Thrombolytic Therapy for Acute Ischemic Stroke: Should it be used in the Community?

1. Thrombolytic Therapy for Acute Ischemic Stroke:Should it be used in the Community? Moritz Haager PGY-5 Nov 17, 2005

2. Cases • STARS flight call • Case 1: • 58yo M in Lethbridge w/ large L MCA stroke onset 1.5 hrs ago • Stroke neurologist in Calgary wants tPA given • Case 2: • 65 yo M in Lethbridge w/ large R MCA stroke onset 2 hrs ago • Stroke neurologist in Calgary wants tPA given

3. Objectives • Review efficacy of tPA in acute ischemic stroke (AIS): what is the current state of the evidence? • Review effectiveness of tPA: Can we expand thrombolytic Tx to non-academic centers?

4. Bad Ideas Part I

5. Scope of the Problem • Canadian Data: • A stroke q10 min • 50,000 – 90,000 cases /yr • 3rd leading cause of death (7% of all deaths) • overall mortality rate is 47.8 per 100 000 population • #1 cause of permanent disability • $2.7 billion / yr = 2.1% of all health care cost

6. Thrombolysis in Acute Ischemic Stroke: is it efficacious? How well does it work in RCT’s?

7. RCT’s of IV Thrombolytics in AIS

8. NINDS:Tissue Plasminogen Activator For Acute Ischemic Stroke N Engl J Med 1995;333:1581-7 • 2 part DBRCT of IV tPA vs placebo of 624 pts w/in 3 hrs of stroke onset • Part I: • ? improvement in neuro deficits w/ tPA at 24 hrs • Part II: • ? improvement in neuro deficits w/ tPA at 3 mo • Inclusion / Exclusion criteria NB: early ischemic changes on CT were NOT part of exclusion criteria

9. NINDS:Tissue Plasminogen Activator For Acute Ischemic Stroke N Engl J Med 1995;333:1581-7 • Efficacy Results: • tPA pts did better at 90d on all neuro scores • Better global outcome score at 90d: • RR 1.9 (1.3–2.9) , p=0.002, ARR 12%, NNT = 8 • NIHSSS≤1 at 90d: • 18.5% vs. 12%; p=0.033, NNT = 15 • mRS ≤1 at 90d: • 23.2% vs 15.8%; p=0.019, NNT = 13.5 • Good outcomes held up at 1 yr f/u as well • Wiatkowski et al. N Engl J Med 1999;340:1781-7 NNT for tPA in MI is 26; mortality 1%

10. NINDS:Tissue Plasminogen Activator For Acute Ischemic Stroke N Engl J Med 1995;333:1581-7 • Safety Results • Mortality at 90d • 17% vs. 21% in placebo, p=0.30 • Intracerebral Hemorrhage • Overall: 10.9% vs. 3.5%, P<0.001, NNH = 14 • Symptomatic: 6.4% vs. 0.6%, P<0.001 NNH = 17

11. Questions regarding NINDS • Are the results valid? • Placebo pts had slightly more severe AIS • No mortality benefit • Only trial to show benefit • Most would point to the <3 hr Tx window • Benefit is small & limited to select pts • How generalizable are these findings?

12. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74 • Meta-analysis of pooled data from 2775 pts treated w/ IV-tPA w/in 6 hrs • Main question was relationship between favorable neuro outcome* & onset to treatment time (OTT) • Used multiple regression model in an ITT fashion *Defined good neuro outcomes as NIHSSS ≤1, mRS ≤1, or BI >95 at 90d

13. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74

14. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74 • Mortality: • Intracranial Hemorrhage: • Risk of a type II PH was 5.9% of the rt-PA patients compared with 1.1% of placebo patients (p<0.0001) • sICH rate not provided • The risk of ICH did not appear to increase w/ time

15. Wardlaw et al. Cochrane Database of Sytematic Reviews, Volume (3) 2005 • Looked at pooled data for 5675 pts from all RCT’s • Significant heterogeneity • any type of thrombolytic (tPA, SK, UK etc) • included both IA & IV administration • Different stroke types & severity • Different dosing regimens • Different use of antithrombotics / anticoagulants • Variable inclusion / exclusion criteria

16. Wardlaw et al. Cochrane Database of Sytematic Reviews, Volume (3) 2005 • Overall results: all lytics vs. placebo • Death or dependancy (mRS >2)* at any time • 53.3% vs. 58% of controls (OR 0.84 [0.75-0.95] p=0.004); NNT = 21 • All cause mortality at any time • 18.2% vs 15.2% in controls (OR 1.33 [1.15-1.53], p=0.0002); NNH = 33 • Symptomatic ICH at any time • 8.7% vs. 2.5% in controls (OR 3.37 [2.68-4.22] p<0.00001); NNH = 16 *Benefit maintained when defined as mRS >1 (OR 0.79, 95% CI 0.69 to 0.90)

18. Bottomline Thrombolysis in AIS ASA in Acute Coronary Syndromes

19. Bad Ideas Part II

20. Thrombolysis in AIS: is it effective? Does t-PA work in the real world?

21. Limitations of Phase IV trials: • Heterogenous settings • Some community only, some mix of academic & community hospitals, some academic only • Some in Europe, some in NA • Heterogenous tPA protocols • AHA, Canadian, original NINDS • Small numbers individually • Different outcome measures used • No control arms – often c/w NINDS data

23. Katzan et al. Use of t-PA for Acute Ischemic Stroke: The Cleveland Area Experience. JAMA 2000; 283: 1151- 1158 • Retrospective chart review of 70 pts treated w/ IV t-PA over 1 yr • AHA guidelines 1996 • 29 hospitals – 10 were teaching sites • Ranged from 10 – 389 admissions for AIS • Median NIHSSS ~12 • Compared their results to “matched controls” who had not gotten t-PA

24. Katzan et al. Use of t-PA for Acute Ischemic Stroke: The Cleveland Area Experience. JAMA 2000; 283: 1151- 1158

25. Katzan et al. Use of t-PA for Acute Ischemic Stroke: The Cleveland Area Experience. JAMA 2000; 283: 1151- 1158 • Comments • “matched” controls from same cohort • Must be a reason why they did not get tPA • What is a community hospital? • Neurologists involved in 95.5% of cases & present in 82% • 10/29 were teaching hospitals • State no significant association b/w AIS admission volume and rate of tPA use BUT: • 4/14 hospitals w/ AIS volume <100 admissions gave tPA • 11/13 hospitals w/ AIS volume >100 admissions gave tPA • Hospitals w/ <100 admissions accounted for 8/70 (11%) pts treated w/ tPA • Hard to compare larger centers & small hospitals • Don’t directly compare complications b/w sites

26. CONNECTICUT: Bravata et al. Thrombolysis for Acute Stroke in Routine Clinical Practice. Arch Intern Med 2002; 162: 1994 – 2001 • Retrospective chart review of 63 t-PA treated pts in 16 hospitals over 18 mo • Followed AHA guidelines 1996 • Only 1 center had 24/7 radiology & neurology • Compared outcomes w/ NINDS data • Baseline Mean NIHSSS 15

27. CONNECTICUT: Bravata et al. Thrombolysis for Acute Stroke in Routine Clinical Practice. Arch Intern Med 2002; 162: 1994 – 2001

28. CONNECTICUT: Bravata et al. Thrombolysis for Acute Stroke in Routine Clinical Practice. Arch Intern Med 2002; 162: 1994 – 2001 • Comments • Hospitals more reflective of Canadian community centers • Huge protocol violation rate • Retrospective • No data on number of pts w/ incomplete data and how they dealt with this • No data on neuro outcomes, or mortality at 30d, 90d • Mortality in NINDS tPA group at 90d was 17%

29. PHOENIX. Frey et al. tPA by telephone: Extending the benefits of a comprehensive stroke center. Neurology 2005;64:154–156 • Prospective comparison of 53 pts given tPA in community (telephone consults for “drip & ship”) vs. 73 at stroke center

30. PHOENIX. Frey et al. tPA by telephone: Extending the benefits of a comprehensive stroke center. Neurology 2005;64:154–156 • Comments • Results suggest pts do better when treated in Stroke Center, but • Community-treated pts were described as older, w/ more severe strokes • Poor methods description – hard to assess • The protocol violation rate is not provided • Not sure if the difference in sICH is significant

31. Reed et al. Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community Hospitals. Stroke. 2001; 32:1832-1840 • Retrospective review of 362 pts treated w/ IV tPA at 137 hospitals • 34% teaching centers, 78% had Neurosurgery • Results • In-hospital mortality 9.9% (6.9 – 13%) • Final Disposition was home in 36% • Multivariate analysis • No significant interaction w/ teaching vs non-teaching hospital, or urban vs rural & likelihood of death

32. Reed et al. Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community Hospitals. Stroke. 2001; 32:1832-1840 • Comments: • Heterogenous collection of “community” hospitals • No baseline NIHSSS scores • No data on protocol violations • No data on symptomatic ICH • No neuro outcome data • Retrospective w/ poorly defined methods

33. CALGARY: Buchan et al. Effectiveness of t-PA in acute ischemic stroke: Outcome relates to appropriateness. Neurology 2000; 54(3): 679 • Prospective cohort of 68 consecutive pts treated w/ IV t-PA at FMC using NINDS protocol over 30 mo period • Baseline Mean NIHSS 15 • Compared outcomes to NINDS

34. CALGARY: Buchan et al. Effectiveness of t-PA in acute ischemic stroke: Outcome relates to appropriateness. Neurology 2000; 54(3): 679

35. CALGARY: Buchan et al. Effectiveness of t-PA in acute ischemic stroke: Outcome relates to appropriateness. Neurology 2000; 54(3): 679 • Comment • Protocol violation associated w/ significantly higher risk of sICH, mortality, & worse neuro outcome • 6/57 (10%) deaths in protocol pts vs 5/11 (46%) in violators (p < 0.01) • Calculated NNT relative to the NINDS study placebo group • NNT = 6 for good outcome (NIHSS score 0 to 1) • NNT = 3 for independence (mRS0-2)

36. CASES: Hill et al. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study CMAJ 2005;172(10):1307-12 • Prospective registry of 1135* t-PA treated AIS pts at 60 Canadian hospitals in 2.5 yrs • 33 community, 27 academic • 10 “high volume” centers = >1 pt treated/mo • Treated 61% of all pts • Median NIHSSS 14 at baseline • Looked at outcomes at 90d * Estimate this accounts for 84% of all AIS pts treated w/ tPA in Canada during study period

37. CASES: Hill et al. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study CMAJ 2005;172(10):1307-12 *mRS adjusted for baseline was 36.8%, which was not significantly different (p = 0.15) from the expected rate of 39.9% based on NINDS data

38. CASES: Hill et al. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study CMAJ 2005;172(10):1307-12 • Multivariate Analysis • Found no significant difference in rate of neuro outcomes or sICH b/w pts treated at: • High volume vs. low volume center • Community vs. academic center • Found significant relationship b/w protocol violation & risk of sICH • 7.8% v. 3.9%; RR 2.0, 95%CI 1.1–3.8 • Predictors of sICH: • Elevated glucose • (OR 1.6, 95% CI 1.2–2.3 per 5-mmol/L increase) • Increased time from stroke onset to Tx • (OR 1.2, 95% CI 1.0–1.5 per 30-minute increase)

39. Conclusions • IV t-PA improves neuro outcomes in select AIS pts in RCTs • Benefit diminishes rapidly with time • IV t-PA has a narrow therapeutic index • Need to select pts carefully & stick to protocol • Multiple case series report results similar to NINDS in routine clinical use • The data to support or refute use of t-PA in community centers is limited & difficult to interpret

40. Conclusions • So should we give t-PA in Lethbridge? • Currently no • Tomorrow maybe yes, provided: • Establishment of detailed protocol • Telephone consult to stroke team at FMC • Transmission of CT images to FMC • Transfer for all t-PA pts to FMC • Rigorous QI/QA process to track & address • Protocol violation rate • Outcomes of pts treated in periphery vs. at stroke center

41. Questions? Bad Ideas Part III

42. Are we just increasing the number of disabled survivors? Lancet 2004; 363: 768–74

43. Barriers to t-PA Tx in CVA • Systematic review: • failure to recognise symptoms of stroke or seek urgent help • Failure to call for and ambulance first • Incorrect triage as non-urgent by paramedics or ED staff • delays in neuroimaging, • Inefficient stroke care pathways • Obtaining informed consent • Physician inexperience & uncertainty w/ giving thrombolytics in CVA • Kwan et al. Age and Ageing 2004; 33: 116–121

44. Kwan et al. Age and Ageing 2004; 33: 116–121

45. Albers et al. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Stroke 2002;33: 493-5. • Analysis of 61 pts treated w/ IV-tPA w/in 3 hrs in a DBRCT • Results • NIHSSS ≤1 at 90d • 60.9% vs. 26.3% in placebo; p=0.01, NNT = 3 • Mortality at 90d • 17.4% vs. 5.3% in placebo; p=0.12, NNH = 8 • sICH at 10d • 13% vs 0% in placebo; p=0.05, NNH = 33

46. ASPECTS The ASPECTS value is calculated from two standard axial CT cuts: -one at the level of the thalamus and basal ganglia -one just rostral to the ganglionic structures. the MCA territory is allotted 10 points -1 point is subtracted for each area of early ischemic change, such as -focal swelling -parenchymal hypoattenuation, A normal CT scan has an ASPECTS value of 10 points Barber et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000; 355: 1670–74

47. ASPECTS • In logistic regression analysis, baseline ASPECTS value ≤7 was a significant predictor of both • Poor functional outcome (OR82 [95% CI 23–290], p<0·001) • Increased risk of symptomatic ICH (OR 14 [2–117], p=0·012) • Kappa was 0.71 – 0.89 depending on training

48. IV t-PA >3 hrs • Meta-analyses suggest modest benefit after 3 hrs – rapidly diminishes w/ time • New strategies to select pts w/ potentially reversible ischemia • DWI/PWI MRI • Clinical – MRI mismatch • CT perfusion imaging (CTP) • Estimates blood volume as ml /100 g brain tissue • Both need further study & validation

49. How does t-PA cause ICH? • Proposed mechanisms • interaction with NMDA receptors, promoting calcium influx into ischemic cells  excitotoxicity • enhances degradative enzymatic activity in the intercellular matrix by up-regulating MMP-9, which leads to disruption of tissue integrity and may predispose to hemorrhage • giving inhibitors of these effects may minimize the side effects & this is under investigation: • caffeine & EtOH in combo • albumin • Magnesium • Hypothermia • Oxygen • Steroids Frey. Recombinant Tissue Plasminogen Activator (rtPA) for Stroke: The perspective at 8 years. Neurologist 2005;11: 123–133

50. EP’s Role in AIS • Emergency Care • Fast recognition of potential CVA & appropriate triage/assessment • Initial Tx • Oxygen • IV rehydration • ECG • Bedside C/S • Pharmacologic control of hyperglycemia & hyperpyrexia • ASA 160 – 235 if no tpA • NPO until swallowing assessed • Fast CT to r/o ICH or other causes • Determination of eligibility for tPA • Dedicated stroke teams & stroke units • Wilson et al. Creating a Canadian stroke system. CMAJ 2001; 164: 1853-1855