3, 42 minutes after PCC treatment and 1.2 the next day. INR = international normalized ratio; PCC = prothrombin complex concentrate Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

41. Poor Outcomes Intracranial hemorrhage typeNumber In-hospital mortality* Discharge mRS (Median IQR) † Intraparenchymal7130 (42.3%5 (3) ‡ Subdural6121 (34.4%3 (4) § Epidural103 Subarachnoid81 (12.5%)3 (3) ICH = intracranial hemorrhage; mRS = modified Rankin Scale; IQR = interquartile range *P = 0.3; † P=0.012; ‡ mRS missing in 9; § mRS missing in 2 Outcome by anticoagulant-associated ICH Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

42. Prothrombin complex concentrates (PCC) therapy rapidly corrected INR in the majority of patients with anticoagulant-associated ICH, yet mortality and morbidity rates remained high Outcomes after anticoagulant-associated ICH can be devastating even with a reversal strategy Conclusion Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

43. Expected number of fatal hemorrhages, intracranial hemorrhages, strokes and deaths with different antithrombotic treatments 1.Eikelboom JW, et al. J Thromb Hemost 2012:10;966-968.

44. The potential role of antidotes Agent Half life AntidoteUse Heparins 1 hr ProtamineCABG LMWH 3-6 hrs Protamine*Rare New OAC 6-18 hrs Nil?? Fonda 17-21 hrs NilRare Warfarin 20-60 hrs K, PCC, FFP Common DAPT 7-10 d Platelets†Common *Protamine (partial). †Platelets (partial for clopidogrel)

45. Management of Bleeding in Patients Treated with Dabigatran Mild bleeding Delay next dose or discontinue treatment as appropriate 1.van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 2.Hankey GJ & Eikelboom JW. Circulation 2011;123:1436-1450

46. Management of Bleeding in Patients Treated with Dabigatran Moderate to severe bleeding Life threatening bleeding Consider rFVIIa or PCC * Charcoal filtration * or hemodialysis Bleeding continues Stop dabigatran Monitor aPTT and TT Oral charcoal (if within 2 hr of drug ingestion) Mechanical compression Fluid replacement and hemodynamic support Blood product support Surgical intervention *Recommendation based only on non-clinical data (no experience in patients) aPTT = activated partial thromboplastin time TT=thrombin time rFVIIa=recombinant factor VIIa PCC=prothrombin complex concentrates Adapted from: 1.van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 2.Hankey GJ & Eikelboom JW. Circulation 2011;123:1436-1450 3.Crowther MA & warkentin TE. J Thromb Hemostat 2009;7 (Suppl 1):107-110 4.Pradax Monograph 2010, Boehringer Ingelheim Canada Ltd

47. Bleeding is the most common complication of antithrombotic therapy Prevention is better than cure Careful management of interruption and general measures are foundation Specific measures (hemostatic agents, charcoal, dialysis) are available but will be rarely needed When considering anticoagulation, all AF patients should have appropriate assessment of both stroke and bleeding risk using validated risk assessment tools In cases of minor bleeding, hold 1 or 2 doses of the anticoagulant and eliminate any unnecessary concomitant medications that may increase bleeding risk Summary/Conclusions

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