Elsevier

The Lancet

Volume 387, Issue 10029, 23–29 April 2016, Pages 1723-1731
The Lancet

Articles
Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials

https://doi.org/10.1016/S0140-6736(16)00163-XGet rights and content

Summary

Background

In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included.

Methods

We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation.

Findings

We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2·49, 95% CI 1·76–3·53; p<0·0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2·6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0·43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3·68, 95% CI 1·95–6·92), those randomised more than 300 min after symptom onset (1·76, 1·05–2·97), and those not eligible for intravenous alteplase (2·43, 1·30–4·55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations.

Interpretation

Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion.

Funding

Medtronic.

Introduction

Endovascular thrombectomy for acute ischaemic stroke has evolved substantially; however, only after the 2015 publication of five clinical trials1, 2, 3, 4, 5 has this procedure been accepted as the standard of care for patients with proximal anterior circulation occlusions.6 Uncertainties remain about the benefit of endovascular thrombectomy in patient groups under-represented in these individual trials, including those who presented to treatment late, are elderly, have mild deficits, and are not eligible for intravenous alteplase.6 Moreover, because these trials were individually moderate in size, data pooling can provide more precise estimates of treatment effects. As investigators from the MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, and EXTEND IA trials, we seek to address these and other questions about the risks and benefits of modern endovascular therapy by analysing pooled individual patient data for thrombectomy after acute ischaemic stroke.

Research in context

Evidence before the study

Evidence to support endovascular therapy for stroke has previously been poor because randomised trials have used thrombectomy devices of low efficacy, insufficiently robust imaging selection criteria, and had long delays from hospital presentation to reperfusion. Five individual trials published in 2015 established that thrombectomy, when done with newer generation devices (mainly stent retrievers), more stringent imaging selection criteria, and more efficient workflow, significantly reduces disability rates after acute ischaemic stroke caused by proximal occlusion of large vessels in the anterior circulation. Because most of these studies were stopped prematurely, they were underpowered to provide convincing evidence of efficacy across some of the subgroups of great relevance to clinical practice. We did an extensive literature search of major online databases including PubMed and Embase for papers published from Jan 1, 2010, to Dec 23, 2015, and did not identify any other published randomised endovascular stroke studies that used modern thrombectomy devices. Study level meta-analyses have been reported but most included patients enrolled without definitive proof of vessel occlusion and who were treated with less effective reperfusion technology. Furthermore, study-level meta-analyses are considered less informative than patient-level meta-analytical approaches due to their inability to adjust for confounding baseline variables, which leads to less precise estimates of treatment effect. To our knowledge no patient-level meta-analyses have been reported.

Added value of this study

In this individual patient meta-analysis of trials published in 2015, we provide additional relevant facts that will enable clinicians to better understand the degree of precision of adjusted effect size estimates, safety outcome estimates, and estimates by clinical subgroups. We show clinical benefits for thrombectomy across a wide range of age and initial stroke severity and for patients eligible and ineligible for intravenous alteplase. Smaller amounts of other baseline variables such as degree of early ischaemic changes on baseline CT or time to treatment were reported and therefore the observed effects should be interpreted within the context of the populations included.

Implications of all the available evidence

The consistent results across different patient populations suggest that benefit from thrombectomy is generalisable to a broad range of patients with large-vessel ischaemic stroke. By providing a more precise treatment effect estimate than each individual trial, our findings allow cost-effectiveness of this intervention at society level to be calculated with higher precision. Our study provides clear evidence that in clinical practice, endovascular therapy for stroke should not be withheld on the basis of advanced age, moderately extensive early ischaemic changes on baseline CT, and moderate or severe clinical deficit.

Section snippets

Study inclusion and procedures

We searched major online databases including Medline and PubMed to identify controlled trials in endovascular stroke published between Jan 1, 2010, and Dec 23, 2015, that used vessel imaging to identify patients with anterior circulation ischaemic stroke and assessed treatment with modern neurothrombectomy devices. Five trials fit these criteria: MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA.1, 2, 3, 4, 5 These trials differed from all previously published trials of endovascular

Results

By pooling data from the five trials, we obtained data for 1287 participants; 634 assigned to endovascular thrombectomy (intervention population) and 653 assigned to standard medical treatment (control population). Baseline characteristics were largely balanced between the populations (table 1), but slightly fewer patients in the intervention group were treated with intravenous alteplase before randomisation (p=0·04). The most common location of the target occlusion was the M1 segment of the

Discussion

In this pooled analysis of patient-level data we show that modern endovascular thrombectomy added to best medical therapy more than doubles the odds of a higher mRS score compared with best medical therapy alone in patients with acute ischaemic stroke due to anterior circulation large vessel occlusion. This analysis confirms benefit of endovascular thrombectomy across a range of subgroups, including in groups of interest such as the elderly, patients not receiving intravenous alteplase, and

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