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Andre Douen MD,PhD,FRCPC,FAHA Adjunct Professor, University of Ottawa Director West GTA Regional Stroke Program, Chief,

THP-Neurosciences. Clinical Stroke Update Etobicoke FHT 2014.06.19. Andre Douen MD,PhD,FRCPC,FAHA Adjunct Professor, University of Ottawa Director West GTA Regional Stroke Program, Chief, Division of Neurology, Trillium Health Partners, Mississauga. Transient ischemic attack.

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Andre Douen MD,PhD,FRCPC,FAHA Adjunct Professor, University of Ottawa Director West GTA Regional Stroke Program, Chief,

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  1. THP-Neurosciences Clinical Stroke Update Etobicoke FHT 2014.06.19 Andre Douen MD,PhD,FRCPC,FAHA Adjunct Professor, University of Ottawa Director West GTA Regional Stroke Program, Chief, Division of Neurology, Trillium Health Partners, Mississauga

  2. Transient ischemic attack A forthcoming stroke is often preceded by a TIA Etiologic not different from definite stroke Clinically < 24-hour duration, but.... New MRI lesions seen in up to 80% of patients with clinical course of TIA TIA and stroke have a similar risk for early recurrent stroke, ~ up to 14% within the first 2 weeks Opportunities for prevention – Rapid W/U in SPC Johnston et al. JAMA 2000; 284: 2901–2906. Warach, Kidwell. Neurology 2004; 62: 359–360. Mohr. Neurology 2004; 62 (8 Suppl 6): S3–S6.

  3. Case 1 Mrs W.S., LLM • 62 y/o obese lawyer with GERD • PMH: • Smoking 1ppd x 30 yrs • No HTN, No DM, No Cholesterol at her last visit in Jan 2013 Douen

  4. Case 1 Mrs W.S. • HPI • Speaking with niece regarding a legal matter when.. • Slurred speech  Loss of speech • Right facial droop, Right arm weak and incoordinated • EMS • Symptoms resolved with 15 min • Patient declines transfer to ER • Elects to wait overnight and call fam doc in AM for a quick visit and head to office after to prepare for prosecuting a medico-legal case Douen

  5. Case Examination in office the next day: BP = 160/90 ; HR 90 and regular. No neurological deficits, but with right carotid bruit Current Meds: Losec, Tylenol prn for back pain Next steps: • DDX ? [Is this a TIA, if not what could it be ?] • If TIA, what’s her risk of recurrent stroke ? • Is there a tool that can help assess this ? • What investigations is needed now ? • What should I do...panic ? [Will I get sued if I make the wrong decision ? ] • Should I start Meds ? • Maybe the ER might be a safe bet ?

  6. Stroke/TIA Mimics • Migraine (aura) • Vertigo • Syncope (vaso-vagal, cardiogenic, metabolic) • Seizure (simple, CPSz, grand mal with “Todd’s”) • Structural brain lesions (tumors, AVM, subdurals, abscess) • Radiculopathies (focal numb/weak) • Neuropathies (focal (CTS, ulnar, radial) or diffuse numb ± weak) • Dementia (confusion) • Neuroses • Stress/Anxiety • Malingering

  7. Case 1 Mrs W.S. • Needs to get back to office ASAP • Thinks this “TIA” thing is non-sense, as she feels she was a bit stressed over the case and that caused her symptoms • Not keen on extensive investigations for such a minor episode • She might comply if she can schedule these in between her practice over the next 2 months • If it was a “TIA” (she is skeptical) then she wants to estimate her risk of recurrence Douen

  8. Stroke Recurrence Antecedent stroke/TIA is the most significant indicator of a possible recurrent stroke High incidence of early recurrent stroke following either TIA or minor stroke Early recognition and treatment significantly reduces the risk of stroke recurrence Johnston et al. JAMA 2000; 284: 2901–2906. Warach, Kidwell. Neurology 2004; 62: 359–360. Mohr. Neurology 2004; 62 (8 Suppl 6): S3–S6.

  9. The ABCD2 Score

  10. The ABCD2 Score 1 1 2 1 0 5

  11. Risk Factors for Stroke Within 90 Days of a TIA The ABCD2 Score High Risk Intermediate Risk Stroke Risk (%) Low Risk ABCD2 Score Lancet 2007;369:283-92.

  12. Case 1 Mrs W.S. • After reviewing ABCD2 and showing her these charts, she is now more agreeable to comply with investigations • She wants to know, how do stroke and TIA occur, and also what investigations she would need • She also wants to know about how soon she can have the studies completed • She will reluctantly cancel appointments to attend these investigations • What can she take to prevent this from recurring? Douen

  13. Pathophysiology: Multiple Mechanisms requiring urgent W/U Antiplatelet (Anticoagulation) Douen

  14. Case Next steps: • DDX ? [Is this a TIA, if not what could it be ?] • If TIA, what’s her risk of recurrent stroke ? • Is there a tool that can help assess this ? • What investigations are needed now ? How soon ? • What should I do...panic ? [Will I get sued if I make the wrong decision ? ] • Should I start Meds ? • Maybe the ER might be a safe bet ?

  15. What investigations would you consider for this patient (why, when)? • ECHO (TEE,TTE) • Routine labs • Carotid doppler • CT scan • ECG • Holter • Angiogram (CTA / MRA)

  16. 2. What priority would you give these investigations? • ECG > ECHO> Telemetry/Holter>Carotid Doppler>CT • CT>Telemetry/Holter>ECHO>Carotid Doppler> ECG • ECHO > Holter > CT>Carotid Doppler > ECG • CT> Carotid Doppler = ECG > Holter > ECHO • CT = ECG = Carotid Doppler > Holter > ECHO

  17. 2. What priority would you give these investigations? • ECG > ECHO> Telemetry/Holter>Carotid Doppler>CT • CT>Telemetry/Holter>ECHO>Carotid Doppler> ECG • ECHO > Holter > CT>Carotid Doppler > ECG • CT> Carotid Doppler = ECG > Holter > ECHO • CT = ECG = Carotid Doppler > Holter > ECHO

  18. 3. Which of the following statements about the management of patients with TIA or minor stroke are correct: a. If possible work-up should be completed within 2-3 days b. Early treatment and intervention could reduce stroke recurrence by 80% c. Early management through a stroke clinic is likely superior to routine out patient management. d. For those with ipsilateral severe stenosis revascularization is recommended within 2 weeks e. All of the above

  19. 3. Which of the following statements about the management of patients with TIA or minor stroke are correct: a. If possible work-up should be completed within 2-3 days b. Early treatment and intervention could reduce stroke recurrence by 80% c. Early management through a stroke clinic is likely superior to routine out patient management. d. For those with ipsilateral severe stenosis revascularization is recommended within 2 weeks e. All of the above

  20. EXPRESSUrgent treatment of TIA and minor stroke Outcome Phase 1 Phase 2 Time to clinic visit- 3 days ( 2 -5) 1 day (0-3) Time to prescription- *20 days (8 -53) 1 day (0-3) 90 day risk of stroke-~10.3% 2.1%** *No prescriptions given. Patients advised to see family MD ** 80% reduction in risk of recurrent stroke

  21. Timeliness of Care In Patients with TIAThe OXVASC Study Neurology 2005;65:371-5.c Neurology 2005;65:371-5.

  22. The Consequences of Delaying Access to CareThe OXVASC Study Stroke Patients Neurology 2005;65:371-5.c Neurology 2005;65:371-5.

  23. Timing of Surgical InterventionThe NASCET and ECST Studies 5 Year ARR In Stroke (%) 0-2 2-4 4-12 >12 Time From Event to Randomization (weeks) Lancet 2004;363:915-24.

  24. Case: Mrs. S • 56 y/o F with HTN, DM, Dyslipid (ASA, Crestor, HCTZ, Amlodipine, Januvia, Diamicron, Metformmin) • Presents with ® hemisphere (MCA) mild stroke • CTA neck and head shows no significant ICA stenosis but with severe stenosis (~ 70%) of right MCA • Treatment • Angioplasty/Stenting ? • Continued aggressive medical management ?

  25. SAMMPRIS Randomized Clinical trialRationale (NEJM 2011, 365:11-993) Management of atherosclerotic intracranial arterial stenosis is an important cause of stroke that is • Percutaneoustransluminal angioplasty and stentingvsagressive medical management • Patients with recent TIA or stroke due to 70 to 99% stenosis of a major intracranial artery • The primary end point was stroke or death within 30 days after enrollment or after revascularization

  26. SAMMPRIS Randomized Clinical trialResults (NEJM 2011, 365:11-993) • Enrollment stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non–stroke-related death, 0.4%) (P 0.002).

  27. SAMMPRIS Randomized Clinical trialConclusions (NEJM 2011, 365:11-993 ; Lancet 2014, 383: 333 – 341) • In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. • Initial benefits maintained in a 32 month follow-up (Lancet 2014)

  28. Case CT brain: Nil acute ECG: AF with HR of 95 Is a Doppler still required ?? Meds: …. ??? What is incidence of AF in acute stroke ??

  29. Case CT brain: Nil acute ECG: AF with HR of 95 Is a Doppler still required ?? YES Meds: …. ??? What is incidence of AF in acute stroke ??

  30. Cardioemboli • AF: • High incidence of paroxysmal AF in acute stroke • 13.5% detection of new onset AF using a combination of serial ECG daily x 3 days plus Holter • Overall ~20 % of acute stroke patient have AF (Douen et al, Stroke 2008) • Up to 3 million people worldwide suffer strokes related to AF each year1-3 1. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf 2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 2. 1991:22(8);983-8 3. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996;27:1760-4

  31. EMBRACE Prolonged Ambulatory Cardiac Monitoring Improves the Detection and Treatment of Atrial Fibrillation in Patients with Cryptogenic Stroke: Primary Results from the EMBRACE Multicenter Randomized Trial Gladstone DJ, International Stroke Conference, Honolulu, 2013 P<0.001 • n=572 (age 73±9yrs;); recent ischemic cryptogenic stroke/TIA, no known AF; 16 stroke centers • Randomized to wear either an event-triggered cardiac monitor up to 30 days or a repeat 24 h Holter • New AF detected among 16% of 30-day monitoring group, vs. 3% in the Holter group (p<0.001) Presented by: Gladstone DJ, International Stroke Conference, Honolulu, HI

  32. AF is associated with a pro-thrombotic state ~5- 17 fold increase in stroke risk Risk of stroke is the same in patients with chronic of PAF2,3 There is a high 30-day mortality (~25%) following cardioembolic stroke4 AF-related stroke has a 1-year mortality of ~50%5 AF increases the risk of stroke 1. Wolf PA, et al. Stroke 1991;22:983-988; 2. Rosamond W et al. Circulation. 2008;117:e25–146; 3.Hart RG, et al. J Am CollCardiol2000;35:183-187; 4. Lin H-J, et al. Stroke 1996; 27:1760-1764; 5. Marini C, et al. Stroke 2005;36:1115-1119.

  33. Stroke Severity in Patients with AF 60% 50% 40% % of patients 30% 20% 10% 0% Disabling (discharge mRS ≥ 2) Fatal Effect of first ischemic stroke in patients with AF (n=597) 59.7% 20% mRS=modified Rankin Scale AF=atrial fibrillation Gladstone DJ et al. Stroke. 2009; 40:235-240

  34. Ischemic Stroke Associated With AF is Typically More Severe Than Stroke due to Other Etiologies 50 41.2% 40 30 % bedridden patients on admission (mRs* = 5) 23.7% (P < 0.0005) 20 10 0 Without AF With AF Odds ratio for bedridden state following stroke due to AF was 2.23 (95% CI, 1.87-2.59; P < 0.0005) *mRS=modified Rankin Scale AF=atrial fibrillation Dulli DA, et al. Neuroepidemiology. 2003;22:118-123.

  35. Population-based study of 3530 patients with ischaemic stroke Marini C et al. Stroke 2005;36:1115–9 Mortality 60 Patients with AF (n=869) 50 Patients without AF (n=2661) 40 Annual mortality rate (%) 30 20 10 0 1 2 3 4 5 6 7 8 Years after stroke Increased mortality after ischemic stroke in patients with AF persists for up to 8 years

  36. Marini C et al. Stroke 2005;36:1115–9 Recurrent stroke after ischemic stroke 10 8 Patients with AF 6 Patients without AF Cumulative probability of recurrence (%) 4 P=0.0398 2 0 0 2 4 6 8 10 12 Months after first stroke AF associated with increased risk of recurrent stroke

  37. Missed Opportunities for Stroke Prevention in AF:Registry of the Canadian Stroke Network 2003-2007 No antithrombotics Dual antiplatelets Single antiplatelet Warfarin: therapeutic Warfarin: sub-therapeutic Preadmission medications in patients with known AF admitted with acute ischemic stroke (high-risk cohort, n=597) Preadmission medications in patients with known AF and a previous ischemic stroke/TIA admitted with acute ischemic stroke (very high-risk cohort, n=323) Need for greater efforts to prescribe and monitor appropriate antithrombotic therapy to prevent stroke in patients with AF Gladstone Stroke 2009;40:235

  38. AF prevalence increases with age 9 8 7 6 5 AF prevalence (%) 4 3 2 1 0 General population >60 years >80 years Age 1. Go AS, et al. JAMA 2001;285:2370-2375.

  39. 10.Patients with AF who has spontaneous intracranial hemorrhage while using OAC should never be placed back on OAC • True • False

  40. 10.Patients with AF who have spontaneous intracranial hemorrhage while using OAC should never be placed back on OAC • True • False Cause of bleed needs to be assessed: • Elevated INR • Concomitant use of antiplatelet agent • Overdose of NOAC • CrCl • Drug abuse • H/o trauma/fall • HGB, plts etc • Risk benefit ratio

  41. CHADS 2 • 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

  42. CHA2DS2-Vasc score Mrs W.S. = 4 (hypertension, age 65-74 yr, female)

  43. 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 favor no antithrombotic therapy *OAC = Oral anticoagulant ASA = Aspirin Skanes AC, et al. Can J Cardiol 2012;28:125-136.

  44. Case - Mrs W.S. Risk: 62-year-old - < 75 : 0 HTN : 1 No h/o CHF : 0 No DM : 0 TIA symptoms : 2 CHADS Risk = 3 CHADS-VASC Risk = 4 (HTN, F, Stroke symptoms)

  45. 11. For patient with cardioembolic (AF) stroke/TIA which of the following Antitrhombotic Agents is recommended for secondary prevention • Warfarin • Dabigatran(Pradax) • Rivaroxaban(Xaralto) • Apixaban(Eliquis) • Clopidogrel+ ASA • ASA/ER Dipyridamole

  46. 11. For patient with cardioembolic (AF) stroke/TIA which of the following Antitrhombotic Agents is recommended for secondary prevention • Warfarin • Dabigatran(Pradax) • Rivaroxaban(Xarelto) • Apixaban(Eliquis) • Clopidogrel+ ASA • ASA/ER Dipyridamole

  47. Challenges of Oral Anticoagulation Therapy (OAC) Narrow efficacy window + multiple interactions hard to use/take1 = 20.0 15.0 INTRACRANIAL BLEED ISCHEMIC STROKE Odds Ratio 10.0 5.0 1.0 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR • Haas S. J Thromb Thrombolysis. 2008;25:52-60. • Adapted from Ezekowitz MD et al. Mayo Clin Proc. 2004;79:904-913.

  48. INR control: clinical trials v. clinical practice INR* control in clinical trial versus clinical practice (TTR**) 66% Clinical trial1 Clinical practice2 44% 38% % of eligible patients receiving warfarin 25% 18% 9% >3.0 INR <2.0 2.0 – 3.0 *INR = International normalized ratio ** TTR = Time in Therapeutic Range (INR2.0-3.0) 1. Kalra L, et al. BMJ 2000;320:1236-1239 * Pooled data: up to 83% to 71% in individualized trials; 2. Matchar DB, et al. Am J Med 2002; 113:42-51.

  49. 12.Despite the challenges of using warfarin, the lack of antidote for the NOAC makes them less valuable than warfarin in cardioembolic prophylaxis in acute stroke • True • False

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