After a stroke, the thrombolytic ('clot-busting') drug alteplase needs to be given as soon as possible, as benefits on clinical recovery and prevention of early deaths fall rapidly as the time to treatment prolongs, according to the latest pooled analysis. The analysis also found that after 4.5 hours from stroke onset, the risks of treatment might outweigh the minimal benefit, concludes the Article published in this week's issue of The Lancet.
Intravenous alteplase treatment within 3 hours of symptom onset has been shown to improve outcomes after ischaemic stroke (those due to the brain being starved of blood). However, several large trials have now been completed so an international team led by Prof Kennedy R Lees (University of Glasgow, Western Infirmary, UK) pooled data from 3670 patients in eight trials to investigate how the benefits and risk of alteplase change with time to treatment. Ischaemic stroke was diagnosed by symptoms and a brain CT scan.
The analysis found that treatment with alteplase until 4.5 hours (270 mins) from stroke onset enhances the chance of favourable outcome. However, the likelihood of good clinical recovery reduces rapidly as the time from onset to treatment lengthens. 3 months after stroke, patients treated with alteplase within 90 minutes were more than two-and-a-half times more likely to have good clinical recovery compared with placebo; while for those given alteplase it by 270 minutes post-stroke, there was only a 22% increased chance of good clinical recovery compared with placebo.
Importantly, the analysis shows for the first time that short-term survival is reduced by treatment that starts late, as mortality increases with times to treatment longer than 4.5 hours. The likelihood of a brain haemorrhage (bleed) as a complication of treatment did not change with time to treatment, suggesting other reasons for early deaths.
"Our analysis showed that the greatest benefit comes from earlier treatment, since net benefit is diminishing and is undetectable in our sample beyond 4.5 hours," say the team. However, alteplase does not result in excellent benefit in most patients, even those treated early, so questions remain. "We need to understand better the factors that prevent alteplase from being effective in individual patients."
The authors conclude that: "Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4•5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4•5 h, risk might outweigh benefit."
In a Comment, Jeffrey L Saver (Geffen School of Medicine, USA) and Steven R Levine (Mount Sinai School of Medicine, USA) note: "We need to increase the proportion of patients arriving at hospital in the first golden hour after ischaemia onset by better educating the public to recognise stroke warning signs and by activating the emergency medical system early". Moreover, they conclude, stroke centres should target "the improvement of hospital-response systems to achieve door-to-needle times of less than 60 min" in most alteplase-treated patients.
Prof Kennedy R Lees (University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow) T) +44-141 211 2780, +447768 782932 E) k.r.lees@clinmed.gla.ac.uk
Prof Werner Hacke (Department of Neurology, University of Heidelberg, Germany) T) +49-6221 - 56 82 11 E) werner.hacke@med.uni-heidelberg.de
Steven R Levine (Stroke Center and Department of Neurology, Mount Sinai School of Medicine, New York) T) + 212-241-1970, +1-516-316-2924 (text only)E) steven.levine@mssm.edu
For full Article and Comment, see: http://press.thelancet.com/alteplase.pdf
Journal
The Lancet