from csrg: thrombolysis for acute ischaemic stroke
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From CSRG: thrombolysis for acute ischaemic stroke
Peter Sandercock, on behalf of Joanna Wardlaw & Veronica Murray
IST-3 Italian Stroke ForumFirenze
13th February 2009
Joanna Wardlaw & Veronica Murray
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
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
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
Methods for the 2009 updateIncluded 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
Methods – data extractedOutcomes 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)
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
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 3.1 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:meta-regression on a variety of factors does not explain it
IV rt-PA < 6hrs only: effect on death or dependency (mRS 3-6)
Odds ratio = 0.78 (0.68-.88)Heterogeneity (Chi2 p=0.007) I2 = 62%
Test for overall effect p=0.0001
= trial completed recently
Wardlaw et al 2008
IV tPA vs control MoriNINDS ECASS
ECASS 2ECASS 3Atlantis A Atlantis B
rt-PA subtotal
thrombolysis better thrombolysis worse
0.1 0.78 1 5 0.1 0.77 1 5
Modified Rankin (mRS): 3 to 6 mRS 2 to 6
Sensitivity analysis: how robust is the result? Does it change with the choice of mRS cut-off?
Heterogeneity highly significant : p=0.007 p= 0.006
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
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
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)
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?
Grazie
Effect of IV rt-PA < 6hrs on death at the end of FU
OR 1.14 (95% CI 0.95-1.30)
IV urokinase
IV streptokinase
IV rt-PA
IV streptokinase+ aspirin
IA pro-urokinase
IA urokinase
IV desmoteplase
Primary outcome: 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)
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