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Primary Care Education Progam

Primary Care Education Progam. Steering Committee. 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

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Primary Care Education Progam

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  1. Primary Care Education Progam

  2. Steering Committee 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

  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. Perspectives on Stroke • About 80% of all strokes are ischemic1 • Effect of first ischemic stroke in patients with AF: 60% are disabling, 20% are fatal2 • 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 death4,5 1Heart and Stroke Foundation; 2Gladstone Stroke 2009;40:235; 3AHA Stroke 1999;30:905-15; 4Gage ArchIntern Med 1996;156:1829; 5Solomon 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. 60% 50% 40% 30% 20% 10% 0% Stroke Severity in Patients with AF Effect of first ischemic stroke in patients with AF (n=597) % of patients AF=atrial fibrillation Gladstone DJ et al. Stroke 2009; 40:235-240 Disabling Fatal

  7. Warfarin in Atrial Fibrillation: • 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% • 1Hart Ann Int Med 2007;146:857; 2Hylek Stroke 2006;37:1075; 3Singer Chest2008;13;3:546S4Gladstone Stroke 2009;40:235;5Matchar Am J Med 2002;113:42; 6Bungard Pharmacotherapy 2000;20:1060

  8. CCS 2012 Update to AF Guidelines Assess Thromboembolic Risk (CHADS2) CHADS2 ≥ 2 CHADS2 = 0 CHADS2 = 1 Increasing stroke risk OAC* No anti-thrombotic ASA OAC* OAC *Aspirin is a reasonable alternative in some as indicated by risk/benefit No additional risk factors for stroke Either female sex or vascular disease Age ≥ 65 yrs or combination of female sex and vascular disease 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 OAC = Oral anticoagulant ASA = Aspirin Skanes AC, et al. Can J Cardiol 2012;28:125-136.

  9. CCS 2012 Update to AF Guidelines *Not yet approved in Canada Skanes AC, et al. Can J Cardiol 2012;28:125-136.

  10. Prevention of Stroke • Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations. Superiority Stroke or Systemic Embolism p-value 0.29 0.90 Dabigatran 110 mg BID <0.001 0.65 Dabigatran 150 mg BID 0.12 0.88 Rivaroxaban 20 mg QD 0.01 0.79 Apixaban 5 mg BID Ischemic Stroke 0.35 1.11 Dabigatran 110 mg BID 0.03 0.76 Dabigatran 150 mg BID 0.59 0.94 Rivaroxaban 20 mg QD 0.42 0.92 Apixaban 5 mg BID 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Comparator better Warfarin better 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.

  11. Reducing the Bleeding Risk • Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations. Intracranial Hemorrhage Superiority p-value <0.001 <0.001 0.30 Dabigatran 110 mg BID 0.41 Dabigatran 150 mg BID 0.02 0.67 <0.001 Rivaroxaban 20 mg QD 0.42 Apixaban 5 mg BID ISTH Major Bleeding 0.003 0.80 Dabigatran 110 mg BID 0.31 0.93 Dabigatran 150 mg BID 0.58 1.04 <0.001 Rivaroxaban 20 mg QD 0.69 Apixaban 5 mg BID 0.50 0.75 1.00 1.25 0.25 HR (95% CI) Comparator better Warfarin better • Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph. Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981

  12. New OAC vs. warfarin in moderate CKD (eGFR <50 ml/min) Stroke or Systemic Embolism 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 Better Warfarin 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

  13. New OAC vs. warfarin in moderate CKD (eGFR <50 ml/min) Major bleeding 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 Better Warfarin 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

  14. Safety Outcomes: RELY Connolly NEJM 2010;363:1876; *Eikelboom Circulation 2011;123:2363

  15. Safety Outcomes*: ROCKET AF *Based on Safety On-Treatment Population Patel N Engl J Med 2011;365:883

  16. Bleeding and Net Clinical Outcomes: ARISTOTLE *Net Clinical Outcome: Stroke, systemic embolism, death, or major hemorrhage • BoehringerIngelheim (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 • 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 • Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations. Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981 • BoehringerIngelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph.

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

  19. Patients unsuitable for new anticoagulants 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 Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc.

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

  21. Patient Profile:Jack 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”

  22. Medical History • 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)

  23. Medical History • 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

  24. Discussion Questions

  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 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. Key Evidence Skanes AC, et al. Can J Cardiol 2012;28:125-136. 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 Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010) Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010 Johnston et al. Ann Neurol 2006; 60: 301–313.

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

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

  31. Key Evidence Lip GY et al. Chest 2010;137:263-272. Skanes AC, et al. Can J Cardiol 2012;28:125-136.

  32. CHADS2 Score(Simple prediction tool for assessing stroke risk) • 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 Gage BF, et al. JAMA. 2001;285:2864-2870.

  33. CHA2DS2-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 TIA1 or TE2 • 1 point for Vascular Disease3 • 1 point for Age 65-74 years • 1 point for Sex category (female gender) 1TIA = Transient ischemic attack; 2TE = Thromboembolism 3Prior myocardial infarction, peripheral artery disease, aortic plaque Lip GY et al. Chest 2010;137:263-272 Olesen JB, et al. BMJ 2011;342:d124 Task Force or the Management of Atrial Fibrillation of the ESC. Eur Heart J 2010;31:236902429

  34. What-if Scenarios • What if this patient has experienced a TIA morerecently, 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

  35. Expert Recommendations • 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

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

  37. Background • 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 Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

  38. CanPro Registry • 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 Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

  39. Low Rate of Thrombotic Events Thrombotic events associated with prothrombin complex concentrates (PCC) therapy • 30 day thrombotic event rate was 5% • Only 3 events within 7d of therapy (2%) 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 Outcome by anticoagulant-associated ICH Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

  42. Conclusion • 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 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 Eikelboom JW, et al. J ThrombHemost 2012:10;966-968.

  44. The potential role of antidotes *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 van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 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 • 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 • Consider rFVIIa or PCC* • Charcoal filtration* or hemodialysis *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 Bleeding continues Adapted from: van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 Hankey GJ & Eikelboom JW. Circulation 2011;123:1436-1450 Crowther MA & warkentin TE. J Thromb Hemostat 2009;7 (Suppl 1):107-110 Pradax Monograph 2010, Boehringer Ingelheim Canada Ltd

  47. Summary/Conclusions

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