Thrombolysis in acute ischaemic stroke – Updated Cochrane Thrombolysis metaanalysis

1. Thrombolysis in acute ischaemic stroke – Updated Cochrane Thrombolysis metaanalysis JM Wardlaw, V Murray, PAG Sandercock University of Edinburgh and Karolinska Institutet, Stockholm Brenda Thomas,Greg del Zoppo, Eivind Berge, Take Yamaguchi

2. Thrombolysis Systematic Review • Continuously updated since 1990 • All randomised controlled trials of any thrombolytic drug versus control • Last update 2003: • 18 trials (n=5675) • Drugs: rt-PA, streptokinase, uro-kinase, rPro-urokinase, • Time windows: 0-3, 0-6 hrs • Brain Imaging : CT • Age over 80 : 42 patients

3. Methods • Material • New trials • New data from existing trials • Methods • Multiple overlapping ascertainment methods • Two independent reviewers extracted data • Odds Ratios (ORs), 95% CI, heterogeneity • Metaregression on some key variables

4. Methods – data sought Previous outcomes : • Intracranial haemorrhage - asymptomatic, symptomatic and fatal • Death early and late, • Poor functional outcome • Infarct early swelling, Previous subgroups : • Time to treatment, • antithrombotic treatment, • stroke severity, • mRS cut point, New subgroups : • type of imaging, CT or MR • CT infarct signs, • stroke subtype, large artery/lacunar

5. What’s new in 2008? 2008: • 8 new trials (n=+1477, total: n=7152) • Drugs: 3 rt-PA; 2 UK; 3 desmoteplase • Route: 2 intra-arterial, 6 intravenous • Time windows: 0-6, 3-4.5, 3-9, 0-24 hrs • Imaging pre randomisation: • CT: 5 • MR: 3 (+1) DWI/PWI mismatch • Age over 80: ≈42

6. 0.91 (0.64, 1.42) 0.94 (0.72, 1.24) 0.77 (0.47, 0.89) 1.09 (0.49, 1.72) 0.55 (0.31, 1.00) 0.57 (0.28, 1.14) 0.85 (0.53, 1.38) 0.82 (0.73, 0.91) Death or dependency at the end of follow-up IV urokinase IV streptokinase IV rt-PA IV streptokinase + aspirin IA pro-urokinase IA urokinase IV desmoteplase Total

7. ECASS 3 Inclusion: 3-4.5 hours Age 18-80 yrs Excluded : NIHSS>25 or CT infarct signs >1/3MCA diabetes and prior stroke stroke in previous 3 months Outcomes: SICH: “any apparently extravascular blood in the brain or within the cranium that was associated with clinical deterioration, as defined by an increase of 4 points or more in the score on the NIHSS, or that led to death and that was identified as the predominant cause of the neurologic deterioration” Good functional outcome: mRS 0-1 vs 2-6

8. ECASS 3 Baseline imbalances rt-PA PLA P Age 64.9 65.6 0.36 NIHSS 10.7 11.6 0.03 9 10 Diabetes 14.8 16.6 0.47 Prior 7.7 14.1 0.03 stroke

9. All drugs and rt-PA Summary of effects, 2008; ORs (95% CI) SICH Late Death or (incl fatal)DeathDependency All drugs 3.3 1.3 * 0.8 * n=7152 2.7 - 4.1 1.1 - 1.5 0.7 - 0.9 p<0.00001 p=0.06 p<0.0001 rt-PA 3.11.1 0.8 * n=3977 2.3 - 4.0 1.0 - 1.4 0.7 - 0.9 p<0.00001 p=0.16 p<0.0001 * Significant heterogeneity confounds interpretation

10. rt-PA trials: 2003 versus 2008 ORs (95% CI) SICH Late Death or (incl fatal) DeathDependency 20033.1 1.2 * 0.8 * n=2955 2.3 - 4.2 0.9 - 1.5 0.7 - 0.9 p<0.00001 p=0.14 p=0.003 2008 3.11.1 0.8 * n=3977 2.3 - 4.0 1.0 - 1.4 0.7 - 0.9 p<0.00001 p=0.16 p<0.0001 * significant heterogeneity confounds interpretation

11. rt-PA trials: 2008 N per 1000 treated, 95% CI Outcome all 0-3 hrs 3-6 hrs SICH 60 70 60 50, 80 40, 100 50, 80 Death100 20 10,40 50, 50 0, 50 Death or60 110 40 Depend. 100, 30 170, 50 80, 10 X = decrease X = increase

12. mRS 2-6 or 3-6 (rt-PA): Similar overall result IV tPA vs control Mori NINDS ECASS ECASS 2 ECASS 3 Atlantis A Atlantis B rt-PA subtotal 2 to 6 Modified Rankin: 3 to 6 0.1 0.78 1 5 10 0.1 0.77 1 5 10 thrombolysis worse thrombolysis better CDSR Oct 2004

13. 0.1 0.2 0.5 1 2 5 10 favours treatment favours control Death or dependency: subgroups OR (95% CI) n Trials n patients Latest time to treatment, all drugs (hours) 3 1 624 4.5 2 1161 6 9 3463 9 3 325 0.62 (0.45, 0.85) 0.85 (0.68, 1.07 0.84 (0.73, 0.96) 0.85 (0.52, 1.39) Treatment time rt-PA (hours) 0.64 (0.5. 0.8) 0.83 (0.7, 0.9) 0-3 5 930 3-6 6 2766

14. 0.1 0.2 0.5 1 2 5 10 favours treatment favours control Subgroups : Imaging (all drugs, all times) OR (95% CI) n Trials n patients Death or dependency 0.79 (0.8, 0.9) CT 10 4808 0.87 (0.6, 1.3) MR DWI/PWI 4 425 SICH CT MR DWI/PWI 4.55 (3.31, 6.27) 7.51 (1.39, 40.54) Death 1.18 (1.01, 1.40) 2.18 (1.09, 4.36) CT MR DWI/PWI

15. Other results, 2008 CT infarct signs and thrombolysis (3 trials): no clear interaction Infarct swelling (5 trials): reduced with rt-PA (OR 0.78, 0.62, 1.00, p=0.05) Metaregression on • Time to treatment (2 methods) • Antithrombotic therapy • Selection by MR DWI/PWI vs CT • ”Stroke severity” (2 methods) • Dose – MI equivalent vs ”stroke” dose • Trial size did not explain differences between trials

16. Conclusion, Update 2008 • Heterogeneity still confounds interpretation • ECASS 3 consistent with existing rt-PA meta-analysis. • Potential for benefit to at least six hours • Limited new knowledge on latest time windows. • Almost complete lack of data on older patients; antithrombotic use; stroke severity/subtype, diabetes • Outcome following selection on MR mismatch not apparently different to CT. • No material change in main outcomes since 2003.

17. Implications • Further data on i.v. rt-PA needed from randomised trials : • Out to at least six hours • Older patients, diabetes, hypertension, stroke subtypes • Clarifying risk factors for haemorrhage and death

18. Competing interests • SITS-MOST Steering and CT adjudication • ECASS 3 CT reading Committee • IST3 Trial Steering Committee and Imaging lead

19. rt-PA 2008- OR and events per 1000 treated rt-PA Effect per 1000 Symptomatic ICH : <3 hrs +70 3-6 hrs +60 Death by three months : <3 hrs 0 +20 3-6 hrs Dead or Dependent : <3 hours -110 - 40 3-6 hours 0.1 0.66 0.84 1.0 1.333.37 10 OR better thrombolysis worse CDSR 2008