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 Forum Firenze 13th February
2009
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Joanna Wardlaw Veronica Murray
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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

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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

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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

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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

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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)

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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 12, 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

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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
  
• n7152 2.7 - 4.1 1.1 - 1.5
  0.7 - 0.9
• plt0.00001 p0.06
  plt0.0001
• rt-PA 3.1 1.1 0.8
• n3977 2.3 - 4.0 1.0 - 1.4
  0.7 - 0.9
• plt0.00001 p0.16 plt0.0001
• Significant heterogeneity confounds
  interpretation
• meta-regression on a variety of factors does not
  explain it

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IV rt-PA lt 6hrs only effect on death or
dependency (mRS 3-6)
trial completed recently
Odds ratio 0.78 (0.68-.88) Heterogeneity (Chi2
p0.007) I2 62 Test for overall effect p0.0001
Wardlaw et al 2008
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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
p0.007 p 0.006
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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
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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

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IMPLICATIONS FOR PRACTICE Even if the EU
approval for thrombolysis is extended to 4.5 hrs,
this will still exclude patients who

• Are aged gt 80 years
• Have very mild stroke or NIHSS gt 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)

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IMPLICATIONS FOR RESEARCH. More randomised trial
evidence needed on effects of i.v. rt-PA

• When used lt6hrs (and beyond 6hrs too?)
• In particular categories of patients
• Aged gt 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?

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• Grazie

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