From CSRG: thrombolysis for acute ischaemic stroke

1. From CSRG: thrombolysis for acute ischaemic stroke Peter Sandercock, on behalf of Joanna Wardlaw & Veronica Murray IST-3 Italian Stroke Forum Firenze 13th February 2009

2. Joanna Wardlaw & Veronica Murray

3. Outline = structure of a review • Competing interests • History of this review • Methods & protocol for update • Types of studies to include • Main outcomes • Planned subgroups • New data included in the update • Analyses • Implications • For clinical practice • For future research

4. Competing interests • JMW: SITS-MOST Steering and CT adjudication • JMW: ECASS 3 CT reading Committee • JMW & PS IST-3 lead investigators • VM IST-3 coordinator for Sweden • IST-3 donation of drug and placebo for first 300 patients from BI • No funding from any pharmaceutical company for this review

5. History of thrombolysis review • Initiated: (before Cochrane collaboration!) 1990, first published in Cochrane Library 1995 • Inclusion criteria: all randomised controlled trials of any thrombolytic drug versus control • Primary outcome: death or dependency (MRS 3-6) at final follow-up. • 2003 update: 18 trials, 5675 patients (only 42 patients aged over 80), drugs = rtPA, streptokinase, uro-kinase, rPro-urokinase, time = 0-6 hrs, Brain Imaging: CT

6. Methods for the 2009 update Included studies • New trials completed since 2003 • New data from existing trials Search strategy • Searches for trials from multiple sources (including Cochrane Stroke Group Specialised Register of Trials) • Two independent reviewers extracted data

7. Methods – data extracted Outcomes assessed in previous review: • Intracranial haemorrhage • Death early and late, • Poor functional outcome • Infarct early swelling, Subgroups in previous review • Time to treatment, • Antithrombotic treatment, • Stroke severity, • mRS cut point, New subgroups : • Type of imaging, CT or MR • Presence of ’infarct signs’ on baseline CT, • Stroke subtype (large artery or lacunar)

8. New trial data added to review • 8 trials (1,477 patients) • Drugs tested: • 3 rt-PA (ECASS-3, EPITHET, Wang) • 2 Urokinase (AUST, MELT) • 3 desmoteplase (DIAS 1&2, DEDAS) • Route: 2 intra-arterial, 6 intravenous • Time from onset: 0-6, 3-4.5, 3-9, 0-24 hrs • Imaging pre randomisation: • CT: 5 • MR: 3 (+1) DWI/PWI mismatch • Age over 80: no new data

9. Summary of effects on main outcomes. Odds Ratios (95% CI) SICH Dead Dead or (incl fatal) dependent 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: meta-regression on a variety of factors does not explain it

10. IV rt-PA < 6hrs only: effect on death or dependency (mRS 3-6) = trial completed recently Odds ratio = 0.78 (0.68-.88) Heterogeneity (Chi2 p=0.007) I2 = 62% Test for overall effect p=0.0001 Wardlaw et al 2008

11. Sensitivity analysis: how robust is the result? Does it change with the choice of mRS cut-off? IV tPA vs control Mori NINDS ECASS ECASS 2 ECASS 3 Atlantis A Atlantis B rt-PA subtotal mRS 2 to 6 Modified Rankin (mRS): 3 to 6 0.1 0.78 1 5 0.1 0.77 1 5 thrombolysis better thrombolysis worse Heterogeneity highly significant : p=0.007 p= 0.006

12. Secondary outcome: effect of iv rt-PA on symptomatic cerebral oedema Odds ratio 0.79 (0.62- 1.01) p = 0.06 Wardlaw et al 2008

13. Summary 2008 • No material change in estimates of effect on major outcomes since 2003. • i.v. rt-PA: • Heterogeneity still confounds interpretation of primary, but not secondary, outcomes • ECASS 3 consistent with existing rt-PA meta-analysis. • Interesting effect on symptomatic cerebral oedema • Evidence of benefit to at least six hours and possibly beyond, but in whom? • Other drugs, other routes: promising but unproven

14. IMPLICATIONS FOR PRACTICE: Even if the EU approval for thrombolysis is extended to 4.5 hrs, this will still exclude patients who: • Are aged > 80 years • Have ‘very mild stroke’ or NIHSS > 25 • Had prior stroke within the last 3 months • Have a history of prior stroke + Diabetes • Arrive at 4.5 to 6.0 hours • Have other relative contraindications specified in the licence (e.g. ‘extensive infarction’, which is not defined in any way)

15. IMPLICATIONS FOR RESEARCH. More randomised trial evidence needed on effects of i.v. rt-PA: • When used <6hrs (and beyond 6hrs too?) • In particular categories of patients: • Aged > 80 • Different subtypes, • Mild stroke, sever stroke • On symptomatic massive cerebral oedema • Clinical and imaging factors that determine • benefit from treatment • risk of symptomatic intracranial haemorrhage • In whom perfusion or angiographic imaging is necessary?

16. Grazie

17. Effect of IV rt-PA < 6hrs on death at the end of FU OR 1.14 (95% CI 0.95-1.30)

18. 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) Primary outcome: 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