1. SITS-MOST main outcome results *Corresponding author: Prof. Nils Wahlgren SITS International Coordination Office Karolinska Stroke Research Department of Neurology Karolinska University Hospital – Solna SE-171 76 Stockholm, Sweden Tel.: +46 8 517 756 00 Fax: +46 8 736 61 58 E-mail: nils.wahlgren@karolinska.senils.wahlgren@karolinska.se Safe implementation of Thrombolysis in stroke- Monitoring Study (SITS-MOST) in Europe Nils 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.

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

3. Maps courtesy of www.theodora.com/maps used with permissionwww.theodora.com/maps 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 Safe Implementation of Treatments for Stroke (SITS)

4. 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

5. 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:

6. Between 2002 and 2006, 6483 patients were recruited to SITS-MOST at 285 active centres 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

7. Number of centres, patients & National coordinators (NC) per country for SITS-MOST CountryNo of centers (%) No of patients (%) NCs / Associate NCs Austria21 (7.4)638 (9.8)F Aichner, M Brainin, R Topakian Belgium23 (8.1)291 (4.5)G Vanhooren, V Thijs, P Laloux Denmark5 (1.8)103 (1.6)K Overgaard, G Boysen Finland17 (6.0)590 (9.1)M kaste, R Roine France11 (3.9)189 (2.9)V Larrue, Marie-Helene Mahagne Germany21 (7.4)1289 (19.9)M Grond, P Ringleb Greece3 (1.1)48 (0.7)K Vemmos, J Rudolf, C Karageorgiou Italy56 (19.6)586 (9.0)D Toni Netherlands3 (1.1)173 (2.7)J Lodder, C Franke Norway21 (7.4)233 (3.6)L Thomassen Portugal4 (1.4)60 (0.9)M Antónia Ferro Spain42 (14.7)1305 (20.1)J Castillo, A Dávalos Sweden35 (12.3)651 (10.0)NG Wahlgren UK23 (8.1)327 (5.0)K Lees, G Ford Total2856483

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

9. Top 15 recruiting centres and local coordinators for SITS-MOST CountryCentre namepatientName of the local Coordinator FinlandHelsinki Uni Central Hospital288Lauri Soinne GermanyUniversity of Heidelberg145M Köhrmann, S Kuelkens FinlandTampere University Hospital125Terttu Erilä SpainHospital Universitari Girona117J Serena Leal GermanyKlinikum Minden116Otto Busse GermanyKreisklinikum Siegen115Markus Diedrichs SpainHospital German Trias i Pujol101Nicolás Vila AustriaChristian-Doppler-Klinik Salzburg93Bernhard Iglseder NetherlandsUniversity Hospital Maastricht83Jan Lodder GermanyKrankenhaus Nordwest79Rudolf Janzen AustriaUniversity Hospital Innsbruck78Johann Willeit GermanyUniv.Hospital Mannheim78M Daffertshofer, J Binder SpainHospital de Bellvitge77Francisco Rubio GermanyUniversitätsklinikum Leipzig73Dietmar Schneider GermanyKlinikum Ludwigsburg73Clemens Veit, Bert Wagner

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: 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.

13. 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.

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. 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

18. 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

19. 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

20. 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

21. 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.

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 Type of centresSICH per SITS-MOST protocol SITS-MOST, Experienced1.6 (1.2- 2.0) SITS-MOST, New1.7 (1.2- 2.6) Pooled RCTNA Type of centresSICH per Cochrane/ NINDS SITS-MOST, Experienced7.3 (6.6- 8.0) SITS-MOST, New7.3 (6.1- 8.7) Pooled RCT8.6 (6.1- 11.1) Type of centresMortality at 3 months SITS-MOST, Experienced10.6 (9.8- 11.6) SITS-MOST, New13.3 (11.6- 15.1) Pooled RCT17.3 (14.1- 21.1) Type of centresIndependent (mRS 0-2) 3 months SITS-MOST, Experienced54.4 (53.0- 55.8 SITS-MOST, New56.0 (53.4- 58.5 Pooled RCT50.1 (45.5- 54.7 Lancet 2007; 369: 275-282.

24. 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.

25. 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.

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 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

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