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Figure 1.
Flowchart of Literature Search and Study Selection
Flowchart of Literature Search and Study Selection
Figure 2.
Functional Outcomes of Endovascular Therapy vs Standard Therapy
Functional Outcomes of Endovascular Therapy vs Standard Therapy

The modified Rankin scale16 measures functional outcome on a 7-point ordinal scale: 0, no symptoms at all; 1, no significant disability despite symptoms; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; 6, death. Data on modified Rankin scale score at 90 days was not available for 19 patients in the endovascular therapy group and 8 patients in the standard medical treatment group in IMS III,28 1 patient in the endovascular therapy group and 3 patients in the standard medical treatment group in ESCAPE,30 and 5 patients in the standard medical treatment group in SWIFT-PRIME32 due to losses to follow-up in these trials.

A, Pooled distribution of modified Rankin scale scores at 90 days stratified by treatment group.

B, Meta-analysis of endovascular therapy vs standard therapy for the outcome of proportional treatment benefit across modified Rankin scale scores at 90 days. Size of data marker for each study is proportional to its weight.

Figure 3.
Secondary Efficacy and Safety Outcomes of Endovascular Therapy vs Standard Therapy
Secondary Efficacy and Safety Outcomes of Endovascular Therapy vs Standard Therapy

Meta-analyses of endovascular therapy vs standard therapy for outcomes of funcitonal independence (modified Rankin scale score 0-2), mortality at 90 days, revascularization at 24 hours, and symptomatic intracranial hemorrhage within 90 days. Size of data marker for each study is proportional to its weight. Revascularization was defined as angiographic restoration of blood flow at the site of arterial occlusion within 24 hours of stroke. Revascularization was assessed at 27 hours in the SWIFT-PRIME32 trial, and this was considered equivalent to 24 hours for the purposes of the present analysis. The revascularization outcome in this trial was based on successful reperfusion (reperfusion ratio ≥90%) on computed tomographic or magnetic resonance perfusion imaging.

Figure 4.
Subgroup and Sensitivity Analyses for Favorable Functional Outcome Reduced Disability at 90 Days
Subgroup and Sensitivity Analyses for Favorable Functional Outcome Reduced Disability at 90 Days

Favorable functional outcome was defined as reduced disability at 90 days. Odds ratios and corresponding confidence intervals among patient subgroups from individual trials were pooled and interactions were evaluated by random-effects meta-analyses.

aThe National Institutes of Health Stroke Scale (NIHSS)18 evaluates the clinical severity of stroke and ranges from 0 to 42, with higher values indicating more severe neurological deficit. An NIHSS score of 20 points was used as a cut-off because scores higher than 20 are considered severe impairment and correspond to a significantly greater risk of intracranial hemorrhage and unfavorable outcome.3436

bThe Alberta Stroke Program Early Computed Tomography Score (ASPECTS)19 is a 10-point topographic score evaluating the presence and severity of early ischemic change on standard computed tomographic (CT) scan in patients with early acute ischemic stroke of the anterior circulation, with a normal CT scan receiving 10 points and a score of 0 indicating diffuse involvement throughout the middle cerebral artery (MCA) territory. An ASPECTS of 7 points was used as a cutoff because scores higher than 7 are associated with poorer functional outcomes and greater risk of intracranial hemorrhage.19

cConfirmed arterial occlusion refers to use of CT angiography or magnetic resonance angiograph (MRA) to confirm arterial occlusion prior to treatment.

dProximal MCA occlusion refers to occlusion of the M1 MCA or 2 or more M2 MCA segments; data on outcomes of M1 vs M2 MCA occlusion were not available.

eIntravenous tissue plasminogen activator (tPA) refers to use of combination therapy (endovascular intervention plus intravenous tPA).

fMethod of thrombectomy was separated based on high (>80%) vs low (<20%) rate of use of retrievable stent devices.

Table 1.  
Descriptive Summary of Included Patients and Randomized Trials Characteristicsa
Descriptive Summary of Included Patients and Randomized Trials Characteristicsa
Table 2.  
Baseline Patient Characteristics and Treatment Parameters by Treatment Group Among Included Randomized Trials
Baseline Patient Characteristics and Treatment Parameters by Treatment Group Among Included Randomized Trials
Table 3.  
Distribution of 90-Day Modified Rankin Scale Scores by Treatment Group
Distribution of 90-Day Modified Rankin Scale Scores by Treatment Group
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Kidwell  CS, Jahan  R, Gornbein  J,  et al; MR RESCUE Investigators.  A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923.
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Goyal  M, Demchuk  AM, Menon  BK,  et al; ESCAPE Trial Investigators.  Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030.
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Campbell  BC, Mitchell  PJ, Kleinig  TJ,  et al; EXTEND-IA Investigators.  Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018.
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Original Investigation
November 3, 2015

Endovascular Thrombectomy for Acute Ischemic StrokeA Meta-analysis

Author Affiliations
  • 1Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
  • 2Division of Neurosurgery, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
  • 3Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
  • 4Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • 5Department of Medicine, Dammam University, Dammam, Saudi Arabia
  • 6Department of Neurology, King Khalid University, Abha, Saudi Arabia
  • 7Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas
  • 8Departments of Neurology, Radiology, and Neurosurgery, Medical College of Wisconsin, Milwaukee
JAMA. 2015;314(17):1832-1843. doi:10.1001/jama.2015.13767
Abstract

Importance  Endovascular intervention for acute ischemic stroke improves revascularization. But trials examining endovascular therapy yielded variable functional outcomes, and the effect of endovascular intervention among subgroups needs better definition.

Objective  To examine the association between endovascular mechanical thrombectomy and clinical outcomes among patients with acute ischemic stroke.

Data Sources  We systematically searched MEDLINE, EMBASE, CINAHL, Google Scholar, and the Cochrane Library without language restriction through August 2015.

Study Selection  Eligible studies were randomized clinical trials of endovascular therapy with mechanical thrombectomy vs standard medical care, which includes the use of intravenous tissue plasminogen activator (tPA).

Data Extraction and Synthesis  Independent reviewers evaluated the quality of studies and abstracted the data. We calculated odds ratios (ORs) and 95% CIs for all outcomes using random-effects meta-analyses and performed subgroup and sensitivity analyses to examine whether certain imaging, patient, treatment, or study characteristics were associated with improved functional outcome. The strength of the evidence was examined for all outcomes using the GRADE method.

Main Outcomes and Measures  Ordinal improvement across modified Rankin scale (mRS) scores at 90 days, functional independence (mRS score, 0-2), angiographic revascularization at 24 hours, symptomatic intracranial hemorrhage within 90 days, and all-cause mortality at 90 days.

Results  Data were included from 8 trials involving 2423 patients (mean [SD] age, 67.4 [14.4] years; 1131 [46.7%] women), including 1313 who underwent endovascular thrombectomy and 1110 who received standard medical care with tPA. In a meta-analysis of these trials, endovascular therapy was associated with a significant proportional treatment benefit across mRS scores (OR, 1.56; 95% CI, 1.14–2.13; P = .005). Functional independence at 90 days (mRS score, 0-2) occurred among 557 of 1293 patients (44.6%; 95% CI, 36.6%-52.8%) in the endovascular therapy group vs 351 of 1094 patients (31.8%; 95% CI, 24.6%-40.0%) in the standard medical care group (risk difference, 12%; 95% CI, 3.8%-20.3%; OR, 1.71; 95% CI, 1.18-2.49; P = .005). Compared with standard medical care, endovascular thrombectomy was associated with significantly higher rates of angiographic revascularization at 24 hours (75.8% vs 34.1%; OR, 6.49; 95% CI, 4.79-8.79; P < .001) but no significant difference in rates of symptomatic intracranial hemorrhage within 90 days (70 events [5.7%] vs 53 events [5.1%]; OR, 1.12; 95% CI, 0.77-1.63; P = .56) or all-cause mortality at 90 days (218 deaths [15.8%] vs 201 deaths [17.8%]; OR, 0.87; 95% CI, 0.68-1.12; P = .27).

Conclusions and Relevance  Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy vs standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization, but no significant difference in symptomatic intracranial hemorrhage or all-cause mortality at 90 days.

Introduction

Quiz Ref IDThe current standard therapy for acute ischemic stroke is intravenous administration of tissue plasminogen activator (tPA).1 Although intravenous tPA improves survival and functional outcomes when administered as early as possible after onset of ischemic stroke,2 its use is limited by the narrow therapeutic time window (<4.5 hours)3 and by important contraindications, including coagulopathy, recent surgery, or stroke or head injury within the past 3 months.4 Ultimately, as few as 10% of patients presenting with ischemic stroke can be eligible for treatment with intravenous tPA.5 Moreover, intravenous fibrinolysis is associated with long recanalization times and poor revascularization rates in proximal large arterial occlusions, and the prognosis of these patients remains poor.6,7

The limitations of intravenous tPA have led to interest in endovascular therapy for acute ischemic stroke. Compared with intravenous tPA, endovascular intervention can recanalize large arterial occlusions earlier and more frequently.810 Whether this translates into more favorable clinical outcomes was assessed in randomized clinical trials that evaluated outcomes of endovascular therapy vs intravenous tPA for ischemic stroke. Results of these trials yielded a varied effect of endovascular treatment, warranting further examination.

Prior systematic reviews examining this treatment11,12 have had limitations, such as inclusion of trials that did not use intravenous tPA as the standard medical therapy in the control group and pooling results from small pilot and observational studies with those of large phase 2 and 3 clinical trials. In this study, we conducted a meta-analysis including complete results from recently published multicenter randomized clinical trials to assess the association between endovascular mechanical thrombectomy and clinical outcomes, including functional outcomes, revascularization, intracranial hemorrhage, and mortality, among patients with acute ischemic stroke. We also aimed to examine whether certain imaging-, patient-, treatment-, or study-related factors were associated with improved outcomes to help define the optimal setting for using endovascular therapy.

Methods
Search Strategy

We undertook a systematic review and meta-analysis based on a predefined protocol (see the Supplement) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement13 and the Cochrane Handbook,14 and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE)15 to examine the level of evidence for all outcomes of interest. We searched, without language restriction, MEDLINE (PubMed and Ovid), EMBASE, CINAHL, Google Scholar, and the Cochrane Library through August 2015. We used, in various relevant combinations, keywords and MeSH terms pertinent to the intervention of interest: endovascular, intra-arterial, tissue plasminogen activator, alteplase, fibrinolysis, intervention, embolectomy, thrombolysis, and thrombectomy; and terms pertinent to the medical condition of interest: ischemia, stroke, cerebrovascular accident, and infarct (see the Search Strategy in the Supplement). References of studies with potential relevance and review articles were manually screened to identify any eligible resources that were not previously identified.

Study Selection

Three reviewers (J.H.B., F.N., and S.A.A.) independently evaluated studies for eligibility. Disagreements between the reviewers concerning the decision to include or exclude a study were resolved by consensus, and if necessary, consultation with a fourth reviewer (W.A.). We regarded studies as eligible for inclusion if they were published randomized clinical trials of adult participants (≥18 years) with acute ischemic stroke managed with endovascular therapy compared with the standard medical care, which includes the use of intravenous tPA. Endovascular therapy was defined as the intra-arterial use of a microcatheter or other device for mechanical thrombectomy, with or without the use of a chemical thrombolytic agent. Studies were included if they reported on functional outcomes using the modified Rankin scale (mRS). This 7-score ordinal scale (eTable 1 in the Supplement) ranges from 0 (no symptoms) to 6 (death).16 We excluded duplicate reports and post hoc analyses. Pilot studies, defined as preliminary investigations assessing the safety and feasibility of endovascular thrombectomy in order to guide the design of a future study or trial, were excluded given concerns related to their small sample size, short follow-up, and study design. We excluded abstracts from meeting proceedings, unless published as full-text reports in a peer-reviewed journal. Moreover, we excluded studies that did not include intravenous tPA in the control standard of care group and studies that did not examine mechanical thrombectomy in the intervention group.

Data Extraction

Three investigators (J.H.B., F.N., and S.A.A.) independently extracted data from the trials’ primary texts, supplementary appendixes, and protocols using data abstraction forms that contained fields for: trial name, year of publication, number and country of centers, sources of funding, recruitment period, number of patients in each treatment group, details regarding trial design (eg, randomization, blinding, allocation concealment), eligibility criteria, intervention, control therapy, baseline patient demographics and comorbidities, efficacy outcomes (eg, mRS scores, revascularization [eTables 2 and 3 in the Supplement], quality of life indices), safety outcomes (eg, intracranial hemorrhage, morbidity, mortality), and outcomes among relevant subgroups of patients. Disagreements between the 3 reviewers were resolved by consensus, and if necessary, consultation with a fourth reviewer (W.A.).

Quality Assessment

Three reviewers (J.H.B., W.A., and S.A.A.) independently performed quality assessment. We used the Cochrane Collaboration’s tool17 to assess the risk of selection, performance, detection, attrition, and reporting biases among the included randomized trials. We judged trials with more than 2 high-risk components as having a moderate risk of bias, and trials with more than 4 high-risk components as having a high risk of bias.

Data Synthesis and Analysis

We calculated, and subsequently pooled in independent meta-analyses, odds ratios (ORs) with corresponding 95% confidence intervals for each outcome of interest. The primary outcome was mRS score at 90 days. We calculated the proportional OR of mRS score for each study by ordinal logistic regression. The proportional OR expresses the common odds for treatment benefit at each cut-off across all 7 scores of the mRS. We also evaluated the secondary outcomes of functional independence (mRS score, 0-2) at 90 days, angiographic revascularization at 24 hours, all-cause mortality at 90 days, and symptomatic intracranial hemorrhage within 90 days. We determined the risk difference for functional independence and calculated the number needed to treat (NNT) as 1/risk difference. Outcomes were analyzed as reported by eligible trials following the intention-to-treat method (ie, based on including all randomized patients and analyzing them according to the groups into which they were randomly assigned).

Furthermore, we examined whether important imaging, patient, or treatment characteristics were associated with improved functional outcome (reduced disability at 90 days) and accounted for between-study heterogeneity. Outcomes of endovascular therapy were compared with standard medical care in key subgroups defined by age, sex, National Institutes of Health Stroke Scale (NIHSS) score,18 Alberta Stroke Program Early Computed Tomography Score (ASPECTS),19 time to randomization, routine use of computed tomography angiography or magnetic resonance angiography to confirm proximal arterial occlusion prior to intervention, arterial location of occlusion on angiographic imaging, use of intravenous tPA, and type of endovascular thrombolysis whether chemical or mechanical. To further evaluate heterogeneity, we conducted sensitivity analyses of the method of thrombectomy by stratifying trials into low (<20%) vs high (>80%) rate of use of stent retrievers (ie, first-generation methods, with thrombolytics, coil retrievers, and aspiration devices vs second-generation methods and techniques, with stent retrievers), and also of older (published in 2013) vs newer studies (published in 2015) to account for important methodological differences between older and newer studies.20

For all meta-analyses, outcomes were pooled using the DerSimonian and Laird random-effects model,21 with weights calculated by the inverse variance method. Heterogeneity across trials was investigated by the Cochran Q test and measured by the I2 statistic, with I2 values exceeding 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively.22 Publication bias was evaluated visually by funnel plots, and quantified by the Egger regression,23 the Begg-Mazumdar test,24 and the Copas selection model.25 Interactions in subgroup and sensitivity analyses were evaluated by random-effects analysis, which assumes the study-to-study variance is the same for all subgroups. A 2-tailed P value of <.05 was considered a criterion for statistical significance. We did not impute any missing data because the data provided in the trials’ primary texts, supplementary appendixes, and protocols were sufficiently granular for robust analyses. Comprehensive Meta-Analysis version 2.2 (Biostat Inc) was used to conduct all statistical analyses.

Results

The search strategy identified 4193 studies, of which data from 8 trials2633 were used, comprising 2423 patients (mean [SD] age, 67.4 [14.4] years), of whom 1131 (46.7%) were women (Figure 1). A total of 1313 patients underwent endovascular therapy and 1110 received standard medical treatment. Included trials and patient characteristics are summarized in Table 1 and detailed in Table 2 and eTable 4 in the Supplement. All 8 eligible studies were multicenter randomized trials, results of which were published between 2013 and 2015. There were similar distributions of patient characteristics, including demographics and comorbidities. Locations of ischemic strokes were all within the anterior circulation distribution, except for 44 patients from 2 trials.26,28 The upper limit of time from stroke onset to endovascular treatment among these trials varied from 5 to 12 hours (mean, [SD], 3.8 [1.2] hours). Overall risk of bias was rated as low in all eligible studies, as assessed using the Cochrane Collaboration’s tool (eFigure 1 in the Supplement). We did not observe significant publication bias based on the Egger regression, the Begg-Mazumdar test, or the Copas selection model (eFigure 2 in the Supplement).

Table 3 presents the distribution of mRS scores separated by trial. Figure 2A provides a graphical summary of pooled shifting across the 7 scores of the mRS between both groups at 90 days. Quiz Ref IDDistribution of mRS scores was more favorable with endovascular therapy relative to standard therapy, with greater proportions of patients in each category of favorable outcome (0, 1, or 2), and smaller proportions in unfavorable categories (4, 5, or 6). In meta-analysis of all 8 trials, endovascular intervention was associated with significant proportional treatment benefit across the mRS scores (OR, 1.56; 95% CI, 1.14-2.13; P = .005; Figure 2B). In addition, endovascular therapy was associated with significantly higher rates of functional independence at 90 days (557 of 1293 patients [44.6%]; 95% CI, 36.6%-52.8%) than standard treatment (351 of 1094 patients [31.8%]; 95% CI, 24.6%-40.0%), for a risk difference of 12.0% (95% CI, 3.8%-20.3%; OR, 1.71; 95% CI, 1.18-2.49; P = .005;Figure 3A). The number needed to treat for endovascular intervention relative to usual medical care for achieving the outcome of functional independence was 8 (95% CI, 5-26).

Secondary outcomes among both examined groups for all trials are detailed in eTable 5 in the Supplement. Rates of angiographic revascularization at 24 hours for endovascular therapy was 75.8% (95% CI, 68.1%-82.2%) vs 34.1% (95% CI, 29.8%-38.7%) for standard therapy (OR, 6.49; 95% CI, 4.79-8.79; P < .001; Figure 3C).Quiz Ref ID There was no significant difference in rates of symptomatic intracranial hemorrhage within 90 days between groups: 5.7% (95%, CI; 4.4%-7.3%) for endovascular therapy vs 5.1% (95%, CI; 3.9%-6.6%) for standard therapy (OR, 1.12; 95% CI, 0.77-1.63; P = .56;Figure 3D). Nor was there significant difference in the rates of all-cause mortality at 90 days: 15.8% (95% CI, 12.7%-19.3%) for endovascular therapy vs 17.8% (95% CI, 14.4%-21.8%) for standard therapy (OR, 0.87; 95% CI, 0.68-1.12; P = .27; Figure 3B). Overall morbidity, including rates of in-hospital medical complications (eg, deep venous thrombosis, myocardial infarction, pneumonia), were not significantly different between the endovascular intervention group and standard treatment group (eTable 5 in the Supplement). The overall quality of evidence, as examined using GRADE, was high (eTable 6 in the Supplement). The outcomes of proportional treatment benefit across the mRS scores, functional independence, and revascularization were rated as high quality; whereas mortality and symptomatic intracranial hemorrhage were rated as moderate quality due to concerns related to imprecision, as detailed in eTable 6 in the Supplement.

Substantial heterogeneity (I2 = 75.4%) was detected in the outcome of functional improvement. Therefore, we conducted multiple subgroup and sensitivity analyses to examine the relative efficacy of endovascular therapy vs standard medical care stratified by key imaging-, patient-, treatment-, and study-related factors. Functional outcomes were significantly better among patients with angiographic imaging confirming proximal arterial occlusion (OR, 2.24; 95% CI, 1.72-2.90, P for interaction <.001), among patients who received the combined therapy of intravenous tPA and endovascular intervention (OR, 2.07; 95% CI, 1.46-2.92; P for interaction = .018), and when stent retriever devices were used for mechanical thrombectomy (OR, 2.39; 95% CI, 1.88-3.04; P for interaction <.001). In addition, comparison of newer vs older trials to evaluate if study-related factors (eg, patient population, thrombectomy technique, advances in imaging) were related to functional outcome revealed statistically significant differences in treatment outcomes stratified by the trial year of publication (P for interaction <.001). Examination of endovascular (chemical vs mechanical) thrombolysis was not feasible, because only 1% of all patients received pure chemical endovascular therapy and less than 17% had combined mechanical and chemical endovascular intervention. In subgroup analyses, there were no differences in treatment outcomes based on age, sex, NIHSS score, time to randomization, ASPECTS or location of arterial occlusion (Figure 4; eFigures 3 and 4 in the Supplement).

Discussion

This study reports detailed analyses of 8 recently published multicenter randomized clinical trials that compared endovascular therapy to the current standard therapy for patients with acute ischemic stroke. The results of this meta-analysis show that compared with standard medical management, endovascular intervention with mechanical thrombectomy was associated with improved functional outcomes and higher rates of functional independence at 90 days. In addition, endovascular intervention, compared with standard medical therapy with tPA, was associated with higher rates of angiographically demonstrated revascularization at 24 hours but was associated with no significant differences in symptomatic intracranial hemorrhage or all-cause mortality at 90 days. Furthermore, sensitivity analyses suggested that the presence of proximal arterial occlusion on angiographic imaging, intravenous tPA combined with endovascular intervention, and use of stent retriever devices for mechanical thrombectomy were important factors associated with improved functional outcomes related to endovascular thrombectomy.

The results of trials included in this study were variable, with a high degree of detected heterogeneity for the primary outcome of mRS score (I2 = 75.9%), justifying use of random-effects models. We qualitatively and quantitatively investigated and addressed this heterogeneity in our analysis. Quiz Ref IDSimilar to initial reports of percutaneous coronary intervention for myocardial infarction, the initial clinical trials of endovascular therapy for acute ischemic stroke, in particular Intra-arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS),26 Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE),27 and Interventional Management of Stroke III (IMS III),28 failed to show a significant benefit of endovascular strategies. However, these trials had several well-recognized limitations, including inconsistent use of vascular imaging to confirm vessel occlusion prior to randomization, variable use of intravenous tPA in the endovascular therapy group, and reliance on less effective and older-generation mechanical devices.20,37,38 These factors were important contributors to heterogeneity in our meta-analysis. These limitations of early trials were addressed in the more recent trials, beginning with Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN).29 The results of MR CLEAN,29 favoring endovascular intervention, prompted interim analyses of the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE),30 Extending the Time for Thrombolysis in Emergency Neurological Deficit—Intra-Arterial (EXTEND-IA),31 and Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT-PRIME)32 trials. The Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT)33 trial was stopped for a preplanned interim analysis. These 4 trials were subsequently halted due to observed benefits in the endovascular therapy group.

Quiz Ref IDIn our analysis, the relative benefit associated with endovascular therapy was increased by concomitant use of intravenous tPA. Evidence in support of this combination therapy is present in the current literature with several possible explanations.39,40 A combination approach takes advantage of the speed of intravenous tPA administration and the greater recanalization potential of endovascular therapy. In addition, early initiation of treatment with intravenous tPA may reduce clot burden, restore a critical amount of blood flow, and facilitate subsequent arterial recanalization by endovascular mechanical thrombectomy.41,42 However, patients who receive tPA and those who do not receive tPA can be different populations. Patients who did not receive intravenous tPA may have had contraindications or late presentation. These may have contributed to the relatively smaller treatment effect reported with mechanical thrombectomy among patients not receiving intravenous tPA that we observed in our study.

In our study, the improvement in functional outcomes associated with endovascular therapy was significantly greater when computed tomography angiography or magnetic resonance angiography were used to confirm proximal arterial occlusion prior to trial enrolment. This is intuitive because the absence of preprocedural vascular imaging may lead to the catheterization of patients without a proximal occlusive clot, and therefore patients who are unlikely to benefit from neuro-interventional treatment.

In the context of acute ischemic stroke, endovascular therapy is often considered, and evaluated as, a single treatment modality. However, a high degree of variability exists in the inherent nature of this therapy, and in reality, endovascular intervention may include a number of different but related strategies, some of which may be more effective than others. Endovascular strategies include chemical clot dissolution with local delivery of tPA, or recanalization of arterial occlusion by clot disruption, aspiration, or retrieval using a microcatheter or one of many mechanical devices. The Merci retriever was the first thrombectomy device to receive US Food and Drug Administration approval in 200443 and was widely used in early trials evaluating endovascular treatments for acute ischemic stroke, including SYNTHESIS,26 MR RESCUE,27 and IMS III.28 Nevertheless, high-quality evidence exists from 2 trials in support of the improved efficacy of newer retrievable stent devices, including the Solitaire Flow Restoration device and Trevo retriever, compared with older devices, such as the Merci retriever.44,45 Thrombectomy therapy was achieved by stent retriever devices in the majority of patients in the MR CLEAN29 and ESCAPE30 trials and in all patients in the EXTEND-IA,31 SWIFT-PRIME,32 and REVASCAT33 trials. In our meta-analysis, the use of stent retrievers for mechanical thrombectomy was a significant source of heterogeneity related to treatment outcomes and significantly affected the relative benefit associated with endovascular therapy compared to optimal medical treatment.

The limitations of our meta-analysis include variability in the design and reporting of included trials that we investigated using prespecified subgroup and sensitivity analyses. However, we could not evaluate some factors due to lack of reported data (eg, general vs local anesthesia, time to treatment, use of intra-arterial thrombolytic agents). Of these, time to treatment may have an important effect on the efficacy of endovascular therapy. Delays of even less than 30 minutes can significantly reduce the probability of functional independence after endovascular therapy.41,42 However, endovascular intervention for stroke is not universally available, and therefore, some of these patients may require transfer to a regional stroke center with neurointerventional capabilities. For this reason and others, it would be prudent to define a precise maximal time window after which treatment is considered relatively futile, similar to what exists for intravenous tPA (<4.5 hours). Previous clinical studies evaluating the importance of time to endovascular therapy have provided mixed results,4648 with current included trials using a variable therapeutic time window, ranging from 5 to 12 hours. Most eligible studies used a time window up to 6 hours from stroke onset. Although REVASCAT33 included a 6-to-8-hour group and ESCAPE30 enrolled 49 patients at 6 to 12 hours, a definitive positive treatment effect has not been demonstrated in these subgroups.20 However, trials evaluating treatment windows extending beyond 6 hours and up to 24 hours are under way, including the Trevo and Medical Management Versus Medical Management Alone in Wake Up and Late Presenting Strokes (DAWN, ClinicalTrials.gov NCT02142283) and Perfusion Imaging Selection of Ischemic Stroke Patients for Endovascular Therapy (POSITIVE, ClinicalTrials.gov NCT01852201) trials.

Furthermore, the type of mechanical device used for endovascular thrombectomy may have a significant influence on revascularization and functional outcomes. Although newer retrievable stent devices were available for use in more recently published trials, the exact outcomes of all types of devices were not recorded in all studies, particularly older trials, preventing a complete comparison of outcomes stratified by the device type. In our sensitivity analyses, stent retrievers were associated with more favorable outcomes than other devices, although results according to the exact device type (eg, Solitaire Flow Restoration device vs Trevo retriever) were not reported. Moreover, some of the subgroup analyses in the present study were limited by relatively smaller sample size and by virtue of patient selection among included trials. For example, age, NIHSS score, and ASPECTS may be associated with the relative benefit of endovascular over standard therapy. However, many of the trials excluded patients with low ASPECTS (ie, <6) and older patients (ie, >80 years) or patients without premorbid independent function, limiting the ability of our meta-analysis to detect differences in treatment benefit related to these variables. These are important considerations because many patients with ischemic stroke are elderly and many present with evidence of advanced ischemia and infarction. Future trials will need to delineate upper age limits and clinical and radiological indicators of utility or futility of endovascular treatment.

This meta-analysis synthesizes evidence from multicenter randomized clinical trials, and may help inform the design and execution of future studies examining the efficacy of endovascular therapy for acute ischemic stroke. Additional trials are needed to systematically study the relationship of patient-, disease-, and treatment-related variables with outcomes following mechanical thrombectomy, and to identify the ideal patient to undergo endovascular therapy. Limits on age, ASPECTS, NIHSS score, and, perhaps most importantly, time to treatment, need to be explored. In addition to optimizing patient selection, trials should explore and define the optimal endovascular therapy with respect to technique, device, regional vs general anesthesia, and dosage of intra-arterial thrombolytic, if any. The relationship of these variables to safety outcomes, such as mortality and morbidity, should also be studied. The results of such studies could inform the development of clinical practice guidelines. Moreover, studies are needed to evaluate the cost-effectiveness of endovascular therapy for the treatment of ischemic stroke. In addition, it may be beneficial for medical personnel involved in the early care of patients with acute ischemic stroke, such as paramedics and emergency physicians, to be trained to identify candidate patients who may benefit from endovascular therapy, and for communication to appropriate neurointerventional staff to be streamlined to mobilize neurointerventional resources and reduce the time from stroke onset to recanalization and reperfusion.

Conclusions

Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy compared with standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization but no significant difference in occurrence of symptomatic intracranial hemorrhage or all-cause mortality at 90 days.

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Article Information

Corresponding Author: Saleh A. Almenawer, MD, Division of Neurosurgery, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main St W, Hamilton, ON, Canada L8S 4L8 (Dr_menawer@hotmail.com).

Author Contributions: Dr Almenawer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Badhiwala, Nassiri, Alhazzani, Spears, Kulkarni, Alshahrani, Reddy, Zaidat, Almenawer,

Acquisition, analysis, or interpretation of data: Badhiwala, Nassiri, Alhazzani, Selim, Farrokhyar, Singh, Alqahtani, Rochwerg, Murty, Alhazzani, Yarascavitch, Zaidat, Almenawer,

Drafting of the manuscript: Badhiwala, Nassiri, Kulkarni, Alqahtani, Murty, Almenawer,

Critical revision of the manuscript for important intellectual content: Badhiwala, Nassiri, Alhazzani, Selim, Farrokhyar, Spears, Singh, Alqahtani, Rochwerg, Alshahrani, Murty, Alhazzani, Yarascavitch, Reddy, Zaidat, Almenawer,

Statistical analysis: Badhiwala, Nassiri, Alhazzani, Almenawer,

Administrative, technical, or material support: Badhiwala, Rochwerg, Murty, Alhazzani, Yarascavitch, Zaidat, Almenawer,

Study supervision: Badhiwala, Farrokhyar, Spears, Kulkarni, Alshahrani, Murty, Zaidat, Almenawer,

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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