Acute Stroke Management 2009

Transcription

1 Acute Stroke Management 2009 Saving the Brain Conference Royal York Hotel January 24, 2009 Frank L. Silver, MD, FRCPC Director, Toronto West Stroke Program Professor of Medicine (Neurology) University of Toronto

2 Disclosures I have given lectures sponsored by Boehringer Ingelheim Canada Ltd., Hoffman LaRoche Canada, Merck Frosst, Pfizer, Sanofi and Servier I have been a member of Stroke Advisory Boards for AstraZeneca Canada, Boehringer Ingelheim Canada, Pfizer, Novo Nordisk, Solvay, and Sanofi I own no shares in any pharmaceutical company

3 Outline: Acute Ischemic Stroke Making the correct diagnosis Approach to management Rationale for fibrinolytic therapy Evidence that it works Risks of thrombolytic therapy The time window

4 Case 46 year old female sudden right-sided weakness and inability to speak at 10:30 hours unable to stand right side paralyzed O/E (11:40 hours) globally aphasia R homonymous hemianopia R hemiplegia R hemi-sensory loss

5 The Management of Acute Ischemic Stroke: Goals Make an accurate and rapid diagnosis: stroke etiology / mechanism Reduce the size of the infarct Avoid secondary complications pneumonia, pulmonary embolism, sepsis, MI Prevent recurrent strokes Educate and Rehabilitate

6 CVA = confused vascular assessment

7 The Definition of Stroke a clinical syndrome characterized by the sudden onset of a focal neurological deficit presumed to be on a vascular basis

8 Mimics seizures with a Todd s paralysis patients with old strokes other focal lesions: tumours, abscess acute confusional state in the elderly Bell s palsy

9 TIA vs. Stroke TIA = brain attack, threatened stroke TIA is a stroke persisting for <24 hours > 60% of TIAs are associated with an area of infarction on MRI (really strokes) True TIA (no damage) lasts <10 minutes

10 Making the Right Diagnosis The Four Questions Is it a stroke? Where is the lesion? What is the vascular supply? What is the lesion? Hemorrhage vs Infarct/Ischemia What is the etiology (mechanism)?

11 Carotid vs. VB Territory Carotid retinal ischemia aphasia cortical sensory loss apraxia, neglect sensory-motor deficit Vertebrobasilar diplopia, vertigo coma at onset crossed sensory loss bilateral motor signs isolated field defect pure motor deficit pure sensory deficit dysarthria dysphagia

12 CT Scan - 12:00 noon

13 Subtle ASPECTS Signs (Alberta of Stroke Early Program Cerebral Early Infarction CT Score) ASPECTS 6 = >1/3 MCA Territory M1 C IC L I M2 M3 2.5 hours post stroke 24 hours post stroke

14 Reducing the Volume of Infarction Protect ischemic neurons Restore perfusion to ischemic tissue Penumbra Infarction

15 Promoting Reperfusion Primary Arterial Supply ISCHEMIC Normal TISSUE Tissue Collateral Supply Surgical Remove arterial obstruction Bypass arterial obstruction Medical Lyse clot Increase collateral blood flow

16 Strategies for Administration of Fibrinolytic Therapy Intravenous on clinical diagnosis + normal CT scan above + angiographically proven arterial occlusion Intra-arterial regional infusion via diagnostic catheter superselective (interventional) catheter IV / IA? best of both worlds

17 Ischemic Stroke: Pathophysiology Large Artery Infarct Small Artery Infarct

18 Ischemic Stroke: Mechanisms BLOOD VESSELS BLOOD HEART

19 The Cause

20 Intra-arterial arterial Fibrinolysis Microcatheter

21 Post Fibrinolytic Therapy

22 CT 24 hours post treatment

23 Fibrinolytic Therapy: Clinical Trials European Cooperative Study (ECAS I) 6 hrs, rt-pa, IV NINDS rt-pa Stroke Trial t-pa, 3 hrs, IV, December 1995 ECASS II IV tpa, 0.9 mg/kg, 6 hrs, Oct 1998 Prolyse in Acute Cerebral Thromboembolism (PROACT) pro-uk, 6 hrs, IA results to be presented Feb 1999\ Australian Streptokinase Trial (ASK) SK, 4 hrs, IV, June 1991 Multicentre Acute Stroke Trial (MAST-E) SK, 6 hrs, IV, Sept 1995 Multicentre Acute Stroke Trial (MAST-I) SK, 6 hrs, IV, Sept 1995 Thrombolytic Therapy in Acute Ischemic Stroke Atlantis Trial t-pa, 3-5 hrs, IV, 1998 (Genentech) ECASS III IV tpa, 0.9 mg/kg, 6 hrs, Sep 2008 IST III (ongoing) n= 1288 (Oct 08) IV tpa < 6 hours

24 NIHDS rt-pa stroke group. NEJM 1995; 333:

25 NIH rt-pa Stroke Study Methodology randomized, double-blind study, 9 centres IV rt-pa (0.9 mg/kg) vs placebo ischemic stroke onset < 3 hours Part 1: clinical improvement at 24 hours > 4 on NIHSS Part 2: clinical outcome at 3 months Barthel Index, mod Rankin, Glasgow outcome, NIHSS NIHDS rt-pa stroke group. NEJM 1995; 333:

26 NIH rt-pa Stroke Study Patient Selection ischemic stroke < 3 hours duration onset clearly defined, stable deficit CT scans shows no hemorrhage no seizure at onset BP < 185/110 no recent surgery, hemorrhage, stroke informed consent NIHDS rt-pa stroke group. NEJM 1995; 333:

27 NIHDS Trial Excellent Recovery NIH Scale Total Death % of Patients t-pa 20 Placebo t-pa t-pa 20 1 Placebo Placebo Death Hemorrhage Haley, Lewandowski, Tilley: Ann Emerg Med 1997;30:

28 NIH rt-pa Stroke Study Clinical Significance first clinical trial to demonstrate an effective intervention for acute ischemic stroke for each 100 patients treated 11 more patients will have an excellent outcome odds ratio = 1.7 ( , p=.008) rt-pa vs placebo NNT = 10 patients must meet the entry criteria for the trial symptomatic ICH increased by 5.8% with rt-pa 0.6 % controls vs. 6.4 % in rt-pa patients NIHDS rt-pa stroke group. NEJM 1995; 333:

29 Benefit of IV tpa (3 hours) An 11% absolute benefit (30 to 50% relative) The absolute benefit of 11% considers only the cures There is an additional 10% absolute reduction in death/severe disability and 5% reduction in moderate disability

30 Since the NINDS tpa Trial tpa approved in the US in June 1996 tpa approved in Canada in February 1999 tpa approved by Europe Union in December 2002 SITSMOST Registry ECSASS 3

31 ProACT II Furlan A, et. al. JAMA 1999

32 PROACT: angiographic inclusions TIMI Grade 0 or TIMI Grade 1

33 ProACT II Furlan A, et. al. JAMA 282: , 1999

34 Cute : Conclusions PROACT patients represent a homogeneous group with a moderate - severe MCA ischemic syndrome NNT = 7 absolute increase in patients reaching independence of 15% despite: long time to treatment and time to recanalization Furlan A, AHA Stroke Meeting, Nashville, Feb 3, 1999

35 Dead or dependent at end of follow-up IV SK vs control IV tpa vs control Mori NINDS ECASS 1 ECASS 2 Atlantis A Atlantis B subtotal 12 trials; 4476 patients IV SK+asp vs asp IA prouk + hep vs hep TOTAL thrombolysis better thrombolysis worse

36 Treatment between 3-6 hours [data compared for 5 trials (2709 patients) with outcomes in both 0-3 and 3-6 hour intervals] No obvious cut off before 6 hours: treatment < 3 hours - 86 more alive and independent for every 1000 patients treated (95% CI more) treatment 3-6 hours - 18 more alive and independent for every 1000 patients treated (95% CI 23 fewer - 59 more)

37 Dead or Dependant: Treatment within 3 hours IV SK vs control IV tpa vs control NINDS ECASS 1 ECASS 2 subtotal 7 trials; trials; patients 1195 patients IV SK+asp vs asp TOTAL thrombolysis better thrombolysis worse G. Gubitz Cochrane Review

38 Cochrane Systematic Review Poor outcome = dead or dependent Treatment within 3 hours 68% control vs 56% rt-pa. 42% reduction in relative odds of being NNT = 8 dead or dependent (2p= ). 126 more patients alive and independent for every 1000 patients treated (95% CI ). G. Gubitz June 1999

39 CASES (Canadian Activase for Stroke Effectiveness Study) 60 sites 25 academic, 35 community 1134 patients

40 Baseline Characteristics Gender 55% male 45% female Handedness 96% right 4% left Symptom side 55% right 44% left 1% bilat Median age 70 (range 20 to 97) Ethnicity caucasian 91.3% asian 4.5% other 4.8% NIHSSS (median) 15 (range 2 to 40) (n = 1134)

41 Adverse Events n= symptomatic ICH 4.5% (95% CI = 3.4% to 65.9%) 15 anaphylactoid/angioedema reactions 1.3% (95% CI= 0.7 to 2.2) Michael Hill, Nov 23, 2001

42 Interventional Management of Stroke Study (IMS) NIH-supported pilot trial assessing safety and feasibility Inclusion Criteria: NIHSSS >10, within 3 hours of onset Protocol: IV rtpa at 0.6 mg/kg, 5% as bolus, followed by angiography. If an arterial occlusive lesion persists, up to 22 mg IA rtpa over 2 hours Outcomes will be compared to the placebo group of the NINDS trial. RESULTS: 80 patients were enrolled from Jan.31,2001 to Oct. 23, 2001 in 15 centres

43 Pooled Analysis of tpa 0-6 hrs N = 2,775 patient, 300 hospitals, 18 countries Mean age = 68; Median NIHSS = 11 Mean onset to treatment (OTT) = 243 min, 33% < 3 hours Favourable Outcome at 3 months (Rankin 0 or 1 / Barthel 95 or 100 / NIHSS 0 or 1) Logistic Regression Model - Outcome vs. OTT Cofounders: age, baseline glucose, baseline NIHSS, baseline diastolic BP, previous hypertension The ATLANTIS, ECASS, and NINDS rt-pa Study Group Investigators: Lancet 2004; 363:

44 * MRS = 0,1 Favourable Outcome at 3 months * tpa-treated treated patients compared to controls Time is Brain N =2775 Pooled analysis of ATLANTIS, ECASS, and NINDS rt-pa stroke trials Lancet 2004; 363:

45 Devices for mechanical thrombolysis Merci Ekos Penumbra

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47 Inclusions Acute ischemic stroke Onset hours Age Exclusions ICH, SAH Symptoms onset unknown, minor, or rapidly improving Severe stroke (deficit NIHSS >25 or CT changes > 1/3 MCA BP >185 systolic or >110 diastolic or need for aggressive treatment Previous stroke and diabetes?? Seizure at stroke onset Stroke, serious head injury, major trauma, major surgery within 3 months Platelets <100,000, heparin, warfarin Glucose < 50 or > 400 mg / dl

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51 Treatment Window 6 3 Time is Brain

52 Patients who show signs and symptoms of hyperacute stroke, usually defined as symptom onset within the previous 4.5 hours, must be treated as time-sensitive emergency cases and should be transported without delay to the closest institution that provides emergency stroke care [Evidence Level C] (ASA, AU, ESO, RCP).

53 Successful Acute Stroke Management rapid triage code stroke standing orders 24 hours CT (technician on-site) tpa protocol stroke unit (stroke team)

54 Hyperacute Stroke Management Goals: Door to CT Scan: 20 minutes Door to Needle: 60 minutes

55 Geographical Distances Sudbury (340 km) North Bay (295 km) Toronto

56 The Solution: the Transporter

57 Telestroke Technology Remote Hospital Home VPN VIDEO CONFERENCE VPN CT IMAGES Efilm Server

58 RCSN Stroke Onset to ED Arrival (Ischemic Stroke) Ontario Ontario n= 19,361 (ischemic stroke patients) 69% 70% 60% 50% 40% 36% 47% RCSN Phase-3 Report: July 1, March 31, %? 20% 9% 10% 0% LSN to Arrival in LSN to Arrival in Transferred from Transported by Data Source: RCSN Phase-3 ED < 2.5 Report: hrs (%) Jul. 1, ED 2003 < 5 -hrs Mar. (%) 31, 2008 other (data ED as (%) of Sep. 25, Ambulance 2008) Ontario s 12 Regional and Enhanced District Stroke Centres External Benchmark: Provincial Average

59 RCSN tpa Rates Ontario n= 19, RCSN Phase-3 Report: July 1, March 31, All stroke All ischemic stroke Ischemic stroke <2.5 hours Data Source: RCSN Phase-3 Report: Jul. 1, Mar. 31, 2008 (data as of Sep. 25, 2008) Ontario s 12 Regional and Enhanced District Stroke Centres External Benchmark: Provincial Average

60 Reasons for not giving tpa in patients arriving within 2.5 hours RCSN Phase-3 Cumulative Report: July 1, March 31, 2007 n = 2,650 patients not given tpa System failure No consent Comorbidities Contra-indications Too severe Too mild 0% 10% 20% 30% 40% 50%

61 y = x R 2 = Pearson r = , p<0.0001, n=1520 Door to Needle Time ER to tpa (Hours) Taking too long to treat Thinking there is still 2 hours to treat when a patient arrives at 1 hour post stroke onset Waiting for every lab result» only exception is INR if patient is on warfarin Waiting for advanced imaging technology» plain CT is all that is required» CTA / CTP or MR / DWI / PWI great if you can do it quickly or only in select cases LSN to ER (Hours)

62 BE A STROKE BUSTER CONCLUSIONS Acute ischemic stroke can be treated IV tpa is effective up to 4.5 hours BUT time is brain The target door-to-needle time is <60 minutes regardless of the available time Telestroke is the solution for hospitals without stroke expertise