Elsevier

The Lancet Neurology

Volume 18, Issue 1, January 2019, Pages 46-55
The Lancet Neurology

Articles
Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data

https://doi.org/10.1016/S1474-4422(18)30314-4Get rights and content

Summary

Background

CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.

Methods

In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0–2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.

Findings

We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30–0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69–0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81–0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.

Interpretation

Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions.

Funding

Medtronic.

Introduction

Endovascular thrombectomy substantially reduces disability in patients with ischaemic stroke due to large vessel occlusion.1 The optimal selection of patients to identify all those who might benefit from this procedure is a key clinical question. A meta-analysis of individual-patient data on endovascular thrombectomy after large-vessel ischaemic stroke showed remarkable consistency in treatment effect across clinical subgroups, although age and clinical severity remained strongly prognostic1 and treatment effect declined with delayed reperfusion.2 Brain imaging is a key prognostic biomarker in stroke patients. The positive trials of endovascular thrombectomy at 0–6 h after ischaemic stroke onset have used different brain imaging selection criteria and the optimal approach to identifying patients who might benefit from thrombectomy using imaging has remained uncertain.3, 4, 5, 6, 7, 8, 9

Imaging selection for ischaemic stroke treatment aims to identify individual pathophysiology, rather than using traditional group-average time thresholds.10 The presence of ischaemic penumbra (electrically non-functioning but metabolically viable brain tissue that is salvageable with rapid cerebral blood flow restoration) forms the rationale for reperfusion therapies. Patients have marked variation in collateral blood flow (via leptomeningeal anastomoses and other pathways) that maintains penumbra distal to an arterial occlusion.11, 12 Penumbral imaging with CT perfusion (CTP) or MRI, when processed in a reproducible manner using validated blood flow parameter thresholds, can estimate both the irreversibly injured ischaemic core and potentially salvageable ischaemic penumbra with reasonable accuracy in the individual patient.13, 14, 15, 16 The difference in volume between the critically hypoperfused tissue (or territory of the occluded artery) and the ischaemic core estimates the salvageable penumbra.

The DAWN17 and DEFUSE 318 trials showed a benefit of endovascular thrombectomy beyond 6 h after stroke in patients with favourable penumbral patterns on CTP or MRI. However, the role of penumbral imaging selection within 6 h of stroke onset remains unclear. Patients with a large estimated ischaemic core (eg, ≥70 mL) are sometimes excluded from reperfusion therapies4, 5, 6, 7 and the positive trials of endovascular thrombectomy have used variable non-contrast CT, CT angiographic collaterals, CTP, and MRI criteria to select patients. Data characterising the clinical benefit of endovascular thrombectomy as ischaemic core volume increases are scarce. The DEFUSE 2 prospective cohort study showed benefit of endovascular reperfusion in patients with favourable perfusion and diffusion MRI (criteria included diffusion MRI lesion volume of <70 mL), while patients without the favourable imaging profile did not benefit.12 By contrast, two retrospective observational studies suggested a benefit of reperfusion in patients with a diffusion MRI lesion volume of at least 70 mL19 or Alberta Stroke Program Early CT Score (ASPECTS) less than 6, which indicates a large ischaemic core.20 Furthermore, subanalysis of pretreatment CTP in 175 patients in MR CLEAN21 found no interaction between ischaemic core volume and treatment effect.

We did a systematic review and meta-analysis of all randomised controlled trials of stent-retriever thrombectomy versus medical therapy within 6 h of stroke to assess the influence of ischaemic core volume and mismatch volume on functional outcome after thrombectomy.

Section snippets

Search strategy and selection criteria

In this systematic review and meta-analysis, we assessed endovascular thrombectomy predominantly performed with stent retrievers versus medical therapy in patients with anterior circulation ischaemic stroke, according to PRISMA guidelines. We searched PubMed for randomised controlled trials published in any language between Jan 1, 2010, and May 31, 2017, using the search string ((“randomised controlled trial” [Publication Type]) AND ((thrombectomy[Title/Abstract]) OR (clot

Results

Seven studies were identified in PubMed, and all were included in the systematic review and meta-analysis (appendix). Of 1764 patients included in the seven randomised controlled trials, penumbral imaging was performed and assessable in 900 (51%). CTP was obtained in 625 (35%) of the 1764 patients, and 34 of these patients were excluded (11 severe motion artefacts, seven no lesion within coverage, two contrast bolus failure, and 14 because of data corruption during transfer from site). Of the

Discussion

Large estimated ischaemic core volume was independently associated with worse functional outcome in patients treated with endovascular thrombectomy and in those who received standard medical therapy. Every 10 mL increase in pretreatment ischaemic core volume reduced the odds of favourable functional outcomes by 20–30%. However, large ischaemic core volume did not prevent benefit of endovascular thrombectomy compared with standard medical therapy in patients who otherwise met eligibility for

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