Elsevier

The Lancet Neurology

Volume 15, Issue 11, October 2016, Pages 1138-1147
The Lancet Neurology

Articles
Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial

https://doi.org/10.1016/S1474-4422(16)30177-6Get rights and content

Summary

Background

Intravenous thrombolysis with alteplase alone cannot reperfuse most large-artery strokes. We aimed to determine whether mechanical thrombectomy in addition to intravenous thrombolysis improves clinical outcome in patients with acute ischaemic stroke.

Methods

THRACE is a randomised controlled trial done in 26 centres in France. Patients aged 18–80 years with acute ischaemic stroke and proximal cerebral artery occlusion were randomly assigned to receive either intravenous thrombolysis alone (IVT group) or intravenous thrombolysis plus mechanical thrombectomy (IVTMT group). Intravenous thrombolysis (alteplase 0·9 mg/kg [maximum 90 mg], with an initial bolus of 10% of the total dose followed by infusion of the remaining dose over 60 min) had to be started within 4 h and thrombectomy within 5 h of symptom onset. Occlusions had to be confirmed by CT or magnetic resonance angiography. Randomisation was done centrally with a computer-generated sequential minimisation method and was stratified by centre. The primary outcome was the proportion of patients achieving functional independence at 3 months, defined by a score of 0–2 on the modified Rankin scale, assessed in the modified intention-to-treat population (ie, patients lost to follow-up and those with missing data were excluded). Safety outcomes were analysed in the per-protocol population (ie, all patients who did not follow the protocol of their randomisation group precisely were excluded from the analysis). THRACE is registered with ClinicalTrials.gov, NCT01062698.

Findings

Between June 1, 2010, and Feb 22, 2015, 414 patients were randomly assigned to the IVT group (n=208) or the IVTMT group (n=204). Four patients (two in each group) lost to follow-up and six (four in the IVT group and two in the IVTMT group) with missing data were excluded. 85 (42%) of 202 patients in the IVT group and 106 (53%) of 200 patients in the IVTMT group achieved functional independence at 3 months (odds ratio 1·55, 95% CI 1·05–2·30; p=0·028). The two groups had no significant differences in mortality at 3 months (24 [12%] deaths of 202 patients vs 27 [13%] of 206; p=0·70) or symptomatic intracranial haemorrhage at 24 h (four [2%] of 185 vs three [2%] of 192; p=0·71). Common adverse events related to thrombectomy were vasospasm (33 [23%] patients) and embolisation in a new territory (nine [6%]).

Interpretation

Mechanical thrombectomy combined with standard intravenous thrombolysis improves functional independence in patients with acute cerebral ischaemia, with no evidence of increased mortality. Bridging therapy should be considered for patients with large-vessel occlusions of the anterior circulation.

Funding

French Ministry for Health.

Introduction

Intravenous administration of alteplase, a tissue plasminogen activator, within 4·5 h of stroke onset improves the chance of a good outcome, and early treatment is associated with proportionally larger benefits.1, 2, 3, 4 However, revascularisation rates are reduced in occlusions of large proximal vessels, and the prognosis for patients with these occlusions remains poor.5, 6 Endovascular treatments increase the chance of successful and rapid recanalisation. Therefore, the use of intravenous alteplase with mechanical thrombectomy should, in theory, combine their respective advantages: quick administration and improved recanalisation.

Several randomised clinical trials have assessed this combined approach. The results of initial trials7, 8, 9 did not show a benefit of this approach, which might be explained by the fact that imaging was not used for diagnosis and localisation of occlusion for some patients and by the low rate of reperfusion. Moreover, these studies did not use the most recent devices (eg, stent retrievers Solitaire and Trevo) that have greatly improved the speed and efficacy of recanalisation. The results of subsequent randomised trials10, 11, 12, 13, 14, 15 have consistently shown that, in patients who receive standard care, mechanical thrombectomy significantly improves revascularisation and functional independence at 3 months with no increase in mortality. Some of these trials selected patients who were most likely to benefit from a combined approach by using imaging characteristics such as ischaemia-associated abnormalities in the Alberta Stroke Program Early CT score (ASPECTS) or cerebral perfusion data to distinguish between permanent lesions and hypoperfused but potentially rescuable penumbra.11, 12, 13, 14 The use of imaging criteria might increase the effect of treatment but might also exclude many patients who could benefit from intra-arterial treatment.

Research in context

Evidence before this study

We searched PubMed with the terms “stroke + thrombectomy” for articles published in English before Dec 31, 2015. Our search returned numerous single-centre or multicentre studies or registry studies in which endovascular treatment improved recanalisation, and eight randomised clinical trials that investigated the effect of endovascular treatment on functional outcomes. The results of the three trials published in 2013 were negative, whereas those of the five trials published in 2015 showed that, in patients receiving standard care, complementary mechanical thrombectomy led to an increased proportion of patients achieving functional independence at 3 months with no increase in mortality.

Added value of this study

The THRACE trial also assessed functional outcomes after treatment with intravenous alteplase for thrombolysis plus mechanical thrombectomy versus intravenous thrombolysis alone in patients with acute cerebral ischaemia. To our knowledge, it is the largest study to show that mechanical thrombectomy is better than standard care alone. Although our results are consistent with those of other recent studies, the THRACE trial is unique because of its wide patient selection, with no imaging-based criteria beyond the requirement for large-vessel occlusion, and its rapid randomisation (<20 min after intravenous thrombolysis initiation), so that fast responders to intravenous alteplase were not excluded. Thus, results of the THRACE trial showed a benefit in functional outcome for the combined approach in a broad population of patients similar to that encountered in routine clinical practice.

Implications of all the available evidence

Mechanical thrombectomy seems to be beneficial and should be considered for a wide range of patients with large-vessel occlusions of the anterior circulation, regardless of age, sex, clinical severity, or intracranial location of the occlusion.

The THRACE (THRombectomie des Artères CErebrales) trial was designed in 2009, before the results of the IMS III trial7 became available, and has a similar protocol.7 In THRACE, we aimed to compare standard treatment—intravenous thrombolysis alone—with intravenous thrombolysis plus mechanical thrombectomy by use of the newest devices to determine their effect on functional independence at 3 months in patients with moderate-to-severe stroke due to an occlusion of a proximal cerebral artery within 4 h of symptom onset.

Section snippets

Study design and participants

THRACE was a randomised controlled trial done in 26 centres in France. Patients with acute ischaemic stroke were eligible for inclusion if they were aged 18–80 years; had a US National Institutes of Health Stroke Scale (NIHSS) score of 10–25; had an occlusion of the intracranial internal carotid artery, the M1 segment of the middle cerebral artery, or the superior third of the basilar artery confirmed by CT or magnetic resonance angiography; could be administered intravenous thrombolysis within

Results

Between June 1, 2010, and Feb 22, 2015, 425 patients were assessed for eligibility, of whom 414 met the inclusion criteria and were randomised (figure 1). On March 3, 2015, the trial steering committee decided to terminate the trial early, after 414 patients were randomised, because the second unplanned interim analysis showed superiority of intravenous thrombolysis plus mechanical thrombectomy over intravenous thrombolysis alone. Two patients withdrew consent after randomisation. Of the

Discussion

Our results confirm those of other recent studies showing that mechanical thrombectomy improves functional independence in patients after acute ischaemic stroke caused by proximal intracranial arterial occlusion. However, our trial differs notably from those earlier studies, particularly with respect to patient selection criteria and delays to randomisation.

The design of the THRACE trial most closely resembles that of IMS III7 in that both studies compared bridging therapy with intravenous

References (25)

  • CS Kidwell et al.

    A trial of imaging selection and endovascular treatment for ischemic stroke

    N Engl J Med

    (2013)
  • OA Berkhemer et al.

    A randomized trial of intraarterial treatment for acute ischemic stroke

    N Engl J Med

    (2015)
  • Cited by (917)

    View all citing articles on Scopus

    THRACE investigators listed at end of paper

    View full text