Introduction

The efficacy of intravenous thrombolysis (IVT) has been previously studied in acute ischemic stroke (AIS) patients when given in the strict time window and in the absence of contraindications [1]. However, the efficacy of IVT is limited in AIS patients with large vessel occlusion (AIS-LVO), with only 6–30% of patients achieving successful recanalization [2]. Moreover, IVT might increase the risk of secondary hemorrhage, which limits its applicability in this patient population [3, 4]. On the other hand, mechanical thrombectomy (MT) has provided higher successful recanalization rates and has, therefore, become the standard of care for patients with AIS-LVO who meet the eligibility criteria for endovascular treatment (EVT) [5, 6].

Given the differences between IVT and MT in procedures, time window, and canalization mechanism, investigators sought to investigate whether the use of IVT prior to MT (known as the bridging therapy) provides greater benefit than MT alone. It has been advocated that IVT prior to MT might shorten the time of successful MT by changing the nature of the blood clot, making it more amenable to mechanical intervention, and dissolving the residual thrombotic material [7, 8]. On the other hand, the administration of IVT in combination with MT might increase the risk of intracranial hemorrhage.

According to the American Stroke Association [6], eligible AIS-LVO patients can still receive IVT and undergo MT. Several studies, both randomized clinical trials (RCTs) and observational studies, have compared MT alone with MT + IVT in patients with AIS-LVO, meeting the criteria for both treatment modalities. However, the results of published studies are inconsistent and inconclusive in terms of functional outcome, secondary intracranial hemorrhage, and mortality [8,9,10,11,12,13].

To date, experts and clinical practice guidelines agree that IVT + MT is statistically superior to MT alone; however, there are some doubts about whether this superiority is significantly sufficient to advocate the use of IVT + MT over MT alone for AIS-LVO. There is a lack of class I evidence on the associated benefits and risks of combining IVT and MT in AIS-LVO compared with MT alone. Therefore, we conducted this systematic review and meta-analysis to synthesize evidence from all published studies on the outcomes of combined bridging therapy and MT compared with MT alone in terms of successful recanalization, complete recanalization, mortality, functional independence, NIH stroke score (NIHSS), and complications.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines during this systematic review and meta-analysis [14]. The methods were done in strict accordance with the Cochrane Handbook of Systematic Reviews and Meta-analysis of Interventions (version 5.1.0).

Eligibility criteria

We included all studies satisfying the following criteria:

  1. 1.

    Population: studies on patients with AIS-LVO

  2. 2.

    Intervention: studies where the experimental or exposed group received IVT + MT

  3. 3.

    Comparator: studies where the control group received MT alone

  4. 4.

    Outcome: we included studies reporting at least one of the following outcomes: mortality rates, successful recanalization, complete recanalization, favorable mRS at 90 days, NIHSS score at baseline, 24 h after the stroke event and/or at discharge from the hospital, onset-to-groin time, procedural time, and complications.

  5. 5.

    Study design: studies with comparative designs, whether RCTs or observational studies comparing the outcomes of MT alone with IVT + MT.

We excluded studies that were not in English and studies on either MT alone or MT combined with IVT without direct comparison between both arms.

Literature search

We performed a comprehensive literature search of four electronic databases (PubMed, Scopus, Web of Science, Cochrane CENTRAL) from inception until 1 January 2022 using this search query (“Mechanical thrombectomy” OR “Endovascular thrombectomy”) AND (Intravenous thrombolysis” OR Alteplase) AND (“Acute Ischemic Stroke” OR AIS). All duplicates were removed, and all references of the included studies were screened manually for any eligible studies.

Screening of the literature search results

Retrieved results from the literature search were screened in two steps. In the first step, the title and abstracts of all articles were screened for eligibility. Then, the full-text articles of eligible abstracts were retrieved and screened for eligibility.

Data extraction

Data were extracted to a uniform data extraction sheet. The extracted data included (1) characteristics of the included studies, (2) characteristics of the population of included studies, (3) risk of bias domains, and (4) outcome measures.

Outcome measures

In the present meta-analysis, we considered the following outcome measures:

Mortality

Defined as the proportion of patients who died; it is represented as the risk ratio (RR) between the two groups.

Successful recanalization

Defined as the proportion of patients with Thrombolysis in Cerebral Infarction (mTICI) grades 2b-3; it is represented as the RR between the two groups.

Complete recanalization

Defined as the proportion of patients with modified Thrombolysis in Cerebral Infarction (mTICI) grade 3; it is represented as the RR between the two groups.

Functional independence or favorable functional outcome

It is defined as achieving modified Rankin Scale (mRS) score of 0–2; it is represented as the RR between the two groups.

NIHSS (change from baseline)

The NIH stroke score will be presented as the mean difference between the two study groups from baseline to endpoint.

Symptomatic intracerebral hemorrhage

The incidence of symptomatic intracerebral hemorrhage (sICH) will be expressed as the RR between the two groups.

Symptomatic intracranial hemorrhage

The incidence of symptomatic intracranial hemorrhage will be expressed as the RR between the two groups.

Parenchymal hematoma

The incidence of parenchymal hematoma will be expressed as the RR between the two groups.

Procedure-related complications

The incidence of procedure-related complications will be expressed as the RR between the two groups.

Onset-to-groin time (in minutes)

It is defined as the time from onset of stroke to groin puncture; it will be represented as the mean difference between the two study groups.

Procedural time (in minutes)

It is defined as the time from groin puncture to recanalization; it will be represented as the mean difference between the two study groups.

Synthesis of results

For outcomes that constitute continuous data, the mean difference (MD) between the two groups from the baseline to the endpoint, with its standard deviation (SD), were pooled in the DerSimonian-Laird random-effect model. In the case of studies reporting data in multiple time points, we considered the last endpoint for the primary analysis. For outcomes that constitute dichotomous data, the frequency of events and the total number of patients in each group were pooled as relative risk between the two groups in the DerSimonian-Laird random-effect model. All statistical analyses were done by Review Manager software (RevMan, version 5.4) for macOS, StataMP version 17 for macOS, and Open Meta[analyst] for Microsoft Windows.

Heterogeneity assessment

Statistical heterogeneity among studies was evaluated by the Chi-square test (Cochrane Q test). Then, the chi-square statistic, Cochrane Q, was used to calculate the I-squared according to the equation: I2 = \(\left(\frac{Q-df}{Q}\right)\times 100\mathrm{\%}\). A Chi-square P value less than 0.1 was considered as significant heterogeneity. I-square values ≥ 50% were indicative of high heterogeneity.

Risk of bias across studies

Two authors independently assessed the quality of included clinical trials in strict accordance with the Cochrane handbook of systematic reviews of interventions 5.1.0 (updated March 2011). We used the quality assessment table provided in (part 2, Chapter 8.5) the same book. For the observational studies, we used New Castle Ottawa Scale (NOS). Any discrepancies between the two assessors were resolved through discussion and including a third assessor. To explore the publication bias across studies, we constructed funnel plots to present the relationship between effect size and standard error. Two methods assessed evidence of publication bias; (1) Egger’s regression test and (2) the Begg and Mazumdar rank correlation test (Kendall’s tau).

Certainty assessment

We conducted a certainty assessment through sensitivity analysis (also called leave-one-out meta-analysis) to test the evidence’s robustness. For every outcome in the meta-analysis, we ran sensitivity analysis in multiple scenarios, excluding one study in each scenario to make sure the overall effect size was not dependent on any single study.

Meta-regression analysis

To test whether the study outcomes were dependent on the onset-to-groin time, we conducted meta-regression analysis models where the effect estimates and the corresponding (standard errors) were plotted against the onset-to-groin time (on the X-axis). The regression coefficient was calculated an omnibus P value of < 0.05 was considered for statistical significance. The meta-regression analysis was done by the Open Meta[Analyst] software of Oxford University’s Center of Evidence-based Medicine.

Results

Literature search results and study selection

Our literature search process retrieved 2752 records. Following titles and abstract screening, 213 articles were eligible for full-text screening. From these 213 studies, 49 studies were included in the meta-analysis. Also, the references of the included studies were manually searched, and no further articles were included. The flow chart of the study selection process is shown in the PRISMA flow diagram in (Fig. 1).

Fig. 1
figure 1

PRISMA flow diagram of the study selection process

Full size image

Study characteristics

The population of the studies was homogenous; all studies enrolled 36,123 patients with AIS-LVO undergoing MT. Four studies were RCTs, while forty-five studies were observational studies. The characteristics of the included studies are summarized in Table 1, while summary and baseline characteristics of populations of these studies are shown in Table 2.

Table 1 Summary of included studies
Full size table
Table 2 Baseline characteristics of the included studies’ populations
Full size table

Risk of bias within studies

The quality of included studies ranged from moderate to high quality according to the Cochrane Risk of Bias Assessment tool for the RCTs and the Newcastle Ottawa Scale for the observational studies. The risk of bias summary is shown in Fig. 2 A and B, while the detailed risk of bias in every study is available in Figs. 1S and 2S in the supplementary file.

Fig. 2
figure 2

Summary of the risk of bias in the included studies; A in randomized controlled trials and B in observational studies

Full size image

Mortality

The pooled RR of mortality favoured the IVT + MT group who had significantly fewer mortality events compared with the MT alone group (16.5% vs. 19.7%; RR 0.75, 95% CI [0.68 to 0.82], p < 0.0001, Fig. 3). The pooled studies were not homogenous (p = 0.02; I2 = 36%). Subgroup analysis of mortality according to the study design showed that the observational studies (0.72, 95% CI [0.65 to 0.80]) but not the RCTs (0.94, 95% CI [0.75 to 1.17]) had statistically significant pooled RR in favor of the IVT + MT group.

Fig. 3
figure 3

Summary of the pooled RR and the corresponding 95% CI for the mortality, successful recanalization, complete recanalization, and functional independence with subgrouping according to study design

Full size image

Complete and successful recanalization

The pooled RR of successful recanalization favoured the IVT + MT group over MT alone (77.7% vs. 75.9%; RR 1.06, 95% CI [1.03 to 1.09], p = 0.0007, Fig. 3). The pooled RR of complete recanalization favoured the IVT + MT group over MT alone (RR 1.06, 95% CI [1.01 to 1.11], p = 0.02, Fig. 3). Subgroup analysis of successful recanalization according to the study design showed that the observational studies (1.07, 95% CI [1.04 to 1.10]) but not the RCTs (1.04, 95% CI [1.00 to 1.09]) had statistically significant pooled RR in favor of the IVT + MT group.

Favorable functional outcome (or functional independence)

The pooled RR of favorable functional outcome favoured the IVT + MT group (45.2% vs. 39%; RR 1.21, 95% CI [1.13 to 1.29], p = 0.00001, Fig. 3). The pooled studies were not homogenous (p = 0.0001; I2 = 52%). Subgroup analysis of favorable functional outcome according to the study design showed that the observational studies (1.25, 95% CI [1.17 to 1.34]) but not the RCTs (0.99, 95% CI [0.89 to 1.09]) had statistically significant pooled RR in favor of the IVT + MT group.

Improvement in NIHSS score

The overall mean difference (MD) of improvement in the NIHSS score from baseline did not favor either groups (MD − 0.34, 95% CI [− 0.80 to 0.11]). Subgroup analysis, according to the time point at which NIHSS score improvement was assessed, did not show any difference between the two groups either at 24 h (MD − 0.45, 95% CI [− 1.04 to 0.13]) or at discharge (MD − 0.70, 95% CI [− 1.51 to 0.11], Fig. 4). The pooled studies were homogenous (p = 0.0005, I2 = 65%). Subgroup analysis of the improvement in NIHSS score according to the study design showed that the observational studies (MD − 0.87, 95% CI [− 1.83 to 0.09]) but not the RCTs (MD − 0.15, 95% CI [− 1.71 to 1.41]) had statistically significant pooled MD in favor of the IVT + MT group (Fig. 4).

Fig. 4
figure 4

Summary of the pooled MD and the corresponding 95% CI for the improvement in the NIHSS score from baseline to endpoint between the study groups with subgrouping according to time of evaluation and study design

Full size image

Complications

Symptomatic intracerebral hemorrhage

The pooled RR of sICH did not favor either of groups (RR 1.00, 95% CI [0.74 to 1.36], p = 0.99, Fig. 5). The pooled studies were homogenous (p = 0.95, I2 = 0%).

Fig. 5
figure 5

Pooled RR and the corresponding 95% CI for the complications

Full size image

Symptomatic intracranial hemorrhage

The pooled RR of symptomatic intracranial hemorrhage did not favor either of groups (RR 0.88, 95% CI [0.70 to 1.10], p = 0.27, Fig. 5). The pooled studies were homogenous (p = 0.20, I2 = 21%).

Any intracranial hemorrhage

The pooled RR of symptomatic intracranial hemorrhage did not favor either of groups (RR 1.13, 95% CI [0.97 to 1.32], p = 0.11, Fig. 5). The pooled studies were homogenous (p = 0.12, I2 = 32%).

Parenchymal hematoma

The pooled RR of parenchymal hematoma did not favor either of groups (RR 1.13, 95% CI [0.82 to 1.56], p = 0.46, Fig. 5). The pooled studies were homogenous (p = 0.13, I2 = 35%).

Procedure-related complications

The pooled RR of procedure-related complications did not favor either of groups (RR 1.13, 95% CI [0.82 to 1.55], p = 0.46, Fig. 5). The pooled studies were homogenous (p = 0.12, I2 = 45%).

Time variables

The overall mean difference (MD) of the onset-to-groin time did not favor either of groups (MD − 9.11 min, 95% CI [− 26.28 to 8.06], p = 0.30). The overall mean difference (MD) of the procedural time did not favor either of the two groups (MD − 2.40 min, 95% CI [− 8.44 to 3.64], p = 0.44; forest plots are available in the supplementary file).

Results of the subgroup analysis

We conducted subgroup analysis for the main outcomes according to the study design (RCTs only vs. observational studies vs. all studies). Observational studies showed an advantage for the IVT + MT over MT alone in terms of mortality, successful recanalization (mTICI 2b-3), and 90-day favorable outcome (0–2), but RCTs did not show the same advantage (Table 3).

Table 3 Summary of the subgroup analysis results, data are stratified according to the study design (RCTs only, observational studies only, and all studies)
Full size table

Results of the meta-regression analysis

We ran multiple meta-regression analysis models to test whether the type of intervention or the onset-to-groin time could significantly influence the effect estimates. Bridging therapy was a significant predictor of less mortality (ß − 0.073; p = 0.003) and more successful recanalization (ß 0.099; p = 0.002) when compared with MT alone as the reference category in the regression model (Table 4). On the other hand, the onset-to-groin time was significantly associated with symptomatic intracranial hemorrhage (ß 0.001; p = 0.017) or any intracranial hemorrhage (ß 0.001, p = 0.026, Fig. 6).

Table 4 Results of the meta-regression analysis of the onset to groin time and other outcomes
Full size table
Fig. 6
figure 6

Results of the meta-regression analysis (A) impact of onset of groin time on the incidence rate of symptomatic intracranial hemorrhage, and (B) impact of the onset-to-groin time on the incidence rate of any intracranial hemorrhage

Full size image

Discussion

Summary of the main findings

The present meta-analysis provides evidence (class 1) that for patients with AIS-LVO, IVT + MT is superior to direct MT alone in terms of the rates of mortality, successful recanalization, complete recanalization, and the favorable functional outcome. Notably, our meta-analysis found that there were no significant differences between the two groups in terms of onset-to-groin time, procedural time, NIHSS scores (at 24 h and discharge), or complications including both hemorrhagic and procedure-related complications.

In terms of the improvement in NIHSS score, the subgroup analysis according to the study design showed consistent findings between RCTs and non-RCTs. However, in terms of mortality, successful recanalization (mTICI 2b-3), and 90-day favorable outcome, observational studies favoured IVT + MT over MT alone while RCTs showed no difference between the two groups (Table 3). RCTs addressing the comparisons between both treatment options are scarce; therefore, most of the evidence synthesized in this systematic review and meta-analysis is built on observational data which might be susceptible to confounding bias. Nonetheless, until further large, better-designed RCTs are conducted, the present meta-analysis provides the most comprehensive, up-to-date, evidence-based guidance on the comparison of MT + IVT versus MT alone in AIS patients. The outcomes of this meta-analysis span most of the clinically important outcomes for decision making including mortality, complete successful recanalization, functional independence on the mRS, NIHSS score, onset-to-groin time, procedural time, and procedure-related complications.

Explanation of the study findings

A few physiological mechanisms have been proposed to explain why MT + IVT might be superior to MT alone. On the one hand, it is suggested that IVT might provide synergistic effects by preparing the microvascular environment before MT. Furthermore, IVT might shorten the procedural time and reduce catheterization attempts [8]. On the other hand, IVT might facilitate the lysis of distal emboli resulting from thrombus fragmentation. Therefore, it might reduce the risk of procedural complications [15, 16].

Agreement and disagreement with previous studies

The first RCT on MT + IVT versus direct MT alone showed that direct MT was not inferior in terms of the functional outcome [15]. Additionally, the bridging therapy did not significantly reduce the numbers or the size of peripheral emboli compared with direct MT [7]. In another RCT by Broeg-Morvay et al. [7], MT + IVT did not provide additional benefits compared with MT alone in patients with no contraindications for IVT. Leker et al. [16] showed in their pilot study that patients who received IVT + MT needed fewer attempts during the EVT, while the study by Balodis et al. [8] showed that recanalization was achieved by the first pass in > 50% of cases within both groups without a significant difference.

A meta-analysis by Mistry et al. [17] examined 13 retrospective studies and found superior benefits of using bridging therapy in combination with IVT over direct MT in terms of mRS score and mortality. A summary of the results of our meta-analysis in comparison with previous meta-analyses is shown in Table 5.

Table 5 Summary of the previous meta-analyses results
Full size table

Significance of the work

This study expands the literature by providing class I evidence that bridging therapy with IVT in combination with MT is superior to the direct MT without IVT for patients with AIS-LVO. A few individual studies and previous meta-analyses revealed that direct MT alone is not inferior to IVT + MT [1,2,3]. Moreover, some of these prior studies suggested that the combination of bridging IVT and MT might be associated with an increased risk of hemorrhagic complications [4]. However, the present meta-analysis showed a significant difference in favor of the bridging therapy. In this study, we analyzed data from 49 studies (4 RCTs and 45 non-RCTs) with a total of 36,123 patients, making it, to the best of our knowledge, the largest and most comprehensive meta-analysis addressing this comparison to date.

Strength points and limitations

This study has several strong points including: (1) We ran comprehensive research on multiple databases finding and including more studies than previously published meta-analyses, (2) We ran multiple sensitivity analyses to test the counterfactual, (3) We conducted all steps according to the guidelines of Cochrane Handbook of Systematic Reviews and Meta-analysis of interventions, (4) This manuscript is reported according to the PRISMA statement, and (5) For all outcomes, we stratified the effect estimates by the study design into RCTs only, non-RCT studies only, and all. This allowed us to synthesize statistically robust evidence without compromising the overall quality of the review.

Nonetheless, this study has a few limitations, including (1) some studies applied pre-selection criteria for assigning patients to the bridging therapy or the direct MT groups; such pre-selection might provide an opportunity to confounding variables to influence the study outcomes. (2) Some studies included only patients for whom IVT was not contraindicated which narrows the external validity of the results; this comparison and results are not applicable in patients for whom IVT is contraindicated since direct MT will be the first-line intervention for this subgroup of patients. (3) This meta-analysis, and also the previous meta-analyses, did not take into consideration the impact of the EVT device on such a comparison. This limitation stems from the lack of data about the used EVT technique in the included patients.

Conclusion

For patients with AIS-LVO, IVT + MT is associated with slightly better rates of survival, successful and complete recanalization, and favorable independence as compared with the direct MT alone. The cost-effectiveness of the bridging therapy combined with MT compared with the direct MT alone should be evaluated in future studies to guide decision-making in the clinical setting. Additionally, since most of the available data are from observational studies, further clinical trials are needed to provide more robust evidence on this comparison.