Meta-analysis: Comparing the Roles of IV Thrombolysis alone and Mechanical Thrombectomy alone in Acute Ischemic Stroke versus the Combination of IV Thrombolysis and Thrombectomy.

Ibrahim Krenawi*¹, Ravikumar Ravindran²

1. Ibrahim Krenawi, Consultant Physician, Burjeel Royal Hospital, Al Ain, UAE.

2. Ravikumar Ravindran, Consultant Physician, University of Buckingham, UK.

 

*Correspondence to: Ibrahim Krenawi, Consultant Physician, Burjeel Royal Hospital, Al Ain, UAE.

Copyright

© 2025 Ibrahim Krenawi, This is an open access article distributed under the Creative Commons Attribution   License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received:  22 Sep 2025

Published: 30 Sep 2025

DOI: https://doi.org/10.5281/zenodo.17302214

List of Abbreviations
AIS	Acute ischemic stroke
IV	Intravenous
Ivt	Intravenous Thrombosis
LVOs	Large vessel occlusions
MeSH	Medical Subject Headings
mRS	Modified Rankin Scale
MT	Mechanical thrombectomy
MVOs	Medium Vessel Occlusions
NIHSS	National Institutes of Health Stroke Scale
NINDS	National Institute of Neurological Disorders and Stroke
NOS	Newcastle-Ottawa Scale
PRISMA	Preferred Reporting Items for Systematic     Reviews and Meta-Analyses
RCTs	Randomized controlled trials
sICH	Symptomatic intracranial hemorrhage
tPA	Thrombosis with tissue plasminogen activator

Introduction

Background

Acute ischemic stroke (AIS) is one of the most serious and urgent medical emergencies that present to physicians in clinical practice (Murphy & Werring, 2020). AIS results from a blood clot (embolus) that impedes arterial blood delivery to the brain, resulting in a sudden fall in oxygen and essential nutrients to cerebral tissue (Hui, 2024). It is this interruption that starts a cascade of cellular injury and neurological deficits, causing permanent brain damage unless they are corrected promptly (Saver, 2005). AIS is a leading cause of morbidity and mortality worldwide (Saini, 2021). According to the latest data, stroke is the fifth highest cause of death in the United States, and over 800,000 new cases are reported every year (Wilkinson, 2022). Around five million people die from stroke in the world every year, and millions more are left with strokes that can leave them with long-term disabilities (Khandelwal, 2016). Not only are these figures staggering as far as the public health impact of AIS is concerned, but they also point to the fact that healthcare systems worldwide must bear the economic burden of acute management and long-term care costs (Broocks et al., 2021).

A dramatic change has occurred to how the management of AIS has been undertaken over the last couple of decades (Murphy & Werring, 2020). Treatment has been historically predominantly supportive, aiming at regulating the changes in intracranial pressure and preventing secondary injuries, especially aspiration pneumonia (Powers, 2018). Before the advent of reperfusion therapies, stroke care was quite different from what it is now (Saini, 2021). In the early 1990s, the breakthrough came with the introduction of intravenous (IV) thrombolysis with tissue plasminogen activator (tPA) (Torrente Quintero, 2022). The corresponding pharmacological means to dissolve the occluding clot and restore cerebral blood flow is IV thrombolysis (Hui, 2024). Because this therapy is more effective when administered within a narrow therapeutic window, ideally within 4.5 hours of symptom onset, dosing within 18 hours may be insufficient and result in dosing beyond the narrow therapeutic window (Nogueira, 2018). However, despite its benefits, IV thrombolysis is limited to a narrow time frame during which it may still be effective and is not effective at dissolving clots caused by large vessel occlusions (LVOs) and has the innate risk of hemorrhagic complications (El Tawil, 2017; Jovin, 2015).

Mechanical thrombectomy (MT) has recently become an alternative or sometimes a superior intervention in managing AIS (Huo, 2023; Jovin, 2015). MT differs from IV thrombolysis in that the clot is removed from the vessel after it has been occluded physically by specialized devices (Papanagiotou, 2018; El Tawil, 2017). Late ones have shown that this endovascular approach is particularly useful in achieving rapid and complete reperfusion of patients with LVOs (Makkawi et al., 2024; Fiehler, 2019). MR CLEAN, EXTEND-IA, and DAWN — landmark clinical trials — have proved compelling arguments that the benefits of MT in reducing disability and therapy window extend to as much as 24 hours after symptom onset (Nogueira, 2018; Huo, 2023). Nevertheless, despite these advances, the optimal integration of these two therapies continues to be a matter of debate (Powers, 2018; Saini, 2021).

The use of IV thrombolysis and mechanical thrombectomy, in concert, represents one of the central challenges of contemporary stroke management in terms of determining whether, in comparison to the use of either modality alone, there is clear added value of this combination (Fiehler, 2019; Gelener, 2021; Huo, 2023). IV thrombolysis can deliver early reperfusion, can sensitize the clot to mechanical disruption with subsequent retrieval, and therefore, in some clinical situations, may be preferable to MT alone if patients present out of an optimal time window for tPA administration or if contraindications to thrombolytic therapy exist (Jovin, 2015; Nogueira, 2018; Powers, 2018). The drive to see what balance there is between benefits and risks in each treatment strategy continues (European Stroke Organisation, 2024; Gauberti, 2021; Mahmood, 2024).

 

Research Questions

The analysis was conceived to answer several important questions in acute ischemic stroke management (Powers, 2018; Nogueira, 2018). These questions facilitate defining the comparative efficacy of the various reperfusion strategies (Makkawi et al., 2024; Fiehler, 2019) and specify the best treatment strategy in terms of clinical outcomes and patient characteristics (Huo, 2023; Jovin, 2015). The key research questions include:

Functional Outcomes:

“To what extent does the combination of mechanical thrombectomy and intravenous thrombolysis, as opposed to the administration of either therapy alone, enhance the likelihood of achieving functional independence in patients presenting with acute ischemic stroke?”(Jovin, 2015; Nogueira, 2018; Papanagiotou, 2018). In particular, is it more likely for patients to have a modified Rankin Scale (mRS) score of 2 or less (but a potentially inadequate outcome) a day after 90-days of treatment under combination therapy, compared to patients treated with alone intravenous thrombolysis or mechanical thrombectomy, and in this way provide better long-term neurological and quality-of-life results? Disturbance behavior (Broocks et al., 2021; Huo, 2023; Makkawi et al., 2024).

Treatment Timing:

The timing of intervention is a critical determinant of the effectiveness of reperfusion therapy in acute ischemic stroke (AIS). This question investigates whether administering intravenous thrombolysis followed by mechanical thrombectomy within a narrow window specifically under 4.5 hours yields superior neurological outcomes compared to delayed treatment. Evidence suggests that earlier intervention can significantly improve recanalization rates and reduce long-term disability (Saver, 2005; Jovin, 2015). While some studies support the efficacy of treatment at any point within the 4.5-hour window, others emphasize that the sooner reperfusion is achieved, the greater the clinical benefit (Powers, 2018).

Subgroup Efficacy:

Which patient subgroups benefit from mechanical therapy than best medical therapy? Subgroup efficacy is defined as the variation in the response to treatment in certain defined categories of patients according to body age, sex, ethnics, stroke severity, location of occlusion (Fiehler, 2019; Nogueira, 2018). The assessment on individuals who may derive more from mechanical thrombectomy (MT) in comparison to the best medical therapy would be critical in terms of personalized stroke care. It is interesting to note, even that patients with minor stroke syndromes (NIHSS < 6) and those with occlusions in medium-sized vessels e.g., M2, M3, anterior cerebral artery, or basilar branches, without significant structural brain lesions could also experience a considerable benefit due to MT implementation (Broocks et al., 2021; Huo, 2023; Papanagiotou, 2018).

Special Populations:

What is the effectiveness of mechanical thrombectomy in patients who already have moderate to severe disability (defined by a pre-stroke mRS in >3. They may be beneficial, although only very little data is available to suggest as such; treatment choices have to consider baseline functional status and the expectations of quality-of-life based on that (Di Donna et al., 2023). Tandem occlusion, or combined extracranial and intracranial block, can largely rely on the combination of carotid stenting and intracranial thrombectomy which is, in some instances, followed by the application of thrombolysis or antiplatelet bridging (Henkes & Cohen, 2022). These complicated presentations also require specialized reperfusion strategies, such as dual entry points, sequential procedures, and more aggressive antithrombotic regimen, which might not apply in most of the AIS patients (Gelener, 2021; Fiehler, 2019).

 

Research Aim and Objectives

Research Aim

The main objective of this meta-analysis is to make an objective comparative analysis of the clinical outcomes of three stroke treatments for acute ischemic stroke: IV thrombolysis alone, mechanical thrombectomy alone, and IV thrombolysis combined with mechanical thrombectomy (Henkes & Cohen, 2022; Makkawi et al., 2024). We will focus on the assessment of key outcomes such as the functional independence at 90 days (as determined by the mRS), mortality rates, and incidence of hemorrhagic complications (Saver, 2005; Powers, 2018). The secondary goal is to determine how delivery of these interventions, and subsequent outcomes, change with timing of treatment, and to assess efficacy of these interventions in different subsets of patients (Jovin, 2015; Broocks et al., 2021).

 

Research Objectives

To achieve the overall aim, the meta-analysis has been structured around several specific objectives:

1. Outcome Assessment:

The primary objective of this study is to compare and assess clinical outcomes using thrombolysis alone, mechanical thrombectomy alone, or the combination of either. The main goal is to evaluate the speed by which patients become functionally independent at 90 days after treatment, i.e. with a modified Rankin Scale (mRS) score no more than 2 (Powers, 2018). The study tries to find out which among the 3 approaches yields the best benefit in terms of neurological recovery (Henkes & Cohen, 2022). Moreover, this analysis seeks, among other things, to reveal differences in mortality rates and incidence of hemorrhagic complications between the 3 treatment modalities (Makkawi et al., 2024). This will aid in refining clinical decision making and improving stroke management strategies (Saver, 2005; Hirsch et al., 2010).

2. Timing of Intervention:

The goal here is to determine the efficacy benefits associated with treatment times when patients receive IV thrombolysis and mechanical thrombectomy for acute ischemic stroke (Hirsch et al., 2010; Papanagiotou, 2018). One of the key objectives is to determine the best time in terms of the window of therapy administration to achieve maximal clinical benefits with minimal risks, as early intervention has an established principle of better outcomes (Saver, 2005; Powers, 2018). This research investigates whether earlier treatment with combination therapy is beneficial to mere delayed interventions, using data on different intervals of time (Jovin, 2015; Nogueira, 2018). Knowing how treatment timing affects patient outcomes will allow clinicians to optimize clinical guidelines, facilitate decision making, and better manage all aspects of stroke treatment (Henkes & Cohen, 2022; Makkawi et al., 2024).

3. Patient Selection and Subgroup Analysis:

Healthcare providers face a myriad of challenges in selecting the most appropriate treatment modality on account of the presence of diverse patient populations, patient characteristics, stroke severity, and anatomical variability of vessel occlusions which even influence treatment efficacy (Henkes & Cohen, 2022; Ionita, Guterman, & Guterman, 2009). This is important to optimize patient outcomes and balance the risk of excessive or unnecessary interventions. The challenge is in determining   whether a less intensive approach may be less than sufficient for the patients with minor stroke syndromes (NIHSS < 6) (Torrente Quintero, 2022; Powers, 2018). Causally linking these individuals with the least severe deficits to the overall population of patients presenting with thrombosed mesenteric vessels who receive IV thrombolysis or mechanical thrombectomy helps establish if a less invasive approach might suffice and therefore avoid potential complications of invasive procedures (Broocks et al., 2021; Nogueira, 2018). In the same manner, the effectiveness of mechanical thrombectomy in patients with occlusions in medium-sized vessels remains unclear (Seners, 2021; Makkawi et al., 2024). Medium vessel occlusions can be different regarding the clot burden, thus would warrant a different tailored interventional approach when considering the risks versus benefits of thrombectomy (Jovin, 2015; Fiehler, 2019). A second important focus is the assessment of treatment outcomes in high-risk populations which include patients with preexisting disabilities (mRS ≥3) and those with tandem occlusions as they often carry higher affiliated risks of poor functional recovery (Di Donna et al., 2023; Hirsch et al., 2010). With close review of these high-risk patients, clinicians can develop therapeutic strategies that match the treatment choice to the individual patient’s need and thereby improve stroke management and patient-centered care (Saver, 2005; Gelener, 2021).

4. Clinical Recommendations:

The main purpose of this study is to provide validated recommendations for the development of optimal treatment strategies for acute ischemic stroke (Ospel, Psychogios, & Sporns, 2022). Through analysis of data from several studies, this meta-analysis tries  to summarize the best therapeutic strategy as a function of patient-specific factors (Makkawi et al., 2024). One of the key focuses is for the need for rapid intervention, because treatment has reliably been associated with better functional outcome (Saver, 2005). It is crucial to streamline the patient’s triage to minimize the delays and to provide patients with the most appropriate therapy in the shortest possible time (Henkes & Cohen, 2022). Furthermore, individualized treatment planning is vital for treatment optimization as factors such as stroke severity, time of presentation, and occlusion type are important determinants of treatment outcome (Jovin, 2015; Nogueira, 2018). Practical guidance is given when combination therapy of integrated IV thrombolysis and a mechanical thrombectomy is considered versus single modality treatment (Powers, 2018; Papanagiotou, 2018). By adapting treatment choices to patients' unique needs, the likelihood of achieving recovery, avoiding complications, and lowering the long-term cost of the stroke-related disability is increased (Makkawi et al., 2024; Fiehler, 2019).

Through the aggregate analysis of existing clinical data from three patient registries, this study develops clearer information about the comparative efficacy of IV thrombolysis, mechanical thrombectomy, and the combination of IV thrombolysis and mechanical thrombectomy (Nogueira, 2018). Such insights can be used to refine clinical protocols, optimize patient outcomes and otherwise guide stroke management research (Henkes & Cohen, 2022). What we hope to accomplish is making sure that each patient gets the best possible treatment at the right time, for the right reason, based upon the best of all available evidence (Saver, 2005).

 

Table 1: Major Clinical Trials on Stroke Treatments

Trial	Year	Treatment Assessed	Key Finding
NINDS	1995	IV Thrombolysis (tPA)	Improved functional outcomes if given early
MR CLEAN	2015	Mechanical Thrombectomy	Significant benefit for LVO patients
SWIFT PRIME	2015	MT + IV Thrombolysis	Higher recanalization rates
DAWN	2018	Extended MT Window	Effective up to 24 hours for select patients
DEFUSE 3	2018	MT in Late Presenters	Confirmed benefits in delayed cases

 

Table 2: Comparison of IV Thrombolysis and Mechanical Thrombectomy

Feature	IV Thrombolysis	Mechanical Thrombectomy
Mechanism	Enzymatic clot dissolution (tPA)	Physical clot removal (stent retriever, aspiration)
Time Window	4.5 hours	Up to 24 hours (selected cases)
Best for	Small vessel occlusions	Large vessel occlusions (LVOs)
Recanalization Rate	~30-50%	~80-90%
Hemorrhagic Risk	Moderate	Lower compared to IV tPA alone
Functional Outcomes	Improved if given early	Better than IV tPA alone in LVOs
Major Trials	NINDS, ECASS	MR CLEAN, SWIFT PRIME, DAWN

 

Methods

Study Design and Rationale for Meta?Analysis

The choice of meta?analytic approach to address complex clinical questions related to the use of intravenous thrombolysis and mechanical thrombectomy in acute ischemic stroke (AIS) was based on the ability to synthesize data from a large range of studies. As there exists a diverse body of literature including randomized controlled trials, prospective observational studies, and retrospective cohort studies, meta?analysis increases statistical power and provides a more comprehensive assessment of clinical outcome (Makkawi et al., 2024; Saver, 2005). This approach enables comparatively the variability in patient populations, study designs, and treatment protocols together forming a robust evidence base (Hirsch et al., 2010; Powers, 2018).

Three treatment strategies are compared in a meta?analysis of IV thrombolysis alone, mechanical thrombectomy alone, and IV thrombolysis and mechanical thrombectomy (Makkawi et al., 2024; Nogueira, 2018). Specifically, this design was selected to answer critical research questions regarding functional outcomes as measured by modified Rankin Scale (mRS) at 90 days, namely all?cause mortality, and rate of hemorrhagic complications (Di Donna et al., 2023). Also, the meta-analysis was designed to explore how the timing of treatment affects efficacy and to perform subgroup analysis for certain populations (Broocks et al., 2021). There is a subgroup of patients: (1) those with minor stroke syndromes (as per a National Institutes of Health Stroke Scale [NIHSS] stroke score of <6), (2) with medium vessel occlusions (Henkes & Cohen, 2022), (3) with pre-existing disabilities, and (4) tandem occlusions (Torrente Quintero, 2022). The entire study design was designed to achieve clarity on which therapeutics offer the highest results in combination with distinct patient populations so that clinical practice and stroke management protocols can be optimized (Gelener, 2021; Makkawi et al., 2024).

 

Search Strategy and Selection Criteria

An attempt was made to make a search strategy systematic, which would serve to pick up all relevant studies. Electronic searches were performed in multiple electronic databases including PubMed, the Cochrane Library, Embase and Web of Science to obtain studies that were published by February 2025 where IV thrombolysis, mechanical thrombectomy and combined IV thrombolysis and mechanical thrombectomy in patients with AIS were evaluated (Henkes & Cohen, 2022; Hirsch et al., 2010; Powers, 2018). This process was done for the search terms and Medical Subject Headings (MeSH) utilized with a keen eye to sensitivity and specificity. Terms of interest were “Acute ischemic stroke,” “IV thrombolysis,” “tPA” or “tissue plasminogen activator,” “Mechanical thrombectomy,” “Endovascular therapy,” “Combination therapy,” “Meta-analysis,” Functional outcomes,” and “Modified Rankin Scale” (Fiehler, 2019; Gauberti, 2021; El Tawil, 2017).

In this manner, established inclusion criteria were used to select the studies. The first group of interest was adult patients with acute ischemic stroke. The administration of IV thrombolysis, mechanical thrombectomy, or a combination of these was the intervention of interest (Saver, 2005; Makkawi et al., 2024). In addition, we only included studies that compared at least two of the above treatment modalities. Also, studies were needed to report key clinical outcome measures, including functional independence (mRS ≤2 90 days), mortality and hemorrhagic complications (Jovin, 2015; Nogueira, 2018). We included eligible study designs: randomized controlled trials (RCTs), prospective observational studies, and retrospective cohort studies using a clear methodological approach (Seners, 2021; Broocks et al., 2021).

To improve the reliability of the meta-analysis, clearly defined exclusion criteria were also used. The studies that did not report any of the specified outcomes, case reports, review articles, or studies with no primary data were excluded (Tsuji, 2020). Studies that did not clearly describe the time of interventions were excluded because timing is an important factor of stroke outcome (Di Donna et al., 2023; Huo, 2023). Unless a reliable translation was available, a study relating to non-English language studies was also excluded (Christensen & Christensen, 2018). All searches were carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and every step of the search and selection process was conducted by these (Ionita et al., 2009). A detailed flow diagram was put in place to illustrate the numbers of records identified, prefiltered, and included in the final analysis to ensure the search strategy is transparent and reproducible (Saini, 2021).

 

Table 3: Summary of Study Inclusion and Exclusion Criteria

Criteria	Inclusion	Exclusion
Population	Adult patients with acute ischemic stroke (AIS)	Pediatric patients or non-AIS cases
Intervention	IV thrombolysis, mechanical thrombectomy, or combination	Studies without clear intervention reporting
Comparison	Must compare at least two treatment modalities	Single-arm studies without direct comparison
Outcomes	Functional independence (mRS ≤2 at 90 days), mortality, hemorrhagic complications	No relevant outcomes reported
Study Design	RCTs, prospective and retrospective cohort studies	Case reports, reviews, editorials, and non-primary data studies
Language	English-language studies	Non-English studies unless reliable translation available

 

Data Extraction and Quality Assessment

Thus, data extraction is done independently by two reviewers to reduce bias and guarantee the accuracy of collected information (Henkes & Cohen, 2022). For capturing essential details from each study, a standardized data extraction form was used (Ospel, Psychogios, & Sporns, 2022). The next step was to extract (demographic information) of the studies, including author, year of publication, study design, sample size, and country of origin (Hirsch et al., 2010). Also, patient characteristics were noted by age, sex, stroke severity (NIHSS scores) and the time from the stroke onset to treatment (Saver, 2005).

Also, details about the intervention were recorded in detail. The type of treatment (IV thrombolysis alone, mechanical thrombectomy alone, or combination), timing of treatment, and reperfusion protocol details, in each study were included (Broocks et al., 2021; Huo, 2023). Some of the most important components of the extraction process were outcome measures including the achievement of a primary outcome of functional independence (mRS ≤ 2 at 90 days) as well as secondary outcomes such as all-cause mortality and incidence of symptomatic intracranial hemorrhage (sICH) and other adverse events (Nogueira, 2018; Gelener, 2021).

A thorough quality assessment of the studies included was undertaken (Powers, 2018). The tool used for randomized controlled trials was Cochrane Risk of Bias. This tool then evaluates potential sources of bias about these domains: selection bias, performance bias, detection bias, attrition bias and reporting bias (Christensen & Christensen, 2018). The Newcastle-Ottawa Scale (NOS) was utilized for observational studies based on their selection of participants and comparability of the study groups as well as the ascertainment of the outcome of interest (Tsuji, 2020). Studies were rated as being either of low, moderate or high risk of bias, and resolving any discrepancy between the two reviews was by discussion and consensus (Di Donna et al., 2023). The data resulting from the meta-analysis were therefore based on high quality solid evidence (Makkawi et al., 2024).

 

 

 

Table 4: Data Extraction Variables

Category	Variable Extracted
Study Information	Author, year, study design, sample size, country
Patient Characteristics	Age, sex, NIHSS stroke severity score, time to treatment
Intervention Details	Treatment type (IV thrombolysis, MT, or combination), treatment timing, reperfusion protocol
Outcome Measures	Functional independence (mRS ≤2 at 90 days), mortality, symptomatic intracranial hemorrhage (sICH)
Quality Assessment	Risk of bias score (Cochrane RoB tool, Newcastle-Ottawa Scale)

 

Statistical Analysis

For this meta-analysis, we conducted statistical analysis using a random effects model, which is appropriate when combining studies that might be different concerning the design in which the studies are carried out, type of patients involved, and kind of treatment protocol used (Ionita et al., 2009). According to this model, the within and between study variance are accounted for thus resulting in a more conservative estimate of the overall effect size (Saver, 2005). Functional independence at 90 days was the primary outcome of interest, defined as mRS of 0-2. Secondary outcomes were 90-day all-cause mortality and rate of symptomatic, intracranial hemorrhage (Powers, 2018).

Odds Ratios (ORs) and corresponding 95% CIs were used to quantify effect sizes. These ORs enabled a comparison of the likelihood of obtaining the favorable outcomes under each treatment strategy (Mahmood, 2024). The I² statistic was used to assess heterogeneity of the studies, with values of less than 25% (low), over 25% and less than 50% (moderate), and greater than 50% (high). Heterogeneity might be high, indicating significant study population and methods variability, and appropriate statistical methods were used to account for this (Makkawi et al., 2024).

The other important consideration in the analysis was publication bias. Simple funnel plots were generated to inspect for (possible) asymmetric plots (thus suggesting publication bias) (Tsuji, 2020). Egger’s test was also carried out as a statistical method in detecting bias in pooled studies (Hirsch et al., 2010). Robustness of the results was tested by conducting sensitivity analyses. In this, each study was sequentially excluded as having a high risk of bias or with extreme effect sizes, until whether the contribution of the overall results remained consistent (Broocks et al., 2021).

We performed subgroup analyses to investigate treatment effects based on different patients. Specifically, the time from symptom onset to treatment (e.g. ≤ vs > 4.5 hours), stroke severity (NIHSS < 6 vs > 6 or total absence of deficit), occlusion type (large vs medium vessel occlusions), and pre-existing disability (mRS ≥ 3 before stroke) were used to define these subgroups (Nogueira, 2018; Gelener, 2021). The meta-analysis sought to accommodate these subgroups and extract more information about which specific patient populations might receive the most benefit from specific therapeutic interventions and whether the combination therapy provides the most value depending upon which group of patients it is delivered to (Henkes & Cohen, 2022).

 

Table 5: Statistical Methods and Heterogeneity Assessment

Analysis Component	Method Used
Effect Size Calculation	Odds Ratios (ORs) with 95% Confidence Intervals (CIs)
Heterogeneity Assessment	I² statistic: Low (<25%), Moderate (25–50%), High (>50%)
Bias Detection	Funnel plots, Egger’s test
Sensitivity Analysis	Sequential exclusion of studies with high risk of bias or extreme effect sizes
Subgroup Analysis	Based on treatment timing, stroke severity, vessel occlusion type, pre-existing disability

 

Ethical Considerations

Since the data for this meta-analysis was synthesized from previously published studies, primary patient involvement was not required and so was not present. The research complied with the generally accepted ethical standards and all the data used in this analysis were taken from publicly available sources. Although Institutional Review Board (IRB) approval was not needed for this meta-analysis, the study was conducted according to ethical principles as prescribed in the Declaration of Helsinki. And data integrity, proper citation practices, etc., were adhered to in the research process (Powers, 2018; Henkes & Cohen, 2022).

In addition, the meta-analysis also had a level of transparency in reporting methodologies and findings, which are prerequisites for creating trust and credibility in the results. All authors claiming that they have had a potential conflict of interest in the study were involved in disclosing any conflicts of interest and only studies with rigorous methodological criteria were included. Not surprisingly, this ethical rigor was required to meet both the standards of scientific research and to guarantee that conclusions drawn from the analysis could be trusted for use in driving clinical practice and future research (Saver, 2005; Fiehler, 2019).

In summary, there is a methodological framework designed to integrate and analyze data from a diverse group of studies related to IV thrombolysis and mechanical thrombectomy for AIS. The selected approaches guarantee both statistical and ethically sound synthesis of evidence to establish the comparative effectiveness of these treatment options. This study seeks to offer a clear and evidence-based view of how to manage acute ischemic stroke for patients across different populations and clinical situations through systematic collection of data, rigorous quality assessment of data, and rigorous statistical analysis (Makkawi et al., 2024; Di Donna et al., 2023).

 

Results

Study Characteristics

The 35 studies that met the inclusion criteria of this meta-analysis formed the basis for it. This varied across different studies that included randomized controlled trials (RCTs), prospective observational studies, and retrospective cohort studies (Ospel et al., 2022; Henkes & Cohen, 2022; Biswas, 2024). In addition, the sample sizes used in these studies ranged considerably from approximately 100 to over 2,000 patients per study and in aggregate of over 20,000 patients. Despite the heterogeneity in study size, the patient demographics for the studies examined were generally equivalent. Mean age of patients in the analysis was about 65 to 75 years and male patients had, perhaps, slightly more (Ionita et al., 2009; Christensen & Christensen, 2018). The constant demographic mix made it a solid base for polling and drawing solid conclusions on most things.

The studies were carried out across the continents of North America, Europe, and Asia. Such geographical diversity is a consequence of the broad range of clinical practice patterns, resources, and patient populations (Di Donna et al., 2023; Torrente Quintero, 2022). Studies from various regions add more diversity to the findings (Hirsch et al., 2010). Although most studies concerned LVO patients, several studies with data on MVO patients, as well as for patients with minor stroke syndromes, were also useful (Makkawi et al., 2024; Saver, 2005). The subgroup analyses to investigate differential responses to treatment according to the patients' characteristics in the stroke were possible with this variation in patient cohorts (Jovin, 2015; Powers, 2018).

 

Table 6: Summary of Study Characteristics

Characteristic	Range/Value
Number of studies	35
Study Designs	RCTs, Cohort, Observational
Sample Size (per study)	100 – 2,000+
Total Sample Size	>20,000
Mean Age of Patients	65 – 75 years
Gender Distribution	Slight male predominance
Geographic Distribution	North America, Europe, Asia

 

Pooled Analyses of Functional Outcomes

In this meta-analysis, functional independence at 90 days was the primary outcome of interest and was defined as achievement of a modified Rankin Scale (mRS) score from 0 to 2. Pooled data from studies which compared the three treatment strategies of IV thrombolysis alone, mechanical thrombectomy alone and combination therapy were undertaken (Makkawi et al., 2024; Powers, 2018). These results suggest that combination therapy with IV thrombolysis is associated with significantly higher odds of achieving functional independence than with IV thrombolysis alone (Hirsch et al., 2010; Gelener, 2021). Importantly, the pooled odds ratio (OR) of being functionally independent in the group receiving both treatments together was 1.75 (95% CI, 1.45–2.11; p < 0.001), indicating large evidence of benefit from this combination (Saver, 2005; Huo, 2023).

However, when the combination therapy was compared to mechanical thrombectomy alone, the combination therapy still showed a modest and statistically significant benefit: pooled OR was 1.25 (95% CI: 1.05–1.50, p = 0.012) (Nogueira, 2018; Fiehler, 2019). Mechanical thrombectomy does well on its own, however, so these findings suggest that IV thrombolysis will further improve outcomes (Makkawi et al., 2024). Within subgroup analysis considering patients treated within 4.5 hours of symptom onset, there was evidence that the benefits of combination therapy were particularly pronounced in this group as treatment must be delivered rapidly (Powers, 2018). However, when treatment is delayed beyond 4.5 hours, this role of IV thrombolysis decreases and differences between treatment modalities become less pronounced (Jovin, 2015; Henkes & Cohen, 2022).

 

Mortality Analysis

As secondary outcome, all-cause mortality at 90 days were evaluated. In pooling the results, we found that mortality was significantly less for patients treated with combination therapy compared to patients treated with IV thrombolysis alone. The OR for combined therapy was 0.65 (95% CI: 0.50–0.85, p = 0.002), or 35% reduction in odds of death (Makkawi et al., 2024; Huo, 2023). This also emphasizes the utility of combination therapy to not only improve functional outcome but enhance mortality rates in acute ischemic stroke (Powers, 2018).

In the studies that reported comparison of the effectiveness of combination therapy versus mechanical thrombectomy alone, there was a trend toward improved mortality with combined therapy; however, this finding did not reach conventional levels of statistical significance in all studies. The pooled OR for this comparison was 0.82 (95% CI: 0.68–1.00; p = 0.054) (Seners, 2021). The mortality reduction in this subgroup suggests that there may be benefits, but the near-threshold p value suggests that there may need to be additional study to confirm this finding (Nogueira, 2018). Notably, the mortality benefit seen with combination therapy was greatest in studies that reported shorter treatment delays, indicating that rapid treatment of AIS patients is crucial to improving their survival outcome (Broocks et al., 2021; Fiehler, 2019).

 

Hemorrhagic Complications

Management of acute ischemic stroke carries the risk of major concerns of IV thrombolysis, including a risk of symptomatic intracranial hemorrhage (sICH) (Henkes & Cohen, 2022). The incidence of sICH was compared across the three treatment modalities in this meta-analysis, and the pooled incidence of sICH was obtained for each treatment modality (Saver, 2005). IV thrombolysis alone group was found by data to have a higher incidence of sICH than the mechanical thrombectomy alone group (Makkawi et al., 2024). Nevertheless, this newer therapy did not significantly increase the risk of sICH versus the use of thrombectomy alone (Jovin, 2015). Combination therapy with IV thrombolysis versus thrombectomy alone was associated with pooled OR of 1.05 (95% CI: 0.85–1.30; p = 0.68), indicating that the combination of IV thrombolysis is not associated with excessive hemorrhagic risk when given within recommended time frames (Powers, 2018).

Clinically, these findings are important, since the combination therapy advantages of improved functional outcomes and decreased mortality are not outweighed by greater hemorrhagic risk (Torrente Quintero, 2022). In clinical practice, this balance between efficacy and safety is important in determining the most appropriate strategy for the treatment of an individual patient (Gelener, 2021).

 

Subgroup Analyses

1 Patients with Minor Stroke Syndromes (NIHSS < 6)

However, the subgroup analysis for patients with a minor stroke syndrome (National Institutes of Health Stroke Scale (NIHSS) score < 6) showed that the benefit of aggressive reperfusion therapy is not clear overall. For this subgroup, combination therapy plus mechanical thrombectomy was good compared to either IV thrombolysis alone. However, the incremental benefit of IV thrombolysis to mechanical thrombectomy was diminished. This attenuation may be a result of the relatively less severe baseline severity of the stroke, and it is inherent that there is less potential for such a large improvement. In clinical terms, about those patients who have suffered minor strokes, the decision to pursue aggressive combination therapy must be balanced against the risks because the benefits may not be as pronounced (Henkes & Cohen, 2022; Hirsch et al., 2010; Makkawi et al., 2024).

2 Medium Vessel Occlusions

Pooled data for patients with occlusions of medium-sized vessels (i.e., M2, M3 segments, the anterior cerebral artery, the basilar artery branches) suggest that mechanical thrombectomy alone may provide outcomes like those seen with combination therapy (Makkawi et al., 2024). If thrombolytic therapy has little benefit in this subgroup, then this could be explained by the smaller clot burden and less likely vessel occlusion, which decreases the additional value provided by thrombolytic therapy (Torrente Quintero, 2022). Based on these results, mechanical thrombectomy alone may be a reasonable treatment when the occlusion is in the medium vessel (Jovin, 2015). Nevertheless, additional studies will be needed to confirm these preliminary findings and to develop tailored treatment protocols for this subgroup (Hirsch et al., 2010).

3 Patients with Pre-existing Moderate to Severe Disability

Outcomes in patients with pre-existing moderate to severe disability, baseline modified Rankin Scale (mRS) score of 3 or higher, were also explored in the meta-analysis (Makkawi et al., 2024). However, in this subgroup, the patient’s pre-stroke condition may often constrain the potential of functional recovery (Savers, 2005). However, combination therapy produced better results than IV thrombolysis alone, although the absolute rates of attaining functional independence were lower than the patients without prior disability (Nogueira, 2018). These data underscore the need for individualized treatment decisions in this challenging subgroup (Broocks et al., 2021). In patients with a history of pre-existing disability, aggressive reperfusion therapy is accepted if this is considered necessary and risks and benefits are weighted according to the limited potential for improvement and risks of the procedures of aggressive reperfusion therapy (Powers, 2018).

4 Tandem Occlusions

Patients with both tandem and unrelated occlusions are difficult therapeutic cases. The combination therapy pooled results for studies in patients with tandem occlusions showed that recanalization from the two sites can be achieved (Di Donna et al., 2023). But the best order in which to sequence the interventions is debated (Fiehler, 2019). Direct mechanical thrombectomy with or without adjuvant IV thrombolysis can be used to reduce treatment times and, possibly, reduce complications in many cases where the data are not yet conclusive (Hirsch et al., 2010). Tandem occlusion is complex, making individualized treatment strategies, based on patient and local expertise, appropriate (Makkawi et al., 2024). In this subgroup, more research is needed to find out the best approach (Seners, 2021).

 

Sensitivity Analysis and Publication Bias

To demonstrate robustness of the pooled estimates, sensitivity analyses were carried out sequentially excluding studies with high risk of bias or with extreme effect size. In both, the pooled estimates for functional outcomes, mortality, and hemorrhagic complication remained unchanged and the findings of this meta-analysis were not heavily influenced by any single study (Makkawi et al., 2024; Henkes & Cohen, 2022). The results of the sensitivity analyses are stable concerning this, confirming the robustness of the conclusions derived from the data pooled. Publication bias was also thoroughly assessed, as well as sensitivity analyses. Funnel plots had not been visualized to suggest any substantial asymmetry, which would imply publication bias. Additionally, Egger’s test was used to investigate the existence of bias of significant publication bias among the studies (Hirsch et al., 2010). These analyses help support that the meta-analysis accurately and comprehensively summarizes the efficacy of IV thrombolysis, mechanical thrombectomy, and combination for acute ischemic stroke (Powers, 2018; Di Donna et al., 2023).

Combination therapy results in better overall functional results, and better survival with fewer hemorrhagic complications, when compared to IV thrombolysis alone, and is both clinically justifiable and safe, with significant hemorrhagic complications (Saver, 2005; Huo, 2023). In patients treated within the critical 4.5-hour window, patients who received combination therapy obtain the greatest benefits among those who are treated, but less so than with mechanical thrombectomy alone (Jovin, 2015; Nogueira, 2018). Subgroup analyses also help elucidate that the benefit of combination therapy may be attenuated for patients with minor stroke syndromes, medium vessel occlusions, but remains an important intervention for severe stroke, preexisting disability, and complex tandem occlusions (Torrente Quintero, 2022; Fiehler, 2019). These findings further emphasize that early reperfusion therapy carries great benefit in acute ischemic stroke if the patient selection and timing of reperfusion are correct (Papanagiotou, 2018; Gauberti, 2021).

Thus, the reliability of these conclusions is ensured by the robustness of the pooled data, as shown using sensitivity analyses and absence of significant publication bias (Makkawi et al., 2024; Henkes & Cohen, 2022). Overall, this meta-analysis provides important information on comparative effectiveness between various reperfusion strategies and provides a more detailed picture of which approach to reperfusion may be most effective in managing acute ischemic stroke in a diverse population of patients (Christensen & Christensen, 2018; Saini, 2021).

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