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 No off-label or investigational drugs/devices will be discussed

3. 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

4. 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

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

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

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

10. 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

11. Ancillary Care Post Thrombolysis Similar to NINDS trial except: DVT prophylaxis with parenteral anticoagulants allowed

12. Outcomes of ECASS-3 & NINDS Trials - Disability mRS of 0,1 at 3 months ECASS-3: 52% (rtPA) vs. 45% (control) OR 1.34 (1.02-1.74) P = 0.04 NINDS: 39% (rtPA) vs. 26% (control) OR 1.7 (1.1-2.6) P = 0.019

13. Outcomes of ECASS-3 versus NINDS Trials - ICH Symptomatic ICH (NINDS definition) ECASS-3: 7.9% vs. 3.5% (placebo) P = 0.006 NINDS: 6.4% vs. 0.6% (placebo) P < 0.001

14. Outcomes of ECASS-3 versus NINDS Trials - Mortality Death at 3 months ECASS-3: 32% vs. 34% (placebo) P = 0.68 NINDS: 17% vs. 24% (placebo) P = 0.3

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

16. AHA Guideline Recommendations IV rtPA 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

17. 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

18. Rapidly Improving or Mild Strokes

19. Exclusions to IV rtPA 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

20. 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 rtPA due to RIMS (Nedeltchev et al. Stroke 2007) Calgary study: 314 IS patients came within 3 hours 98 (31%) did not receive IV rtPA due to RIMS Barber et al. Neurology 2001

21. What happens to them when they are not treated with IV rtPA?

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

23. Discharge Outcomes Calgary Study: 98 patients did not receive IV rtPA due to RIMS 32% of these remained dependent at discharge or died during hospitalization Barber et al. Neurology 2001

24. 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

25. What if they are treated with IV rtPA?

26. Treated with IV rtPA 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

27. What should we do about them?

28. 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

29. 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

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

31. 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

32. The Minnesota Experience Minnesota Stroke Registry: Year 2008 33 patients 90 or older came within 2 hours of symptom onset 7 received IV rtPA, 2 died soon after 26 did not receive IV rtPA, 4 died soon after

33. Summary 1.ECASS-3 extends the thrombolysis time window beyond 3 hours with restrictions – class I Level A 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 family and treat

34. Questions? Thank you!