1. “ Remember that stroke patient you treated last night…” What to Expect following tPA Use in Acute Ischemic Stroke The INSTINCT Trial NIH / NINDS R01 NS050372

2. Background Stroke patients, properly treated with tPA, have an 11% absolute greater chance of a normal outcome compared to untreated patients. Current Treatment Rates are 1-3% of all ischemic strokes Accurate expectations can enhance both physician and patient understanding of the risks of both tPA treatment and non-treatment

3. Objectives Present outcome data on tPA use in stroke from the NINDS trial and other Phase III studies –Short-term –Long-term Review outcome data on tPA use outside of investigational studies… effectiveness Understand the outcome feedback information systems to be used locally in the INSTINCT trial

4. IV thrombolysis - background Small trials in late 1960s and 1970s Used streptokinase + anticoagulation or urokinase Used a long treatment window (up to 36 hours) High mortality First studies with tPA (dose finding) emerged in early 1990s

5. IV studies overview (publication date) NINDS rt-PA (1995) ECASS (1995) MAST-I (1995) MAST-E (1996) ASK (1996) ECASS II (1998) ATLANTIS (1999-2001)

6. NINDS Stroke rt-PA Two part trial Part 1 – (291) 4 point improvement in NIHSS in 24 hours Part 2 – (333) 3 month clinical outcome Multi-center randomized placebo control trial “Permuted block design” NEJM 1995;333:1581

7. Part 1 results NEJM 1995;333:1581

8. Part 1 No significant difference at 24 hours based on NIHSS improvement of 4 points 1 However, a post hoc analysis demonstrated that picking any number other than 4 for this would have demonstrated a benefit 2 The study did not demonstrate a benefit at 24 hour by pre-specified primary endpoint 1.NEJM 1995;333:1581 2.Annals Emerg Med. 1997;30:676

9. Part 2 OR for favorable outcome 1.7 (1.2-2.6) Versus placebo – rt-PA treated patients about 30% more likely to have minimal or no disability Put another way, 12% absolute difference – NNT about 8 NEJM 1995;333:1581

10. Outcomes

11. What are the risks? Symptomatic ICH 6.4% with rt-PA Only 0.6% with placebo Mortality is not significantly different at 3 months NEJM 1995;333:1581

12. NINDS rt-PA 10 years later Still controversial Many patients treated in less than 90 minutes – which does not reflect usual reality Despite limitations – did show a benefit versus placebo (no we are not just “curing” a bunch of TIA’s) Is the only FDA approved pharmacologic therapy currently Is recommended by the ASA / AHA

13. European Cooperative Acute Stroke Study (ECASS) Randomized, prospective, double-blind placebo controlled 75 hospitals in 14 European countries 620 patients 1.1 mg/kg rt-PA or placebo within 6 hours Age 18-80 Exclusions CT showing > 33% MCA infarction - excluded JAMA. 1995;274:1017

14. ECASS - exclusions JAMA. 1995;274:1017

15. ECASS Demographics JAMA. 1995;274:1017

16. ECASS - results 33 (0.035) 2 JAMA. 1995;274:1017

17. ECASS – more on results JAMA. 1995;274:1017

18. Protocol violations - deadly JAMA. 1995;274:1017

19. Hemorrhages No difference in overall hemorrhages More parenchymal hematomas in rt-PA group JAMA. 1995;274:1017

20. ECASS – summary points Higher dose Long treatment window High number of protocol violations (almost 20%) Extremely high mortality in patients with PV Suggestion of some improvement in protocol rt- PA treated patients Increased mortality in rt-PA treated patients overall

21. Multi-centre Acute Stroke Trial - Italy Randomized “open” trial 622 patients 4 groups –Streptokinase alone –Aspirin alone –Both –Neither Lancet. 1995;346:1509

22. MAST-I results Aspirin + streptokinase increased 10 day mortality (to 34% from 13% for neither) Trend (NS) towards increased mortality with streptokinase alone 9% ARR for streptokinase versus aspirin (death and disability at 6 months) Major lesson : probably should not mix lytics and aspirin Lancet. 1995;346:1509

23. MAST – E (Europe) Multicenter, double blind, controlled trial of streptokinase vs. placebo 310 patients (enrollment stopped early) up to 6 hours Could use heparin (and they did about 2/3 rd of the time) Hypotension only 0.6% ! No difference in efficacy (disability) at 6 months Increase in 10 day mortality (34% vs 18%) 6 month mortality not significantly different NEJM 1995;335:145

24. Australian Streptokinase Trial (ASK) 340 patients within 4 hours Streptokinase or placebo Only 3 patients treated in less than 90 minutes! Hypotension noted in 33% 12.6% sICH (treated) versus 2.4% untreated Significantly increased death rate in those treated over 3 hours JAMA 1996;276:961

25. If you allow 4 hours you will get four hours JAMA 1996;276:961

26. ECASS 2 trial 0.9 mg/kg rt-PA within 6 hours 800 patients Only 81 rt-PA treated patients within 3 hours (placebo 75 in 3 hr) No significant difference in mortality No difference in primary endpoints (disability) Conclusion of investigators – its safe! (but it doesn’t work…) Lancet. 1998;352:1245

27. ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Acute Ischemic Stroke) Main study – did not show a benefit of rt- PA within 6 hours (or from 3-5 hours) Did a sub-group analysis of < 3 hr Only accepted up to age 79 Stroke. 2002;33:493; JAMA 1999;282:2019

28. ATLANTIS 0-3hr Stroke. 2002;33:493

29. ATLANTIS bottom line Another study which suggests treating after 3 hours is bad Subgroup analysis agrees with NINDS study findings

30. Study Locatio n DrugDoseTime Exclusion criteria Atlantis A (1991-93) USrt-PA 0.9 mg/kg (max: 90 mg) 0-6 Blood pressure (BP) NINDS (1991-94) USrt-PA 0.9 mg/kg (max: 90 mg) 0-3 (1:59)* Blood pressure MAST-I (1991-95) Italy, UK, Portugal streptokinase 1.5 million u 0-6 hours ECASS 1 (1992-94) Europert-PA 1.1mg/kg (max: 100mg) 0-6 (4:24)* CT evidence of early infarct; age MAST-E (1992-94) France, UK streptokinase 1.5 million u 0-6 h (4:36)** Mild stroke ASK Trial (1992-94) Australiastreptokinase 1.5 million u 0-4 (3:28) Age; minor stroke Atlantis B (1993- 98) USrt-PA 0.9 mg/kg (max: 90 mg) 3-5 (4:36)** Blood pressure; age ECASS 2 (1996-98) Europe ANZ* rt-PA 0.9 mg/kg (max: 90 mg) 0-6 BP; CT evidence of early infarct; age * mean; ** median time onset-to-treatment;

31. tPA Safety Meta Analysis 15 published, open-label studies in non- selective patient populations 2,639 treated patients Symptomatic ICH rate 5.2% [95% CI 4.3 to 6.0] Total death rate 13.4% Very favorable outcome 37.1% Protocol deviations 19.8% Graham, G. D. Stroke 2003;34:2847-2850

32. “But what about outcomes in the community setting…” “Community physicians cannot duplicate the results of specialized stroke teams in an academic setting” –can’t diagnose a stroke –can’t tell the time of onset –can’t get a CT interpretation –can’t follow a checklist of inclusions/exclusions

33. 29 Cleveland area hospitals 70 patients treated with tPA 50% protocol deviations 16% symptomatic ICH 96% with neurologist involved Katzan IL et al: JAMA. 2000 Mar 1;283(9):1151-8. “Ad hoc” Delivery Systems 1997-98 Cleveland, OH

34. Graham, G. D. Stroke 2003;34:2847-2850 Mortality rate vs Percentage of Protocol Deviations in each of 12 studies reporting death rates

35. With support: CCHS Stroke QI Plan Protocol, stroke paging system, CME and performance reports June 2000 – June 2001 results: –47 patients treated –Protocol deviations 17% –Symptomatic ICH 6% Katzan IL et al: Stroke. 2003 Mar;34(3):799-800

36. INSTINCT Preliminary Data Safety of Community Use of tPA (SCUT) Retrospective, observational study of tPA use at 4 Michigan hospitals without dedicated tPA-stroke teams 1/1/96 to 1/1/2005 Comparisons to NINDS trial Sites not from selected INSTINCT population Scott PA, Frederiksen SM, Caveney AF, … Sandretto AM, Barsan WG, Silbergleit R. Safety of Community Use of tPA. Presented 2007 ASA ISC; San Francisco, CA; Feb 7, 2007.

37. Outcome Measures Primary Outcome Measure –Mortality rate at one year as measured by the National Death Index Secondary Outcome Measures –Rate of symptomatic ICH within 10 days of treatment –Rate of total intracerebral hemorrhage –rt-PA treatment guideline violations –Temporal performance measures

38. Results: EP Experience 273 patients treated by 95 individual EPs Median number of treatments per physician was 2, the mode was 1

39. Results: Patient Characteristics Similar to NINDS –Mean age 68 –45% female –DM, HTN, stroke Higher proportion of patients with disability prior to stroke Median and mean initial NIHSS = 13

40. Results: Treatment Times Mean onset-to-tx time = 154 min Median = 160 min Very similar to NINDS 90 – 180 min group

41. Results: ICH Rate of ANY ICH within 36h of tx: 9.9% –RR 0.94, 95% CI 0.58 – 1.51 to NINDS tPA Rate of Symptomatic ICH by CT criteria (PH- 2): 6.6% –RR 1.03, 95% CI 0.56 -1.9 to NINDS tPA

42. Results: 1-Year Mortality 27.8%; consistent with NINDS tx and placebo

43. Results: Treatment Guideline Violations ED violations: 71 / 273 (26%) –61% time (median 15 min over 180 min) –11% hypertension Post-admission violations (24h): 25% –36% hypertension –39% anti-platelet agents early –25% anticoagulant use early

44. Results: Neurologic Recovery (at discharge; mean 8 days)

45. Importance to INSTINCT Extensive evidence regarding safety of tPA use outside acute stroke teams Educational methods in INSTINCT originated and enhanced from those at preliminary sites Reinforces probability of success of study

46. Results from local treatment Customize case study for local site

47. The Impact (T.E. Dec 2003, 37 yo female RN)

48. INSTINCT Hospitals

49. Trial Specifics Multi-center, randomized, controlled trial testing a multi-level, systems-based, educational intervention Intervention based on adult education and behavior change theory Tailored to local needs by identifying local barriers Based on clinical pilot data

50. Feedback Mechanisms Targeted messaging –Content –Process Critical Incident Defusing On-site visits –Mock codes Telephone access to Brain Injury Group

51. Lessons Learned Protocol, Protocol, Protocol Multiple stakeholder “buy-in” Backup for tough cases Monitor treatments and outcomes Feedback Address system barriers

52. Okay, I have lectured for 3 hours Here is a clinical scenario And - all of a sudden you awaken! You have a dense left hemiparesis Your NIHSS is 11 You don’t get complicated migraines and you are well adjusted! WHAT ARE WE GOING TO DO?

53. Summary Points NINDS rt-PA trial only trial to show improvement and is only FDA approved pharmacotherapy Other acute IV trials are heterogeneous Community use of tPA with protocols is safe Feedback mechanisms designed to enhance proper use of tPA in stroke

54. The Current National Stroke Reality

55. A Vision of the Future…