1. S afe I mplementation of T hrombolysis in S troke Slide presentation adapted from http://www.acutestroke.org/http://www.acutestroke.org/

2. In 2002, European Union regulatory authority EMEA approved rt-PA for stroke CONDITIONALLY Age 18-80 In high quality stroke centres with stroke units with certain monitoring requirements Within 3 hours of an ischaemic stroke

3. There were two major conditions for this approval: Safety monitoring of all treated patients in SITS (SITS-MOST) until 2005 (prolonged to April 2006) RCT to study effect of rt-PA in patients with symptoms onset since 3–4.5h (ECASS III) EU approval with conditions:

4. Recruitment SITS-MOST 2003-2006: 6,483 patients 285 active centres 2003:12003:22004:12004:22005:12005:22006:1 0 50 100 150 200 250 300 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 PatientsCentres

5. Results, baseline: Variables Data are median (IQR) or % SITS-MOST n=6483 Pooled RCT Placebo 0-3h n=465 Pooled RCT Alteplase 0-3h n=464 Age, years 68 (59-75)67.1 (60- 74)69.6 (61- 75) Females 39.840.240.1 Hypertension 58.760.759.7 Diabetes Mellitus 16.018.921.1 Atrial Fibrillation 23.920.020.7 Congestive heart failure 7.515.313.2 Previous stroke 10.112.713.8 Aspirin 29.828.836.4 Lancet 2007; 369: 275-282.

6. Results, baseline: Variables Data are median (IQR) or % SITS-MOST n=6483 Pooled RCT Placebo 0-3h n=465 Pooled RCT Alteplase 0-3h n=464 NIHSS, excluding item 1212 (8-17)14 (9-19)13 (8-18) Blood glucose (mg/dl)116 (101-139)124 (106-151)119 (104-158) Weight in kg75 (68-85)79.4 (66- 90.7)75 (65-84) Systolic blood pressure (mm Hg) 150 (137-166)152 (140- 170)156 (140-170) Diastolic blood pressure (mm Hg) 81 (74-90)86 (77-95.5)84 (78-92) Stroke onset to treatment time (minutes) 140 (115-165)138 (90-165)140 (90-168) Lancet 2007; 369: 275-282.

7. Type of haemorrhages at 22-36h imaging: Lancet 2007; 369: 275-282. HI 1: small petechiae along the margins of the infarct HI 2: a more confluent petechiae within the infarct area but without space-occup. effect PH 1: blood clot(s) not exceed. 30% of the infarct area w. some mild space-occup. effect PH 2: blood clots exceeding 30% of the infarct area with significant space occup. effect

8. SICH 107/ 6444 1.41.72.0 RCT Active arm Preliminary Clinical Outcome, 95% CI 0%6%10%15%20%25% 40%50%55%45% 2% 4% 8% Lancet 2007; 369: 275-282. SITS-MOST Results *at post-treatment imaging 22-36h SITS-MOST main outcomes 2003-2006, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) SITS definition of SICH: PH2* + NIHSS ≥ 4 points or death within 24 hours

9. RCT Active arm 0%6%10%15%20%25% 40%50%55%45% 2% 4% 8% Lancet 2007; 369: 275-282 SITS-MOST Results *at post-treatment imaging <7d SITS-MOST main outcomes 2003-2005, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) Preliminary Clinical Outcome, 95% CI SICH 296/ 6442 4.14.65.1 ECASS definition of SICH: Any haemorrhage + NIHSS ≥ 4 points or death within 7 days

10. RCT Active arm 0%6%10%15%20%25% 40%50%55%45% 2% 4% 8% Lancet 2007; 369: 275-282 SITS-MOST Results *at post-treatment imaging <7d SITS-MOST main outcomes 2003-2005, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) Preliminary Clinical Outcome, 95% CI SICH 468/ 6438 6.77.37.9 RCT definition of SICH: Any haemorrhage + NIHSS ≥ 1 points or death within 7 days

11. RCT Active arm 0%6%10%15%20%25% 40%50%55%45% 2% 4% 8% Lancet 2007; 369: 275-282. SITS-MOST Results SITS-MOST main outcomes 2003-2005, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) Preliminary Clinical Outcome, 95% CI Mortality 701/ 6218 SICH (any worsening + any bleeding) 468/ 6438 6.77.37.9 10.511.312.1 53.554,856.0 Independence 3 months (mRankin0-2) 3362/ 6136

12. Result of SITS-MOST compared with randomised controlled trials – modified Rankin Scale at 3 months Red colours: ADL*-independent Blue colours: ADL*-dependent Black colour: Dead 19 20 13 19,9 22 16 15,9 8 11 14,7 14 13,9 12 20 5,3 7 7 11,4 18 SITS-MOST RCT active rt-PA RCT placebo mRS 0 mRS 1 mRS 2 mRS 3 mRS 4 mRS 5 mRS 6 0%20%40%60%80%100% DeadRecovered +10% +4,8% *Activities of daily living Lancet 2007; 369: 275-282.

13. 6% 8% 10% 12% 14% 16% 18% 20% 45% 50% 55% 60% 1% 2% 3% SITS-MOSTRCT ExperiencedNew SICH rates per SITS-MOST 1.6 (1.3-2.0)1.7 (1.2- 2.6)NA SICH rates per NINDS/Coch rane 7.3 (6.6- 8.0)7.3 (6.1- 8.7)8.6 (6.3- 11.6) Mortality within 3 months 10.6 (9.8- 11.6)13.3 (11.6- 15.1)17.3 (14.1- 21.1) Independence (mRS, 0-2) at 3 months 54.4 (53.0- 55.8)56.0 (53.4- 58.5)50.1 (45.5- 54.7) Main outcome by site’s previous experience with thrombolysis in stroke before joining SITS-MOST Pooled RCT SITS-MOST, Experienced SITS-MOST, New Lancet 2007; 369: 275-282.

14. Conclusions:  These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3h of stroke onset, even by centres with limited prior experience of thrombolytic therapy for acute stroke.  SITS-MOST has fulfilled its purpose outlined by EMEA to show that i.v stroke thrombolysis is safe under the treatment conditions  Now it is also important that ECASS 3 is completed successfully so that we can receive a permanent licence for rt-PA  The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.

15. Further conclusions: safe but still underused  Although the recruitment to SITS-MOST and SITS-ISTR (more than 12,000) is beyond expectations, less than 2% of all stroke patients receive thrombolysis in EU  Following the publication of SITS-MOST main outcomes national publications for each EU country are planned to state the current level of thrombolysis implementation  This will also be the starting point for the project SITS 2009 @ 5%, which aims to reach this level of implementation (or more) in 3 years – all current SITS centres and those not yet active are invited to participate

16. Why should clinicians spend time putting patients into SITS? Ongoing audit of local results against national and international standards Especially important when starting a thrombolysis service Instant summaries of outcomes for the local centre downloadable form the sitedownloadable But: important to include all patients. Selective use of the database will bias outcomes.

17. SITS thrombolysis register Jun 2009 StokeUKWorld No registered1053,19427,988 % much better in 24 h 40%33%31% % much better at 7d54%43%41% % no symptoms at all at 3 mo25%15%18% % SICH*0%1%1% % signif. deterioration<=24 h9%9%12% % deaths22%22%14% Door to needle time82 min**66 min65 min Onset to needle time150 min150 min145 min Age676867 Baseline NIHSS141412 TACI51%48%36% * defined as confluent haemorrhage (not just petechial) and clinical deterioration e.g. NIHSS change>4 within 24 h or death and PH2 or PHr2 at 22-36 h. ** 98 min to Jan 2008! 85 min to March 2008! And 62 min from May 2009

18. ECASS III RCT alteplase versus placebo 3-4.5 h post stroke onset N=821 Median time to treatment 3:59 h:min tPAPlacebo Favourable outcome52%45%p=0.04 e.g.Rankin 0-1 at 3 mo Symptomatic ICH2.4%0.2%P=0.008 Mortality7.7%8.4%P=0.7

19. ECASS III caveats Baseline imbalance NIHSS 1 point worse in placebo group at randomization SC heparin was allowed

20. EPITHET Study 101 patients, median NIHSS 14 mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI) before and 3-5 d after rx alteplase 3-6 h after stroke onset non-significantly lower infarct growth and significantly increased reperfusion in patients who had mismatch Phase III trials beyond 3 h warranted Davis et AK, Lancet Neurol. 2008;7(4):299-309.

21. What % of stroke patients received thrombolysis for stroke in USA in 2007? rt-PA approved for stroke since 1995 Audit of 4,750 hospitals, ~ 500,000 patients with ischaemic stroke (2005-7) ~12,000 (2.4%) patients treated with rt-PA Proportion treated varied: 0-23% 60% of hospitals did not give rt-PA at all. Kleindorfer et al AHA Stroke Conference 2009 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

22. What % of stroke patients received thrombolysis for stroke in USA in 2007? rt-PA approved for stroke since 1995 Audit of 4,750 hospitals, ~ 500,000 patients with ischaemic stroke (2005-7) ~12,000 (2.4%) patients treated with rt-PA Proportion treated varied: 0-23% 60% of hospitals did not give rt-PA at all. Kleindorfer et al AHA Stroke Conference 2009 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

23. Cochrane systematic review of of thrombolysis with rt-PA Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (in Press) 11 trials, including ECASS-3 3977 patients tpa vs control RCT data on only 42 patients > 80 yrs Follow-up short: primary outcome @ 3months. Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

24. IV rt-PA < 6h. ~4000 patients, 1920 outcome events ‘death or dependency (mRS 3-6)’ Odds ratio = 0.78 (0.68-.88) Heterogeneity (Chi 2 p=0.007) I 2 = 62% Test for overall effect p=0.0001 Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (submitted) 926 999 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

25. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: 6000 patients from 300 centres in 36 Countries IST-3 collaborators meeting Capetown 2006

26. IST3 Why another trial? Areas of Uncertainty to explore Risks Risks Symptomatic cerebral haemorrhageSymptomatic cerebral haemorrhage DeathDeath Benefits Benefits Reduced ‘death or dependency’Reduced ‘death or dependency’ ?reduction in massive cerebral oedema??reduction in massive cerebral oedema? Subgroup analyses: effect of Subgroup analyses: effect of Time to treatmentTime to treatment AgeAge Stroke severityStroke severity Risk factors for intracerebral haemorrhageRisk factors for intracerebral haemorrhage Appearance of CT scanAppearance of CT scan

27. Mild, or rapidly improving strokes (NIHSS < 4) 2 hours ago, this man developed right hemiparesis, now rapidly improving. NIHSS < 4, so rt-PA not approved Many such patients recover without rt-PA, BUT 15-30% later deteriorate suddenly -> disabling stroke IST-3 will include ~ 600 with NIHSS < 5 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

28. Vertebro-basilar territory ischaemic strokes Acute cerebellar infarct Excluded from previous trials of iv rt-PA Time window for treatment unclear Is there benefit from iv thrombolysis for such patients? IST-3 will include ~ 200 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

29. Stroke patients > 80 years Patients over 80 have been excluded from randomised trials and the licence In the UK 30% of all strokes are aged > 80 = 31,000 ischaemic stroke patients each year automatically excluded from thrombolysis IST-3 will recruit > 1000 patients > 80 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

30. Severe stroke (NIHSS > 25) This man had a large MCA infarct NIHSS > 25, rt-PA not approved for him He spent many months in hospital He was very disabled IST-3 will include ~ 300 such patients Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

31. Impact of iv rt-PA on symptomatic cerebral oedema Odds ratio 0.79 (0.62- 1.01) p = 0.06 Wardlaw et al 2008 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

32. Taking part in IST-3 Support form IST-3 team Support form IST-3 team Extends therapeutic window, more experience in thrombolysis Extends therapeutic window, more experience in thrombolysis

33. Consent for IST-3 10% (one in 10) will make a better than expected recovery 5% (one in 20) will have a fatal brain haemorrhage

34. If IST-3 positive, how many stroke patients per year in UK might avoid being ‘dead or dependent’ with each treatment? UK has 130,000 strokes/yr % treated Number treated per year Number treated per year Number avoiding death/dep. Number avoiding death/dep. Aspirin80%1040001350 Stroke Unit 60%780004370 Thrombolysis < 3h 1 2.4%3100200 Thrombolysis < 6h 2 30%390001800 1.USA 2004 MEDPAR average. Kleindorfer. Stroke 2008: 39: 924-8 2.If IST-3 widens treatment indication? Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

35. Hacke W et al. 16th European Stroke Conference; June 1, 2007; Glasgow, Scotland. DIAS-2: Clinical response rates at 90 days End pointPlacebo, n=63 (%) 90 µg/kg, n=57 (%) 125 µg/kg, n=66 (%) Clinical response rate46.047.436.4 All-cause mortality at 90 days 4 (6.3)3 (5.3)14 (21.2) ICH at 72 h0 (0)2 (3.5)3 (4.5)

36. DIAS-4 Desmoteplase 90ug/kg bolus Within 9 h of symptom onset All patients need CT angio before randomization Inclusion depends on results of CT angio

37. LINKS  http://www.acutestroke.org/ for SITS http://www.acutestroke.org/ google sits stroke  http://www.dcn.ed.ac.uk/ist3/ for IST3 http://www.dcn.ed.ac.uk/ist3/ google ist3  http://www.thrombolysis.info/ for thrombolysis docs http://www.thrombolysis.info/ google thrombolysis.info

39. Research and Governance  SITS Register  ECASS-3  IST-3  DIAS-3 C. Roffe 4-day Thrombolysis Course Stafford University 10 06 09