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)