1. Hyperacute management of TIA and minor stroke. Shelagh Coutts MD FRCPC Associate Professor, Clinical Neurosciences Calgary Stroke Program, Calgary Stroke Program,

2. Objectives To review prognosis of TIA and minor stroke. To review prognosis of TIA and minor stroke. To describe the utility of CT/CTA in assessment of these patients. To describe the utility of CT/CTA in assessment of these patients. To discuss treatment options for TIA/minor stroke. To discuss treatment options for TIA/minor stroke.

3. Stroke Risk Risk of stroke following a TIA is high: 10% within 90 days 50% of these within the first 48 hours 20-40% of strokes are preceded by a TIA or non disabling stroke. Golden Opportunity for Stroke Prevention!

4. What is a TIA in practice TIA is a patient that has resolved when assessed by a physician (usually not a neurologist). TIA is a patient that has resolved when assessed by a physician (usually not a neurologist). This is frequently the definition used. This is frequently the definition used. Likely many of the patients in all of the large epidemiological studies had not resolved completely. Likely many of the patients in all of the large epidemiological studies had not resolved completely. Really this is a collection of “Minor cerebrovascular events”. Really this is a collection of “Minor cerebrovascular events”.

5. We have a mountain to climb

6. Conditions Misdiagnosed as TIA Migraine aura Migraine aura Syncope, postural hypotension Syncope, postural hypotension Seizure Seizure Vertigo Vertigo Transient Global Amnesia Transient Global Amnesia Anxiety/Hyperventilation Anxiety/Hyperventilation Confusion Confusion Unexplained fall Unexplained fall Peripheral nerve palsy Peripheral nerve palsy

7. ABCD 2 Score Derived a 7 point score to stratify the clinical risk of stroke after TIA: A: age > 60 years – 1 point A: age > 60 years – 1 point B: BP (systolic>140, diastolic>90)- max 1 point B: BP (systolic>140, diastolic>90)- max 1 point C: clinical –weakness =2, speech only = 1, C: clinical –weakness =2, speech only = 1, D: Duration, >60 minutes =2, D: Duration, >60 minutes =2, 10-59 =1, <10 =0. 10-59 =1, <10 =0. D: Diabetes mellitus =1 D: Diabetes mellitus =1 Johnston, SC, Lancet 2007;369:283-292.

8. In practice ABCD2 not that useful ABCD2 >5: Sensitivity of 31.6% for stroke at 7 days and 29.2% at 90 days. ABCD2 >5: Sensitivity of 31.6% for stroke at 7 days and 29.2% at 90 days. ABCD2 >2: Sensitivity of 94.7%, specificity of 12.5% for stroke at 7 days. ABCD2 >2: Sensitivity of 94.7%, specificity of 12.5% for stroke at 7 days. Overall reliability poor – Overall reliability poor – AUC: 0.56 (0.47–0.65) ED physician; or 0.65 (0.57–0.73) coordinating centre AUC: 0.56 (0.47–0.65) ED physician; or 0.65 (0.57–0.73) coordinating centre Perry et al. CMAJ 2011:183(10): 1137–1145.

9. High risk TIA Symptom onset within the last 48 hours with any one of the following: Symptom onset within the last 48 hours with any one of the following: Motor deficit lasting more than 5 minutes Speech deficit lasting more than 5 minutes (Atrial fibrillation with TIA)

10. EXPRESS 80% reduction in recurrent stroke risk by urgent implementation of known treatments Rothwell et al, Lancet 2007;370:1432

12. What this means? Timing is everything. Timing is everything. High risk TIA: motor or speech symptoms lasting >5 minutes within last 48hours. High risk TIA: motor or speech symptoms lasting >5 minutes within last 48hours. Extremely early assessment makes the standard TIA/stroke labels difficult to apply. Extremely early assessment makes the standard TIA/stroke labels difficult to apply. All risk is not explained by ABCD2 score. All risk is not explained by ABCD2 score. What role does imaging play in risk assessment beyond clinical characteristics? What role does imaging play in risk assessment beyond clinical characteristics?

13. DWI identifies true ischemia ~50% of all TIA’s associated with permanent damage. Especially if it lasts > 1 hour. Even brief symptoms cause areas of permanent injury Kidwell C et al. Stroke 1999; 6:1174-1180.

14. Event free survival time for new stroke Coutts SB et al. Annals of Neurology 2005;57:848-854

15. TIA etiology predicts recurrence Large artery disease has the highest early risk of recurrence. Large artery disease has the highest early risk of recurrence. This appears to be independent of DWI status. This appears to be independent of DWI status. Not only carotid disease, but also vertebrobasilar disease and intracranial atherosclerosis. Not only carotid disease, but also vertebrobasilar disease and intracranial atherosclerosis.

16. What about CT? For many sites MRI is unavailable emergently For many sites MRI is unavailable emergently Intracranial and extracranial stenosis/occlusion has the highest early risk. Intracranial and extracranial stenosis/occlusion has the highest early risk. Most patient get CT brain. Most patient get CT brain. Arch to vertex CT Angiography (CTA) can quickly identify high-risk vascular lesions and can easily accompany CT brain. Arch to vertex CT Angiography (CTA) can quickly identify high-risk vascular lesions and can easily accompany CT brain.

17. CT And MRI in the Triage of TIA and minor Cerebrovascular events to identify High risk patients. (CATCH) Assess the use of CT/CTA in the prediction of recurrent events and disability in minor stroke/TIA. Assess the use of CT/CTA in the prediction of recurrent events and disability in minor stroke/TIA. Prospective enrollment with informed consent of consecutive high risk TIA and minor stroke (NIHSS<4) patients presenting to the ED assessed by a stroke neurologist within 24 hours of onset. Prospective enrollment with informed consent of consecutive high risk TIA and minor stroke (NIHSS<4) patients presenting to the ED assessed by a stroke neurologist within 24 hours of onset.

18. Methods CT/CTA positive metric: Acute ischemic change on CT or symptomatic intracranial or extracranial vessel occlusion or stenosis ≥ 50%, ipsilateral to the clinically relevant ischemic brain tissue. 1 CT/CTA positive metric: Acute ischemic change on CT or symptomatic intracranial or extracranial vessel occlusion or stenosis ≥ 50%, ipsilateral to the clinically relevant ischemic brain tissue. 1 Primary outcome: recurrent stroke within 90 days. Primary outcome: recurrent stroke within 90 days. Secondary outcome: disability at 90 days(mRS >2) Secondary outcome: disability at 90 days(mRS >2) 1. Coutts et al. IJS. 2009; 4:448

19. Results 510 patients enrolled in 29 months. 510 patients enrolled in 29 months. Follow up was available in 98% of patients. Follow up was available in 98% of patients. Median time from symptom onset to CTA was 5.5 hours, to MRI 17.5 hours. Median time from symptom onset to CTA was 5.5 hours, to MRI 17.5 hours. CT/CTA positive metric was present in 171 patients (34%). CT/CTA positive metric was present in 171 patients (34%). 58% of patients were DWI positive. 58% of patients were DWI positive. Median NIHSS 1. Median NIHSS 1. Coutts et al. Stroke. 2012:43: 1013-7

20. Primary outcome 36 recurrent events (7.1% 95%CI: 5.0-9.6). 36 recurrent events (7.1% 95%CI: 5.0-9.6). 19 progression, 17 recurrence. 19 progression, 17 recurrence. Median time to event 1 day (IQR 7.5). Median time to event 1 day (IQR 7.5).

21. an VariableRecurrent stroke % (n/N) No recurrent stroke % (n/N) Hazard Ratio (CI 95 ) Age 60 or greater81 (29/36)69 (321/463)1·8 (0·8-4·0 ) Female sex47 (17/36)41 189/4631·3 (0·7-2·5) Diabetes Mellitus22 (8/36)15 (68/463)1·6 (0·7-3·5) Hypertension61 (22/36)56 (259/463)1·2 (0·6-2·4) Current smoker11 (4/36)16 (72/463)0·7 (0·3-2·0) BP ≥ 140 or ≥ 90 mmHg78 (28/36)73 (340/463)1·2 (0·6-2·7) Ongoing symptoms in ER78 (28/36)60 (279/463)2·2 (1·02-4·9) Motor weakness69 (25/36)64 (295/463)1·3 (0·6-2·6) Speech disturbance22 (8/36)31 (145/463)0·64 (0·3-1·4) Acute ischemia on CT14 (5/36)12 (56/463)1·2 (0·5-3·0) Carotid occlusion or stenosis  50% 19 (7/36)9 (40/463)2·4 (1·05-5·5) Intracranial occlusion39 (14/36) 8 (38/463)6.1 (3.1-11.8) CT/CTA positive metric67 (24/36)32 (147/463)4·0 (2·0-8·0) DWI positive75 (27/36)57 (262/463)2.2 (1.05-4.7)

22. Results In the multivariable analysis the only variable that remained predictive of the primary outcome was apriori designated CT/CTA positive metric. In the multivariable analysis the only variable that remained predictive of the primary outcome was apriori designated CT/CTA positive metric.

23. CT/CTA positive

24. MRI positive

25. Disability 74 of 499 (15% 95%CI: 12-18%) had a disabled outcome. 74 of 499 (15% 95%CI: 12-18%) had a disabled outcome. Coutts et al. Stroke. 2012:43:3018-22

26. Effect of recurrent events Of 74 patients with disabled outcome, 55 (74%) had no recurrent stroke and 19 (26%) had a recurrent event. Of 74 patients with disabled outcome, 55 (74%) had no recurrent stroke and 19 (26%) had a recurrent event. Out of the 463 patients who did not have a recurrent event 55 were disabled (12%). Out of the 463 patients who did not have a recurrent event 55 were disabled (12%). By contrast 19/36 (53%) patients were disabled after a new event. By contrast 19/36 (53%) patients were disabled after a new event.

27. Putting this all together

28. Canadian Stroke Network Secondary Stroke Prevention guideline update 2012.

29. Who should get a CTA High risk TIA (motor or speech symptoms >5 minutes) or persistent focal symptoms within 48 hours of onset. High risk TIA (motor or speech symptoms >5 minutes) or persistent focal symptoms within 48 hours of onset. Rule out dissection (vertebral or carotid artery) – focal neurological symptoms in the setting of neck pain, recent trauma, neck manipulation etc. Rule out dissection (vertebral or carotid artery) – focal neurological symptoms in the setting of neck pain, recent trauma, neck manipulation etc.

30. 32 year old male. Transient tinnitus right ear, then 10 minutes of right sided weakness. Resolved.

31. Ideal Care. Where are we headed? CTA used to stratify very early risk. CTA used to stratify very early risk. MR as the major screening tool for the brain. MR as the major screening tool for the brain. Antiplatelet therapy immediately. Antiplatelet therapy immediately. Rapid access to carotid endarterectomy. Rapid access to carotid endarterectomy. Immediate use of anticoagulants for atrial fibrillation. Immediate use of anticoagulants for atrial fibrillation. Timing of statins? BP management? Timing of statins? BP management? Clinical trials for novel treatments –eg POINT, TEMPO Clinical trials for novel treatments –eg POINT, TEMPO

32. What’s next for treatment? TEMPO-1: Phase II dose escalation safety study of low dose TNK in minor stroke patients with intracranial occlusion. TEMPO-1: Phase II dose escalation safety study of low dose TNK in minor stroke patients with intracranial occlusion. Treatment within 12 hours of symptom onset. Treatment within 12 hours of symptom onset. Multi-centre Canadian trial. Multi-centre Canadian trial. Still looking for other sites. Still looking for other sites.

33. Imaging is key in the assessment of TIA and minor stroke Confirming the diagnosis can be helpful. Confirming the diagnosis can be helpful. Need to know why it happened to prevent the next one. Need to know why it happened to prevent the next one. The earlier we make the assessment the more likely we can intervene. The earlier we make the assessment the more likely we can intervene. We need large coordinated trials in these patients. Target high risk patients. We need large coordinated trials in these patients. Target high risk patients.

34. Questions? scoutts@ucalgary.ca

35. 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

36. 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

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

38. 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

39. 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

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

41. 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%

42. 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

45. 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

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

50. 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

51. World Stroke Congress 2010 Seoul, South Korea

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

53. 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

54. 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

55. 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

56. 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

57. Stroke and ischaemic events: RELY-ABLE ® 57 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

58. 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 58 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

59. 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 59 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

60. 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

61. 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

62. 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

63. 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

65. 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

66. 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

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

68. Stroke risk in patients with previous TIAs and Stroke

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

70. 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

71. 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

72. 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

73. New Oral Anticoagulants Guidelines and tips Starting/stopping Switching/swapping Measuring/monitoring Philip Teal MD FRCPC Sauder Family & Heart and Foundation Professor of Stroke Neurology University of British Columbia

74. Disclosures Honorariums (past 5 years) – Steering Committees, advisory boards, sponsored talks Boehringer Ingelheim Sanofi Aventis BMS Bayer Roche Canada Pfizer Servier Clinical trial participation – Sanofi Aventis – Boehringer Ingelheim – Bayer

75. Objectives Risk stratification schemes 2012 Canadian Atrial Fibrillation Guidelines Starting OAC post stroke Monitoring the new OACs Starting/ Stopping

76. The Stroke Service Perspective on AF  Patients referred for advise on primary or secondary stroke prevention in atrial fibrillation (outpatients)  Unrecognized, undiagnosed atrial fibrillation-first recognition on presentation with a major stroke  Recognized atrial fibrillation, untreated or undertreated presenting with a first or recurrent stroke  Intracerebral hemorrhage on anticoagulation  Poor outcomes with acute stroke therapies in atrial fibrillation – challenges for acute reperfusion therapies  Cryptogenic strokes that subsequently are attributed to unrecognized paroxysmal Afib 76

77. The Stroke Service Perspective on AF  Shortcomings of traditional antithrombotic therapies ASA, warfarin, dilemmas with NOACs (new oral anticoagulants)  Errors in stratification of patients into low, medium, high stroke risks  Stroke Severity in atrial fibrillation  Intracerebral hemorrhage on anticoagulation  Poor outcomes with acute stroke therapies in atrial fibrillation 77

78. VGH Stroke Service – Week of Aug 19th YY 80 year old man Afib, untreated JH 56 year old man with afib and MAVR. sub therapeutic 78

79. VGH Stroke Service – Week of Aug 19th YD 62 year old man with AF, stopped warfarin HG 86 year old woman with AF. “falls”

80. VGH Stroke Service – Week of Aug 19th JT 71 year old woman with Afib, untreated PT 81 year old man with Afib procedural stop

81. VGH Stroke Service – Week of Aug 19 th GM 66 year old man post cardioversion, no Rx PS 59 year old man post gastroscopy, procedural stop

82. Hyperdense MCA Sign

83. Large territory strokes in Afib

84. Quantifying the Risk

85. CCS 2012 Guidelines: We recommend that all patients with AF or AFL (paroxsymal, persistent, or permanent), should be stratified for Stroke (e.g. CHADS 2 ) and for risk of bleeding (e.g. HAS-BLED), and that most patients should receive either an oral anticoagulant or ASA (Strong Recommendation, High quality Evidence) Candian Journal of Cardiology 28 (2012) 125-136

86. AF Is Classified By Episode Duration And the Ability To Return To Sinus Rhythm Permanent (Refractory to cardioversion and/or accepted) Persistent (not self-terminating) Paroxysmal (self-terminating — usually within 7 days) 1st Detected ACC/AHA/ESC 2006 guidelines. J Am Coll Cardiol 2006;48:854-906. Recurrent if ≥2 episodes

87. Prediction of Stroke in AF: CHADS 2 Risk FactorScore C= CHF1 H=hypertension1 A= age ≥ 751 D= diabetes1 S= stroke/TIA2 Adapted from Cairns JA, et al. Can J Cardiol. 2011; 27:74–90. CHADS 2 score % Stroke / yr

88. CHA 2 DS 2 -VASc Score Sum Of: Points Congestive Heart Failure / Left Ventricular Dysfunction 1 Hypertension1 Age ≥ 75 Years2 Diabetes Mellitus1 Prior Stroke or TIA or Systemic Embolism 2 Vascular Disease1 Age > 65 but < 751 Sex Category – Female1 CHA 2 DS 2 - VASc Score Stroke Rate per Year (%/yr) Recommended Therapy 00ASA 11.3OAC or ASA 22.2 OAC 33.2 44.0 56.7 69.8 79.6 86.7 915.2 Lip Chest 2010;137:263; Camm Eur Heart J 2010;31:2369 Patients with a CHADS 2 score of 0 or 1 may still be at increased risk of stroke. The CHA 2 DS 2 -VASc score may be useful in these patients to ensure consideration of all stroke risk factors:

89. LetterClinical CharacteristicPoints HHypertension1 AAbnormal Liver or Renal Function 1 point each 1 or 2 SStroke1 BBleeding1 LLabile INRs1 EElderly (age > 65 yr)1 DDrugs or Alcohol 1 point each 1 or 2 Maximum 9 points Bleeding Risk – HAS-BLED Score Pisters R et al. Chest. 2010 Nov;138:1093-100

90. Warfarin-associated ICH INR 2.7 INR 2.2

91. 74 year old, minor fall. On warfarin INR 2.1

92. Predictors of CNS Bleeding on OAC Advanced age > 75 years Hypertension (systolic BP > 160) History of cerebrovascular disease Intensity of anticoagulation Agents used - new OACs vs VKA Concomitant ASA / clopidogrel Leukoariosis on CT/MRI Microbleeds of T2*/GRE/SWI MRI sequences

93. Connolly SJ, et al; for the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361(12):1139-51; Connolly SJ, et al; for the RE-LY Investigators. N Engl J Med. 2010;363(19):1875-6 (updated); Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365(10):883-91; Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011;365(11):981-92. Data obtained from intention-to-treat analysis Warfarin Better Novel Anticoagulant Better 0.5 12 Apixaban* 5mg BID Rivaroxaban 20mg QD Dabigatran 150mg BID Dabigatran 110mg BID RE-LY ROCKET-AF ARISTOTLE TRIALOAC Agent 0.5 1 Relative Risk (95% CI) * Not approved in Canada for stroke prevention in AF patients # P value = superiority New Oral Anticoagulants vs. Warfarin † All-Cause Stroke or Systemic Embolism P Value # P = 0.01 P = 0.30 P < 0.001 P = 0.12 † Not intended as cross-trial comparison

94. Connolly SJ, et al; for the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-51; Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883-91; Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981-92. Data obtained from intention-to-treat analysis Novel Anticoagulant Better Warfarin Better 1 Apixaban* 5mg BID Rivaroxaban 20mg QD Dabigatran 150mg BID Dabigatran 110mg BID RE-LY ROCKET-AF ARISTOTLE TRIAL OAC Agent Relative Risk (95% CI) New Oral Anticoagulants vs. Warfarin † Intracranial Hemorrhage P Value # P < 0.001 P = 0.02 * Not approved in Canada for stroke prevention in AF patients # P value = superiority † Not intended as cross-trial comparison 0.25 0.50 0.75

95. Connolly SJ, et al; for the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-51; Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883-91; Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981-92. Data obtained from intention-to-treat analysis Novel Anticoagulant Better Warfarin Better 0.512 Rivaroxaban 20mg QD Apixaban* 5mg BID Dabigatran 110mg BID Dabigatran 150mg BID RE-LY ROCKET-AF. ARISTOTLE TRIAL OAC Agent Relative Risk (95% CI) New Oral Anticoagulants vs. Warfarin † All-Cause Mortality P Value # P = 0.051 P = 0.13 P = 0.073 P =0.047 † Not intended as cross-trial comparison * Not approved in Canada for stroke prevention in AF patients # P value = superiority 0.75

96. RE-LY ® ICH subgroup analysis: sites/rates of ICH – dabigatran 110 mg BID vs warfarin 1 BID = twice daily; CI = confidence interval; D = dabigatran; ICH = intracranial haemorrhage; NS = non-significant; RR = relative risk N/rate (%/yr) D 110 mg BIDWarfarin All ICH (n=154)27/0.2390/0.76 Intracerebral (n=71) 14/0.1246/0.39 Subdural (n=70) 10/0.0836/0.31 Subarachnoid (n=13) 3/0.038/0.06 Warfarin better 2.0 Dabigatran better 0 Dabigatran 110 mg BID vs warfarin 0.30 (0.19, 0.45); P<0.001 0.51.01.5 96 0.30 (0.16, 0.54); P<0.001 RR (95% CI); P value 0.27 (0.12, 0.55); P<0.001 0.37; P=NS Significantly lower rates of ICH, intracerebral, and subdural haematoma with dabigatran 110 mg BID 1.Hart RG et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Am Heart J 2012; 4-5

97. CCS Atrial Fibrillation Guidelines 2012: Prevention of Stroke and Systemic Thromboembolism in Atrial Fibrillation and Flutter John A Cairns, MD, FRCPC, Stuart Connolly, MD, FRCPC, Gordon Gubitz, MD, FRCPC Sean McMurtry, MD, PhD, FRCPC, Mario Talajic, MD, FRCPC Carl Van Walraven, MD, FRCPC, MSc

98. Atrial Fibrillation Guidelines

99. Anticoagulant indicated Assessing the Risk of Stroke Female with vascular disease? Hypertension? Diabetes? Prior stroke? Any other risk factor for stroke? > Age 65?

100. AF Guidelines Recommendations We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (e.g., CHADS2) and for the risk of bleeding (e.g., HAS-BLED), and that most patients should receive either an oral anticoagulant or ASA. (Strong Recommendation, High Quality Evidence) *Once approved by Health Canada. We suggest, that when OAC therapy is indicated, most patients should receive dabigatran or rivaroxaban or apixaban* in preference to warfarin. (Conditional Recommendation, High Quality Evidence) 2012 UPDATE

101. Values and Preferences: This recommendation places a relatively high value on comparisons to warfarin showing that dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention; dabigatran and rivaroxaban no more major bleeding and apixaban has less; dabigatran, rivaroxaban, and apixaban have less intracranial haemorrhage; and all three new OACs are much simpler to use. AF Guidelines Recommendations

102. New Oral Anticoagulants: Drug Interactions DABIGATRANRIVAROXABANAPIXABAN P-gp inhibitors * (e.g., ketoconazole verapamil, quinidine, amiodarone) Potent CYP3A4 and P-gp inhibitors ‡ (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors [ritonavir]) Potent CYP3A4 and P-gp inhibitors ‡ (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors) P-gp inducers † (e.g., Rifampicin carbamazepine, St. John’s Wort) Potent CYP3A4 and P-gp inducers ‡‡ (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone) Potent CYP3A4 and P-gp inducers ‡‡ (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone) *P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban † P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban ‡ Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban ‡‡ Combined potemt CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban Note: Concomitant administration of NSAIDs, aspirin or clopidogrel may increase bleeding time for rivaroxaban, dabigatran and apixaban. Apixaban not yet approved in Canada for stroke prevention in patients with atrial fibrilliation. 1. Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd. 2. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc. 3. Granger C, et al. N Engl J Med 2011;365:981-992.

103. When to Start OAC Post-Stroke ?

104. Spontaneous Hemorrhagic Transformation – 7 days post stroke

105. Starting OCA post-Stroke Pre-treatment CT scan on all symptomatic patients. TIAs – may start immediately after ICH excluded Minor/mod strokes – may start within 3-7 days Major strokes – the bigger the stroke the longer you wait (2-4 weeks) New OACs – wait at least 2 weeks post-stroke prior to starting http://www.esostroke.org/pdf/ESO%20http://www.esostroke.org/pdf/ESO%20 Guidelines update Jan 2009

106. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines CHEST 2012; 141(2)(Suppl):e601S–e636S We recommend initiation of oral anticoagulation therapy within 2 weeks of a cardioembolic stroke; however, for patients with large infarcts or other risk factors for hemorrhage, additional delays are appropriate.

107. Selecting the Optimal Patient Consider for: Those with unexplained poor warfarin control Unavoidable drug-drug interactions New patients with atrial fibrillation Avoid in: Patients well-controlled on warfarin (TTR ≥ 65%) Renal failure ( CrCl < 30 mL/min ) Mechanical heart valve replacement Combination of GI disease + elderly Poor adherence Cost concerns Schulman & Crowther. Blood 2012;119:3016-23

108. Important Patient Characteristics Age Be aware of dose adjustment > age 80 Extremes of weight Limited data on if / how dose should be adjusted Renal Function AVOID in patients with CrCl < 30 mL/min CAUTION - ? dose adjustment needed in patients with CrCl 30-50mL /min

109. Assess the patient’s renal function Estimated creatinine clearance must be ≥30 ml/min to consider using dabigatran or rivaroxaban Stop warfarin and monitor INR Initiate dabigatran or rivaroxaban when INR ≤ 2.0 Dabigatran: Twice daily dosing Rivaroxaban: In the morning or evening with a meal Evaluate risk factors for bleeding on dabigatran or rivaroxaban Low body weight (e.g., <50 kg) Older age (e.g., ≥75 years) Concomitant use of ASA, clopidogrel or NSAID Use dabigatran 150 mg BID regimen unless there is increased risk for bleeding; in that case use dabigatran 110 mg BID Use rivaroxaban 20 mg once daily; for patients with increased risk for bleeding use 15 mg once daily, including in patients with estimated creatinine clearance between 30-49 mL/min : Switching patients from warfarin to newer anticoagulants

110. Clinical Monitoring The lack of “required” monitoring is convenient, however: Remember! Clinical status Reinforce adherence Drug interactions Patient education for bleeding

111. Lab Monitoring: When Is It Needed ? Pre-procedure safety: elective and urgent, particularly in the setting of renal dysfunction Bleeding Acute thromboembolic event Suspected underdose or overdose

112. Renal Function Monitoring Depends on age, pre-existing renal function, co- morbidities, other medications and choice of NOAC CrCl Monitoring > 50 Yearly + with clinical deterioration 30 - 50 Q6 months + with clinical deterioration < 30 Contraindicated

113. Dabigatran aPTT: curvilinear dose response van Ryn. Thromb Haemost 2010;103:1116-27 Hemoclot ® TT Assay: linear dose response

114. Rivaroxaban *Tripodi. J Thromb Haemost 2011;9:226-8 PT / INR Dose response (sensitivity) varies by PT reagent INR is not linear at therapeutic drug levels ISI of the reagent must be calibrated for rivaroxaban, not warfarin*

115. Lab Monitoring Summary Monitoring of Drug Level Dabigatran Hemoclot ® Rivaroxaban & apixaban Anti-Xa Assessment of “Reversal” Dabigatran aPTT Rivaroxaban & apixaban PT / INR

116. Pre-Procedure Use of Dabigatran * Use of dabigatran contraindicated Schulman & Crowther. Blood 2012;119:3016-23 Renal function (CrCl, mL/min) Half-life (hr) (range) ≥ 5015 (12-34) 30 - 4918 (13-23) < 30*> 27 (22-35) Standard risk High risk 1 day2 days 2 days (consider aPTT pre) 4 days (consider aPTT pre) 4 days (aPTT pre) 6 days (aPTT pre) Timing of last dose pre-procedure

117. Renal function (CrCl, mL/min) Half-life (hr) (range) ≥ 3012 (11-13) < 30*Unknown Standard risk High risk 1 day2 days 2 days (INR pre) 4 days (INR pre) Timing of last dose pre-procedure Pre-Procedure Use of Rivaroxaban * Use of rivaroxaban contraindicated Schulman & Crowther. Blood 2012;119:3016-23

118. Reversing Anticoagulation XII XI IX VIII VII Fibrin clot V I X II Oral IIa inhibitor Dabigatran Oral Xa inhibitor Rivaroxaban Apixaban 1.The further down the cascade the anticoagulant acts, the harder to reverse 2.Inhibitors are harder to reverse than deficiencies

119. Potential Considerations in Selection of OAC Age Gender Diabetes Prior stroke history Moderate or excellent renal function CHADS 2 score HASBLED score Cost Personal preference

120. 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 (Dabigatran, rivaroxaban) 1. Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd. 2. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc.

121. Summary of 2010 CCS AF Guidelines: Patients Requiring Surgery Cairns et al. Can J Card 2011 27:74-90

122. Perioperative Management of Anticoagulant Therapy Alteration of oral anticoagulant regimen may not be necessary for most patients undergoing low risk procedures: – Dental procedures, joint and soft tissue injections and arthrocentesis, cataract surgery, and upper endoscopy or colonoscopy with or without biopsy For other invasive and surgical procedures, oral anticoagulation needs to be withheld: – Decision whether to pursue an aggressive strategy of perioperative administration of intravenous heparin or subcutaneous low molecular- weight heparin should be individualized based on an estimation of the patient’s risks of thromboembolism and bleeding and the patient’s preference Douketis J, et al. Chest 2008;133:299S-339S; Dunn AS and Turpie AGG. Arch Intern Med 2003;163:901-908

123. Patients with Low to Moderate Stroke Risk (CHADS 2 ≤2): Discontinue antithrombotic therapy before procedure: – ASA or clopidogrel for 7-10 days – Warfarin for 5 days if INR within 2-3 range – Dabigatran for 2 days – Rivaroxaban for 2 days Reinstate antithrombotic therapy once post-procedure hemostasis restored ( ~24 hrs) Cairns et al. Can J Card 2011 27:74-90 Surgical / Diagnostic Procedures: Summary of 2010 Canadian Cardiovascular Society (CCS) Guidelines

124. Acute Stroke in Setting of Dabigatran Obtain aPTT and/or thrombin time – If normal treat as if not on dabigatran If elevated assume therapeutic level of anticoagulation – No IV TPA – Consider intra-arterial treatment based on: Availability/experience Deficit warrants intervention Demonstrable arterial occlusion +/- mismatch

125. Thank you

126. Timing of Discontinuation After LAST Dose of Dabigatran Before Surgery Creatinine Clearance Timing of discontinuation after last dose of dabigatran before surgery Standard risk of bleeding High risk of bleeding > 50 mL/min24 hours2 – 4 days > 30 mL/min ≤ 50 mL/minAt least 48 hours4 days ≤ 30 mL/min2 – 5 days> 5 days Adapted from Van Ryn Thomb Haemost 2010;103:1116