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. 2016 Dec 1;10(3):151–160. doi: 10.1177/1756285616680549

Endovascular thrombectomy with or without systemic thrombolysis?

Georgios Tsivgoulis 1,✉, Aristeidis H Katsanos 2, Dimitris Mavridis 3, Anne W Alexandrov 4, Georgios Magoufis 5, Adam Arthur 6, Valeria Caso 7, Peter D Schellinger 8, Andrei V Alexandrov 9
PMCID: PMC5349372  PMID: 28344654

Abstract

Objectives:

Current recommendations advocate that pretreatment with intravenous thrombolysis (IVT) should first be offered to all eligible patients with emergent large vessel occlusion (ELVO) before an endovascular thrombectomy (ET) procedure. However, there are observational data that question the safety and efficacy of IVT pretreatment in patients with ELVO.

Methods:

We performed a meta-analysis of the included subgroups from ET randomized controlled trials (RCTs) to evaluate the comparative efficacy between direct ET without IVT pretreatment and bridging therapy (IVT and ET) in patients with ELVO.

Results:

We included a total of seven RCTs, including 1764 patients with ELVO (52.8% men). Patients receiving bridging therapy (IVT followed by ET) had lower rates (p = 0.041) of 90-day death/severe dependency (modified Rankin Scale-score of 5–6; 19.0%, 95% CI: 14.1–25.1%) compared with patients receiving only ET (31.0%, 95% CI: 21.2–42.9%). Moreover, patients receiving IVT and ET had a nonsignificant (p = 0.389) trend towards higher 90-day functional independence rates (51.4%, 95% CI: 42.5–60.1%) compared with patients undergoing only ET (41.7%, 95% CI: 24.1–61.7%). Finally, shift-analysis uncovered a nonsignificant trend towards functional improvement at 90 days for bridging therapy over ET (cOR = 1.28, 95% CI: 0.91–1.89; p = 0.155). It should be noted that patients included in the present meta-analysis were not randomized to receive IVT, and thus the two groups (bridging therapy versus ET monotherapy) may differ in terms of baseline characteristics and, in particular, in terms of onset to groin puncture time and thus the risk of confounding bias cannot be ruled out.

Conclusion:

Despite the limitations and the risk of confounding bias, our findings contradict the recent notion regarding potential equality between ET and bridging therapy in ELVO patients and suggest that IVT and ET are complementary therapies that should be pursued in a parallel and noncompeting fashion.

Keywords: acute ischemic stroke, emergent large vessel occlusion, intravenous thrombolysis, mechanical thrombectomy, meta-analysis

Introduction

A series of recent randomized controlled trials (RCTs) has established endovascular thrombectomy (ET) as a safe and highly effective treatment for acute ischemic stroke (AIS) patients with emergent large vessel occlusion (ELVO) in the anterior circulation [Tsivgoulis et al. 2014; Badhiwala et al. 2015]. Since the vast majority (>80%) of patients with ELVO randomized in these RCTs into ET and standard therapy (ST) were pretreated with intravenous thrombolysis (IVT) [Goyal et al. 2016], current American Heart Association (AHA)/American Stroke Association (ASA) [Powers et al. 2015] and European Stroke Organisation (ESO) [Fiehler et al. 2016] recommendations advocate that pretreatment with IVT should first be offered to all eligible patients with ELVO before an ET procedure.

On the other hand, observational data from small single-center studies suggest that direct ET (without IVT pretreatment) might be equally effective to bridging therapy (IVT pretreatment followed by ET) in patients with ELVO eligible for systemic thrombolysis, and question the utility of IVT pretreatment [Kass-Hout et al. 2014; Leker et al. 2015; Broeg-Morvay et al. 2016; Weber et al. 2016]. Moreover, a recent Swiss study highlighted that pretreatment with IV tissue-plasminogen activator (tPA) in patients with ELVO undergoing ET is associated with potential side effects including higher risk of intracerebral hemorrhage, time delays for the initiation of endovascular therapy and preclusion of use of antiplatelets and heparin following tPA infusion [Broeg-Morvay et al. 2016].

In view of the former considerations, we performed a meta-analysis of the available groups included in RCTs comparing ET with stent-retrievers to ST to evaluate the comparative efficacy between direct ET and bridging therapy (IVT and ET) in patients with ELVO in terms of functional outcomes.

Methods

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses [Liberati et al. 2009]. The PRISMA checklist is provided on the online supplement. Eligible RCTs comparing ET with stent-retrievers to ST were identified by searching MEDLINE, SCOPUS and the CENTRAL Register of Controlled Trials. The following keywords were used in all database searches: ‘endovascular therapy’, ‘mechanical thrombectomy’, ‘acute ischemic stroke (AIS)’, ‘cerebrovascular ischemia’ and ‘stent-retriever’. We imposed no language or other restrictions. The last literature search was performed on 20 September 2016 by two independent reviewers (GT and AHK) and reference lists of all retrieved articles were also examined to identify studies that may have been missed by the initial database search.

In each eligible study, we employed the Cochrane Collaboration’s risk of bias tool to address potential biases, and in each quality item the corresponding risk of bias was categorized as low, high or unclear [Higgins et al. 2011]. After bias assessment, the following reported outcomes on AIS patients with ELVO randomized in the included RCTs, according to their IVT pretreatment status, were extracted for each included study protocol independently by two authors (GT, AHK):

We performed mixed-effects subgroup analyses, according to IVT pretreatment history of both FI and poor outcome at 90 days using available data from all reported RCTs of ET with stent-retrievers. The study-to-study variance (tau-squared) was assumed to be the same for all subgroups. Tau-squared was first computed within subgroups and then pooled across subgroups. Heterogeneity between studies was assessed with the Cochrane Q and I2 statistics, as per the Cochrane Handbook [Deeks et al. 2011]. We additionally performed an ordinal logistic regression analysis of individual patient data on the distribution of 3-month mRS scores (shift analysis) between IVT and non-IVT pretreated patients [Saver and Gornbein, 2009].

Statistical analyses were conducted using the Comprehensive Meta-analysis Version 2 software (Borenstein, Hedges, Higgins, Rothstein; Biostat, Englewood NJ, 2005) and the Stata Statistical Software (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP), while for the graphical representation of bias assessment we used the Review Manager (RevMan) Version 5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Results

The PRISMA flowchart is presented in Figure 1. Electronic databases searches yielded 100 eligible studies, while one other record was identified through conference proceedings searching. After removing duplicate studies, the titles and abstracts from the remaining 101 studies were screened and 9 potentially eligible studies for the meta-analysis were retained. After retrieving the full-text version of the aforementioned nine studies, two studies were excluded. More specifically, SYNTHESIS (A randomized controlled trial between locoregional intra-arterial (IA) and systemic IVT with Alteplase in AIS) was excluded, since patients without ELVO were enrolled in the trial, while patients randomized in the endovascular arm were precluded from IVT [Ciccone et al. 2013]. The IMS (Internventional Management of Stroke) III trial was excluded since the vast majority of patients randomized in the endovascular arm were treated with IA thrombolysis or with mechanical thrombectomy using first-generation devices (MERCI and PENUMBRA) [Broderick et al. 2013].

Figure 1.

Figure 1.

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Flow chart presenting the selection procedure of eligible studies.

ELVO, emergent large vessel occlusion; ET, endovascular thrombectomy; IA, intra-arterial; IVT: intravenous thrombolysis.

A total of 7 RCTs including 1,764 patients with ELVO (52.8% men) fulfilled our predefined inclusion/exclusion criteria and were included in both the quantitative and qualitative synthesis. Baseline characteristics of the 7 RCTs (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, REVASCAT, THRACE and PISTE) [Berkhemer et al. 2015; Goyal et al. 2015; Campbell et al. 2015a; Saver et al. 2015; Jovin et al. 2015; Muir et al. 2016; Bracard et al. 2016] are summarized in Table 1. All patients randomized to ET were pretreated with IVT in 4 RCTs (EXTEND-IA [Campbell et al. 2015a], PISTE [Muir et al. 2016], SWIFT-PRIME [Saver et al. 2015] and THRACE [Bracard et al. 2016]), while a total of 108 patients were randomized to ET without previous treatment with systemic thrombolysis in the remaining three trials (ESCAPE [Goyal et al. 2015], MR CLEAN [Berkhemer et al. 2015] and REVASCAT [Jovin et al. 2015]).

Table 1.

Baseline characteristics of randomized controlled trials included in the meta-analysis.

Study name Patients Mean age (years) Males (%) Median NIHSS (IQR) or (range)** ET (n, %*) IVT (n, %**)
ESCAPE 315 70.5 47.6% 16 (13–20) 165 (52%) No: 45 (27%)
Yes: 120 (73%)
EXTEND-IA 70 69.4 49% 17 (13–20) 35 (50%) Yes: 35 (100%)
MR CLEAN 500 65 58.3% 17 (14–21) 233 (47%) No: 30 (13%)
Yes: 203 (87%)
PISTE 65 65.5 44.6% 18 (6–24) 33 (51%) Yes: 33 (100%)
REVASCAT 206 66.4 52.3% 17 (14–20) 103 (50%) No: 33 (32%)
Yes: 70 (68%)
SWIFT-PRIME 196 65.7 50.5% 17 (13–20) 98 (50%) Yes: 98 (100%)
THRACE 412 62.8 53.4% 18 (15–21) 204 (49.5%) Yes: 204 (100%)
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ET, endovascular thrombectomy; IQR, interquartile range; IVT, intravenous thrombolysis; NIHSS, National Institute of Health Stroke Scale.

*

among all patients; **among patients randomized to ET.

Bias assessment (Figure 2a and 2b) was performed only in the published studies [Berkhemer et al. 2015; Campbell et al. 2015a; Goyal et al. 2015; Jovin et al. 2015; Saver et al. 2015; Bracard et al. 2016], as the full-text of one RCT was not published at the time of the literature search [Muir et al. 2016] and thus complete and accurate bias assessment for this trial was considered impossible. Selection bias was considered generally low, as, in all trials, the initial randomization of included participants to ET or ST was performed adequately. However, it should be noted that in one trial the method of ET was left to the discretion of the interventionist [Berkhemer et al. 2015], while in two other trials the neurointerventionalists used not a single, but every available thrombectomy device to achieve reperfusion [Goyal et al. 2015; Bracard et al. 2016]. Even though there is a theoretical risk of introducing unmeasured biases both within subgroup and across subgroups in these trials, we considered that the aforementioned approaches were dictated by technical issues and thus were unlikely to introduce systematic biases.

Figure 2.

Figure 2.

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Risk of bias (a) summary that reviews authors’ judgments about each risk of bias item for each included study and (b) graph that reviews authors’ judgments about each risk of bias item presented as percentages across all included studies.

As all studies reported open-label treatment with blinded end-point evaluation (PROBE design), we considered that the outcome measure was likely not influenced by the lack of double blinding. Industry financial support was reported in all trials, except for two trials reporting mainly public financial support (Figure 2(a) and (b)) [Berkhemer et al. 2015; Bracard et al. 2016].

Patients treated with bridging therapy had significantly (p = 0.041) lower rates of 90-day death or severe dependency (19.0%, 95% CI: 14.1–25.1%), in comparison with patients treated only with ET (31.0%, 95% CI: 21.2–42.9%; Figure 3). There was substantial heterogeneity (for the outcome of 90-day mRS 5–6) in the subgroup analysis of patients treated with bridging therapy (I2 = 68.5%, p for Cochrane Q = 0.004), while we detected no significant heterogeneity in the subgroup analysis of patients treated only with ET (I2 = 33.7%, p for Cochrane Q = 0.221). Patients receiving IVT and ET had a nonsignificant (p = 0.389) trend towards higher 90-day functional independence rates (51.4%, 95% CI: 42.5–60.1%) compared with patients undergoing only ET (41.7%, 95% CI: 24.1–61.7%, Figure 4). We detected significant heterogeneity (for the outcome of 90-day mRS 0-2) both in the subgroup analysis of the bridging therapy group (I2 = 81%, p for Cochrane Q < 0.001) and for the subgroup analysis of the ET monotherapy group (I2 = 75%, p for Cochrane Q = 0.018). Finally, shift analysis uncovered no significant difference for bridging therapy over ET alone in terms of functional improvement at 90 days (common OR = 1.28, 95% CI: 0.91–1.89, p = 0.155, Figure 5).

Figure 3.

Figure 3.

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Subgroup analyses of the percentages of patients with death or severe dependency (three-month mRS-scores of 5–6) stratified by pretreatment with IVT. All patients were randomized in the ET group of the included seven randomized controlled clinical trials.

ET, endovascular thrombectomy; IVT, intravenous thrombolysis;

Figure 4.

Figure 4.

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Subgroup analyses of the percentages of patients with functional independence (3-month mRS-scores of 0–2) stratified by pretreatment with IVT. All patients were randomized in the ET group of the included seven randomized controlled clinical trials.

ET, endovascular thrombectomy; IVT, intravenous thrombolysis;

Figure 5.

Figure 5.

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Distribution of mRS scores at 90 days in patients randomized in the ET group of the included seven randomized controlled clinical trials, stratified by pretreatment with IVT.

ET, endovascular thrombectomy; IVT, intravenous thrombolysis.

Discussion

The results of the present meta-analysis suggests that pretreatment with IVT prior to initiation of ET in patients with ELVO may be associated with lower rates of death or severe dependency at three months. These findings contradict the recent observational, single-center studies [Kass-Hout et al. 2014; Leker et al. 2015; Broeg-Morvay et al. 2016; Weber et al. 2016] reporting potential equality between ET and bridging therapy in patients with ELVO.

Bridging therapy with IVT and ET may be associated with important benefits including tPA-induced fibrin degradation leading to easier detachment of a clot from the vessel wall with the stent-retriever, potential augmentation of the collateral circulation (which is known to be related with higher revascularization rates and better functional outcomes in patients treated with endovascular reperfusion therapies) and recanalization of distal thrombi located in small vessels that are not accessible to endovascular devices [Barreto, 2011; Grotta and Hacke, 2015]. However, an important caveat exists in the interpretation of our findings. Our results only support the use of systemic thrombolysis prior to ET in IVT eligible patients and do not support pretreatment with IVT as a necessary inclusion criterion to select patients with ELVO for ET. On the contrary, our previous meta-analysis [Tsivgoulis et al. 2016b] coupled with the findings of an individual patient data meta-analysis of 5 RCTs that has recently been reported by a Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration [Goyal et al. 2016] strongly advocates the efficacy of ET in comparison to ST in patients who are ineligible for IVT.

On the one hand, bridging therapy should be regarded as an imperative option in cases of insuperable groin puncture delays, but on the other IVT pretreatment should not be used as an excuse to delay prompt ET initiation in cases of ELVO patients arriving directly to a comprehensive stroke center. In addition, direct ET could probably emerge as a more attractive therapeutic option compared with bridging therapy in certain patient subgroups or clinical settings such as:

  • (1) ICA occlusion with need for stenting during the endovascular treatment [Mokin et al. 2012];

  • (2) high thrombus burden in tandem ICA/MCA occlusions [Dorn et al. 2016] that have a very low probability of successful recanalization with IVT [Tsivgoulis et al. 2015c];

  • (3) patients with cumulative relative contraindications to IVT, e.g. anticoagulant pretreatment with an international normalized ratio of less than 1.7, novel oral anticoagulant intake within 48 h [Jauch et al. 2013] or patients already on double antiplatelet therapy [Anderson et al. 2016] and

  • (4) elderly patients with high cerebral microbleed burden (>10) on pretreatment emergent MRI scan [Tsivgoulis et al. 2016c].

Certain limitations in the present report need to be acknowledged. First and most important, patients treated with ET that were included in the present meta-analysis were not randomized to receive IVT and placebo. Consequently, the two groups (bridging therapy versus ET monotherapy) may differ in terms of baseline characteristics and in particular in terms of onset to groin puncture time and thus risk of confounding bias cannot be ruled out. An unbiased comparison is impossible without randomized individual patient data, since only then IVT eligible patients undergoing direct ET could be directly compared with those receiving bridging therapy. Second, substantial heterogeneity was detected for both outcome variables (mRS scores 0–2 and mRS scores 5–6) in the bridging therapy group across the seven included trials. The presence of the aforementioned heterogeneity may partly be explained by potential differences in baseline characteristics between the two groups. Third, the ET monotherapy group was substantially smaller (n = 108) than the bridging therapy group (n = 763) and this different sample size may lead to confounding results.

In view of the former methodological shortcomings the present report may serve only for hypothesis generation and for potential sample size estimation of a future RCT that will compare directly bridging therapy to ET alone. According to the findings of this analysis, and assuming a randomization ratio of 1:1 between bridging therapy and ET groups with an alpha of 0.05 and 80% power, a total sample of 408 patients would be needed to detect a 12% absolute difference (Number Needed to Harm = 8) in 90-day death or severe dependency and 962 patients would be necessary to detect a 9.7% absolute difference (number needed to treat = 10) in functional independence at 90 days. Within the setting of such a RCT an additional subgroup analysis among anterior circulation, ELVO patients could also be of particular importance, since patients with middle cerebral artery or internal carotid artery occlusions might exhibit different risks and benefits from IVT regarding both hemorrhagic transformation and distal embolization risks.

Until the results from such RCTs become available, we consider that all tPA-eligible patients with ELVO should receive IVT pretreatment according to current international recommendations [Powers et al. 2015; Fiehler et al. 2016], without delaying access to ET. On the other hand, contraindication to IVT should not be used as an argument to preclude ET from patients with ELVO who are otherwise eligible for endovascular reperfusion therapy. In the new era of acute stroke treatment, IVT and ET are complementary therapies that should be pursued and administered in parallel in a swift and noncompeting fashion [Campbell et al. 2015b; Tsivgoulis et al. 2016d].

Footnotes

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Georgios Tsivgoulis has been supported by the European Regional Development Fund – Project St Anne’s University Hospital, Brno – International Clinical Research Center (FNUSA-ICRC) (No. CZ.1.05/1.1.00/02.0123). Dr Adam Arthur has received research support from Penumbra, Sequent and Siemens, Inc. Dr Peter Schellinger received honoraria and travel grants from Boehringer Ingelheim, Sanofi, Bayer, BMS, Pfizer, Daiichi, Navigant, Reneuron, and Covidien

Conflict of interest statement: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Adam Arthur has served as a consultant for Medtronic, Microvention, Penumbra, Sequent, Siemens and Stryker, Inc.

Contributor Information

Georgios Tsivgoulis, Second Department of Neurology, Attikon University General Hospital, School of Medicine, University of Athens, Iras 39, Gerakas Attikis, Athens, 15344, Greece.

Aristeidis H. Katsanos, Second Department of Neurology, Attikon University General Hospital, School of Medicine, University of Athens, Athens, Greece Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece

Dimitris Mavridis, Department of Primary Education, University of Ioannina, Ioannina, Greece Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.

Anne W. Alexandrov, Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA Australian Catholic University, Sydney, Australia

Georgios Magoufis, Acute Stroke Unit and Department of Interventional Neuroradiology, Metropolitan Hospital, Piraeus, Greece.

Adam Arthur, Department of Neurosurgery, Semmes-Murphey Neurologic and Spine Institute, University of Tennessee Health Science Center, Memphis, TN, USA.

Valeria Caso, Stroke Unit, University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy.

Peter D. Schellinger, Departments of Neurology and Neurogeriatry, Johannes Wesling Medical Center, Minden, Germany

Andrei V. Alexandrov, Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

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