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Efficacy of endovascular therapy for basilar and vertebral artery occlusion: A systematic review and meta-analysis of randomized controlled trials

Open AccessPublished:December 24, 2022DOI:https://doi.org/10.1016/j.ejim.2022.12.011

      Abstract

      Background

      The best management for acute basilar artery occlusion (BAO) has increasingly been clarified by recent randomized controlled trials (RCTs). We conducted a systematic review and meta-analysis of RCTs comparing endovascular therapy (EVT) vs best medical management (BMM).

      Methods

      We searched PubMed, Embase, the CENTRAL, and ClinicalTrials.gov from January 1, 2000, to November 20, 2022. We included RCTs comparing EVT vs BMM in BAO or bilateral vertebral artery occlusion (VAO). Primary outcome was ambulation (modified Rankin Scale score [mRS] 0–3) at 90 days. Secondary outcomes were independence (mRS 0–2) at 90 days, death by 90 days, and symptomatic intracranial hemorrhage (sICH). Risk ratio (RR) with 95% CI was used as a measure of the association of EVT vs BMM with outcomes.

      Results

      Final analyses included 4 RCTs with 988 patients with BAO or VAO. Pooled results showed that EVT vs BMM was associated with an increased rate of 90-day ambulation (RR 1.54, 95% CI 1.16–2.05), independence (RR 1.83, 1.08–3.08) and a reduced risk of mortality (RR 0.76, 0.65–0.89), but an increased risk of sICH (RR 7.48, 2.27–24.62) and the benefits might be confined to patients with BAO but not patients with VAO. EVT effect was modified by occlusion location with the basilar artery, with greatest benefit for proximal, intermediate benefit for middle, and least benefit for distal occlusions.

      Conclusion

      EVT compared with BMM might be associated with an increased rate of ambulation, independence and survival but with an increased risk of sICH in patients with acute BAO.

      Keywords

      1. Introduction

      Basilar artery occlusion (BAO), which accounts for approximately 10% of all ischemic strokes due to intracranial proximal large artery occlusions, is associated with high mortality and severe disability [
      • Mattle H.P.
      • Arnold M.
      • Lindsberg P.J.
      • Schonewille W.J.
      • Schroth G.
      Basilar artery occlusion.
      ]. Although endovascular therapy (EVT) with highly effective thrombectomy devices is of substantial benefit in acute ischemic stroke due to large vessel occlusions in the anterior circulation [
      • Lee M.
      • Saver J.L.
      Reperfusion of the ischaemic brain by endovascular thrombectomy and thrombolysis.
      ], the first two published randomized controlled trials had not shown that EVT significantly increases the rate of being ambulatory (modified Rankin Scale [mRS] score 0 to 3) or being independent (mRS score 0 to 2) at 90 days after an acute ischemic stroke due to BAO when compared with best medical management groups. Relatively few participants and inadequate statistical power in single randomized controlled trials, high cross-over rates, and enrolling patients with bilateral intracranial vertebral artery occlusion (VAO), rather than BAO, may have attenuated signals of efficacy [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      .
      Two additional randomized controlled trials to evaluate the efficacy of EVT on BAO or bilateral intracranial VAO were been published recently [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      . Recommendations based on the results of individual trials can be misleading owing to the risk of both false-positive and false-negative results [
      • Peto R.
      Why do we need systematic overviews of randomized trials?.
      ]. To achieve a more robust estimate of the efficacy and safety of EVT for acute ischemic stroke due to BAO or bilateral intracranial VAO, we conducted a systematic review and meta-analysis of randomized controlled trials comparing EVT plus best medical management vs best medical management to date.

      2. Methods

      This study was performed in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis: The PRISMA Statement [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group PRISMA
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. This study was a meta-analysis and did not need Institutional Review Board or ethics committee approval. The protocol was registered with PROSPERO (CRD42022330685).

      2.1 Search methods and resources

      We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the clinical trial registry maintained at ClinicalTrials.gov from January 1, 2000, to November 20, 2022 using the following terms: basilar artery occlusion or vertebrobasilar artery occlusion or posterior circulation stroke and endovascular therapy or endovascular thrombectomy or endovascular treatment or mechanical thrombectomy or intra-arterial therapy. We restricted our search to randomized controlled trials. There were no language restrictions.

      2.1.1 Study selection

      Criteria for inclusion of a study were: (1) study design was a randomized controlled trial; (2) patients had acute BAO or bilateral intracranial VAO; (3) trials compared EVT plus best medical management (with intravenous thrombolysis if suitable) vs. best medical management (with intravenous thrombolysis if suitable); and (4) trials reported an endpoint of mRS score 0 to 3 at 90 days. Studies were excluded if (1) study design was a registry, case report, case-control, or cohort, or (2) patients assigned to active arm only receiving intra-arterial fibrinolysis. One investigator (CHL) extracted the data and another investigator (ML) reviewed the extracted data. Any discrepant judgments were resolved by joint discussion.

      2.1.2 Study quality assessment

      Since all of the included studies were randomized controlled trials, we assessed the overall bias (e.g. bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result) by using the RoB-2 tool [
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ].

      2.1.3 Statistical analysis

      The analysis plan was performed on an intention-to-treat basis. Because acute BAO is the most devastating type of ischemic stroke, all relevant randomized controlled trials adopted mRS 0 to 3 to assess the efficacy of EVT for these patients [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ,
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      ]. We therefore defined the primary outcome of this study as mRS 0 to 3 (i.e. being ambulatory) at 90 days [
      • Saver J.L.
      • Chaisinanunkul N.
      • Campbell B.C.V.
      • et al.
      Standardized nomenclature for modified rankin scale global disability outcomes: consensus recommendations from stroke therapy academic industry roundtable XI.
      ]. The secondary outcomes were functional independence (mRS score 0 to 2) at 90 days [
      • Saver J.L.
      • Chaisinanunkul N.
      • Campbell B.C.V.
      • et al.
      Standardized nomenclature for modified rankin scale global disability outcomes: consensus recommendations from stroke therapy academic industry roundtable XI.
      ], mortality by 90 days, and symptomatic intracranial hemorrhage detected on neuroimaging within 3 days after initiation of treatment. The secondary imaging outcome was basilar artery patency assessed on computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) at 24 to 72 h.
      We computed the random-effects estimate based on the inverse variance method when 2 or more studies provided sufficient data for a given outcome. Risk ratio (RR) with 95% confidence interval (CI) was used as a measure of the association of EVT vs best medical management with primary and secondary outcomes. All reported P values were two-sided, with significance set at <0.05. Heterogeneity was assessed by a P value determined by the use of χ2 statistics and I2 statistics, and I2 values of 0% to 29%, 30% to 49%, 50% to 74%, and 75% to 100% consider to represent not important, moderate, substantial, and considerable inconsistency, respectively [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ].
      A subgroup analysis based on the primary outcome was conducted according to baseline National Institutes of Health Stroke Scale (NIHSS) scores (< 10 vs ≥10), occlusion site (BAO vs bilateral intracranial VAO), intravenous thrombolysis (yes vs no), location of BAO (proximal vs middle vs distal), and randomization window (within 6 h vs within 12 h vs > 12 to 24 h). To identify any trial that might have exerted a disproportionate influence on the summary treatment effect, we conducted a sensitivity test by removing each individual trial from the meta-analysis one at a time. Publication bias was assessed visually by a funnel plot displaying standard error as the measure of sample size and RR as the measure of treatment effect [
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ]. The Cochrane Collaboration's Review Manager Software Package (RevMan, version 5.4) was used for this meta-analysis.

      3. Results

      We identified eight full articles for detailed assessment, of which two were excluded for being review articles, one for only using intra-arterial urokinase in the active arm [
      • Macleod M.R.
      • Davis S.M.
      • Mitchell P.J.
      • et al.
      Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke.
      ], and one for being an observational study [
      • Writing Group BASILAR
      • Zi W.
      • Qiu Z.
      • et al.
      Assessment of endovascular treatment for acute basilar artery occlusion via a nationwide prospective registry.
      ]. Therefore, the final analysis included four randomized controlled trials (Supplementary Fig. 1) [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ,
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      ]. Characteristics of the included trials are shown in Table 1 [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ,
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      ]. Two trials included patients with BAO [
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ,
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      , and another two trials included patients with BAO or bilateral intracranial VAO [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      Overall, 988 patients (686 men [69.4%]; mean age, 66 years) with acute stroke due to BAO (970 patients) or bilateral intracranial VAO (18 patients) were enrolled with 556 (56.3%) participants randomly assigned to the EVT arm and 432 (43.7%) to the control arm. Among the four included trials, three were conducted in China [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      and one in six European countries plus Brazil [
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ]. EVT had to be feasible within six hours of BAO in the Basilar Artery International Cooperation Study (BASICS) trial [
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ], eight hours in the Basilar Artery Occlusion Endovascular Intervention versus Standard Medical Treatment (BEST) trial [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ], 12 h in the Endovascular Treatment for Acute Basilar Artery Occlusion (ATTENTION) trial [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ], and between 6 and 24 h in the Basilar Artery Occlusion Chinese Endovascular (BAOCHE) trial 0.6 One trial enrolled patients with baseline NIHSS score ≥10 [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ], one trial with baseline NIHSS score ≥6 [
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      ], and two trials did not require patients to have a minimal NIHSS score to be included [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      . Reperfusion on digital subtraction angiography in EVT arm, assessed by modified Thrombolysis in Cerebral Infarction (TICI), showed that modified TICI 2b or 3 was 71% in the BEST trial [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ], 72% in the BASICS trial [
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ], 93% in the ATTENTION trial [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ], and 88% in the BAOCHE trial [
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      ].
      Table 1Characteristics of included trial.
      BASICS
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      BEST
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ATTENTION
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      BAOCHE
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      CountriesEurope and BrazilChinaChinaChina
      Study duration2011–20192015–20172021–20222016–2021
      Inclusion criteria

      Onset < 6 h, Basilar artery occlusion confirmed by CTA/MRA, NIHSS ≥ 10, (age >85y, NIHSS<10 allowed after 2015)

      Onset < 8h, BA and V4 occlusion by CTA/MRA/DSA, premorbid mRS 0–2, age>18y

      Onset 〈12 h, BA occlusion confirmed by CTA/MRA/DSA, NIHSS ≥ 10, pc-ASPECT 〉 8 (age > 80y), pc-ASPECT > 6 (age <80y)

      Premorbid mRS:0–2 if age <80y, 0 if age > 80y
      6–24 h, CTA/MRA/DSA confirm BA, bilateral V4 occlusion, age 18∼80y, NIHSS ≥ 6, pc-ASPECT ≥6, mid-pons index ≤ 2, premorbid mRS ≤ 1
      ComparisonEVT vs BMMEVT vs BMMEVT vs BMMEVT vs BMM
      Age, years67656764
      Sample size (men)300 (65%)131 (76%)340 (68%)217 (73%)
      Baseline NIHSS22322420
      Baseline pc- ASPECTS10898
      IVT121 (79%)18(27%)69 (30%)15 (14%)
      Medical history
      Hypertension93 (60%)45(68%)162 (72%)90(82%)
      AF44 (29%)18(27%)45(20%)14(13%)
      smoking64 (61%)22(33%)62 (27%)34 (32%)
      Dyslipidemia43 (32%)3 (5%)61 (27%)4 (4%)
      DM32 (22%)10 (15%)48 (21%)30 (27%)
      Etiology
      Embolic51 (35%)14 (21%)46 (20%)11 (10%)
      ICAD53 (36%)37 (56%)90 (40%)75 (68%)
      Onset to reperfusion, minutesN/A400 (269–526)414 (288–528)790 (626–1000)
      Crossover rates
      EVT to BMM2%5%1%1%
      BMM to EVT5%22%3%4%
      Device used in EVT group
      2nd generation Stent retriever53/118 (45%)64/77 (83%)Only stent retriever:11/226 (5%)103/110 (94%)
      Suction58/118 (49%)N/AOnly aspiration:77/226 (34%)

      Combined technique:110/226 (49%)
      3/110 (3%)
      PTA30/138 (22%)3/77 (4%)PTA with or without stenting in intracranial:88/226 (39%)40 (36%)
      stenting23/137(17%)20/77 (26%)PTA with or without stenting in extracranial:18/226 (8%)41 (37%)
      TICI 2b or 3 in EVT arm63/88 (72%)45/63 (71%)208/223 (93%)89/101 (88%)
      sICH definitionHeidelberg bleeding classificationECASS-II criteriaSIT-MOST criteriaSIT-MOST criteria
      Acronym of trials: BASICS: Basilar Artery International Cooperation Study; BEST: Basilar Artery Occlusion Endovascular Intervention versus Standard Medical Treatment; ATTENTION: Endovascular Treatment for Acute Basilar Artery Occlusion; BAOCHE: Basilar Artery Occlusion Chinese Endovascular.
      AF: atrial fibrillation; BMM: best medical management; CTA: computed tomographic angiography; DM: diabetes mellitus; DSA: digital subtraction angiography; EVT: endovascular therapy; ICAD: intracranial atherosclerosis disease; IVT: atrial fibrillation; MRA: magnetic resonance angiography; mRS: modified Rankin Scale; N/A: not available; pc-ASPECTS: posterior circulation Acute Stroke Prognosis Early Computed Tomography Score; PTA: percutaneous transluminal angioplasty; sICH: symptomatic intracranial hemorrhage; TICI: Thrombolysis in Cerebral Infarction.
      Heidelberg bleeding classification: hemorrhagic transformation of infarcted brain tissue, intracerebral hemorrhage both within and outside infarcted brain tissue, intracerebral hemorrhage outside the infarcted brain tissue, or intracranial–extracerebral hemorrhage and an increase of 4 points or more in the NIHSS score or an increase of 2 points or more in 1 of the 11 NIHSS subcategories).
      ECASS-II: intracranial hemorrhage on imaging and an increase of 4 or more points on the NIHSS.
      SITS-MOST: local or remote parenchymal hematoma type 2, subarachnoid hemorrhage and/or intraventricular hemorrhage, combined with 4 or more points in NIHSS.
      The ROB-2 tool showed that overall risk of bias was high for all included trials because high risk was found in the item of bias due to deviations from intended interventions (Supplementary Table).
      Ambulation (mRS score 0–3) at 90 days
      Pooled results from the random-effects model of the four included trials showed that EVT compared with best medical management was associated with a higher proportion of patients with ambulation at 90 days in patients with acute BAO or bilateral intracranial VAO (45.1% vs 29.6%, RR 1.54, 95% CI 1.16 to 2.05, P = 0.003; number needed to treat [NNT]= 6). This represented 160 more ambulatory patients per 1000 treated with EVT compared with best medical management. There was substantial heterogeneity among included trials (I2 = 60%) (Fig. 1A).
      Fig. 1
      Fig. 1Ambulation and independence
      Legends: Risk ratio of (A) ambulation (modified Rankin scale score 0 to 3), and (B) independence (modified Rankin scale score 0 to 2), with EVT vs BMM in acute stroke due to basilar or intracranial vertebral artery occlusion.
      BMM: best medical management, EVT: endovascular therapy.
      Independence (mRS score 0–2) at 90 days
      Pooled results from the random-effects model of the four included trials showed that EVT compared with best medical management was associated with a higher proportion of patients with functional independence at 90 days in patients with acute BAO or bilateral intracranial VAO (34.9% vs 20.6%, RR 1.83, 95% CI 1.08 to 3.08, P = 0.02; NNT = 6). This represented 171 more independent patients per 1000 treated with EVT compared with best medical management. There was considerable inconsistency among included trials (I2 = 79%) (Fig. 1B).
      Mortality by 90 days
      Pooled results from the random-effects model of the four included trials showed that EVT compared with best medical management was associated with a lower risk of mortality by 90 days in patients with acute BAO or bilateral intracranial VAO (35.6% vs 45.4%, RR 0.76, 95% CI 0.65 to 0.89, P = 0.0004; NNT = 9). This represented 109 fewer deaths per 1000 patients treated with EVT compared with best medical management. Heterogeneity was not important among included trials (I2 = 0%) (Fig. 2A).
      Fig. 2
      Fig. 2Mortality and symptomatic intracranial hemorrhage
      Legends: Risk ratio of (A) mortality, and (B) symptomatic intracranial hemorrhage, with EVT vs BMM in acute stroke due to basilar or intracranial vertebral artery occlusion.
      BMM: best medical management, EVT: endovascular therapy.
      Symptomatic intracranial hemorrhage
      The definition of symptomatic intracranial hemorrhage varied among included trials. Symptomatic intracranial hemorrhage was defined according to the Heidelberg Bleeding Classification [
      • von Kummer R.
      • Broderick J.P.
      • Campbell B.C.V.
      • et al.
      The heidelberg bleeding classification; classification of bleeding events after ischemic stroke and reperfusion therapy.
      ] in the BASICS trial [
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ], according to the second European Cooperative Acute Stroke Study (ECASS II) [
      • Hacke W.
      • Kaste M.
      • Fieschi C.
      • et al.
      Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II).
      ] in the BEST trial [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ], and according to the modified Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST) criteria [
      • Wahlgren N.
      • Ahmed N.
      • Dávalos A.
      • et al.
      Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.
      ] in the ATTENTION and BAOCHE trials [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      .
      Pooled results from the random-effects model of the four included trials showed that EVT compared with best medical management was associated with a higher risk of symptomatic intracranial hemorrhage within 3 days after the initiation of treatment in patients with acute BAO or bilateral intracranial VAO (5.5% vs 0.5%, RR 7.48, 95% CI 2.27 to 24.62, P = 0.0009, number needed to harm = 31). This represented 32 more symptomatic intracranial hemorrhages per 1000 patients treated with EVT compared with best medical management. Heterogeneity was not important among included trials (I2 = 0%) (Fig. 2B).
      Basilar artery patency
      Pooled results from the random-effects model of the four included trials showed that EVT compared with best medical management was associated with a higher proportion of patients with basilar artery patency assessed on CTA or MRA at 24 to 72 h (89.3% vs 39.3%, RR 2.50, 95% CI 1.38 to 4.54, P = 0.003; NNT = 2). This showed that 427 more patients per 1000 were found to have basilar artery patency on CTA or MRA during 24 to 72 h after treatment with EVT compared with best medical management. There was considerable inconsistency among included trials (I2 = 91%) (Supplementary Fig. 2).
      Clinical and radiological outcomes of EVT in BAO or bilateral intracranial VAO are presented in the Table 2.
      Table 2Clinical and radiological outcomes of endovascular therapy vs control in acute basilar artery occlusion.
      Number of included trialsEVTBMMRisk differenceRisk ratio (95% CI)
      mRS 0–3 at 90 days445.1% (251/556)29.6% (128/432)15.5%1.54 (1.16–2.05)
      mRS 0–2 at 90 days434.9% (194/556)20.6% (89/432)14.5%1.83 (1.08–3.08)
      Mortality by 90 days435.6% (198/556)45.4% (196/432)−9.8%0.76 (0.65–0.89)
      sICH within 3 days45.5% (30/548)0.5% (2/413)5.0%7.48 (2.27–24.62)
      Basilar-artery patency on CTA or MRA at 1–3 days389.3% (317/335)39.3% (95/242)50.0%2.50 (1.38–4.54)
      BMM: best medical management; CI: confidence interval; CTA: computed tomographic angiography; EVT: endovascular therapy; MRA: magnetic resonance angiography; mRS: modified Rankin Scale, sICH: symptomatic intracranial hemorrhage.
      Sensitivity test
      A sensitivity test excluding individual trials yielded pooled results similar to the overall pooled estimates of the primary outcome.
      Subgroup analysis
      EVT compared with best medical management was associated with a higher proportion of patients with ambulation in BAO (odds ratio 1.97, 95% CI 1.17 to 3.32) [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ,
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ] but not in bilateral intracranial VAO (odds ratio 0.04, 95% CI 0.01 to 0.16; odds ratio instead of RR was used because only odds ratio was available from the BEST trial [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ]) (Supplementary Fig. 3). EVT effect was modified by occlusion location with the basilar artery, with greatest benefit for proximal (RR 2.03, 95% CI 1.41 to 2.91), intermediate benefit for middle (RR 1.48, 95% CI 1.05 to 2.09), and least benefit for distal occlusions (RR 1.09, 95% CI 0.82 to 1.45) (Fig. 3). Otherwise, heterogeneity was not important in subgroup analyses with different randomization windows (within 6 h vs within 12 h vs > 12 to 24 h; Supplemental Fig. 4) or concomitant treatment with or without intravenous thrombolysis (Supplementary Fig. 5) and heterogeneity was moderate in patients with NIHSS score < 10 vs ≥10 (Supplemental Fig. 6).
      Fig. 3
      Fig. 3Location of basilar artery occlusion (proximal vs middle vs distal)
      Legends: A subgroup analysis based on the primary outcome (i.e. ambulation) according to location of basilar artery occlusion (proximal vs middle vs distal) in acute stroke due to basilar artery occlusion. There were 301 patients with proximal, 258 with middle, and 211 patients with distal basilar artery occlusion locations.
      BMM: best medical management, EVT: endovascular therapy.
      Publication bias
      There was no obvious publication bias shown in the funnel plot (Supplemental Fig. 7).

      4. Discussion

      Our systematic review and meta-analysis, comprising four randomized controlled trials with 988 individuals with acute ischemic stroke due to BAO or bilateral intracranial VAO, revealed that EVT added to best medical therapy compared with best medical therapy alone was associated with a higher proportion of patients with ambulation and independence at 90 days. Also, EVT compared with best medical management was associated with a lower risk of mortality by 90 days but associated with a higher risk of symptomatic intracranial hemorrhage. Still, due to high heterogeneity among included trials, the pooled results of this systematic review and meta-analysis can only be considered as a preliminary suggestion, rather than clinical guidance supported by robust evidence.
      BAO is the most devastating type of ischemic stroke. Prior registry data showed that EVT compared with medical management might be associated with better functional outcomes and with reduced mortality in acute ischemic stroke due to BAO [
      • Writing Group BASILAR
      • Zi W.
      • Qiu Z.
      • et al.
      Assessment of endovascular treatment for acute basilar artery occlusion via a nationwide prospective registry.
      ]. However, current guidelines from American Heart Association/American Stroke Association and European Stroke Organization did not recommend EVT to be used in patients with BAO [
      • Powers W.J.
      • Rabinstein A.A.
      • Ackerson T.
      • et al.
      Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ,
      • Turc G.
      • Bhogal P.
      • Fischer U.
      • al Ket
      European Stroke Organisation (ESO)- European Society for Minimally invasive neurological therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke.
      , due to pending of published randomized controlled trials to support such an intervention. The current systematic review and meta-analysis of randomized controlled trials suggested that EVT in addition to best medical management in acute BAO might be beneficial.
      There would be 182 more ambulatory patients per 1000 treated with EVT compared with best medical management in acute stroke with a large ischemic region due to occlusion of the internal carotid artery or M1 segment of the middle cerebral artery [
      • Yoshimura S.
      • Sakai N.
      • Yamagami H.
      Endovascular therapy for acute stroke with a large ischemic region.
      ]. Also, there would be 200 more independent patients per 1000 treated with EVT compared with best medical management in acute stroke due to large vessel occlusion in the anterior circulation [
      • Goyal M.
      • Menon B.K.
      • van Zwam W.H.
      • et al.
      Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
      ]. Although the degree of benefit conferred by EVT in BAO seems slightly less than EVT in internal carotid artery or M1 occlusion, the current results might still be sufficient to support the use of EVT in acute stroke due to BAO.
      Furthermore, EVT compared with best medical management was associated with a lower risk of mortality by 90 days in acute stroke due to BAO whereas EVT did not significantly reduce mortality by 90 days in acute stroke due to large vessel occlusion in the anterior circulation [
      • Lee M.
      • Saver J.L.
      Reperfusion of the ischaemic brain by endovascular thrombectomy and thrombolysis.
      ,
      • Yoshimura S.
      • Sakai N.
      • Yamagami H.
      Endovascular therapy for acute stroke with a large ischemic region.
      ,
      • Goyal M.
      • Menon B.K.
      • van Zwam W.H.
      • et al.
      Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
      . In best medical management arms, mortality rates were 45.4% in BAO vs 18.9% in anterior circulation large vessel occlusion [
      • Goyal M.
      • Menon B.K.
      • van Zwam W.H.
      • et al.
      Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
      ]. The beneficial impact of EVT on mortality in acute BAO might further highlight the importance of EVT to be used in these patients.
      The Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration suggested that risk of symptomatic intracranial hemorrhage did not differ between EVT and best medical treatment groups in acute ischemic stroke due to proximal vessel occlusions in the anterior circulation (RR 1.06, 95% CI 0.63 to 1.80) [
      • Goyal M.
      • Menon B.K.
      • van Zwam W.H.
      • et al.
      Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
      ] whereas this systematic review suggested such a risk was higher in the EVT group than in the best medical management group for patients with acute BAO or bilateral intracranial VAO. Symptomatic intracranial hemorrhage is less likely to be found in patients with posterior circulation infarcts than patients with total anterior circulation infarcts following intravenous thrombolysis [
      • Sung S.F.
      • Wu C.S.
      • Hsu Y.C.
      • Tseng M.C.
      • Chen Y.W.
      Oxfordshire community stroke project classification but not NIHSS predicts symptomatic intracerebral hemorrhage following thrombolysis.
      ]. Indeed, the symptomatic intracranial hemorrhage rate in best medical management arms was 0.5% in BAO vs. 4.3% in anterior circulation large vessel occlusion [
      • Goyal M.
      • Menon B.K.
      • van Zwam W.H.
      • et al.
      Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
      ]. On the other hand, the symptomatic intracranial hemorrhage rate in the EVT arms was 5.5% in BAO vs. 4.4% in the anterior circulation large vessel occlusion [
      • Goyal M.
      • Menon B.K.
      • van Zwam W.H.
      • et al.
      Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
      ]. Among included trials, over 30% of patients with BAO assigned to EVT arm also received angioplasty and/or stenting due to intracranial atherosclerosis disease, which might contribute to an increased risk of symptomatic intracranial hemorrhage. Still, the benefits of EVT for an increased rate of ambulation and independence, as well as a reduced risk of death in patients with BAO are likely to outweigh the increased risk of symptomatic intracranial hemorrhage.
      Substantial heterogeneity among included trials were found for the effect size of EVT on the primary outcome in patients with acute BAO or bilateral intracranial VAO. There are several potential explanations. First, later performed trials had lower cross-over rates than earlier randomized controlled trials. Second, there was considerable inconsistency of EVT effect on occlusion location with the basilar artery, with greatest benefit for proximal, intermediate benefit for middle, and least benefit for distal occlusions. Third, there was considerable inconsistency of efficacy of EVT among patients with BAO vs bilateral intracranial VAO. EVT was beneficial in patients with BAO but might be harmful in patients with bilateral intracranial VAO. Fourth, successful reperfusion, represented by TICI 2b or 3 was different among these 4 include trials: about 71% in 2 trials [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ,
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      , but about 90% in another 2 trials [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      . The improved reperfusion rates in later-performed trials likely reflects continued advances in EVT technology. Since the benefit of EVT is strongly associated with increasing degrees of reperfusion [
      • Liebeskind D.S.
      • Bracard S.
      • Guillemin F.
      • et al.
      eTICI reperfusion: defining success in endovascular stroke therapy.
      ], it is reasonable that benefit conferred by EVT was more prominent in trials with higher reperfusion rates [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ,
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      . Fifth, time windows of treatment and rates of intravenous thrombolysis varied among included trials. Although subgroup analyses did not find an association of these baseline characteristics with the primary outcome, the disparity of these factors might still contribute to the heterogeneity of effect size of EVT on the primary outcome in patients with acute BAO.

      4.1 Limitations

      Our study has several limitations. There were some differences in baseline characteristics between these included trials. First, the randomization time window was different between trials. Intravenous thrombolysis was given in 79% of patients in the BASICS trial [
      • Langezaal L.C.M.
      • van der Hoeven E.
      • Mont'Alverne F.J.A.
      • et al.
      Endovascular therapy for stroke due to basilar-artery occlusion.
      ], about 30% in the ATTENTION trial [
      • Tao C.
      • Nogueira R.G.
      • Zhu Y.
      • et al.
      Trial of endovascular treatment of acute basilar-artery occlusion.
      ] and BEST trial [
      • Liu X.
      • Dai Q.
      • Ye R.
      • et al.
      Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.
      ], and 13% in the BAOCHE trial [
      • Jovin T.G.
      • Li C.
      • Wu L.
      • et al.
      Trial of thrombectomy 6 to 24 H after stroke due to basilar-artery occlusion.
      ], which might reflect the different randomization window of included trials. Three out of four trials were conducted in China. Intravenous thrombolysis is less frequently used in China, mostly because it is not free of charge. Intracranial pathology is different in Asian population as compared to Caucasians, and possibly a lower dose of tPA was used. It might be necessary to evaluate whether the current findings could be generalized to other ethnicities/races. Second, although NNTs for different time windows (i.e. grouping patients treated within 6 h, within 12 h, > 12 h to 24 h) would be very informative for the stroke clinicians, such information could not be known because the BEST trial and the ATTENTION trial did not provide number of patients with mRS 0 to 3 of each group in different time windows, and overall NNT could not counted accordingly. Third, as the trials reported different cutoff value (e.g. age and baseline posterior circulation Acute Stroke Prognosis Early Computed Tomography Score [pc-ASPECTS]), a study-level meta-analysis for heterogeneity of treatment effect by different patient factors could not be undertaken by pooling all included trials. Individual participant data meta-analyses of all available trials would be particularly useful.

      5. Conclusions

      This systematic review and meta-analysis of randomized controlled trials suggests that EVT plus best medical management compared with best medical management might be associated with a higher proportion of patients with ambulation at 90 days among patients with acute ischemic stroke due to vessel occlusions in the posterior circulation, but the benefits might be confined to patients with BAO but not patients with bilateral intracranial VAO. Also, EVT compared with best medical management might be associated with a higher proportion of patients with independence and survival at 90 days but might be associated with a higher risk of symptomatic intracranial hemorrhage. EVT effect might be modified by occlusion location with the basilar artery, with greatest benefit for proximal, intermediate benefit for middle, and least benefit for distal occlusions.

      Sources of funding

      None.

      Disclosures

      Dr Saver reported being an employee of the University of California, which has patent rights in retrieval devices for stroke. The University of California received payments on the basis of clinical trial contracts for the number of participants enrolled in multicenter clinical trials sponsored by Medtronic, Stryker, Cerenovus, BrainsGate, NONO Inc, and Boehringer Ingelheim (prevention only). The University of California receives grant support from the National Institutes of Health (NIH) for Dr Saver's service in leadership roles in the National Institute of Neurological Disorders and Stroke StrokeNet national clinical trial network and from Diffusion Pharma for Dr Saver's leadership role in the PHAST-TSC multicenter trial. Dr Saver reported serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr Saver received any payments for this voluntary service. Dr Saver paid for his own travel. Dr Saver reported receiving contracted hourly payments and travel reimbursement for services as a scientific consultant advising on rigorous trial design and conduct to Medtronic, Stryker, Cerenovus, BrainsGate, Boehringer Ingelheim (prevention only), NONO Inc, BrainQ, and Abbott; contracted stock options for services as a scientific consultant advising on rigorous trial design and conduct to Rapid Medical; and personal fees from Johnson & Johnson and Novo Nordisk.

      Author contributions

      Chun-Hsien Lin: acquisition of data, analysis and interpretation of data, wrote the first draft
      David S Liebeskind: critical revision of manuscript for intellectual content
      Bruce Ovbiagele: critical revision of manuscript for intellectual content
      Meng Lee; study concept and design, acquisition of data, analysis and interpretation of data, critical revision of manuscript for intellectual content
      Jeffrey Saver: study supervision, critical revision of manuscript for intellectual content

      Data sharing statement

      • No additional data are available.

      Acknowledgements

      None.

      Appendix. Supplementary materials

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