1. Maximizing IV Thrombolytic Therapy in Acute Ischemic Stroke Kamakshi Lakshminarayan, MD PhD Assistant Professor Neurology & Epidemiology University of Minnesota Great Lakes Regional Stroke Network October 8, 2009

2. Disclosures K Lakshminarayan receives research grant support from the NIH and CDC Presentation will deal with a currently off label use of tPA

3. Agenda Maximizing Opportunities for tPA delivery Expanded time window for treatment Management of rapidly improving or mild strokes IV thrombolysis in the elderly

4. Classes of Recommendations Class I: Evidence for and/or general agreement that the treatment is useful and effective Class II: Conflicting evidence and/or a divergence of opinion about usefulness/efficacy of a treatment –IIa: Weight of evidence or opinion is in favor of the treatment. – IIb: Usefulness is less well established by evidence or opinion. Class III: Evidence and/or general agreement that the treatment is not useful and in some cases may be harmful

5. Levels of Evidence Level A : Data derived from multiple RCT Level B: Data derived from single RCT or nonrandomized studies Level C: Consensus opinion of experts

6. An Expanded Time Window is Needed

7. Intravenous Thrombolytic Therapy: The Minnesota Stroke Registry Quarter 2, 2008 to Quarter 2, 2009 Ischemic Stroke 3050 YES 1431 (47%) YES 417 (29%) Numerator: YES 112 (27%)* NO 305 (73%) YES 177 (58%) NO 128 (42%)* NO 1014 (71%) 10/1014 received IV tPA NO 1619 (53%) 7/1619 received IV tPA Time and date last well known documented Came within 2 hours of symptom onset Received IV tPA Documented contraindications *The thrombolytic therapy performance measure calculation is the numerator, indicated by the box labeled Numerator, divided by the denominator, the sum of the boxes indicated by the (*).

8. When are patients arriving? Time HoursNPercent 0-231513 > 2-3.51627 > 3.5-62119 > 639116 Missing130655 Minnesota Stroke Registry: 2008

9. An Expanded Time Window Will Help Minnesota Stroke Registry: Less than 1/3 of patients with documented times come within 2 hours of symptom onset

10. Widening the time window for IV tPA treatment to 4.5h: 3 reports 1.Pooled analysis of early 0-6 h IV tPA placebo controlled trials – Lancet 2004 2.Registry comparing cohorts treated with IV tPA < 3 vs. 3-4.5 h – Lancet 2008 3.RCT of tPA vs. placebo in 3-4.5 h – ECASS-3 NEJM 2008

11. IV tPA: Pooled analysis of outcome vs. onset to treatment (OTT) time Six randomized controlled IV tPA trials 2775 patients 0-6 h OTT 0.9 mg/kg (except ECASS I - 1.1 mg/kg) Median NIHSS = 11 (moderate deficit) The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators, Lancet 2004

12. Continued... OTT Odds Ratio for normal at 3 mo. Hemorrhage 0-1.5 h2.813.1% 1.5-3 h1.555.6% 3-4.5 h1.405.9% 4.5-6 h1.156.9% The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators, Lancet 2004

13. IV tPA: observational study of outcome & OTT <3 vs. 3-4.5 h European Union phase IV study Compared outcome: OTT 3-4.5 h – 664 patients OTT <3 h – 11,865 patients All received 0.9 mg/kg tPA 3-4.5 h patients slightly younger (65 vs. 68) and had lower median NIHSS (11 vs. 12) Safe Implementation of Treatments in Stroke (SITS) Investigators, Lancet 2008

14. Continued... OTT % normal at 3 mo. ICH <3 h40%7.3% 3-4.5 h41%8.0% Safe Implementation of Treatments in Stroke (SITS) Investigators, Lancet 2008

15. ECASS-3 Trial Multi-center prospective randomized controlled trial –tPA n=418 –Placebo n=403 Treat within 3-4.5 hours of symptom onset Median time to treatment 4 hours tPA dosing regimen the same

16. Similarities to NINDS tPA Trial Similar inclusion and exclusion criteria But additional exclusions: –Age over 80 years –NIHSS > 25 –Any oral anticoagulant use –Previous stroke + DM

17. Ancillary Care Post Thrombolysis Similar to NINDS trial except: DVT prophylaxis with parenteral anticoagulants allowed within 24 hours

18. Summary of ECASS-3 % Normal at 3 mo. Symptomatic ICH tPA*52%7.9% Placebo**45%3.5% Hacke, N Engl J Med 2008 *OR 1.34 (1.02-1.74) P = 0.04 **p = 0.006

19. AHA Guideline Recommendations IV tPA is recommended for selected patients who may be treated within 3 hours of symptom onset of ischemic stroke Class I, Level A

20. AHA Guideline Recommendations IV tPA should be administered for those who can be treated 3-4.5 hours after symptom onset with similar exclusionary criteria as for within 3 hour window + age > 80, oral anticoagulant use, NIHSS > 25, history of stroke + DM Class I, Level B In those with above additional exclusionary criteria – utility is not well established, needs further study Class IIb, Level C

21. Diffusion of Trial Evidence into Practice: Minnesota Stroke Registry September 25, 2008: ECASS-3 published NEJM May 28, 2009: AHA guideline recommendations on the expanded window online YearTotal IVTIVT w/in 3hIVT 3-4.5hIVT ? time 20088676 (88%)*6 (7%)4 (5%) 2009 Q14137 (90%)4 (10%)0 2009 Q24842 (88%)5 (10%)1 (2%) *% refers to all IV tPA cases as denominator

22. Rapidly Improving or Mild Strokes

23. Exclusions to IV tPA NINDS Trial: Patients excluded if rapidly improving or minor symptoms (RIMS) AHA Guidelines: Neurological signs should not be clearing spontaneously Neurological signs should not be minor & isolated

24. How Often Does This Occur? Minnesota Stroke Registry 2008 data: –315 IS patients came within 2 hours –76 (24%) did not receive IV tPA due to RIMS Case series: –876 IS patients with 24 hours –162 (19%) did not receive IV tPA due to RIMS Nedeltchev et al. Stroke 2007 Calgary study: –314 IS patients came within 3 hours –98 (31%) did not receive IV tPA due to RIMS Barber et al. Neurology 2001

25. What happens to them when they are not treated with IV tPA?

26. Discharge Outcomes Minnesota Stroke Registry: 76 patients no tPA due to RIMS Prior to this stroke 69 (91%) ambulated independently At d/c 38 (50%) ambulated independently!

27. And….. Case Series: 41 patients not treated due to RIMS 11/41 (27%) died or not discharged home due to worsening (6) or persistent “mild deficit” (5) Smith et al. Stroke 2005

28. And….. Calgary Study: 98 patients did not receive IV tPA due to RIMS 32% of these remained dependent at discharge or died during hospitalization Barber et al. Neurology 2001

29. Outcomes at 3 Months Case series 162 patients with RIMS: Favorable: 75% (122 patients, mRS 0,1) Unfavorable: 25% (40 patients, mRS > 1) –mRS 2 = 16% –mRS 3, 4 = 7% –Dead = 1% –2 recurrent strokes No difference in outcomes between mild and rapidly improving Nedeltchev Stroke 2007

30. What if they are treated with IV tPA?

31. Treated with IV tPA Case Series: 19 patients with rapid improvement were treated at mean NIHSS of 5 [range 1-6] 3 month outcomes: –one patient died due to recurrent stroke from AF –NIHSS at 3 months in remaining was 0, mRS range 0-1 Baumann et al. Stroke 2006

32. What should we do about them?

33. Management of Rapidly Improving or Minor Strokes RIMS that have poor outcomes are a heterogeneous group 1.TIA – subsequently have strokes during hospitalization 2.Mild strokes – worsen during hospitalization 3.Seemingly mild strokes with low NIHSS but have gait ataxia or cognitive deficit not captured on the NIHSS Smith et al. Stroke 2005

34. Management 1.TIA If clear resolution of symptoms restart the clock if symptoms recur unless there are imaging correlates of tissue damage (DWI) Neuro-checks every 30-60 minutes for 1 st 12 hours 2.Mild strokes – do not restart clock Need clinical trials to guide treatment decisions since this population were not included in the original trials

35. Elderly Patients Limited data on thrombolysis in the elderly Cochrane meta-analysis: 42 patients > 80 years in thrombolysis RCT –NINDS trial included a few patients over 80 years –ECASS-3 did not –IST-3 does and is still recruiting till 2011 Anecdotal reports on nonagenarians and centenarians being treated

36. Thrombolysis in the Elderly Main worry is the risk of ICH Systematic review of 6 cohort studies found similar likelihood of symptomatic ICH OR 1.22 (95% CI 0.77-1.94) Three times higher odds of dying after thrombolysis for those > 80 Similar in those without thrombolysis – three times higher odds of dying

37. Summary 1.ECASS-3 extends the thrombolysis time window beyond 3 hours with restrictions – class I Level B 2.Clinical trials are needed to evaluate thrombolysis in those with mild deficits or rapidly improving strokes 3.Paucity of data on elderly – await IST-3. Community practice is to discuss with patient and family and treat

38. Questions? Thank you!