STROKE UPDATE

1. STROKE UPDATE Carlos S. Kase, M.D. Department of Neurology Boston Medical Center Medicine Grand Rounds New England Baptist Hospital March 17, 2011

2. Ischemic Stroke (85%) Hemorrhagic Stroke (15%) Large Vessel (30%) Intracerebral Hemorrhage (10%) Cryptogenic (15%) Cardioembolic (25%) Lacunar (15%) Subarachnoid Hemorrhage (5%) STROKE MECHANISMS ? Albers GW, et al. Chest. 2001;119:300S-320S. Albers GW. Personal communication. February 27, 2003. Rosamond WD, et al. Stroke. 1999;30:736-743.

3. ADVANCES IN CEREBROVASCULAR • DISEASE • Treatment of Acute Ischemic Stroke • Secondary Stroke Prevention

4. ADVANCES IN CEREBROVASCULAR • DISEASE • Treatment of Acute Ischemic Stroke • IV Thrombolysis • IA Thrombolysis • Embolectomy

5. ADVANCES IN CEREBROVASCULAR • DISEASE • Treatment of Acute Ischemic Stroke • IV Thrombolysis • IA Thrombolysis • Embolectomy

6. NINDS t-PA Study NEJM 1995;333:1581-7 • First proven effective therapy for acute stroke • Double-blind, randomized, 624 pts. • t-PA 0.9 mg/kg (max. 90 mg) IV over 1 hour • Treatment started < 3 hrs. from stroke onset • CT documenting absence of hemorrhage • No anticoagulants/antiplatelets for 24 hrs.

8. IV tPA Declining Benefit over Time Hacke W, et al. Lancet 2004;363:768-74

9. IV tPA Declining Benefit over Time 4½ h. Hacke W, et al. Lancet 2004;363:768-74

10. NEJM 2008;359;1317-29

14. Stroke 2009;40:2945-8 The eligibility criteria for treatment in this time period are similar to those for persons treated at earlier time periods, with any one of the following additional exclusion criteria: Patients older than 80 years, those taking oral anticoagulants, those with a baseline National Institutes of Health Stroke Scale score >25, or those with both a history of stroke and diabetes.

15. ADVANCES IN CEREBROVASCULAR • DISEASE • Treatment of Acute Ischemic Stroke • IV Thrombolysis • IA Thrombolysis • Embolectomy

17. (Prolyse in Acute Cerebral Thromboembolism)

18. PROACT II 180 patients 6-hour window MCA stem or division occlusion 121 proUK (9 mg) IA; 59 control Efficacy: Rankin 0-2 at 90 days Safety: Rate of symptomatic ICH, mortality

19. PROACT II TRIAL Furlan A, Higashida R, Wechsler L, et al. - JAMA 1999;282:2003-11 Randomized trial of IA pro-Urokinase+heparin v. heparin in angiographically-documented MCA occlusion • RESULTS • Rankin < 2 at 3 months in 40% r-proUK, 25% control (p=.04) • Symptomatic ICH in 10% r-proUK, 2% control (p=.06) • Recanalization 66% r-proUK, 18% control (p<.001) • Mortality 25% r-proUK, 27% control

21. Diagnostic Imaging Evaluation • Head CT without contrast: r/o ICH • CTA: Evaluation for large artery occlusion • CTP: Evaluation of perfusion mismatch • MRI: Extent of infarct on DWI • MRA: Large artery occlusion • MRP: Evaluation of perfusion mismatch

22. Perfusion Mismatch Penumbra =Tissue at Risk CBV Cerebral Blood Volume MTT Mean Transit Time

23. Perfusion Match No Penumbra CBV Cerebral Blood Volume MTT Mean Transit Time

24. Diagnostic Evaluation: MRI DWIPWI

25. Diagnostic Evaluation

26. ADVANCES IN CEREBROVASCULAR • DISEASE • Treatment of Acute Ischemic Stroke • IV Thrombolysis • IA Thrombolysis • Embolectomy

27. Intra-arterial thrombectomy • Mechanical removal of thrombus: • MERCI trial • Embolectomy device (Merci Retriever) • to open occluded intracranial large vessels within 8 hours of symptom onset • All patients ineligible for intravenous tPA • Outcomes • - Recanalization and safety • - Neurological outcome at 90 days in recanalized vs. non-recanalized patients Smith WS, et al. Stroke 2005;36:1432-8

30. 0 - 3 4½ 6 - 8 IV tPA extended window MERCI MR Rescue trial Intra-arterial Thombolysis/ Thrombectomy IV t-PA 0 - 8 TIME (HOURS) ACUTE ISCHEMIC STROKE TREATMENT OPTIONS

31. ADVANCES IN CEREBROVASCULAR • DISEASE • II. Secondary Stroke Prevention • Risk factor control • Anti-platelet agents • Anticoagulants • Interventional procedures

32. ADVANCES IN CEREBROVASCULAR • DISEASE • II. Secondary Stroke Prevention • Risk factor control • Anti-platelet agents • Anticoagulants • Interventional procedures

33. (Perindopril Protection Against Recurrent Stroke Study)

36. Stroke 2008;39:1647-52

37. Stroke 2008;39:1647-52

38. ATRIAL FIBRILLATION

40. IIa Inhibitors XII Direct thrombin inhibitors XI IX VII VIII X Direct Thrombin Inhibitors Tested: Ximelagatran New: Dabigatran V II I Fibrin Clot

41. IIa Inhibitors XII Direct thrombin inhibitors XI IX VII VIII X Direct Thrombin Inhibitors Tested: Ximelagatran New: Dabigatran V Ximelagatran As effective as warfarin Hepatotoxic II I Fibrin Clot

42. IIa Inhibitors XII Direct thrombin inhibitors XI IX VII VIII X Direct Thrombin Inhibitors Tested: Ximelagatran New: Dabigatran V Ximelagatran As effective as warfarin Hepatotoxic II I Fibrin Clot

43. pp. 1139-1151

44. pp. 1139-1151 18,113 patients randomized Design: Open-label, Non-Inferiority trial Median treatment duration: 2 years 951 centers in 44 countries December 2005 to March 2009

45. Stroke / Systemic Embolism – RE-LY Study P < 0.001 (NI) P < 0.001 (SUP) RRR: 45% 1.69 1.53 % per year 1.11 182/6,025 134/6,076 199/6,022

47. Major bleeding and components Data represent %/year

48. Net clinical benefit and components * Major Bleeding Events Data represent %/year

50. Dabigatran for Stroke Prevention in AF:Pros and Cons Pros NI/superior to warfarin Fixed-dose Rapid onset of action No need x monitoring No drug/food interactions Lower rates of ICH No hepatotoxicity Cons Open-label design Short f/u period (2 years) Small absolute risk reduction Increase in rate of MI Increase rate GI bleeding Lack of antidote More expensive than warfarin