Emergent Treatment of Acute Ischemic Stroke Including the

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

ACUTE ISCHEMIC STROKE • Complex medical illness resulting from thromboembolism v. Parts of the brain irreversibly injured v. 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

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

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

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

Neuroprotection in Cerebral Ischemia: Clinical Trials Drugs Mode of action Result Nimodipine Voltage-dependent Ca++ antagonist no efficacy Flunarizine ditto no efficacy Isradipine ditto trial discontinued, no efficacy Selfotel Competitive NMDA antagonists trial discontinued, adverse effects Aptiganel Noncompetitive NMDA antagonist ditto Dizolcipine ditto Dextrorfan ditto Racemide ditto phase III planned Magnesium noncompetitive NMDA Antagonist, voltage-dependent Ca++ antagonist pilot study (+), ongoing trial (IMAGES study) GV 150526 glycine site antagonist no efficacy Eliprodil polyamine site antagonist no efficacy Ca++ channel antagonists NMDA receptor antagonists Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001; 11(Suppl 1): 60 -70

Presynaptic glutamate release inhibitors Lubelozole Na*channel blockade, modulates NOS No efficacy Fosphenytoin Modulates Na+ channel No efficacy Propentophylline Inhibits adenosine transport Adverse effects Clomethiazole GABA agonist, modulates Cl channel No overall clinical efficacy, improvement in TACl, ongoing trial NBQX AMPA receptor antagonist Trial discontinued, adverse effects Bay x 3702 5 -HT agonist Phase III trial GM-1 Non-NMDA antagonist No clinical efficacy Nalmefene K-selective opiate antagonist No clinical efficacy BMS-204352 K channel agonist Phase III clinical trial Blood substitute Phase II trial, adverse effects Other ionic channel inhibitors Hemodilution DCLHb Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001; 11(Suppl 1): 60 -70

Antioxidants inhibiting free radicals Tirilizad Inhibits lipid peroxidation No efficacy Ebselen Gluthatione peroxidaselike action No efficacy Enlimomab Antiadhesion antibodies Trial completed, no clinical efficacy, adverse effects Hu 23 F 2 G Antiadhesion antibodies No efficacy Piracetam Membrane modulator No clinical efficacy, possible efficacy<7 h, new PASS II trial Citiocline Antioxidant, phosphatidylcholine synthesis Possible benefit in medium-sized infarets (2, 000 mg/day) b. FCF Neurotropic factor Trial discontinued, adverse effects Drugs acting against late damage Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001; 11(Suppl 1): 60 -70

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

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

HEMODILUTION AND INDUCED HYPERTENSION • Altering blood flow by altering viscosity or increasing perfusion pressure v. Used successfully to treat vasospasm after SAH v. Can be complicated by myocardial ischemia, heart failure, or pulmonary edema v. 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

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

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

HEMORRHAGIC COMPLICATIONS EMERGENT ANTICOAGULATION Placebo/control Anticoagulant 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% FISS - nadroparin

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% HAEST - dalteparin 7. 5% 8. 5% TAIST - tinzaparin 3. 1% 3. 3% - 4. 7%

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%

CONCLUSIONS AND RECOMMENDATIONS EMERGENT ANTICOAGULATION • Emergent anticoagulant therapy causes a modest increase of symptomatic intracranial or systemic bleeding • No evidence in lowering the risk of early recurrent stroke v. 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

EFFECTS OF ASPIRIN ON OUTCOMES AFTER STROKE Lancet 1997 349: 1641 -49

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

OUTCOMES Aspirin and placebo clopidogrel n = 6259 % Death, MI, or stroke 11. 5 Vascular death 5. 5 Myocardial infarct 6. 7 Stroke 1. 4 Major hemorrhage 2. 7 Life threatening 1. 8 Aspirin and n = 6303 % 9. 3 5. 1 5. 2 1. 2 3. 6 2. 1

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

• 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

CONCLUSIONS AND RECOMMENDATIONS ANTIPLATELET 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

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

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

INTRA-ARTERIAL PROUROKINASE PROACT - II STUDY Randomized, clinical trial - 54 centers 121 Patients - pro. UK 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

OUTCOMES AT 90 DAYS PROACT - II STUDY Modified Rankin Scale 0 - 2 Baseline NIHSS Score Pro. UK Heparin % Odds 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

RECANALIZATION AND INTRACRANIAL BLEEDING PROACT-II STUDY Recanalization Pro. UK (%) 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

TRIALS OF STREPTOKINASE Trial MAST - E Dead/disabled Symptomatic hemorrhage MAST - I Dead/disabled (with aspirin) Symptomatic hemorrhage (with aspirin) ASK Dead/disabled Symptomatic hemorrhage Placebo/control Streptokinase 81. 8% 2. 6% 79. 5% 21. 2% 68. 0% 59. 0% 64. 0% 6. 0% 10. 0% 0. 6% 43% 3% 48% 13%

NINDS PART 1

NINDS PART 2

Favorable Outcomes at Three Months Persons Treated Within Ninety Minutes rt-PA n=157 Placebo n=145 Odds Ration Relative Risk P-value Barthel 53% 38% 1. 8(1. 2 -2. 9) 1. 4(1. 1 -1. 8) 0. 010 Rankin 40% 28% 1. 7(1. 0 -2. 6) 1. 4(1. 0 -1. 9) 0. 035 Glasgow 43% 32% 1. 6(1. 0 -2. 5) 1. 3(1. 0 -1. 8) 0. 057 NIHSS 34% 20% 2. 0(1. 2 -3. 4) 1. 7(1. 1 -2. 5) 0. 008 New England Journal of Medicine, 1995; 333: 1581 -1587.

Favorable Outcomes at Three Months Persons Treated Within 91 -180 Minutes rt-PA n=157 Placebo n=145 Odds Ration Relative Risk p-value Barthel 51% 38% 1. 6(1. 1 -2. 5) 1. 3(1. 0 -1. 7) 0. 026 Rankin 45% 2. 4(1. 5 -3. 7) 1. 8(1. 3 -2. 4) <0. 001 Glasgow 47% 30% 2. 0(1. 3 -3. 2) 1. 6(1. 2 -2. 1) 0. 002 NIHSS 34% 21% 2. 0(1. 2 -3. 2) 1. 6(1. 1 -2. 3) 0. 008 New England Journal of Medicine, 1995; 333: 1581 -1587.

TRIAL OF ALTEPLASE GIVEN 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

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

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

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

TRIAL OF ALTEPLASE ACUTE 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

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

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 v. Telephone consultations v. Teleradiology v. Telemedicine

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

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 v. Severity of surgery v. Consultation with surgeon § Recent serious bleeding – generally < 4 weeks

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

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

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 v Diastolic blood pressure < 110 mm Hg v § Monitor blood pressure repeatedly § Can lower blood pressure if sufficient time

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 v. Poor prognosis without treatment v. Likely will not respond to treatment v. Higher risk of hemorrhage

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

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 v v v Dense artery sign Obliteration of insular cortex Hypodensity of the lenticular nuclei Obliteration of hemispheric sulci Loss of gray-white matter junction hemisphere

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 v Seriously ill patients and elderly v § Alternative therapies not available § Prognosis of patient without treatment

MANAGEMENT AFTER ADMINISTRATION OF rt-PA • Avoid central venous/arterial punctures • Avoid placing nasogastric tube • Avoid placing indwelling bladder catheter • Monitor blood pressure carefully • Admit to a skilled nursing facility

REGIMEN TO CONTROL HYPERTENSION AFTER TREATMENT WITH rt-PA BLOOD PRESSURE DIASTOLIC SYSTOLIC RESPONSE 105 - 120 mm Hg or 180 - 230 mm Hg Repeat as needed IV labetalol - 10 mg 121 - 140 mm Hg or > 231 mm Hg IV labetalol - 20 mg Repeat as needed IV sodium nitroprusside >140 mm Hg - 10 mg/kg/min IV sodium nitroprusside 0. 5

Thrombolytic therapy currently is the best treatment for patients with acute stroke There is considerable room for improvement Likely to have new therapies Improving blood flow Neuroprotective medications Likely to have combinations of therapies May select therapies on a case-by-case basis

POTENTIAL STRATEGIES FOR TREATMENT OF PATIENTS WITH ACUTE ISCHEMIC STROKE • Combination of intravenous and intra-arterial thrombolysis • Combination of pharmacological and mechanical thrombolysis • Combination of thrombolysis and neuroprotective agents • Combination of thrombolysis and new antithrombotic agents • In the field administration of neuroprotective agents

NEW THERAPIES BEING TESTED • New thrombolytic agents – plasminogen activators • New antithrombotic agents: – Thrombin inhibitors – Antiplatelet agents • Volume expansion and hemodilution: – Albumin • Neuroprotective agents: – Magnesium

STATEMENT ON THROMBOLYSIS TREATMENT OF ACUTE STROKE • Emergency Departments should work with EMS and community so that all parties know what the hospital’s capabilities are regarding acute stroke care. • Further studies are needed to define more clearly those patients most likely to benefit from fibrinolytic therapy in acute ischemic stroke. • Intravenous t. PA may be an efficacious therapy for the management of acute ischemic stroke if properly use incorporating the guidelines of NINDS. American College of Emergency Physicians 26 March 2002

• There is insufficient evidence at this time to endorse the use of intravenous t. PA in clinical practice when systems are not in place to ensure that the inclusion/exclusion criteria established b the NINDS guidelines for t. PA use in acute stroke are followed. • The decision for an emergency department to use intravenous t. PA for acute stroke should begin at the institutional level with commitments from hospital administration, the emergency department, neurology, neurosurgery, radiology and laboratory services to ensure that the systems for the safe use of fibrinolytic agents are in place. American College of Emergency Physicians 26 March 2002

Thrombolytic therapy is mandating changes in treatment of stroke Engine that is driving stroke care Treating stroke like a life-threatening disease Time is brain