Individual patient meta-analysis supports tPA stroke benefits

By Eleanor McDermid

The benefits of intravenous tissue plasminogen activator (tPA) outweigh the risks in acute stroke patients treated within 4.5 hours of symptom onset, reports the Stroke Thrombolysis Trialists' Collaboration.

The meta-analysis of individual patient data involved 6756 participants of nine randomised trials who received tPA within 4.5 hours of stroke onset.

Among these patients, there was an absolute increase of 6.8% in the number who achieved an excellent outcome (modified Rankin Scale [mRS] 0-1) and this outweighed the absolute increase in the number who had a fatal intracerebral haemorrhage (ICH), at 2.2%, or died within 90 days, at 0.9%.

The risks and benefits varied according to initial stroke severity, but there was a consistent proportional benefit, report Colin Baigent (University of Oxford, UK) and study co-authors in The Lancet Neurology.

The absolute increase in the number of patients with an excellent outcome was 8.0% among those with mild stroke (National Institutes of Health Stroke Scale [NIHSS] 0-4) but just 1.0% among those with very severe stroke (NIHSS≥22). But even patients with the most severe strokes had a net benefit; they had an absolute reduction in poor outcomes of 0.6%, composed of a 2.8% reduction in severe disability (mRS=5) offset by a 2.1% absolute increase in mortality.

In a linked commentary, Stefan Kiechl and Johann Willeit, both from Medical University of Innsbruck in Austria, highlight the generally poorer treatment response in this subgroup, suggesting that this can, in theory, be improved, initially with ultra-rapid treatment initiation and mechanical thrombectomy, and in the longer term with novel drugs to reduce the bleeding risk.

Of note, the risk of type 2 parenchymal haemorrhage, which occurred in 4.1% of patients overall (6.8% tPA-treated vs 1.3% controls), did not vary according to the time elapsed between symptom onset and tPA initiation. The same was true for symptomatic ICH by the SITS-MOST definition and for fatal ICH.

The commentators also draw attention to the findings for very elderly patients. The risk of symptomatic ICH was no greater in those older than 80 years than in younger patients, and the risk-benefit ratio of tPA treatment was unaffected by patient age.

This indicates that stroke thrombolysis can be used "in a broad range of settings, even beyond the restriction of its initial licensing", they write.

Kiechl and Willeit conclude that the analysis "thoroughly addresses the absolute excess risk of intracerebral haemorrhage attributable to alteplase-essential information for clinical decision-making".

They draw analogies with the advent of oral anticoagulants intensifying the discussion about bleeding risk in atrial fibrillation patients. The current study "should initiate analogous developments in stroke thrombolysis for the benefit of patients with ischaemic stroke", they say.

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