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. IV urokinase IV streptokinase IV rt-PA IV streptokinase + aspirin IA pro-urokinase IA urokinase IV desmoteplase Death or dependency at the end of follow-up Total 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)

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-PAPLA P Age64.965.60.36 NIHSS10.711.60.03 910 Diabetes 14.816.6 0.47 Prior 7.714.10.03 stroke

9. All drugs and rt-PA Summary of effects, 2008; ORs (95% CI) SICH Late Death or (incl fatal) Death Dependency 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 3.1 1.1 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) Death Dependency 2003 3.1 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 3.1 1.1 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 Death 10 0 20 10, 40 50, 50 0, 50 Death or 60 110 40 Depend. 100, 30 170, 50 80, 10 X = decrease X = increase

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

13. Death or dependency: subgroups 0.1 0.2 0.5 1 2 5 10 favours treatment favours control n Trials n patients OR (95% CI) 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) 0-3 5 930 3-6 6 2766 0.64 (0.5. 0.8) 0.83 (0.7, 0.9)

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

15. 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 Other results, 2008

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 better thrombolysis worse 0.1 0.66 0.84 1.0 1.33 3.37 10 OR Symptomatic ICH : <3 hrs Death by three months : <3 hrs Dead or Dependent : <3 hours 3-6 hours +60 - 40 -110 +20 rt-PA Effect per 1000 3-6 hrs +70 3-6 hrs 0 CDSR 2008