ACUTE ISCHEMIC STROKE

1. Emergent Treatment of Acute Ischemic Stroke, Including the Intravenous Administration of Thrombolytic Therapy

2. ACUTE ISCHEMIC STROKE • Complex medical illness resulting from thromboembolism • Parts of the brain irreversibly injured • Other areas dysfunctional (penumbra) • Penumbra might be salvageable if interventions started • Time is an important variable in effective management • Time window might differ between treatments

3. Yatsu FM, Villar-Cordova C. Atherosclerosis. In: Stroke. Pathophysiology, Diagnosis, and Management. Barnett HJM et al (eds) Philadelphia. Churchill-Livingstone, 1998

4. THERAPIES TO TREAT ISCHEMIC STROKE • Restoring, maintaining, or improving blood flow • Neuroprotective agents • Membrane stabilization • Counteract effects of excitatory transmitters • Antagonize free radicals • Halt apoptosis • Slow metabolism

5. NEUROPROECTIVE AGENTS • Large number of agents tested in clinical trials • No evidence of efficacy in improving outcomes • Side effects are common • Disturbances of consciousness or behavior • Seizures • Cardiac arrhythmias or conduction defects • At present, no neuroprotective agent can be recommended

6. Neuroprotection in Cerebral Ischemia: Clinical Trials Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001;11(Suppl 1):60-70

7. Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001;11(Suppl 1):60-70

8. Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001;11(Suppl 1):60-70

9. Carotid endarterectomy Endovascular treatment Induced hypertension Antiplatelet agents Other operations Hemodilution Anticoagulants Thrombolytic agents MEASURES TO IMPROVE OR RESTORE BLOOD FLOW TO THE BRAIN

10. SURGICAL AND ENDOVASCULAR PROCEDURES • Anecdotal evidence supports the use of surgical procedures • Limited evidence means that no recommendation • Endovascular treatment shows great promise • Angioplasty, stenting or mechanical thrombolysis • Combined with intra-arterial thrombolysis • Urgent endovascular therapy is a consideration if available • Will need considerable additional research

11. HEMODILUTION AND INDUCED HYPERTENSION • Altering blood flow by altering viscosity or increasing perfusion pressure • Used successfully to treat vasospasm after SAH • Can be complicated by myocardial ischemia, heart failure, or pulmonary edema • LMW dextran complicated by allergic reactions • Trials of hemodilution for treatment ischemic stroke not successful • At present, not recommended for treatment of acute ischemic stroke

12. ANTICOAGULANTS • Rationale for urgent administration of heparin • Halt propagation of thrombus • Prevent early recurrent embolization • Maintain collateral flow • Adjunct to mechanical or pharmacological thrombolysis • Until recently, limited evidence for safety and efficacy • Several recent trials provide strong evidence

13. TRIALS OF ANTICOAGULATION • Tested unfractionated heparin, LMW heparin, danaparoid • Most trials tested subcutaneous therapy – only 1 trial of intravenous, adjusted dose therapy • Most trials have not used a weight-based regimen • Most trials have involved late entry (up to 48 hours) • One large trial was unblinded and did not require CT prior to treatment

14. HEMORRHAGIC COMPLICATIONS EMERGENT ANTICOAGULATION Placebo/control Anticoagulant FISS - nadroparin 1% 0 IST - heparin 0.3% 0.7% – 1.8% TOAST - danaparoid 0.9% 2.9% FISS-bis - nadroparin 2.8% 3.7% – 6.1% HAEST - dalteparin 1.8% 2.8% TAIST - tinzaparin 0.2% 0.6% – 1.4%

15. PREVENTION OF EARLY RECURRENT STROKE EMERGENT ANTICOAGULATION Placebo/control Anticoagulant FISS - nadroparin 4.7% 1% - 1.9% IST - heparin 2.2% 1.6% - 1.8% TOAST - danaparoid 1.1% 1.1% HAEST - dalteparin 7.5% 8.5% TAIST - tinzaparin 3.1% 3.3% - 4.7%

16. FAVORABLE (best) OUTCOMES EMERGENT ANTICOAGULATION Placebo/control Anticoagulant FISS - nadroparin 35.2% 47.5% - 55.8% IST - heparin 17.0% 17.1% - 17.3% TOAST - danaparoid 47.0% 49.4% FISS-bis - nadroparin 56.8% 57.2% - 59.2% HAEST - dalteparin 21.3% 22.8% TAIST - tinzaparin 42.5% 38.3% - 38.4%

17. CONCLUSIONS AND RECOMMENDATIONSEMERGENT ANTICOAGULATION • Emergent anticoagulant therapy causes a modest increase of symptomatic intracranial or systemic bleeding • No evidence in lowering the risk of early recurrent stroke • Including among patients with cardioembolism • No evidence in halting neurological worsening • No evidence in improving neurological outcomes • No data to recommend emergent anticoagulation for most patients with acute ischemic stroke

18. EFFECTS OF ASPIRINON OUTCOMES AFTER STROKE Lancet 1997 349:1641-49

19. CURE • Randomized trial patient with unstable angina pectoris or non-ST segment myocardial infarction • Enrolled within approximately 14 hours or onset of symptoms • All patients received aspirin 75 - 325 mg/day • 1/2 - Clopidogrel 300 mg initial dose followed by 75 mg/day • Followed for approximately 9 months N Engl J Med, 2001;345:494-502

20. OUTCOMES Aspirin Aspirin and placebo and clopidogrel n = 6259 n = 6303 % % Death, MI, or stroke 11.5 9.3 Vascular death 5.5 5.1 Myocardial infarct 6.7 5.2 Stroke 1.4 1.2 Major hemorrhage 2.7 3.6 Life threatening 1.8 2.1

21. ABCIXIMAB IN ACUTE STROKE STUDY • Randomized, double-blind, dose-escalation study that enrolled 74 patients • Four dose tiers (abciximab bolus or bolus followed by infusion) • 54 patients assigned abciximab and 20 patients assigned placebo • Treated within 24 hours of onset of stroke - 38 sites • One-half treated with 12 hours and others 12 - 24 hours • Stratified enrollment baseline NIHSS score: 4 - 14, 15 and above • Followed with brain imaging studies Stroke, 2000;31:601-609

22. No cases of symptomatic intracranial hemorrhage • Asymptomatic hemorrhagic changes on CT - abciximab: 10, placebo: 1 • Minor non-neurological bleeding – abciximab: 10, placebo: 4 • Thrombocytopenia (non-serious) – abciximab: 4 • Rankin score < 1 at 3 months – abciximab: 19, placebo: 4 • Barthel index > 95 at 3 months – abciximab: 27, placebo: 8

23. CONCLUSIONS AND RECOMMENDATIONSANTIPLATELET AGENTS • Aspirin can be started within hours of stroke – modest benefit • Aspirin should not be considered as an alternative to other interventions – such as rt-PA • The combination of aspirin and clopidogrel holds promise but safety and efficacy in stroke is not known • The GP IIb/IIIa agents are being tested – uncertain utility

24. RATIONALE FOR PHARMACOLOGICAL THROMBOLYSIS • Ischemic stroke is usually due to thromboembolic occlusion • Natural clot lysins promote recanalization – but effect delayed • Thrombolytic agents • Speed clot lysis • Restore perfusion to the brain • Permit delivery of other medication

25. INTRA-ARTERIAL ADMINISTRATION OF THROMBOLYTIC AGENTS • Potential advantages • Higher concentration of medication at site • Lower systemic doses might improve safety • Potential disadvantages • Facilities not widely available • Time required to mobilize resources • No head-to-head comparisons with IV therapy

27. INTRA-ARTERIAL PROUROKINASEPROACT - II STUDY Randomized, clinical trial - 54 centers 121 Patients - proUK and heparin 59 Patients - heparin Outcomes measured at 90 days Blinded to treatment allocation Slight or no disability Furlan et al, JAMA 1999; 282:2003-2011

28. OUTCOMES AT 90 DAYS PROACT - II STUDY Modified Rankin Scale 0 - 2 Baseline ProUK Heparin % Odds NIHSS Score n % n % Diff Ratio 4-10 points 10/16 63 5/8 63 0 1.00 11-20 points 34/75 45 9/37 24 21 2.58 21-30 points 4/30 13 1/14 7 6 2.00 Furlan et al, JAMA 1999; 282:2003-2011

29. RECANALIZATION AND INTRACRANIAL BLEEDING - PROACT-II STUDY Recanalization ProUK (%) Heparin (%) 1 Hour 4% -- 2 Hours 19% 2% Symptomatic hemorrhage 10% 2% CT hemorrhage - 1 day 35% 13% Furlan et al, JAMA 1999; 282:2003-2011

30. TRIALS OF STREPTOKINASE Trial Placebo/control Streptokinase MAST - E Dead/disabled 81.8% 79.5% Symptomatic hemorrhage 2.6% 21.2% MAST - I Dead/disabled 68.0% 59.0% (with aspirin) 64.0% Symptomatic hemorrhage 0.6% 6.0% (with aspirin) 10.0% ASK Dead/disabled 43% 48% Symptomatic hemorrhage 3% 13%

31. NINDS PART 1

32. NINDS PART 2

33. Favorable Outcomes at Three Months Persons Treated Within Ninety Minutes New England Journal of Medicine, 1995;333:1581-1587.

34. Favorable Outcomes at Three MonthsPersons Treated Within 91-180 Minutes New England Journal of Medicine, 1995;333:1581-1587.

35. TRIAL OF ALTEPLASEGIVEN 3 - 5 HOURS AFTER ONSET OF STROKE Randomized, double-blind clinical trial at 140 centers in North America. 613 patients enrolled, 39 < 3 hours, 547 3-5 hours, 24 > 5 hours, 3 no Rx. Received dose of alteplase used in NINDS trials Comparison of 272 patients - alteplase, 275 patients - placebo Mean NIHSS score was 11 Clark et al, JAMA 1999; 282:2019-2026

36. OUTCOMES - ATLANTIS Alteplase Placebo Excellent recovery - 90 days 34.0% 32.0% Symptomatic ICH - 10 days 7.0% 1.1% Asymptomatic ICH - 10 days 11.4% 4.7% Mortality - 90 days 7.0% 4.4% Clark et al, JAMA 1999; 282:2019-2026

37. CLEVELAND EXPERIENCE WITH rt-PA JULY 1997 - JUNE 1998 3,948 Patients seen at 29 hospital in area 70 Patients (1.8%) received rt-PA Treated only 10.4% of patients seen < 3 hours Approximately one-half of hospital treated 0 Katzan et al, JAMA 2000; 283: 1151-1158

38. OUTCOMES AND EXPERIENCE CLEVELAND, OHIO Symptomatic hemorrhage in 11 of 70 cases (15.7%) In-hospital mortality among 70 cases - 15.7% In-hospital mortality among non-treated cases - 5.1% Deviation in protocol in 50% of cases Treated outside time - 12.9% Received anticoagulants or platelet agents - 37.1% Katzan et al, JAMA 2000; 283: 1151-1158

39. TRIAL OF ALTEPLASEACUTE ISCHEMIC STROKE 0.9 mg/kg IV - 0 - 6 hours of onset Placebo-controlled, 1-1 randomization 142 patients at 42 sites in North America 71 - alteplase, 71 - placebo Mean NIHSS score of 13 Clark et al Stroke, 2000 31:811-816

40. To date, no head-to-head comparisons of intravenous versus intra-arterial therapy • Intravenous (rt-PA) < 3 hours • Intra-arterial (Pro UK) < 6 hours • No evidence that intra-arterial therapy is either more effective or safer

41. PHYSICIAN EXPERTISE • Because time is critical, many patients will need to be treated in a community setting • Strategy of early treatment locally and transfer to a major medical center • Need to bring expertise to hospital • Telephone consultations • Teleradiology • Telemedicine

42. ALGORITHM FOR DECISIONS ABOUT USE OF rt-PA TO TREAT ISCHEMIC STROKE QUESTION # 1 WHEN DID THE STROKE OCCUR? • Ascertain time of onset of stroke – must be < 3 hours • Ask patient and observers – most conservative time • Not time of last neurological worsening • If a prior TIA with resolution, time starts with new event • Most patients with stroke during sleep are excluded • If CT shows stroke “older” than 3 hours, reassess time of onset

43. QUESTION # 2 ANY RECENT MEDICAL ILLNESSES THAT WOULD MAKE THE ADMINSTRATION OF rt-PA PARTICULARLY DANGEROUS? • Recent ischemic stroke – generally < 4 weeks • Recent trauma – including falls with the stroke • Recent myocardial infarction – generally < 4 weeks • Recent surgery – generally < 2 weeks • Severity of surgery • Consultation with surgeon • Recent serious bleeding – generally < 4 weeks

44. QUESTION # 3 ANY MEDICATIONS THAT MIGHT MAKE THE ADMINISTRATION OF rt-PA PARTICULARLY DANGEROUS? • Issues related primarily to the use of anticoagulants • Warfarin – patients with atrial fibrillation • Level of anticoagulation • Heparin – administration for treatment of stroke • Heparin – administration to maintain IV line • Will be influenced by baseline coagulation tests • Antiplatelet aggregating agents are OK

45. QUESTION # 4 ANY ABNORMALITIES ON BASELINE COAGULATION TESTS? • Prothrombin time/ INR < 1.7, prefer < 1.4 • APTT < few seconds upper limits of normal • Platelet count – normal • Should not try to reverse anticoagulants QUESTION # 5 ANY EVIDENCE OF ACTIVE BLEEDING? • Overt signs of bleeding are critical • Do not screen urine or stool for occult bleeding

46. QUESTION # 6 ANY FINDING ON MEDICAL EXAMINATION THAT WOULD MAKE ADMINISTRATION OF rt-PA PARTICULAR DANGEROUS? • Arterial blood pressure is most critical • Systolic blood pressure < 185 mm Hg and • Diastolic blood pressure < 110 mm Hg • Monitor blood pressure repeatedly • Can lower blood pressure if sufficient time

47. QUESTION # 7 WHAT IS THE PATIENT’S NEUROLOGICAL STATUS? • Decisions influenced by the NIHSS score. • Would not treat a patient with mild neurological deficit • Would not treat who has dramatic improvement • Complex issue of treating a patient with severe deficit • Poor prognosis without treatment • Likely will not respond to treatment • Higher risk of hemorrhage

48. Consciousness 0 - 3 Commands 0 - 2 Orientation 0 - 2 Language 0 - 3 Articulation 0 - 2 Neglect 0 - 2 Eye Movement 0 - 2 Motor Upper (R/L) 0 - 4 Lower (R/L) 0 - 4 Face 0 - 3 Sensory 0 - 2 Coordination 0 - 2 Visual Fields 0 - 3 NIH STROKE SCALE

49. QUESTION # 8 WHAT ARE THE RESULTS OF THE CT STUDY? • Any evidence of intracranial hemorrhage precludes treatment • Evidence of major infarction on CT – patients with severe stroke • Dense artery sign • Obliteration of insular cortex • Hypodensity of the lenticular nuclei • Obliteration of hemispheric sulci • Loss of gray-white matter junction hemisphere

50. QUESTION # 9 DO THE PATIENT AND FAMILY UNDERSTAND THE POTENTIAL BENEFITS AND RISKS OF TREATMENT? • At present, only effective therapy • Therapy can not be given with impunity • Risk of hemorrhagic transformation • Seriously ill patients and elderly • Alternative therapies not available • Prognosis of patient without treatment