SITS-MOST main outcome results

1. SITS-MOST main outcome results Safe implementation of Thrombolysis in stroke- Monitoring Study (SITS-MOST) in EuropeNils Wahlgren*, Niaz Ahmed, Antoni Dávalos, Gary A Ford, Martin Grond, Werner Hacke, Michael G Hennerici, Markku Kaste, Sonja Kuelkens, Vincent Larrue, Kennedy R Lees, Risto Roine, Lauri Soinne, Danilo Toni, Geert Vanhooren, for the SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study . Lancet 2007; 369: 275-282. *Corresponding author: Prof. Nils Wahlgren SITS International Coordination Office Karolinska Stroke ResearchDepartment of NeurologyKarolinska University Hospital – SolnaSE-171 76 Stockholm, Sweden Tel.: +46 8 517 756 00 Fax: +46 8 736 61 58 E-mail: nils.wahlgren@karolinska.se

2. Main outcome variables in SITS-MOST Primary • Symptomatic ICH • Mortality Secondary • Independence

3. Safe Implementation of Treatments for Stroke (SITS) • The aim of SITS is to maintain and improve safety and efficacy during broad implementation of stroke treatments • International network of 500 centres in 30 countries • Main tool is an interactive database including 12,800 patients – thrombolysis dominating intervention • Performs research on stroke treatment strategies Maps courtesy of www.theodora.com/maps used with permission

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

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

6. Between 2002 and 2006, 6483 patients were recruited to SITS-MOST at 285 active centres Patients Centres 7,000 300 6,000 250 5,000 200 4,000 150 3,000 100 2,000 50 1,000 0 0 2003:1 2003:2 2004:1 2004:2 2005:1 2005:2 2006:1 SITS-MOST 2003-2006: 6,483 patients 285 active centres

7. Number of centres, patients & National coordinators (NC) per country for SITS-MOST

8. Number of centres and patients per country for SITS-MOST

9. Top 15 recruiting centres and local coordinators for SITS-MOST

10. Background and Purpose: • SITS-MOST was designed to control for the rate of symptomatic intracerebral haemorrhage (SICH), mortality and independence for activities of daily living (ADL independence) compared to the active arms of prior Randomised Controlled Trials (RCTs).

11. Background and Purpose: • SITS-MOST was designed to control for the rate of symptomatic intracerebral haemorrhage (SICH), mortality and independence for activities of daily living (ADL independence) compared to the active arms of prior Randomised Controlled Trials (RCTs). • This report is based on final data between Dec 2003 and April 2006. The last new patient in SITS-MOST was entered on 30th April, 2006.

12. Results, baseline: Lancet 2007; 369: 275-282.

13. Results, baseline: Lancet 2007; 369: 275-282.

14. Local haemorrhages at 22-36h imaging: Lancet 2007; 369: 275-282.

15. Remote haemorrhages at 22-36h imaging: Lancet 2007; 369: 275-282.

16. Type of haemorrhages at 22-36h imaging: Lancet 2007; 369: 275-282.

17. SITS-MOST main outcomes 2003-2006, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) 4% 0% 6% 10% 15% 20% 25% 2% 8% 40% 45% 50% 55% SITS-MOST Results RCT Active arm Preliminary Clinical Outcome, 95% CI SITS definition of SICH: PH2* + NIHSS ≥ 4 points or death within 24 hours SICH 107/ 6444 1.4 1.7 2.0 *at post-treatment imaging 22-36h Lancet 2007; 369: 275-282.

18. SITS-MOST main outcomes 2003-2005, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) 4% 0% 6% 10% 15% 20% 25% 2% 8% 40% 45% 50% 55% 4.1 4.6 5.1 SITS-MOST Results RCT Active arm Preliminary Clinical Outcome, 95% CI ECASS definition of SICH: Any haemorrhage + NIHSS ≥ 4 points or death within 7 days SICH 296/ 6442 *at post-treatment imaging <7d Lancet 2007; 369: 275-282

19. SITS-MOST main outcomes 2003-2005, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) 4% 0% 6% 10% 15% 20% 25% 2% 8% 40% 45% 50% 55% SITS-MOST Results RCT Active arm Preliminary Clinical Outcome, 95% CI RCT definition of SICH: Any haemorrhage + NIHSS ≥ 1 points or death within 7 days SICH 468/ 6438 6.7 7.3 7.9 *at post-treatment imaging <7d Lancet 2007; 369: 275-282

20. SITS-MOST main outcomes 2003-2005, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals) 4% 0% 6% 10% 15% 20% 25% 2% 8% 40% 45% 50% 55% SITS-MOST Results RCT Active arm Preliminary Clinical Outcome, 95% CI Mortality 701/ 6218 10.5 11.3 12.1 Independence 3 months (mRankin0-2) 3362/ 6136 53.5 54,8 56.0 SICH (any worsening + any bleeding) 468/ 6438 6.7 7.3 7.9 Lancet 2007; 369: 275-282.

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

22. New SITS-MOST centres with little or no experience in stroke thrombolysis before joining SITS-MOST Lancet 2007; 369: 275-282.

23. Main outcome by site’s previous experience with thrombolysis in stroke before joining SITS-MOST Lancet 2007; 369: 275-282.

24. Main outcome by site’s previous experience with thrombolysis in stroke before joining SITS-MOST 45% 50% 55% 60% 6% 8% 10% 12% 14% 16% 18% 20% 1% 2% 3% Pooled RCT SITS-MOST, Experienced SITS-MOST, New Lancet 2007; 369: 275-282.

25. Conclusions: • These data confirm thatintravenous 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.

26. 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 projectSITS 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

27. SITS-MOST is over but the SITS register continues The SITS register is an expanding tool for quality improvement of stroke interventions SITS may now be used as a general stroke register for interested stroke centres / countries SITS now plans to launch randomised trials on thrombectomy and other interventions

28. THANKS! SITS-MOST is a unique achievement THANKS to all participants, patients THANKS to Boehringer-Ingelheim for excellent collaboration Good luck to all to reach the 5% national level of treated patients before end of 2009