Research in context
Evidence before this study
We did a systematic review of PubMed between Jan 1, 2006, and March 1, 2019, for randomised controlled trials published in English using the search terms “stroke” AND either “randomized” OR “randomised” AND either “thrombolysis” OR “alteplase” OR “tPA”. In the EXTEND trial, patients randomly assigned to alteplase after automated CT or MRI perfusion imaging were found to have improvement in excellent functional outcome compared with placebo; however, the strength and precision of findings were limited by the modest sample size (n=225). The ECASS4-EXTEND trial randomly assigned 119 patients after visual assessment of perfusion-diffusion MRI, and found no statistically significant benefits of alteplase. EPITHET was a phase 2 randomised trial of alteplase 3–6 h after stroke onset using perfusion-diffusion MRI, in which 70 patients were treated within the 4·5–6 h time window. Although the overall results of the trial were neutral, in patients treated 4·5–6 h after stroke onset, thrombolysis reduced relative infarct growth and increased the rate of reperfusion. Effective reperfusion was associated with good neurological and functional outcome.
Added value of this study
This systematic review and meta-analysis of individual patient data quantifies the benefits and risks of intravenous alteplase for patients with ischaemic stroke beyond 4·5 h from when they were last known to be well. The proportion of patients with excellent functional outcome (return to all usual activities) at 3 months was significantly higher in the alteplase group than the placebo group. The proportion of patients with functional improvement (≥1 point reduction in modified Rankin Scale score) at 3 months was also significantly higher in the alteplase group than the placebo group. Although a higher proportion of patients in the alteplase group had symptomatic intracerebral haemorrhage than the placebo group, no significant difference in mortality was observed between the groups. Patients with a perfusion imaging mismatch (indicating salvageable brain tissue) detected with automated software in core laboratory analysis had significant benefit from alteplase, whereas those without perfusion mismatch detected by automated software did not, although this comparison was underpowered and formal statistical interaction was not demonstrated.
Implications of all the available evidence
Patients with ischaemic stroke 4·5–9 h after stroke onset or with wake-up stroke with evidence of salvageable brain tissue using CT perfusion or perfusion-diffusion MRI who were given intravenous alteplase have improved functional outcomes compared with those given placebo. Patients given alteplase had an increased risk of symptomatic intracerebral haemorrhage, consistent with the findings from previous trials of alteplase for stroke, but this increased risk does not offset the net benefit of thrombolysis. The benefit to risk ratio seems to be larger in patients who meet automated perfusion mismatch criteria.