Endovascular thrombectomy (EVT) has become a standard treatment for acute ischemic stroke patients caused by a large vessel occlusion in the anterior circulation (1–3). A subsequent analysis of individual patient data from five randomized trials showed that the effect of EVT was not influenced by prior intravenous thrombolysis (IVT), raising the question of whether treatment with IVT before EVT is still necessary (3). A post hoc analysis of the Solitaire With the Intention for Thrombectomy (SWIFT) and Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR) studies indicates that EVT combined with standard alteplase treatment does not appear to provide a clinical benefit over EVT alone (4). In contrast, a meta-analysis of 13 studies suggested a better functional outcome, lower mortality, and higher rate of successful recanalization in patients treated with EVT and bridging IVT (5). However, in these 13 studies, a substantial number of patients with stroke received EVT alone who are not eligible for IVT due to unknown onset of stroke symptoms or contraindications to IVT. The eligibility for IVT may lead to group imbalances in stroke etiology, risk factors, and time to treatment. Thus, to eliminate the confusion about the eligibility for IVT between groups, the benefit and risk of direct EVT vs. EVT with prior IVT should be determined for patients with stroke who are eligible for IVT. To test the hypothesis that EVT alone was non-inferior to combined IVT and EVT in patients with a large vessel occlusion in the anterior circulation treated within 4.5 h of onset, three recent large randomized controlled trials were conducted (6–8). In this study, we intended to conduct a meta-analysis including complete results from recently published randomized controlled trials to compare effectiveness and safety between direct EVT and bridging therapy (EVT with prior IVT) for acute ischemic stroke with large vessel occlusions. Both included patients in direct EVT and bridging therapy groups who had no contraindications to IVT. Our results may provide more pieces of evidence to develop best practice guidelines for patients with acute ischemic stroke with large vessel occlusions.

This systematic review and meta-analysis was conducted using a pre-specified protocol following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (9).

In this meta-analysis, we comprehensively compared direct EVT vs. EVT with prior IVT for a large sample of acute ischemic stroke patients caused by a large vessel occlusion in the anterior circulation within 4.5 h from onset. We found that EVT with prior IVT does not appear to provide a functional outcome at 3 months over direct EVT for acute ischemic stroke patients who were eligible for treatment with both IVT and EVT. In addition, compared with direct EVT, the combination of IVT and EVT was non-inferior concerning early recanalization and reperfusion [TICI score 2b/3 after EVT or its equivalents], sICH, mortality at 90 days, 3-month excellent outcome (mRS 0–1).

Our findings are in contrast with the results of previous retrospective studies that reported worse functional outcomes in patients experiencing an acute ischemic stroke due to a large vessel occlusion who received general EVT alone compared with those who EVT with prior IVT (13–15). Previous meta-analysis studies also have examined differences between EVT with prior IVT vs. EVT alone, which have observed a trend toward higher rates of functional independence and successful recanalization among patients treated with IVT + EVT compared with patients treated only with EVT (5, 16, 17). In contrast to the aforementioned studies, a patient-level, pooled, post hoc analysis of the SWIFT and STAR studies revealed that treatment of patients experiencing an acute ischemic stroke due to a large vessel occlusion with IVT before EVT does not appear to provide a clinical benefit over EVT alone (4). However, there were important imbalances regarding inclusion criteria between groups in these studies, which make the data somewhat difficult to interpret. Most of the patients received EVT alone with contraindications for IVT treatment, including an extended period after known symptom onset, the unknown onset of stroke symptoms, or contraindications to IVT. Furthermore, to find randomized evidence to support or refute the role of IVT + EVT compared with EVT alone for patients with acute ischemic stroke, pooled analyses of randomized studies were conducted and attempted to resolve this issue, while the conclusions of these studies were also based on patients with contraindications to Tissue Plasminogen Activator (tPA), thus increasing the risk for bias and confounding. In consist with the results of our study, a meta-analysis conducted by Kaesmacher et al., which used only Recombinant Tissue Plasminogen Activator (rt-PA)–eligible patients did not find any benefit of EVT alone over EVT with prior intravenous alteplase (18). However, a common limitation of the aforementioned studies was that these meta-analyses pooled data mainly from retrospective cohort studies where the choice of EVT alone or EVT with prior intravenous alteplase for a given patient experiencing an acute ischemic stroke due to a large vessel occlusion was not randomized. Thus, the results of these meta-analyses may be confounded by indication and selection bias since all major guidelines recommend IVT in eligible patients before EVT (19).

Using IVT leading to favorable outcomes may associate with early recanalization for patients in the EVT with prior intravenous alteplase group. However, data from recent trials suggested that such early recanalization does not occur often. In the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) and Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trials, only eight of 216 patients (3.7%) and eight of 165 patients (4.8%) randomized to MT had TICI 2b or 3 on the first angiography run, respectively (1, 20). The chance of early recanalization in response to IVT is associated with the location of the occlusion, with M2 or M3 occlusions responding effectively compared with distal ICA occlusions. In the DEVT trial, the middle cerebral artery M2 occlusions were excluded. Thereby, higher rates of successful reperfusion before thrombectomy were seen with combined intravenous alteplase and EVT in the DIRECT-MT and SKIP trials but not in the DEVT trial.

The benefit of recanalization after acute ischemic stroke is highly time-sensitive (21), thus the time delay due to the preparation of alteplase administration, which might be considered to be disadvantaged. A post hoc analysis of the MR CLEAN trial revealed that the median door-to-groin-puncture time was 11 min longer in non-transferred patients in the IVT + EVT group, which indicates that administration of IVT might contribute to a small delay in the start of EVT (22). However, this meta-analysis showed either no significant or no clinically relevant differences in most pre-specified time intervals. Although several time intervals were shorter in the direct EVT group, no significant differences were found in randomization to puncture time or arrival to arterial puncture between the treatment groups, and the mean time delay due to the preparation of alteplase administration was only about 3 min in SKIP study (16 min [IQR, 11–24] vs. 19 min [13–27], P = 0.38).

The results of this study are not sufficient to support clinical practice and paradigm shift toward direct EVT for patients with acute ischemic stroke from large-vessel occlusion. However, they support the hypothesis that EVT alone was non-inferior to combined IVT and EVT in these patients. Moreover, the results of this study are probably a consequence of the standardized workflow instituted in all three randomized clinical trials, which may not have been present in individual centers participating in previous non-randomized studies. Furthermore, strengths of the present meta-analysis include the conduction and report of the analysis according to the PRISMA.

However, a common limitation of these studies was that all three trials were conducted in East Asia, limited racial/ethnic diversity, thus increasing the risk for bias and confounding. Second, additional three randomized clinical trials (MR CLEAN-NO IV [ISRCTN80619088], SWIFT DIRECT [NCT03192332], and DIRECT-SAFE [NCT03494920]) to examine whether MT alone is non-inferior to combined IVT plus MT are ongoing. An updated meta-analysis may be needed in the future. Third, we were only able to get part of the data among the included trials. Some of the baseline characteristics were unavailable. Thus, we could not conduct some subgroup analysis, such as by baseline NIHSS score, occluded artery, and time to treatment. Despite these limitations, our study represented the best available pieces of evidence regarding EVT alone was non-inferior to combined IVT and EVT on the outcomes of patients with acute ischemic stroke with large-vessel occlusion in the anterior circulation.

The pooled data from our meta-analysis of RCTs suggested that among patients with acute ischemic stroke in the anterior circulation within 4.5 h from the onset, EVT alone was non-inferior to combined IVT and EVT.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

LL conceived the study. T-FW, G-CC, and JC collected the data and drafted the manuscript. H-SC, LL, and JC revised the manuscript and language. All authors contributed to the article and approved the submitted version.

The work was supported by grants from the National Nature Science Foundation of China (No. 81901217).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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