Endovascular thrombectomy and medical therapy versus medical therapy alone in acute stroke: A randomized care trial

doi:10.1016/j.neurad.2017.01.126

Journal of Neuroradiology

Volume 44, Issue 3, June 2017, Pages 198-202

https://doi.org/10.1016/j.neurad.2017.01.126 Get rights and content

Abstract

Background

Until recently, the benefits of endovascular treatment in stroke were not proven. Care trials have been designed to simultaneously offer yet-to-be validated interventions and verify treatment outcomes. Our aim was to implement a care trial for patients with acute ischemic stroke.

Methods

The study was offered to all patients considered for endovascular management of acute ischemic stroke in one Canadian hospital. Inclusion criteria were broad: onset of symptoms ≤ 5 h or at any time in the presence of clinical-imaging mismatch and suspected or demonstrated proximal large vessel occlusion. Exclusion criteria were few: established infarction or hemorrhagic transformation of the target symptomatic territory and poor 3-month prognosis. The primary outcome was mRS ≤ 2 at 3 months. Patients were randomly allocated to standard care or standard care plus endovascular treatment. ClinicalTrials.gov: Identifier NCT02157532.

Results

Seventy-seven patients were recruited in 19 months (March 2013–October 2014) at a single center. Randomized allocation was interrupted when other trials showed the benefits of endovascular therapy. At 3 months, 20 of 40 patients (50.0%; 95% CI: 35%–65%) in the intervention group had reached the primary outcome, compared to 14 of 37 patients (37.8%; 95% CI: 24%–54%) in the control group (P = 0.36). Eleven patients in the intervention group died within 3 months compared to 9 patients in the standard care group.

Conclusion

A care trial was implemented to offer verifiable care to acute stroke patients. This approach offers a promising means to manage clinical dilemmas and guide uncertain practices.

Introduction

Until recently, intravenous (i.v.) tissue plasminogen activator (tPA) was the only acute stroke recanalization treatment proven to improve patient outcomes [1], [2]. Despite i.v. thrombolysis, patients with severe stroke continued to suffer high mortality (20–25%) and dependency (50%) [3]. While successful vessel recanalization using endovascular treatments was reported in 2012 [4], [5], disappointing results from randomized trials of endovascular treatment followed in 2013, showing no clear benefit for patient outcomes [6], [7], [8]. Dissatisfied with how we had been practicing interventions without evidence and to improve on the design and conduct of previous trials, we conceived the Endovascular acute stroke intervention (EASI) trial, a pragmatic study of mechanical thrombectomy versus standard care. Unlike other trials, EASI was a care trial [9] with the primary goal to prudently offer patients the opportunity to receive a promising yet unproven treatment. In a care trial, patients are not primarily selected to be participants in a research protocol designed to answer a research question. Rather, the promising but non-validated intervention that clinicians wish to use is regulated by trial methodology, every step of which is designed in the best interest of current patients [9].

EASI was accruing patients at a promising rate when the Steering committee (SC) decided to stop randomized allocation following the release of the Mr Clean trial results in 2014 [10]. Here, we report the use of care trial methods to practice mechanical thrombectomy for acute stroke patients during the period of time when clinical uncertainty was present.

Section snippets

Study design

The primary aim of the trial was to offer a promising but unproven endovascular intervention for patients with acute ischemic stroke caused by proximal vessel occlusion, while simultaneously protecting patients from the risks involved in using an invasive treatment whose benefit was yet to be established. In this context of uncertainty and until the better option was identified, optimal care was to be offered as a 50% chance of getting the promising treatment, and a 50% chance of getting

Results

Between March 2013 and October 2014, all consecutive 77 patients referred for endovascular treatment were recruited into EASI. No patients received thrombectomy outside the study and no patients or representatives refused or withdrew consent. The trial continued until the public dissemination of the MR CLEAN results, whereupon actions were immediately taken to continue recruiting but to offer thrombectomy to all patients, waiting for a DSMB response to the question of trial continuation. After

Discussion

This study shows that a care trial can be implemented in the management of patients with acute ischemic stroke. At a time when uncertainty prevailed, EASI permitted clinicians to offer patients a chance to receive a promising yet unproven treatment. Premature interruption of the trial prevented the recruitment of a sufficient number of patients to provide significant results.

EASI was designed after three major but unsuccessful trials (Synthesis expansion [7], Mr-Rescue [8], and IMS-3 [6]), all

Conclusion

EASI supports the feasibility of using care trials for patients with acute cerebrovascular disease. Care trials provide an innovative way to simultaneously care for patients using unproven treatments while efficiently providing real-time, RCT evaluation of the care delivered.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Study funding: investigator led clinical trial without public or industrial funding.

This manuscript has not been published elsewhere and is not being submitted simultaneously to another journal.

Authors’ contributions

“Conception and design, or acquisition of data, or analysis and interpretation of data”; “drafting the article or revising it critically for important intellectual content”; “final approval of the version to be published”; “agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved”. I, Jean Raymond, corresponding author, attest that each author has contributed to all

Disclosure of interest

The authors declare that they have no competing interest.

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Endovascular treatment (EVT) has become standard of care for patients with anterior circulation large vessel occlusion (LVO) stroke, with indications having recently expanded to late time-window and large ischemic core patients. There is conflicting evidence on whether EVT reduces mortality or only disability. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the effect of EVT on mortality and severe disability.
We systematically searched PubMed, Web of Science, Scopus, and Embase on November 15, 2023, to identify phase 3 RCTs comparing EVT to best medical treatment (BMT) in patients with anterior circulation LVO stroke in a common effects meta-analysis. The primary outcome was mortality at 3 months. Secondary outcomes were moderately severe or severe disability (modified Rankin Scale (mRS) score 4–5) at 3 months.
18 studies comparing EVT to BMT were included, with a total of 4309 patients; 2159 that were treated with EVT, and 2150 treated with BMT. Mortality was significantly lower in the EVT group than in the BMT group (odds ratio (OR): 0.81, 95% CI: 0.70–0.94). Proportions of moderately severe or severe disability (OR: 0.55, 95% CI: 0.48–0.62) were also significantly lower in patients treated with EVT.
This meta-analysis suggests that EVT reduces both mortality and moderately severe or severe disability in patients with anterior circulation LVO stroke.
Diagnosis and management of tandem occlusion in acute ischemic stroke
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Approximately 20–30% of patients with acute ischemic stroke, caused by large intracranial vessel occlusion, have a tandem lesion, defined as simultaneous presence of high-grade stenosis or occlusion of the cervical internal carotid artery and thromboembolic occlusion of the intracranial terminal internal carotid artery or its branches, usually the middle cerebral artery. Patients with tandem lesions have usually worse outcomes than patients with single intracranial occlusions, and intravenous thrombolysis is less effective in these patients. Although endovascular thrombectomy is currently a cornerstone therapy in the management of acute ischemic stroke due to large vessel occlusion, the optimal management of extracranial carotid lesions in tandem occlusion remains controversial. Acute placement of a stent in the cervical carotid artery lesion is the most used therapeutic strategy compared with stented balloon angioplasty and thrombectomy alone without carotid artery revascularization; however, treatment strategies in these patients are often more complex than with single occlusion, so treatment decisions can change based on clinical and technical considerations. The aim of this review is to analyze the results of different studies and trials, investigating the periprocedural neurointerventional management of patients with tandem lesions and the safety, efficacy of the different technical strategies available as well as their impact on the clinical outcome in these patients, to strengthen current recommendations and thus optimize patient care.
Perceptions on basilar artery occlusion management in China versus other countries: Analysis of the after the BEST of BASICS (ABBA) survey
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Uncertainty remains on the optimal management of basilar artery occlusion (BAO). Two large randomized controlled trials (RCTs) in 2019 and 2021 demonstrated neutral results with respect to the use of endovascular therapy (EVT) for BAO. This study aimed to understand regional variation in physicians' perceptions towards the treatment of BAO as stratified by physician respondents from China versus outside China, prior to the publication of studies demonstrating a benefit of EVT for BAO.
An international online survey was conducted of stroke neurologists and neurointerventionalists from January to March 2022. Survey questions evaluated physician opinions toward the use of EVT in BAO, as well as the clinical and imaging features underlying treatment decisions. Respondents were dichotomized as either from China or from other countries and differences between groups were analyzed.
There were 1245 physician respondents across 73 countries of which 295 (23.7%) were from China. Compared to respondents from the rest of the world, respondents from China were more likely to be interventionalists (71.5% vs 35.0%; p < 0.0001). Overall, more than 95% of respondents believed that EVT was superior to medical therapy under certain circumstances. Chinese respondents were more likely to believe that further RCTs were necessary than respondents from other countries (93.6% vs 76.2%; p < 0.0001). Chinese respondents were more likely to use advanced imaging in later time windows and use a premorbid mRS threshold of ≤2 for BAO selection to EVT.
Most stroke physicians believe EVT is beneficial in selected patients with BAO. Clinical and imaging modality differences were observed in the selection criteria used for EVT. There was greater inclination to enroll all trial eligible patients in a BAO RCT by respondents from China as compared to other parts of the world.
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Citation Excerpt :
Many physicians declined participation or did not enroll patients because they preferred to use case-by-case reasoning rather than submit patients to randomized allocation of treatment options, and many patients refuse participation because they wanted their doctor to ‘rise above the uncertainty’ and choose the best option for their particular circumstances. Manuscripts reporting our accumulating experience with care trials have repeatedly been turned down before eventual acceptance for publication [31,33,34,36–38], in spite of being rigorously reported using the CONSORT statement [39]. A detailed example of criticisms from reviewers has been published [33].
Pragmatic care trials have been designed to provide optimal neurovascular care in the presence of uncertainty. The feasibility, benefits, and drawbacks of using this novel approach remain unknown.
We report the progress of 9 randomized trials integrated into routine practice to guide the endovascular or surgical treatment of intracranial aneurysms, arteriovenous malformations, and acute stroke. We review the criticisms and commentaries we have received and discuss the corresponding ethical and scientific concepts that need to be revised to practice outcome-based neurovascular care.
Pragmatic care trials were used to address long standing dilemmas regarding rival management options or to offer innovative treatments for 1212 neurovascular patients recruited in an elective or acute care context. Adopting care trial methodology had an immediate impact on clinical practice, replacing unrepeatable treatment decisions by 1:1 randomized allocation whenever reliable knowledge about best management was not available. The care trial approach transformed unfounded medical practice into verifiable outcome-based medical care and reserved authoritative recommendations for care options that had previously been validated. Criticisms we have encountered include mainly the pragmatic trial design choices, with insufficient selection of patients and clinicians, too-flexible protocols, lack of funding and feasibility.
Care trials can be integrated into neurovascular practice. Although they remain a work in progress, the approach curtails the practice of unverifiable medicine and offers patients optimal care in the presence of uncertainty.
Effectiveness of Endovascular Therapy for Patients with Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials
2020, World Neurosurgery
Citation Excerpt :
The initial electronic searches produced 2851 articles; of them, 2788 were excluded due to irrelevant topics and duplication. The remaining 63 full articles were reviewed; of them, 13 were included in the final analysis.7,8,14-18,29-34 Fifty studies were excluded due to: study reporting the same patients (n = 37), observational design (n = 8), and no appropriate control (n = 5).
This meta-analysis of published randomized controlled trials (RCTs) aimed to investigate the efficacy and safety of endovascular therapy (ET) for patients with acute ischemic stroke.
The summary relative risks (RRs) with corresponding 95% confidence intervals were calculated to measure the effectiveness of ET using a random-effects model.
Thirteen RCTs including 3408 patients were identified among 2851 initial electronic citations. Overall, the summary RR indicated that ET significantly increased the incidence of a modified Rankin Scale score of 0–2 (RR, 1.50; P < 0.001), asymptomatic intracerebral hemorrhage (IH) (RR, 1.42; P = 0.001), subarachnoid hemorrhage (RR, 2.36; P = 0.001), and major complications due to non-intracerebral bleeding (RR, 1.47; P = 0.014). However, ET had no significant effects on the risk of 7-day death (P = 0.827); death after 30 days (P = 0.085); symptomatic IH (P = 0.288); type 1 (P = 0.413), type 2 (P = 0.300), and total parenchymal hematoma (P = 0.160); intraventricular hemorrhage (P = 0.244); early neurologic deterioration (P = 0.570); recurrent stroke (P = 0.830); and symptomatic edema (P = 0.485).
The findings of this meta-analysis suggest the incidence of a modified Rankin Scale score of 0–2 in patients who received ET was significantly increased. Moreover, the harmful effects of ET might exist due to greater risk of asymptomatic IH, subarachnoid hemorrhage, and non-intracerebral bleeding, and these results should be verified by further large-scale long-term RCT.
A randomized pilot study of patients with tandem carotid lesions undergoing thrombectomy
2020, Journal of Neuroradiology
The optimal management of patients with tandem lesions (TL), or cervical internal carotid artery (c-ICA) steno-occlusive pathology and ipsilateral intracranial occlusion, who are undergoing endovascular thrombectomy (EVT) remains unknown. We sought to establish the feasibility of a trial designed to address this question.
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Of 301 patients included in EASI between 2013 and 2018, 24 (8.0%) with TL were randomly allocated to acute stenting (n = 13) or no stenting (n = 11). Baseline characteristics were balanced. Eight (61.5%; 95% CI 35.5%–82.3%) and 7 (63.6%; 95% CI 35.4%–84.9%) patients, respectively, had a favorable outcome (mRS 0–2; P = 1.0). One non-stented patient had a symptomatic intracerebral hemorrhage.
This pilot trial of patients with TL undergoing EVT suggests that a sufficiently powered larger TL trial comparing acute c-ICA stenting to no stenting is feasible.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02157532.

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Original ArticleEndovascular thrombectomy and medical therapy versus medical therapy alone in acute stroke: A randomized care trial

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Study design

Results

Discussion

Conclusion

Funding

Authors’ contributions

Disclosure of interest

Lancet

Lancet

J Clin Epidemiol

Tissue plasminogen activator for acute ischemic stroke

N Engl J Med

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

N Engl J Med

Patient outcomes with endovascular embolectomy therapy for acute ischemic stroke: a study of the national inpatient sample: 2006 to 2008

Stroke

Endovascular therapy after intravenous t-PA versus t-PA alone for stroke

N Engl J Med

Endovascular treatment for acute ischemic stroke

N Engl J Med

Original Article
Endovascular thrombectomy and medical therapy versus medical therapy alone in acute stroke: A randomized care trial