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S afe I mplementation of T hrombolysis in S troke

S afe I mplementation of T hrombolysis in S troke. Slide presentation adapted from http://www.acutestroke.org/. In 2002, European Union regulatory authority EMEA approved rt-PA for stroke CONDITIONALLY. • Within 3 hours of an ischaemic stroke. • Age 18-80.

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S afe I mplementation of T hrombolysis in S troke

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  1. SafeImplementation of Thrombolysis in Stroke Slide presentation adapted from http://www.acutestroke.org/

  2. 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

  3. 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)

  4. Recruitment 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

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

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

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

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  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 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

  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 site But: important to include all patients. Selective use of the database will bias outcomes.

  17. SITS thrombolysis register Jun 2009 Stoke UK World No registered 105 3,194 27,988 % much better in 24 h 40% 33% 31% % much better at 7d 54% 43% 41% % no symptoms at all at 3 mo 25% 15% 18% % SICH* 0% 1% 1% % signif. deterioration<=24 h 9% 9% 12% % deaths 22% 22% 14% Door to needle time 82 min** 66 min 65 min Onset to needle time 150 min 150 min 145 min Age 67 68 67 Baseline NIHSS 14 14 12 TACI 51% 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 tPA Placebo Favourable outcome 52% 45% p=0.04 e.g.Rankin 0-1 at 3 mo Symptomatic ICH 2.4% 0.2% P=0.008 Mortality 7.7% 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 • 11 trials, including ECASS-3 • 3977 patients tpa vs control • RCT data on only 42 patients > 80 yrs • Follow-up short: primary outcome @ 3months. Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (in Press) 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)’ 926 999 Odds ratio = 0.78 (0.68-.88) Heterogeneity (Chi2 p=0.007) I2 = 62% Test for overall effect p=0.0001 Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (submitted) 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 • Symptomatic cerebral haemorrhage • Death • Benefits • Reduced ‘death or dependency’ • ?reduction in massive cerebral oedema? • Subgroup analyses: effect of • Time to treatment • Age • Stroke severity • Risk factors for intracerebral haemorrhage • Appearance 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 Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009 Wardlaw et al 2008

  32. Taking part in IST-3 • Support form IST-3 team • 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 • USA 2004 MEDPAR average. Kleindorfer. Stroke 2008: 39: 924-8 • If IST-3 widens treatment indication? • Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

  35. DIAS-2: Clinical response rates at 90 days Hacke W et al. 16th European Stroke Conference; June 1, 2007; Glasgow, Scotland.

  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 google sits stroke • http://www.dcn.ed.ac.uk/ist3/for IST3 google ist3 • http://www.thrombolysis.info/for thrombolysis docs google thrombolysis.info

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

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