Elsevier

The Lancet

Volume 394, Issue 10193, 13–19 July 2019, Pages 139-147
The Lancet

Articles
Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data

https://doi.org/10.1016/S0140-6736(19)31053-0Get rights and content

Summary

Background

Stroke thrombolysis with alteplase is currently recommended 0–4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.

Methods

In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0–1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036.

Findings

We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15–2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23–76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81–2·96, p=0·66).

Interpretation

Patients with ischaemic stroke 4·5–9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.

Funding

None.

Introduction

Current guidelines recommend thrombolysis with intravenous alteplase for acute ischaemic stroke up to 4·5 h from stroke onset on the basis of individual patient data from randomised trials that included patients according to non-contrast CT brain and clinical criteria.1 These criteria exclude a substantial proportion of patients who present more than 4·5 h after stroke onset or who have unknown onset (eg, wake-up stroke). The WAKE-UP trial2 demonstrated the benefit of intravenous thrombolysis with alteplase in patients with stroke symptoms on waking by identifying an MRI pattern suggestive of stroke with an onset of less than 4·5 h. This method of selection increases the proportion of patients eligible for treatment, but other research3 showed that this selection approach only identifies around 62% of patients who are within the 0–4·5 h time window. Furthermore, this approach excludes patients who might have salvageable brain tissue, despite presenting more than 4·5 h after stroke onset.

An alternative approach is to use CT perfusion or perfusion-diffusion MRI to identify patients with potentially salvageable brain tissue, regardless of time from stroke onset. Reperfusion beyond 4·5 h after stroke onset is associated with favourable clinical outcomes in patients with perfusion mismatch.4, 5, 6, 7 Patient selection on the basis of perfusion mismatch to identify treatment-responsive patients with salvageable brain tissue who have presented more than 4·5 h after stroke onset has been established for endovascular thrombectomy in patients with large vessel occlusion 6–24 h after the time they were last known to be well.8, 9, 10 Intravenous thrombolysis could potentially treat a broader range of patients.

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.

We did a meta-analysis of individual patient data to test the hypothesis that intravenous alteplase improves functional outcomes compared with placebo in patients with ischaemic stroke 4·5–9 h after onset or wake-up stroke who were imaged with CT perfusion or perfusion-diffusion MRI.

Section snippets

Search strategy and selection criteria

We did a systematic search of PubMed for randomised controlled trials published in English between Jan 1, 2006, and March 1, 2019, using the search terms “stroke” AND either “randomized” OR “randomised” AND either “thrombolysis” OR “alteplase” OR “tPA”. Trials of intravenous alteplase versus placebo in adults (aged ≥18 years) with hemispheric ischaemic stroke more than 4·5 h after stroke onset or wake-up stroke who had pretreatment imaging with CT perfusion or perfusion-diffusion MRI were

Results

Our search strategy identified three trials that met the eligibility criteria: EXTEND,12, 13 ECASS4-EXTEND,17, 18 and EPITHET.5 The three included trials compared intravenous alteplase with placebo (0·9 mg/kg, maximum 90 mg delivered as a 10% bolus and 90% infusion over 1 h). The phase 3 EXTEND randomised controlled trial12, 13 compared alteplase with placebo in patients 4·5–9·0 h from stroke onset and patients with wake-up stroke using automated CT perfusion or MRI perfusion-diffusion mismatch

Discussion

This meta-analysis of pooled individual patient-level data has shown that thrombolysis with intravenous alteplase in patients with acute ischaemic stroke 4·5–9 h after stroke onset or wake-up stroke, who were imaged with CT perfusion or perfusion-diffusion MRI, improves functional outcomes compared with placebo. The frequency of symptomatic intracerebral haemorrhage was around 4% higher in the alteplase group than the placebo group, which is consistent with the results of previous trials1 of

References (24)

  • RG Nogueira et al.

    Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct

    N Engl J Med

    (2018)
  • GW Albers et al.

    Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging

    N Engl J Med

    (2018)
  • Cited by (317)

    View all citing articles on Scopus
    *

    Contributed equally

    Contributed equally

    Investigators listed in the appendix

    View full text