Bridging therapy (the combination of intravenous [IV] and

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1 Bridging Therapy in Acute Ischemic Stroke A Systematic Review and Meta-Analysis Mikael Mazighi, MD, PhD; Elena Meseguer, MD; Julien Labreuche, BS; Pierre Amarenco, MD Background and Purpose Pending the results of randomized controlled trials, the benefit and safety of bridging therapy (combined intravenous and intra-arterial thrombolysis) remain to be determined. The aim of this analysis was to give reliable estimates of efficacy and safety outcomes of bridging therapy. Methods We conducted a systematic review of all studies using bridging therapy published between January 1966 and March Results The literature search identified 15 studies. The pooled estimate for recanalization rate was 69.6% (95% CI, 63.9% 75.0%). Meta-analysis on clinical outcomes showed a pooled estimate of 48.9% (95% CI, 42.9% 54.9%) for favorable outcome, 17.9% (95% CI, 12.7% 23.7%) for mortality, and 8.6% (95% CI, 6.8% 10.6%) for symptomatic intracranial hemorrhage. In meta-regression analysis, the shorter mean time to intravenous treatment, the greater the recanalization rate (per 10-minute decrease: OR, 1.24; 95% CI, ) and the lower mortality rate (per 10-minute decrease: OR, 0.75; 95% CI, ). By using the control groups of intravenous alteplase-treated patients in 8 studies, bridging therapy was associated with a favorable outcome (OR, 2.26; 95% CI, ), but no differences in mortality or symptomatic intracranial hemorrhage outcomes were found. Conclusions Bridging therapy is associated with acceptable safety and efficacy in stroke patients. Time to intravenous treatment is critical to improve recanalization rates and favorable outcomes. (Stroke. 2012;43: ) Key Words: acute stroke alteplase combined thrombolysis bridging therapy endovascular therapy meta-analysis recombinant tissue plasminogen activator Bridging therapy (the combination of intravenous [IV] and intra-arterial [IA] thrombolysis) is part of the therapeutic armamentarium in the daily practice of several stroke centers. As time to recanalization has emerged as a new goal in acute stroke care, 1,2 combining the speed of IV alteplase administration and the higher recanalization rates of the IA route 3,4 is a relevant approach. Controlled studies have reported the feasibility and efficacy of bridging therapy in terms of recanalization rates, 1 but a positive clinical impact has only been observed in a select population of IV alteplase nonresponder patients. 5 These findings raise the question of the target population for bridging therapy. It is not yet clear whether it should only be considered for IV alteplase nonresponder patients, or whether the small sample size of the other studies is the main explanation for the absence of any significant clinical benefit. In the study showing a significant favorable outcome at 3 months, higher morbidity and mortality were associated with bridging therapy, with higher symptomatic hemorrhage and death rates. 5 Beyond recanalization rates, favorable clinical outcomes and safety need to be assessed. Pending the results of an ongoing randomized controlled trial 6 comparing the bridging approach with IV alteplase administration (the unique recommended therapy for patients with acute ischemic stroke), bridging therapy is considered an investigational technique. We therefore conducted a systematic review of all studies that used bridging therapy in acute ischemic stroke patients to describe this practice and to give reliable estimates of efficacy and safety outcomes of this therapeutic approach. Materials and Methods Search Strategy and Study Selection We identified all observational and interventional studies published between January 1996 and March 2011 that reported recanalization or clinical outcomes in acute ischemic stroke patients treated by a combined IV/IA strategy. We searched the PubMed database using the following search terms: thrombolysis; thrombolytic; fibrinolysis; tissue plasminogen activator; endovascular; intra-arterial; and intravenous in combination with stroke. Searches were restricted to Received August 9, 2011; accepted January 9, Louis Caplan, MD, was the Guest Editor for this paper. From the INSERM U-698 (M.M., J.L., P.A.), Clinical Research in Atherothrombosis, and Denis Diderot University (M.M., E.M., P.A.), Paris VII, Neurology and Stroke Department, Hôpital Bichat, Paris, France. The online-only Data Supplement is available with this article at STROKEAHA /-/DC1. Correspondence to Mikael Mazighi, Department of Neurology and Stroke Centre, Bichat University Hospital, 46, rue Henri Huchard, Paris, France. mikael.mazighi@bch.aphp.fr 2012 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Mazighi et al Bridging Therapy Meta-Analysis 1303 studies published in English and conducted in humans. One author (J.L.) selected potentially relevant articles based on title and abstract and obtained the full text for detailed review. We also searched the reference lists of retrieved articles and published review articles for additional studies. Studies were selected using the following criteria: (1) involving acute ischemic stroke patients aged 18 years or older eligible for IV treatment; (2) reporting numbers (or percentages) of recanalization or clinical outcomes in acute ischemic stroke patients treated by a combined IV/IA approach; and (3) retrospective or prospective studies with 10 patients treated by a combined IV/IA approach. We did not select studies according to treatment strategy, bridging therapy protocol, or the reported clinical outcome definitions. We also screened duplicate publications based on the same datasets (ie, when data overlapped with data in other included studies); only the publications with the most complete data were included. Data Extraction Data were independently extracted by 2 authors (J.L. and M.M.) using a standardized form and any disagreement was resolved by consensus. We did not contact the authors of the studies to request incomplete or unpublished data. The following data were collected: report characteristics (first author s name, journal, year of publication); study design (country, study period, number of centers, retrospective/prospective analysis, bridging therapy protocol [indication for IA therapy, IV agents, and dose, type of IA approach, including number of patients treated by chemical thrombolysis and those treated by mechanical revascularization therapy]); study sample (sample size, age, sex, admission National Institutes of Health Stroke Scale [NIHSS], location of the clot, time from symptom onset to IV treatment, time from symptom onset to conventional angiography, time from symptom onset to IA treatment); and data on and definitions of outcomes (recanalization, favorable functional outcome, mortality, symptomatic intracranial hemorrhage [sich]). We differentiated 2 types of bridging therapy protocol according to the indication for use of IA treatment: rescue bridging therapy (defined as the use of IA treatment in case of failure of IV therapy based on worsening clinical condition or an absence of clinical improvement) or direct bridging therapy (defined as a prespecified therapeutic approach independently of clinical status after IV therapy initiation). We did not consider in the study sample patients who were eligible for bridging therapy but did not receive IA therapy; the reasons for not receiving IA treatment were noted. We classified target vessels into 2 groups according to the presence or absence of isolated middle cerebral artery (MCA) occlusion. For studies with a control group of patients treated with IV treatment alone, we also extracted the clinical outcome among controls to provide information on the treatment benefit-to-risk ratio of a combined IV/IA strategy. Clinical Outcome Definitions Clinical outcomes included a favorable functional outcome, mortality, and sich. The preferred definition was a modified Rankin score of 0 to 2 at 90 days for favorable functional outcome, all cause death at 90 days for mortality outcome, and hemorrhage on the follow-up CT/MRI scan associated with an increase of 4 points in NIHSS score for sich outcome, as performed in the ongoing randomized trial. 6 When the preferred definition was not available, the authors definition was adopted. Statistical Analysis In order to determine the pooled proportions of different outcomes (recanalization, functional outcome, mortality, and sich), we first transformed individual proportions into a quantity using the Freeman-Tukey variance stabilizing arcsine transformation. 7 For all outcomes, we quantified the between-study heterogeneity using a homogeneity test based on Cochran Q statistics and by calculating the I 2 statistics. Because we anticipated a large heterogeneity, considering the absence of recommendations for the use of bridging therapy, the DerSimonian-Laird random-effects model 8 was used to pool the transformed proportions, followed by a back-transformation to provide the pooled proportion in the original scale. For each clinical outcome, we performed a sensitivity analysis by restricting the meta-analysis to the studies using the same definition used in the ongoing randomized controlled trial. 6 To explore potential sources of heterogeneity, we performed univariate meta-regression analyses using logistic-normal random models. 9 The following study-level covariates were examined: indication for bridging therapy (direct versus rescue); use of mechanical revascularization as adjunctive IA treatment; mean time to IV treatment; IV dose (0.9 mg versus 0.6 mg); mean age; proportion of men; mean admission NIHSS score; and rate of isolated MCA occlusion. For studies using a case-control design, we calculated the OR of clinical outcomes using the control group of patients treated with IV treatment alone as the reference. Because the Interventional Management of Stroke (IMS) I and II studies 10,11 used the same selected historical group of National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (alteplase)-treated patients with baseline NIHSS score 10, we used the pooled Interventional Management of Stroke I/II data to calculate the individual OR. Individual OR were combined using the DerSimonian and Laird random-effect model. Sensitivity analyses were performed by excluding studies using a control group with IV responders. Statistical testing was conducted at the 2-tailed -level of 0.05, except for tests for homogeneity in which -level of 0.10 was chosen. Data were analyzed using the SAS software version 9.1 (SAS Institute, Cary, NC) and Cochrane Collaboration s Review Manager software package (RevMan edition 4.2.7). Results The literature search identified citations. After reviewing the titles and abstracts, 45 articles were read in full, and 15 were judged eligible for inclusion (online-only Supplemental Figure I, The main methodological and baseline characteristics of included studies are presented in Table 1. 1,5,10 22 Eleven (73%) of the included studies were single-center studies. Three of the 4 multicenter studies were pivotal trials on a combined IV/IA approach (1 using phase 1 design 22 and 2 using single-arm design 10,11 ). The remaining multicenter study was an ancillary analysis of pooled data from 2 single-arm trials and was designed to assess the safety and efficacy of a mechanical retrieval device. 13 A prospective data collection was clearly specified in 9 studies 1,5,10,11,13,16,17,20,22 and an independent determination of neurological outcomes was specified in 5 studies. 11,14,17,21,22 Overall, the 15 studies included 559 stroke patients treated with a combined IV/IA approach. Study durations ranged from 10 months 10 to 8 years. 18 As shown in Table 1, various bridging therapy protocols were used. Eight of the studies had a direct protocol, whereas 7 used rescue therapy. All but 1 of the studies used IV alteplase treatment at a dose of 0.6 or 0.9 mg/kg. Eleven studies used IA lysis (different agents and doses) as first-line adjunctive treatment, 5 of which used additional mechanical revascularization. In 2 of the remaining 4 studies, the choice of IA therapy was at the discretion of the neurointerventionalist. 5,15 Baseline patient characteristics varied across the studies as shown in Table 1. The mean time to IV treatment ranged from 110 minutes 16 to 165 minutes. 5 Among the 13 studies with available data on clot location, the most frequent target vessel was the MCA (63% of cases), with a rate range of 43% to 100%. The outcomes of the individual studies are reported in Table 2. When studies were

3 1304 Stroke May 2012 Table 1. Design and Baseline Characteristics of Included Studies Source, Y Country (Centers) and Study Period Rubiera, Spain (single center) Bonvin, Switzerland (single center) Shi, North America (multicenter) Kim, Korea (single center) Mazighi, France (single center) Burns, United States (single center) Sugiura, Japan (single center) Wolfe, United States (single center) IMS II, North America (multicenter) Shaltoni, United States (single center) Flaherty, United States (single center) Sample Size Indication Bridging Therapy Protocol IV Alteplase Dose, mg IA Therapy 42 Rescue 0.9 rtpa ( 20 mg) and/or clot disruption and/or clot retrieval 30 Rescue 0.5 rtpa ( 0.4 mg/kg) clot retrieval (n 8) 48 Rescue 0.9 or 0.6 Clot retrieval rtpa (n 17) 18 Rescue 0.9 Clot disruption and urokinase ( U) 50 Direct 0.6 rtpa (0.3 mg/kg) clot retrieval (n 20) 33 Direct 0.9 Reteplase (n 14) and/or clot disruption and/or clot retrieval (n 25) 16 Direct 0.6 rtpa ( 10 mg) and clot disruption 41 Rescue 0.6 rtpa (0.3 mg/kg) clot disruption Mean Age, Y Men, % Mean Baseline NIHSS Onset to IV Treatment Interval Times, min Onset to Arteriography Onset to IA Occlusion, Isolated MCA, % * * * * Direct 0.6 rtpa (0.3 mg/kg) Rescue 0.9 Reteplase ( 6 U)or alteplase or urokinase clot disruption (n 52) * Direct 0.6 rtpa (0.3 mg/kg) * 129* Lee, Korea (single center) 21 mo 16 Rescue 0.9 Urokinase ( U) IMS I, North America (multicenter) 2001 Suarez, United States (single center) EMS, United States (multicenter) Total or weighted mean 62 Direct 0.6 rtpa (0.3 mg/kg) * Direct 0.6 rtpa (0.3 mg/kg) or urokinase ( U) * Direct 0.6 rtpa (0.3 mg/kg) * 156* EMS indicates Emergency Management of Stroke; IA, intra-arterial thrombolysis; IMS, Interventional Management of Stroke; IV, intravenous thrombolysis; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; rtpa, recombinant tissue-type plasminogen activator (alteplase). *Values are median. Data available for all eligible patients (n 81 for IMS II; n 62 for Flaherty; n 80 for IMS I; n 17 for EMS).

4 Mazighi et al Bridging Therapy Meta-Analysis 1305 Table 2. Rates of Recanalization and Clinical Outcomes in the Included Studies Recanalization Source, Y Any Complete Favorable Outcome Mortality sich Rubiera, (59.5) 10 (23.8) 18 (42.9)* 19 (45.2)* 5 (11.9)* Bonvin, (56.7) 8 (26.7) 13 (43.3)* 0* 1 (3.3)* Shi, (72.9) (37.8)* 13 (27.1)* 5 (10.4)* Kim, (88.9) 12 (66.7) 12 (66.7) 1 (5.6) 1 (5.6)* Mazighi, (86.0) 34 (68.0) 27 (54.0)* 9 (18.0)* 5 (10.0)* Burns, (72.7) 13 (39.4) 11 (33.3) 4 (12.1)* 4 (12.1)* Sugiura, (87.5) 7 (43.8) 10 (62.5) 1 (6.3)* 0 Wolfe, (65.9) 12 (29.3) 19 (46.3)* 11 (26.8)* 5 (12.2)* IMS II, (60.0) 2 (3.6) 21 (38.2)* 13 (16.0)* 8 (9.9)* Shaltoni, (72.5) (55.1) 12 (17.4) 4 (5.8) Flaherty, (59.1) 10 (22.7) 20 (45.5)* 10 (22.7)* 5 (11.4)* Lee, (75.0) 9 (56.3) 11 (68.8)* 1 (6.3)* 1 (6.3)* IMS I, (56.5) 7 (11.3) 25 (40.3)* 11 (17.8)* 5 (6.3)* Suarez, (75.0) 9 (37.5) 19 (79.2) 4 (16.7) 0* EMS, (81.8) 6 (54.5) 5 (45.5)* 3 (27.3)* 2 (18.2) Values are n (%). EMS indicates Emergency Management of Stroke; IMS, Interventional Management of Stroke; sich, symptomatic intracranial hemorrhage. *Indicates that the clinical outcomes were defined by the same criteria applied in the ongoing randomized controlled trial. 6 Data available for all eligible patients (n 81 for IMS II; n 80 for IMS I). combined, the pooled estimate for recanalization rates (partial or complete) was 69.6% (95% CI, 63.9% 75.0%; Table 3). When only complete recanalization rates were considered (13 studies), this decreased to 35.1% (95% CI, 23.0% 48.2%). Results of the meta-analysis on clinical outcomes are shown in Table 3. A large heterogeneity across studies was found for recanalization, favorable, and fatal outcomes. Similar results were found in sensitivity analyses restricted to studies that used the same clinical outcome definition than Interventional Management of Stroke III trial 6 (Table 3); in this analysis, no heterogeneity was found for favorable outcome. In univariate meta-regression analyses (Table 4), the time to IV treatment impacted significantly the recanalization and Table 3. Pooled Rates of Recanalization and Clinical Outcomes mortality rates. The lower the mean time to IV treatment, the greater the recanalization rate (OR per 10 minutes decrease, 1.24; 95% CI, ) and lower the mortality rate (OR per 10 minutes decrease, 0.75; 95% CI, ). Recanalization was also positively related to the rate of patients treated for isolated MCA occlusion (P 0.011). Mortality was also positively impacted by higher mean study age (P 0.002) and NIHSS score (P 0.063). In addition, rate of patients treated for isolated MCA occlusion and baseline NIHSS score were identified as source of heterogeneity for favorable outcome. The rate of patients with favorable outcome increased with increasing rate of patients treated for isolated MCA occlusion (OR per 10% increase, 1.29; 95% CI, Outcome Studies, n Patients, n Pooled Rates (95% CI) P Value* I 2,% Main analysis Partial or complete recanalization ( ) Complete recanalization ( ) Favorable outcome ( ) Mortality ( ) sich ( ) Sensitivity analysis Favorable outcome ( ) Mortality ( ) sich ( ) CI indicates confidence interval; sich, symptomatic intracranial hemorrhage. *P associated with 2 test for heterogeneity. Including patients eligible for bridging therapy not treated by intra-arterial therapy from Interventional Management of Stroke trials. Restricted to studies with clinical outcome closest to the Interventional Management of Stroke III definition. 6

5 1306 Stroke May 2012 Table 4. Impact of Study-Level Covariates* on Recanalization and Clinical Outcomes in Univariate Meta-Regression Analyses Outcome Study-Level Covariates Partial or complete recanalization Studies, n OR (95% CI) P Value Mean time to IV treatment ( ) Rate of isolated MCA ( ) occlusion Favorable outcome Rate of isolated MCA ( ) occlusion Mean baseline NIHSS ( ) Mortality Mean age ( ) Mean time to IV treatment ( ) Mean baseline NIHSS ( ) CI indicates confidence interval; IV, intravenous thrombolysis; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio. *Only sources of heterogeneity at P 0.10 are reported. OR calculated per 10-min decrease in mean time to IV treatment. OR calculated per 10% increase in the rate of isolated MCA occlusion. OR calculated per 1-point increase in mean baseline NIHSS. OR calculated per 10-y increase in mean age ) and with decreasing NIHSS score (OR per 1-point increase, 0.89; 95% CI, ). Eight studies compared the clinical outcomes of patients treated with IV/IA or IV treatment alone (online-only Supplemental Table I shows definitions and baseline characteristics of the control groups). Among them, the same selected historical group of Neurological Disorders and Stroke alteplase-treated patients was used in the 2 single-arm pivotal trials. 10,11 The combined analyses showed a significant crude difference in favorable outcome between IV/IA-treated and IV-treated patients (OR, 2.26; 95% CI, ; Figure A), with a high heterogeneity across studies (I 2 74%) mainly attributable to different control group definitions. After excluding the 2 studies using a control group with IV responders, 12,14 the combined OR was unchanged (2.20; 95% CI, ; Figure 1A). No differences in mortality or sich outcomes were found (Figure 1B, 1C). Discussion In this meta-analysis, pooled estimates associated with bridging therapy were 69.6% for recanalization rates, 48.9% for favorable outcome, 17.9% for mortality, and 8.6% for sich. Although these positive efficacy and safety findings favor the bridging therapy approach, the heterogeneity of patient populations included in the studies and the variability in IA techniques limit definitive conclusions. Heterogeneity is illustrated by IV recombinant tissue plasminogen activator dose before endovascular therapy. This point is critical to define the optimal recombinant tissue plasminogen activator regimen for combined IV and IA thrombolysis (ie, 0.9 mg/kg or 0.6 mg/kg). A previous meta-analysis suggested that 0.9 mg/kg IV recombinant tissue plasminogen activator before IA thrombolysis is safe and may be associated with higher recanalization rates and better functional outcome at 3 months. 23 In the present meta-analysis, no difference was found between the 2 dosages (ie, 0.9 mg/kg or 0.6 mg/kg) in respect to recanalization, functional outcome, mortality, or sich (all P 0.50). The sich rates were similar to those observed in PROACT-II 24 but superior to those in IV trial or registries (such as Neurological Disorders and Stroke trial 25 or SITS-ISTR registry 26 ), in which sich rates were reported, respectively, 10%, 6%, and 2.5%. The population who underwent bridging therapy included patients with documented large artery occlusions, which was not the case in the Neurological Disorders and Stroke trial 25 or SITS-ISTR registry. 26 Also, the stroke severity was different, as illustrated by the median baseline NIHSS score, which was 9 in the Neurological Disorders and Stroke trial, in the SITS-ISTR registry, 26 and 17 in this meta-analysis. As reported for IV alteplase studies, 27 time to IV treatment impacted significantly on recanalization and mortality rates. Shorter time to IV treatment improved both the recanalization rate (OR per 10-minute decrease, 1.24; 95% CI, ) and the mortality rate (OR per 10-minute decrease, 0.75; 95% CI, ). These findings are crucial with respect to the variability of the time to IV alteplase therapy. In the studies included in the meta-analysis, time to IV alteplase administration varied from 110 to 165 minutes, showing the need to establish precise goals for time to treatment administration. Although recanalization should be achieved as soon as possible, 1 the timing for endovascular therapy initiation after IV therapy remains to be assessed. Clot lysis is a timeconsuming process and if patients are taken too early for IA, they may not be given enough time to recanalize with IV alone and may be potentially exposed to an excessive risk. A recent meta-analysis on thrombectomy in acute ischemic stroke patients 4 showed that patients presenting with isolated MCA occlusion and treated with thrombolysis achieved higher recanalization rates and best clinical outcomes. In our meta-analysis, the rate of favorable outcome increased with an increasing rate of patients treated for isolated MCA occlusion (OR per 10% increase, 1.29; 95% CI, ). This suggests that patients with isolated MCA occlusion are probably good candidates for bridging therapy, and not only those who are IV alteplase nonresponders. 5 The suspected higher morbidity and mortality associated with bridging therapy 5 was not confirmed in this meta-analysis. In fact, no differences in mortality or sich were observed between bridging therapy and IV alteplase-treated patients. Furthermore, in the analysis restricted to the 8 studies with IV alteplase control groups, patients treated with bridging therapy experienced a better clinical outcome (OR, 2.26; 95% CI, ). Our study has several potential limitations. First, it is possible that some relevant studies were not taken into account because we limited the literature search to reports published in English. In addition, we analyzed various small observational studies in which heterogeneity in the quality of data may be an issue. Because of the limitations of metaregression analysis on aggregated data, 28 the impact of time to IV treatment and occlusion site on outcomes should be

6 Mazighi et al Bridging Therapy Meta-Analysis 1307 Figure. Crude Odds Ratios of Favorable (A), Mortality (B), and sich (C) Outcomes for Comparisons Between IV/IA- and IV-Treated Patients in Individual and Combined studies. *Excluding studies using a control group with IV responders. 12,14 Including patients eligible for bridging therapy not treated by IA therapy from IMS trials. CI indicates confidence interval; IA, intra-arterial thrombolysis; IMS, Interventional Management of Stroke; IV, intravenous thrombolysis; sich, symptomatic intracranial hemorrhage; OR, odds ratio. interpreted with caution and should be replicated using individual data. Similarly, the post hoc meta-analysis of comparisons of efficacy and safety of bridging therapy with IV alteplase alone should also be interpreted with caution. The major limitations of this analysis were the use of comparative case reports, the lack of adjustment on baseline case-control differences, and the limited statistical power. Finally, beyond time to recanalization, other factors may influence clinical prognosis, such as ASPECTS score and collateral flow. The lack of data on the latter parameters in the majority of the analyzed studies is certainly a limit in the evaluation process of combined IV/IA thrombolysis. Conclusions Pending the results of ongoing randomized trials, such as Interventional Management of Stroke III, the results from this meta-analysis support bridging therapy as a therapeutic approach in patients with documented arterial occlusion. Patients with isolated MCA occlusions are probably the best candidates, but the present findings reinforce the need to shorten the time to treatment and, in this context, the additional IA approach probably should be started as soon as possible and not considered only as a rescue strategy. Acknowledgments Sophie Rushton-Smith, PhD, provided editorial assistance on the final version of this manuscript. Sources of Funding This study was supported by a grant from the SOS-ATTAQUE CEREBRALE association. None. Disclosures References 1. Mazighi M, Serfaty JM, Labreuche J, Laissy JP, Meseguer E, Lavallee PC, et al. Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study. Lancet Neurol. 2009;8: Khatri P, Abruzzo T, Yeatts SD, Nichols C, Broderick JP, Tomsick TA, et al. Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. Neurology. 2009;73: Mazighi M, Labreuche J. Bridging therapy in acute ischemic stroke: are we ready for a new standard of care? Stroke. 2011;42: Rouchaud A, Mazighi M, Labreuche J, Meseguer E, Serfaty JM, Laissy JP, et al. Outcomes of mechanical endovascular therapy for acute ischemic stroke: a clinical registry study and systematic review. Stroke. 2011; 42: Rubiera M, Ribo M, Pagola J, Coscojuela P, Rodriguez-Luna D, Maisterra O, et al. Bridging intravenous-intra-arterial rescue strategy

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