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Should more patients with acute ischaemic stroke receive thrombolytic treatment?

BMJ 2009; 339 doi: (Published 11 November 2009) Cite this as: BMJ 2009;339:b4584
  1. Joanna M Wardlaw, professor of applied neuroimaging 1,
  2. Peter A G Sandercock, professor of neurology1,
  3. Veronica Murray, senior scientist2
  1. 1Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU
  2. 2Division of Medicine, Danderyd Hospital, Karolinska Institutet, SE-182 88 Stockholm, Sweden
  1. Correspondence to: J M Wardlaw joanna.wardlaw{at}
  • Accepted 24 June 2009

In developed countries, stroke is the third most common cause of death and the most common cause of dependency in adults. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) was licensed for use in highly selected patients within three hours of acute ischaemic stroke in the United States in 1996 on the basis of the National Institutes of Neurological Disorders and Stroke (NINDS) randomised controlled trial (n=624),1 which showed substantially lower combined rates of death or dependency with this treatment (140/1000 fewer) despite an excess of symptomatic intracranial haemorrhage (60/1000 more). The Cochrane review of all data from randomised trials of rt-PA and a meta-analysis of individual patient data agreed with these findings.2 3 In Europe, a conditional licence for use within three hours in highly selected patients was granted in 2002 on the basis of the NINDS trial plus data from two European randomised controlled trials (n=930).4 5

However, six years after European and 10 years after US licensing, fewer than 10% of eligible patients receive thrombolysis—1-7% in the US,6 7 3% in Canada,8 3% in Germany,9 and 3.3% in Sweden (—and use of rt-PA varies greatly between European countries.10 Clinicians and managers are uncertain about how widely to use rt-PA in routine clinical practice.11 The fact that treatment licenses are based on data from fewer than 1000 randomised patients with narrow entry criteria, the substantial excess of symptomatic intracranial haemorrhage, plus the restricted licence conditions may worry many clinicians.

What is the evidence of the uncertainty?

In 2009, a systematic review of all randomised trials comparing thrombolysis with control (mostly placebo) in patients with acute ischaemic stroke analysed 26 trials of various thrombolytic drugs, 11 of which tested rt-PA up to six hours after stroke (n=3977) (figure).12 Compared with control, rt-PA given up to six …

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