Comparative Effectiveness of Intravenous Thrombolysis plus Mechanical Thrombectomy versus Mechanical Thrombectomy Alone in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

The treatment of acute ischemic stroke due to large artery vessel occlusion has experienced dramatic development within the last decade, with a variety of therapeutic approaches emerging that are increasingly well adapted to individual patient circumstances [1, 2]. The current guidelines recommend that patients with acute ischemic stroke from a large arterial occlusion undergo intravenous thrombolysis (IVT) within 4.5 h of stroke onset [3]. Furthermore, in addition to IVT, standards also recommend mechanical thrombectomy (MT) in the case of a treatable large arterial occlusion. This approach is based on the premise that IVT can initiate recanalization and potentially improve microvascular flow, thereby enhancing the efficacy of subsequent MT [1]. Depending on stroke patterns, both procedures can each be performed alone or together [1, 4].

While IVT itself is an effective therapy, MT alone is also effective in treating acute ischemic stroke, improving outcomes among patients ineligible for IV alteplase [2] in particular. The question is whether MT alone is as effective as MT plus systemic lysis (also called bridging therapy or BT), especially for patients eligible for IVT. Some studies suggest that MT alone may be non-inferior to bridging therapy (BT) in terms of efficacy and safety, and may be associated with a significant benefit if the time between symptom onset and expected administration of IVT is no more than 2 h and 20 min [5].

A meta-analysis comparing direct endovascular thrombectomy (DEVT) alone and BT found statistically significant non-inferiority of DEVT compared to BT with regard to 90-day functional independence, mortality, and successful reperfusion. Interestingly, the symptomatic intracranial hemorrhage (sICH) rate was superior in the DEVT group [2]. Another study found no significant difference in the risk of sICH between the BT and MT alone groups after adjusting for confounders [4].

The choice between BT and MT alone should consider individual patient factors including the timing of stroke onset, the size and location of the occlusion, and the patient’s overall health status. While BT remains the standard of care for eligible patients, MT alone is a viable option, particularly when IVT is contraindicated or when rapid reperfusion is necessary.

The aim of our study was to refine treatment protocols and identify which patient subgroups with ischemic stroke due to large vessel occlusion benefit most from intravenous alteplase plus endovascular treatment compared to endovascular treatment alone. We compare both methods regarding successful recanalization (TICI 2b-3), NIHSS scores, functional outcomes (mRS, Barthel Index), mortality rates, symptomatic intracerebral hemorrhage rates, and median final lesion volume on follow-up imaging. Our goal was to determine which treatment is more effective in practice, guiding future stroke management guidelines.

This systematic review was conducted in accordance with the guidelines outlined in the Cochrane Handbook of Systematic Reviews of Interventions [6] and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines [7]. The prespecified protocol for this review is registered with PROSPERO (CRD42024498238). We conducted the analysis using Review Manager (RevMan) Version (7.5.0) [8].

Inclusion criteria:

Population: studies about patients with large cerebral artery occlusion or tandem lesions.

• Intervention: studies in which the experimental group received bridging therapy (intravenous alteplase and MT).

• Comparator: studies in which the control group received MT only.

• Study design: only randomized clinical trials were included.

Exclusion criteria:

Studies that met the following criteria were excluded: (1) case reports, case series, or observational studies; (2) review articles or meta-analyses; (3) animal studies; (4) conference abstracts and letters; (5) descriptive studies or studies that did not report our predefined outcomes.

This review included studies involving patients with large cerebral artery occlusion or tandem lesions who underwent BT, comprising intravenous alteplase administration followed by MT. Studies in which the control group received MT alone were also included. Eligible studies were required to report clear efficacy and safety outcome measures. Only randomized clinical trials were considered for inclusion. Conversely, studies meeting the following exclusion criteria were excluded: (1) case reports, case series, or observational studies; (2) review articles or meta-analyses; (3) animal studies; (4) conference abstracts and letters; (5) descriptive studies or those failing to report predefined outcomes.

We conducted a comprehensive search across multiple databases including PubMed, Scopus, Embase, and Web of Science (WOS) with no restrictions on language or publication date. This systematic search was carried out for all studies published up until January 2024, utilizing a combination of search terms related to MT, endovascular therapy, and large cerebral artery occlusion. The search strategy included terms such as “mechanical thrombectomy,” “endovascular thrombectomy,” “bridging therapy,” “intravenous thrombolysis,” and specific descriptors for large vessel ischemic stroke. Articles identified during the search were imported into the Covidence website [9] for deduplication and initial screening based on title and abstract. Three review authors independently assessed the relevance of the search results, with potential studies undergoing further eligibility screening by two additional reviewers. Any discrepancies were resolved through discussion with the first author.

Three review authors independently extracted relevant data from the included studies using predefined data extraction forms available online. The extracted data encompassed two main aspects: (1) baseline characteristics of study participants, including age, sex, weight, occlusion site, time from stroke onset to randomization, time from randomization to start of alteplase, median ASPECTS (IQR) score, history of stroke, hypertension, atrial fibrillation, CTP admission, mismatch (%), eTICI score of more than 2c, angiographic improvement, TMAX >6 volume, infarct expansion rate, LKW to reperfusion, Barthel Index of 95–100 at 90 days, improved angiographic eTICI score, and study location; and (2) examined outcomes such as mRS at 90 days, vasospasm, mortality, successful reperfusion, NIHSS mean difference (MD), serious adverse events within 90 days, Barthel Index score of 95–100 at 90 days, improvement in the modified Rankin scale at 90 days, median final lesion volume on follow-up imaging (mL), time from stroke onset to groin puncture, infarction in new territory at 5–7 days, large or malignant MCA infarction, and need for embolization of new territory. Data extraction was conducted separately for the intervention group and the comparative group.

Categorical data were expressed as event count and number of participants, while continuous outcomes were expressed as median, interquartile range, and number of participants. A fourth review author meticulously checked the extracted data and addressed any missing data to ensure data integrity and accuracy before proceeding with the analysis. Any disagreements arising were resolved through discussion among the review authors.

To assess the risk of bias (RoB) in each study included, two review authors utilized the Cochrane RoB tool for randomized trials version 2 (ROB2) [10]. This tool evaluates seven domains: (1) sequence generation (selection bias), (2) allocation sequence concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcome data (attrition bias), (6) selective outcome reporting (reporting bias), and (7) other potential sources of bias. For each domain, we categorized the risk as “low risk,” “some concerns,” or “high risk” based on predetermined criteria and followed the algorithms suggested by ROB 2.0 to make final judgments. This rigorous assessment allowed us to evaluate the quality and reliability of the studies included and ensure the validity of our findings.

Primary outcome measures:

• Improvement in NIHSS score.

• 90-day modified Rankin Scale (mRS) score.

Secondary outcome measures:

• Successful recanalization before thrombectomy.

• Successful recanalization (TICI 2b-3) after thrombectomy.

• Symptomatic intracerebral hemorrhage.

• Mortality.

• Barthel Index score of 95–100 at 90 days.

• Improvement in modified Rankin scale at 90 days.

• Median final lesion volume on follow-up imaging (mL).

• Time from stroke onset to groin puncture.

For outcomes that constitute dichotomous data, the risk ratio (RR), along with its confidence interval (CI), was pooled in the Mantel-Haenszel random-effect model. For outcomes that constitute continuous data, the MD between the two groups from the baseline to the endpoint, with its CI, was pooled in the random-effect model.

As shown in Figure 1, 3,353 studies were identified in the initial search. After removing duplicates, 2,214 studies remained. Following the screening of titles and abstracts, 2,176 studies were excluded, leaving 38 articles for full-text screening. Of these, eight articles [4, 11‒18] met the eligibility criteria and were included in our study.

Study and treatment characteristics are summarized in Table 1. The analysis included 2,638 participants. The most common artery occlusion across the studies was M1, the first segment of the middle cerebral artery. The intervention used in all studies was BT, with thrombectomy alone as the comparator. Additional details are provided in Table 1 for a more comprehensive examination of study and treatment characteristics.

The RoB assessment is illustrated in Figure 2. Seven RCTs were classified as having low RoB, while one RCT was deemed to have moderate RoB.

Five studies reported NIHSS score improvements after 24 h, and three studies reported improvements after 7 days. The meta-analysis using a fixed-effects model indicated that improvement in the NIHSS score from baseline favored the BT group (MD 0.96, 95% CI: [0.73–1.20], p < 0.00001). Subgroup analysis showed that the BT group had better improvement after 24 h (MD 0.94, 95% CI: [0.56–1.32], p < 0.00001) and after 7 days (MD 0.98, 95% CI: [0.67–1.29], p < 0.00001), as shown in Figure 3.

Eight studies (n = 2,638 patients) reported the frequency of patients with a favorable outcome based on the mRS score (ranging from zero to 2). The pooled RR for a favorable outcome (mRS 0–2) did not favor either technique (RR 1.05, 95% CI: [0.97–1.13]), as shown in Figure 4.

Five studies (n = 2,085 patients) reported the frequency of successful recanalization achieved with IVT before MT. The pooled RR for successful recanalization favored the BT group (RR 2.42, 95% CI: [1.43–4.10], p = 0.001), shown in Figure 5.

Eight studies (n = 2,523 patients) reported the frequency of successful recanalization (TICI 2b–3) for both techniques. The pooled RR for successful recanalization (TICI 2b–3) favored the BT group (RR 1.05, 95% CI: [1.01–1.09], p = 0.009), as shown in Figure 6.

Four studies (n = 1,294 patients) reported the Barthel Index. The pooled relative risk (RR) of a Barthel Index score of 95–100 at 90 days did not favor either technique (RR 1.13, 95% CI: [0.93–1.37], p = 0.22), as shown in Figure 7.

Six studies (n = 1,308 patients) reported improvement in the modified Rankin Scale at 90 days. The overall MD in improvement in mRS from baseline did not favor either technique (MD -0.04, 95% CI: [−0.22–0.13], p = 0.63), as shown in Figure 8.

Eight studies (n = 4,731 patients) reported the frequency of symptomatic intracerebral hemorrhage (ICH). The pooled RR for ICH did not favor either technique (RR 1.23, 95% CI: [0.88–1.74], p = 0.23), as shown in Figure 9.

Seven studies (n = 2,420 patients) reported 90-day mortality. The pooled RR for mortality did not favor either technique (RR 0.91, 95% CI: [0.75–1.10], p = 0.34), as shown in Figure 10.

Three studies (n = 1,308 patients) reported the median final lesion volume. The overall MD in the median final lesion volume did not favor either technique (MD −4.16, 95% CI: [−9.41–1.09], p = 0.12), as shown in Figure 11.

Five studies (n = 3,985 patients) reported the time from stroke onset to groin puncture. The analysis using a fixed-effects model showed that the MT alone group had a shorter time from onset of stroke to puncture (MD 9.91, 95% CI: [4.31–15.52], p = 0.005), as shown in Figure 12.

The main results of our meta-analysis comparing BT (combination of IVT and MT) to thrombectomy alone in stroke patients with a large artery occlusion revealed that both treatment strategies are safe and effective measures. Functional outcomes, mortality rates, and rates for symptomatic intracerebral hemorrhages and long-term recovery parameters such as Barthel Index scores and mRs scores were comparable for patients treated using both modalities. However, our analysis showed some advantages for the BT group. Patients treated with BT were more likely to achieve successful recanalization before and after the thrombectomy procedure. This increased success in restoring blood flow is likely why these patients showed more significant improvements in their neurological status (as measured by the NIHSS) both at 24 h and at 7 days after treatment compared to those who received thrombectomy alone.

We compared our findings to those of previous meta-analyses within the same domain. Cuadra-Campos et al. [19], in their meta-analysis of six randomized open-label clinical trials, found no significant difference in functional independence between the two groups (48.8 vs. 50.7%), although the BT group had slightly better outcomes (OR = 0.93, 95% CI: 0.79–1.09, p = 0.37; I² = 0%). They also found that successful reperfusion was higher in the BT group (OR = 0.75, 95% CI: 0.60–0.94, p = 0.01; I² = 0%). Similarly, Wang et al.’s review, comprising 29 observational studies and one RCT, yielded results favoring BT in terms of functional independence, mortality, and recanalization rates, with ORs of 0.67, 1.23, and 1.07, respectively [2]. Conversely, the non-inferiority meta-analysis by Charles B. Majoie et al. [20] highlighted that combining IVT with endovascular treatment was not inferior to endovascular treatment alone based on the mRS score at 90 days. While we are presenting these newer significant clinical findings, it is important to note that our meta-analysis included a larger number of patients across eight clinical trials. Additionally, our statistical approach provides a more accurate depiction of effect size estimates, making our results more reliable, and enhances the evidence base for guiding treatment decisions.

We found that BT was more effective in achieving successful recanalization both before and after thrombectomy compared to thrombectomy alone. Patients who received BT were significantly more likely to have their blood flow restored before the thrombectomy procedure, likely due to the clot-dissolving effects of IVT. This preliminary restoration of blood flow helps make the subsequent mechanical removal of the clot more effective.

Furthermore, even after the thrombectomy procedure, patients in the BT group continued to show better outcomes. The combined approach of IVT and MT seems to facilitate a more thorough and efficient restoration of blood flow, leading to higher rates of successful recanalization (TICI 2b–3). These findings align with previous studies [19, 21] and suggest that the initial use of IVT can enhance the effectiveness of the subsequent mechanical intervention.

By starting the reperfusion process earlier with IVT, BT not only aids in breaking down the clot but also primes the affected vessels for more effective mechanical clot removal. This dual approach appears to offer a synergistic benefit, resulting in better overall recanalization rates compared to MT alone. However, it is important to consider that BT might also increase the risk of hemorrhagic transformation, which can complicate the recanalization process.

Patients treated with BT had a greater improvement in NIHSS score from baseline compared to those treated with thrombectomy alone. This finding is supported by our fixed-effect model analysis, which showed that the improvement in NIHSS from baseline significantly favored the BT group. Additionally, subgroup analysis indicated that this improvement was consistent both after 24 h and after 7 days. This significant improvement highlights the potential benefits of combination therapy. The initial administration of IVT may help in reducing clot burden and facilitating better mechanical removal of the clot, leading to early and effective reperfusion. This early reperfusion likely results in reduced infarct size and improved neurological function, which is reflected in the NIHSS scores.

While previous studies, such as those by Campbell et al. [22], suggested that MT alone might lead to better neurological outcomes, our findings indicate that the combination approach of BT actually provides greater improvement in neurological status, emphasizing the importance of achieving early and effective reperfusion, which is more readily accomplished with the dual approach of BT.

However, it is important to note that while NIHSS scores reflect immediate neurological improvement, they may not always translate into better long-term functional independence or quality of life, as measured by metrics like mRS scores. Therefore, while BT shows significant short-term neurological benefits, further studies are needed to evaluate its impact on long-term outcomes and overall quality of life for stroke patients.

The importance of the time from stroke to puncture cannot be overstated in the treatment of acute ischemic stroke. Studies have shown that faster treatment leads to better outcomes for patients, with each minute delay resulting in a loss of 1.9 million neurons and a decrease of 3–4% in the likelihood of a good outcome [23]. In 2015, the Society of Neurointerventional Surgery set benchmarks for quality assurance, recommending a door-to-puncture time of <60 min and a door-to-reperfusion time of <90 min [24]. However, despite these efforts, delays in prehospital care, specifically from symptom onset to hospital door arrival (onset-to-door time) persist in some cases, potentially undermining the benefits achieved during in-hospital treatment [25]. Our analysis revealed that the time from stroke onset to groin puncture was shorter in the thrombectomy alone group than in the BT group. This is consistent with the existing literature, which has shown that MT alone is associated with faster treatment times than BT [23]. While there was a statistically significant difference of just 10 min between the times from stroke onset to puncture for the MT alone compared to the BT group, it is uncertain whether this small difference would significantly affect patient outcomes.

While our analysis of sICH found no significant difference in the risk of sICH between the MT and BT groups (RR, 1.18; 95% CI: [0.86–1.62]; p = 0.32), our findings are consistent with some studies in the literature but diverge from others. Kolahchi et al. reported significantly higher rates of sICH in the BT group compared to MT (OR = 0.73 [95% CI, 0.56–0.96], I² = 0%, p = 0.02), particularly in the non-RCT subgroup and the combined group of patients with occlusion of the anterior and/or posterior circulation [26]. However, the absence of significant differences in the anterior group analysis and subgroup analysis of RCT and non-RCT studies complicates the interpretation of their results. This discrepancy might be attributed to variations in study designs or other unaccounted factors across studies. Similarly, Cuadra-Campos et al. found no statistically significant differences in the risk of sICH between the MT and BT groups [19]. These findings align with our meta-analysis results and suggest that, overall, both treatment strategies are associated with comparable rates of sICH.

Nevertheless, it is important to recognize the potential for publication bias and the inherent limitations of the studies included in our analysis. Variability in patient populations and methodologies could introduce biases and confounders that could influence the observed outcomes. Additionally, the definition and assessment of sICH vary between studies, potentially affecting the comparability of results.

To our knowledge, this is the only study to provide a pooled effect for a large number of dependent variables. Although the previous meta-analysis [19] provided a comparable number of included studies, they predominantly utilized OR for risk analysis, we employed RR for several reasons. First, the outcomes assessed in our study, including sICH, mortality, recanalization, and functional outcome measured by an mRS score of 0–2, were binary events, making RR more suitable. RR allows for a direct comparison of event risks between patients with AIS receiving different treatment strategies, facilitating a clear understanding of relative risk associations. RR is easier to interpret in clinical settings compared to OR, which can be challenging to grasp intuitively. It also allowed us to quantify risk differences between treatment groups more directly, especially given the predominance of RCTs in our analysis. Moreover, RR provides a clearer measure of the impact of intervention on adverse events and functional outcomes, aiding clinicians in making informed decisions and assessing risks more accurately in clinical practice. Thus, in addition to adding a substantial amount of new data, our statistical approach provides a more accurate depiction of effect size estimates, thereby enhancing the evidence base for guiding treatment decisions and optimizing patient care.

To further contextualize our findings, we considered the guidelines provided by Powers et al. [11]. The guidelines issued by the American Heart Association/American Stroke Association offer evidence-based recommendations for healthcare professionals involved in the care of patients with stroke. They affirmed the critical role of reperfusion therapies, such as IVT and endovascular thrombectomy, in optimizing patient outcomes. Our findings align with these recommendations, particularly regarding the importance of timely intervention and need for individualized treatment approaches based on patient characteristics and stroke severity.

Although our meta-analysis provides valuable insights into treatment outcomes, it is essential to interpret our findings in the broader stroke care landscape outlined in the guidelines by Powers et al. [11]. Clinical decision making should consider factors such as patient eligibility, treatment accessibility, and institutional resources to ensure the most effective and appropriate treatment for each patient.

Our meta-analysis is also subject to a number of limitations, which should be acknowledged at this point. In a field with a relatively new established therapeutic measure (MT), it can be expected that there will only be a limited amount of investigations available for analysis. Therefore, a major limitation of this study is the small number of studies included in the analysis. Furthermore, no data were available on parameters related to vascular status, which might have influenced the selection of patients for inclusion in one of the studies concerned, and we were therefore unable to determine the reasons such parameters were used to exclude potentially eligible patients. However, we also need to underline the comprehensive character of our analysis: we considered all available studies of relevance on the topic, an aspect that makes our meta-analysis highly relevant with regard to recommendations for clinical practice.

BT, combining IVT and MT, is more effective than MT alone, showing greater improvements in NIHSS scores and higher rates of successful reperfusion before and after thrombectomy. Although MT alone had a shorter time from stroke onset to groin puncture by 9.91 min, this did not result in better NIHSS improvements at 24 h or 7 days. While NIHSS scores indicate immediate neurological improvement, they may not predict long-term functional independence. Thus, further studies are needed to assess its impact on long-term outcomes and quality of life.

The prespecified protocol for this review is registered with PROSPERO (CRD42024498238). An ethics statement was not required for this study type since no human or animal subjects or materials were used.

The authors have no potential conflicts of interest to declare with respect to the research, authorship, and/or publication of this article.

The authors have received no financial support for the research, authorship, and/or publication of this article.

Ali Hammed MD, Almonzer Al-Qiami, Christian Tanislav, MD: conceptualized and designed the study and performed data analysis. Ali Hammed, Almonzer Al-Qiami and Christian Tanislav, MD: wrote the manuscript. Josef Rosenbauer MD, Asmaa Zakria Alnajjar, and Rawan Hamamreh: contributed to writing and editing the manuscript. Elsayed Mohamed Hammad, Zina Otmani, Ahmad Alzawahreh, Nada G.Hamam, and Eman Ayman Nada: performed data extraction and assessed the RoB. Karel Kostev, DMSc, PhD, and Gregor Richter MD: reviewed and provided critical feedback on the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.