Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials

Emberson J, Lees KR, Lyden P et al., for the Stroke Thrombolysis Trialists’ Collaborative Group
The Lancet, Early Online Publication, 6 August 2014. doi:10.1016/S0140-6736(14)60584-5

Background

Intravenous alteplase is a recombinant tissue plasminogen activator that is approved for the treatment of acute ischaemic stroke. Although analyses of pooled data from randomised data suggested that alteplase is beneficial if administered to patients within 4.5 hours, the benefit decreases with increasing treatment delay [1,2]. The risk-benefit balance is less clear when alteplase is given later after onset of symptoms, to older patients, or after very severe of mild strokes. International guidelines give varying recommendations on routine use of alteplase, and marketing authorisations also vary between countries, concerning age restrictions and severity of stroke.
The IST-3 study included 3035 patients randomly assigned to alteplase or control up to 6 hours after the onset of stroke [3]. Benefitting from individual-patient data from IST-3 and other trials of alteplase, this analysis explores the extent to which treatment delay affected the effect of alteplase and aimed to establish whether age or stroke severity affected treatment effects. Data of 6756 participants from nine trials (eight of which randomised to alteplase or placebo (n=3721), and one assigning patients to alteplase or open control (n=3035)).

Main results

• Alteplase significantly increased the odds of a good outcome, with earlier treatment resulting in significantly greater proportional benefit. The time at which alteplase has no benefit was estimated to be 6.3 hours (95%CI: 5.0-13.8), and at 5.1 hours, the lower boundary of the 95%CI first crossed 1.0.
• In predefined subgroups of treatment delay, alteplase significantly increased the odds of a good outcome, when given within 3.0 hours (OR: 1.75, 95% CI: 1.35–2.27; P<0.0001), or between 3.0 h and 4.5 h (OR: 1.26, 95% CI: 1.05–1.51, P=0.0132), but not after 4.5 h (OR: 1.15, 95% CI: 0.95–1.40, P=0.15).
• The effect of alteplase treatment was similar for patients of 80 years old or younger, and patients over 80 years. No evidence was found that older age shortened the period during which alteplase could effectively be given.
• No difference of efficacy was seen for patients with the least or most severe strokes.
• Alteplase increased the likelihood of type 2 parenchymal haemorrhages within 7 days (6.8% vs. 1.3%, OR: 5.55, 95%CI: 4.01-7.70, P<0.001). Fatal type 2 parenchymal haemorrhages within 7 days were also more frequent with alteplase (2.7% vs. 0.4% in control, OR: 7.14, 95%CI: 3.98-12.79, P<0.0001).
• Alteplase did not increase the risk of other early causes of death, nor on later causes of death. No significant excess overall mortality was seen at 90 days (17.9% vs. 16.5%, HR: 1.11, 95%CI: 0.99-1.25, P=0.07).

Conclusion

This meta-analysis of individual-patient data shows improved odds of a good stroke outcome when alteplase treatment is started within 4.5 h after ischaemic stroke, with earlier treatment resulting in bigger proportional and absolute benefits. Proportional benefits were similar among older and younger patients, and did not depend on severity of stroke. Early increases in fatal intracranial haemorrhage are seen with alteplase, but on the longer run (3-6 months) no significant increase of mortality sis seen.

Editorial comment [4]

“This pre-planned analysis of pooled individual data for 6756 patients from all the major trials of thrombolysis for treatment of stroke, showed that overall, thrombolysis with alteplase unequivocally resulted in more patients with an excellent neurological outcome at 3–6 months compared with control. This overall outcome included an increase in the number of early fatal intracerebral haemorrhages, but the result is definitive. Thrombolysis is an effective treatment, especially when given fast.
Audits show that patients with ischaemic stroke are offered thrombolysis too rarely or, if they are offered it, too slowly.The question now is not whether we can extend the window for treatment. Rather, how do we get everyone treated faster and how do we dispel preconceived notions about not treating older patients or those with milder strokes? We must move from the proven science to policy and systems of care.”

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References

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