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Cardioembolic Stroke

Cardioembolic Stroke. Andre Douen MD, PhD, FRCPC, FAHA Adjunct Professor, University of Ottawa, Director West GTA Regional Stroke Program, Chief, Division of Neurology, Trillium Health Centre, Mississauga. Case 1 Mrs W.S., LLM. 62 y/o obese lawyer with GERD PMH: Smoking 1ppd x 30 yrs

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Cardioembolic Stroke

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  1. Cardioembolic Stroke Andre Douen MD, PhD, FRCPC, FAHA Adjunct Professor, University of Ottawa, Director West GTA Regional Stroke Program, Chief, Division of Neurology, Trillium Health Centre, Mississauga

  2. 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 2010

  3. 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

  4. Case 1 Examination in office the next day: BP = 160/90 ; HR 90 and regular. No neurological deficits, but with right carotid Bruits. Current Meds: Losec, Tylenol prn for back pain Diagnosis: TIA

  5. Case 1 • 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

  6. Q1. What do you think her stroke risk might be within the next month: a. ~ 2% b. ~ 8% c. ~ 20% d. She’ll almost certainly re-stroke e. Her risk can only be measured over 3 months

  7. Q1. What do you think her stroke risk might be with in the next month: a. ~ 2% b. ~ 8% c. ~ 20% d. She’ll almost certainly re-stroke e. Her risk can only be measured over 3 months

  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. CT brain : Nil acute. ECG : AF with HR of 95 Is a Doppler still required ?? What is incidence and prevalence of AF?? Meds : ???

  13. CT brain : Nil acute. ECG : AF with HR of 95 Is a Doppler still required ?? YES What is incidence and prevalence of AF ?? Meds : ???

  14. EPIDEMIOLOGY Both Incidence/Prevalence increases with age. • Estimated Prevalence: • ~1% of general population, 0.1% < 60 years of age • 1-4% 60-80 years of age • 9% > 80 years of age • Estimated Incidence: •  50 years of age: 0.5% /1000 /year •  70 years of age: 9.7% /1000 /year • Gender: Male > Female • Overall AF affects: • ~200,000 - 250,000 Canadians • 2.2 million Americans

  15. Cardioemboli • AF : • High incidence of paroxysmal AF in acute stroke • 13.5% detection of new onset AF • Overall ~20 % of acute stroke patient with 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

  16. 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 PAF There is a high 30-day mortality (~25%) following cardioembolicstroke AF-related stroke has a 1-year mortality of ~50% 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.

  17. Q2. Because of high risk of spontaneous GI bleeds from angiodysplasia and spontaneous intracranial hemorrhages OAC should be used with extreme caution or not at all in elderly patients (> 80 yrs old) with AF • True • False

  18. Q3. The patients who benefit the most from OAC therapy are those with AF in the age group 65-75 and with no other medical issues. • True • False

  19. Q2a.Because of high risk of spontaneous GI bleeds from angiodysplasia and spontaneous intracranial hemorrhages OAC should be used with extreme caution or not at all in elderly patients (> 80 yrs old) with AF • True • False

  20. Q3a. The patients who benefit the most from warfarin therapy are those with AF in the age group 65-75 and with no other medical issues. • True • False

  21. Q4. Recent studies have shown that ASA+Plavix is superior to ASA alone and equally efficacious to warfarin for cardio-embolic (AF) stroke prophylaxis. Warfarin = ASA+Plavix > ASA • True • False

  22. Q4a.Recent studies have shown that ASA+Plavix is superior to ASA alone and equally efficacious to warfarin for cardio-embolic (AF) stroke prophylaxis. Warfarin = ASA+Plavix > ASA • True • False

  23. 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.

  24. Case 1 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)

  25. Q5. For patient with cardioembolic (AF) stroke/TIA which of the following Antithrombotic Regimens are recommended for secondary prevention • Warfarin • Warfarin + ASA • Warfarin + clopidorgrel b. Dabigatran(Pradax) c. Rivaroxaban(Xaralto) • Apixaban(Eliqus) • All of the above

  26. Q5. For patient with cardioembolic (AF) stroke/TIA which of the following Antithrombotic Regimens are recommended for secondary prevention • Warfarin • Warfarin + ASA • Warfarin + clopidorgrel b. Dabigatran(Pradax) c. Rivaroxaban(Xaralto) • Apixaban(Eliqus) • All of the above

  27. 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.

  28. Warfarin for Atrial Fibrillation Adequacy of Anticoagulation inPatients with AF in Primary Care Practice INR above target6% No warfarin65% INR intarget range15% Subtherapeutic INR 13% Samsa GP, et al. Arch Intern Med 2000;160:967.

  29. Underutilisation of VKA despite prior TIA or stroke AF patients with previous TIA or ischaemic stroke, considered to be suitable for anticoagulation and admitted with acute ischaemic stroke (Ontario 2003-2007) No antithrombotics15% Warfarin–therapeutic 18% Dual antiplatelet therapy 3% Single antiplatelet agent 25% Warfarin–subtherapeutic39% n=323 • Adapted from Gladstone et al. Stroke 2009;40:235-40.

  30. INR >3.0 INR <2.0 INR =2.0-3.0 Suboptimal INR control worldwide (2008-2011) The TTR is only ~50% in a global AF registry * * * * * * 67 59 54 47 44 36 40 38 34 N=1802 N=1127 N=1975 N=2536 N=896 N=1089 N=2520 N=1951 N=1278 *p≤0.005 vs. North America • Adapted from Healey et al. Presented at the ESC meeting on Sunday August 28, 2011 - http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=1355

  31. New OAC • DabigatranEtexilate (Direct Thrombin Inhibitor) in Atrial Fibrillation (RE-LY) • Rivaroxaban (Factor Xa inhibitor)in Atrial Fibrillation (ROCKET-AF) • Apixaban (Factor Xa inhibitor)in Atrial Fibrillation (AVERROES; ARISTOTLE) Pros : No Monitoring Rapid onset of action Similar or better bleeding profile to warfarin Con : No antidote, no clear way of measuring effect

  32. Clinical program to demonstrate the efficacy & safety of apixaban for the prevention of stroke & SE in NVAF patients1 • A total of 23,799 patients were randomised in the clinical program, including 11,927 randomised to apixaban1 • *Patients with ≥2 of the following: age ≥80 years, body weight ≤60 kg, or a serum creatinine level ≥1.5 mg/dL (133 μmol/L)1. Apixaban SmPC 2012. 2. Granger et al. N Engl J Med 2011;365:981-92. 3. Connolly et al. N Engl J Med 2011;364:806-17.

  33. ARISTOTLE: Apixaban was superior to warfarinin preventing stroke or systemic embolism 4 Warfarin 21% RRR 3 Apixaban Patients with event (%) 2 HR 0.79 (95% CI: 0.66-0.95) p<0.001 for non-inferiorityp=0.01 for superiority 1 0 0 6 12 18 24 30 Months • Adaptedfrom Granger et al. N Engl J Med 2011;365:981-92.

  34. ARISTOTLE: Apixaban significantly reduced the risk of major bleeding* vs. warfarin 8 Warfarin 31% RRR 6 Patients with event (%) 4 Apixaban HR 0.69 (95% CI: 0.60-0.80); p<0.001 2 0 0 6 12 18 24 30 Months • * Major bleeding was defined according to ISTH criteria Adapted from Granger et al. N Engl J Med 2011;365:981-92.

  35. AVERROES: Study Design1,2 Event Driven* Mean follow-up: 1.1 years • The primary objective of the trial was to determine if apixaban was superior to ASA for the prevention of the composite outcome of stroke or systemic embolism. • Primary efficacy outcome: Stroke or systemic embolism • Primary safety outcome: Major bleeding N=5599 Apixaban 5.0 mg oral BID(2.5 mg in select patients* [6.4%]) • Patient Population • Patients ≥50 years with NVAF and ≥1 risk factors for stroke • Not receiving VKA therapy (demonstrated or expected to be unsuitable for VKA) Randomised, double-blind,double-dummy ASA 81-324 mg QD** • *Patients with ≥2 of the following: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 μmol/L). **The selection of an ASA dose of 81, 162, 243, or 324 mg was at the discretion of the investigator with 91% of subjects receiving either an 81-mg (64%) or 162-mg (27%) dose at randomisation. 1. ApixabanSmPC. 2. Connolly et al. N Engl J Med 2011;364:806-817. Date of preparation: December 2012

  36. AVERROES: Apixaban was superior to ASAin preventing stroke or systemic embolism* 0.05 ASA 55% RRR 0.04 Apixaban 0.03 Cumulative Hazard 0.02 HR 0.45 (95% CI: 0.32-0.62) p<0.001 for superiority 0.01 0.00 0 3 6 9 12 30 Months • *Primary efficacy outcomeAdapted from Connolly et al. N Engl J Med 2011;364:806-17.

  37. AVERROES: Apixaban was superior to ASAin preventing stroke or systemic embolism* 0.05 ASA 55% RRR 0.04 Apixaban 0.03 Cumulative Hazard 0.02 HR 0.45 (95% CI: 0.32-0.62) p<0.001 for superiority 0.01 0.00 0 3 6 9 12 30 Months • *Primary efficacy outcomeAdapted from Connolly et al. N Engl J Med 2011;364:806-17.

  38. Recent Oral Anticoagulation Trials:Stroke or Systemic Embolism The new oral anticoagulant agents are consistently associated with a numerically lower risk for stroke or systemic embolism compared to warfarin† Data obtained from intention-to-treat analysis †Not intended as cross-trial comparison Apixaban not yet approved in Canada for stroke prevention in patients with atrial fibrilliation • Connoly SJ, et al. N Engl J Med 2009;361:1139-1151. • Patel MR, et al. N Engl J Med 2011;365:883-891. • Granger C, et al. N Engl J Med 2011;365:981-992

  39. Recent Oral Anticoagulation Trials:Hemorrhagic Stroke The new oral anticoagulantsare consistently associated with a numerically lower riskof hemorrhagic stroke compared with warfarin† †Not intended as cross-trial comparison Data obtained from intention-to-treat analysis Apixaban not yet approved in Canada for stroke prevention in patients with atrial fibrilliation • Connoly SJ, et al. N Engl J Med 2009;361:1139-1151. • Patel MR, et al. N Engl J Med 2011;365:883-891. • Granger C, et al. N Engl J Med 2011;365:981-992

  40. Recent Oral Anticoagulation Trials:Major Bleeding HR (95% CI) New Agent Better Warfarin Better †Not intended as cross-trial comparison Data obtained from intention-to-treat analysis Apixaban not yet approved in Canada for stroke prevention in patients with atrial fibrilliation • Connoly SJ, et al. N Engl J Med 2009;361:1139-1151. • Patel MR, et al. N Engl J Med 2011;365:883-891. • Granger C, et al. N Engl J Med 2011;365:981-992

  41. CCS 2012 Update to AF Guidelines Skanes AC, et al. Can J Cardiol 2012;28:125-136.

  42. CCS 2012 Update to AF Guidelines Skanes AC, et al. Can J Cardiol 2012;28:125-136.

  43. Case 1 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)

  44. Case 1 Patient started on warfarin (physician decision) because has “no insurance”; CrCl 37 INRs Q 2 weeks with many absent readings due to busy schedule : April 15 = 2.7 April 30th = 3.4 May 15 = 1.7 May 30th = no reading June 15th = 1.6 June 30th = 3.2 July 15th = no reading

  45. Scenarios and treatment options#1 August 2nd patient asymptomatic but comes in for regular f/u visit. Options: • Repeat labs (CBC, CrCl, INR) • Discuss strategies for adherence and “optimizing” INR levels • Switch ? (safety, LU, compliance)

  46. Scenarios and treatment options#2 August 2nd admitted with L sided paralysis. CT brain normal, symptoms resolve slowly over 2hrs; INR 1.6. Diagnosis TIA Options: • Repeat labs (CBC, CrCl) • Discuss strategies for adherence and “optimizing” INR levels • Switch ? (safety, LU, compliance)

  47. Scenarios and treatment options#3 August 2nd admitted with L sided paralysis. CT brain normal, symptoms resolve slowly over 2hrs; INR 2.3 Options: • Other labs (CBC, Cr, CrCl) • Persist with warfarin but discuss strategies for adherence and “optimizing” INR levels • Switch ? (safety, LU, compliance)

  48. Scenarios and treatment options#4 Patient asymptomatic but comes in for regular f/u visit; ; CrCl now 30 Options: • Other labs (CBC, INR) • Discuss strategies for adherence and “optimizing” INR levels • Switch ? (safety, LU, compliance, CrCl)

  49. Scenarios and treatment options#5 Admitted with mild L sided weakness. CT brain shows small R basal ganglia ischemic insult; INR 1.6, CrCl40 Options: • Other labs (CBC) • Discuss strategies for adherence and “optimizing” INR levels • Switch ? (safety, LU, compliance)

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