Introduction

Acute ischemic stroke (AIS) is the primary cause of disability and mortality worldwide [1]. Recanalization is essential for salvaging the ischemic penumbra and improving the overall prognosis of AIS. Intravenous thrombolysis (IVT) is the first reperfusion therapy that is effective for AIS [2]. Several pivotal randomized-controlled trials in 2015 [3,4,5,6,7,8] demonstrate that endovascular thrombectomy (EVT) is more effective than IVT in improving the prognosis of patients suffering from AIS due to a large vessel occlusion (LVO). Guidelines have recommended IVT combined with EVT for patients who meet the criteria for both treatment modalities [9,10,11].

Several recent studies have shown conflicting results when comparing the outcomes of IVT plus EVT versus EVT alone. For example, two randomized controlled trials (RCTs) [12, 13] have demonstrated that direct EVT is not inferior to IVT plus EVT in eligible patients, whereas other RCTs [14,15,16,17] have failed to establish non-inferiority or have suggested inferiority. This might be attributable to heterogeneity in the stroke population and the distinct reactions to IVT plus EVT. Hence, it is crucial to consider individual patient characteristics and variables when determining the optimal reperfusion strategy.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia and a significant risk factor for cardioembolic stroke, contributing to one-third of AIS cases worldwide [18]. It is associated with a five-fold increase in the incidence of AIS, leading to an inferior functional outcome and increased mortality in ischemic stroke patients [19]. The efficacy of IVT before EVT in patients with AF remains controversial [20]. Additionally, IVT before EVT may increase the risk of bleeding, particularly in AF patients receiving anticoagulant therapy [21]. Therefore, it is crucial to consider the potential benefits and risks of IVT before EVT in this patient population.

Given the clinical specificity and absence of randomized data on AIS-LVO patients with AF, we conducted a systematic review and meta-analysis to assess the safety and efficacy of IVT plus EVT and direct EVT in this patient population.

Methods

Data availability statement

All data generated or analyzed during this study are included in this article (and/or) in its supplemental materials.

Standard protocol approval, registration, and patient consent

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [22], and the study protocol (INPLASY202390015) has been registered with the International Protocol Registration Platform for Systematic Reviews and Meta-Analyses (INPLASY, https://inplasy.com/). This study does not require ethics committee approval or written informed consent from patients.

Data sources and study selection

RCTs or observational cohort studies were systematically searched in PubMed, EMBASE, and Cochrane Library using the keywords “stroke,” “atrial fibrillation,” “intravenous thrombolysis,” and “mechanical thrombectomy.” Studies were selected based on the following PICO (patients, interventions, comparators, and outcomes) criteria: (1) patients, AIS- LVO combined with AF; (2) intervention, IVT plus EVT; (3) comparator, direct EVT; and (4) outcomes, 3-month good clinical outcome (modified Rankin score of 0–2 [23]), symptomatic intracerebral hemorrhage (sICH), successful reperfusion (thrombolysis in cerebral infarction (TICI) scores of 2b to 3 [23]), and 3-month mortality.

The literature search was independently performed by 2 investigators (BQJ and HXD). The full search strategy is shown in Supplementary eTable 1.

Data extraction

Two investigators (BQJ and HXD) independently extracted data using a standardized form. Data extracted include data source, type of study, study duration, sample size, age, sex, baseline National Institutes of Health Stroke Scale (NIHSS), Alberta Stroke Program Early CT Score (ASPECTS), high blood pressure, diabetes, dyslipidemia, previous stroke, previous cardiovascular disease, smoking history, time from onset to admission, time from onset to puncture, time from puncture to reperfusion, first author’s name, year of publication, and primary endpoint(s).

Quality and risk of bias assessments

The risk of bias in each study was critically assessed by two independent investigators (BQJ and HXD) using the Newcastle–Ottawa Scale (NOS) [24]. Any discrepancies were resolved by discussion with the corresponding author (ZXQ). All studies were scored for selection, comparability, and outcomes. A study with an NOS score of 7 or higher is considered high quality.

Statistical analysis

In pairwise meta-analyses, the corresponding odds ratios (ORs) and 95% confidence intervals (95% CIs) for the outcome events were calculated for the direct EVT and IVT plus EVT groups. Pooled estimates were determined using a random effects model (DerSimonian and Laird) [25]. Statistical heterogeneity across trials was assessed by the Cochran Q test with a significance level of p < 0.1 and quantified by the I2 statistic [26], with an I2 value greater than 50% indicating substantial heterogeneity. Publication bias was evaluated using funnel plots. All statistical analyses were performed using Review Manager (RevMan v.5.3).

Results

Literature search and screening

Of the initially identified 1331 articles, 315 were removed due to duplication, and 1010 were excluded due to ineligibility. Six records were retained for full-text screening, and two additional studies were identified by expert advice. Ultimately, 8 studies [27,28,29,30,31,32,33,34], involving 6798 patients, met our inclusion criteria and reported relevant outcomes (Fig. 1).

Fig. 1
figure 1

Flow chart of literature search and study selection

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Study characteristics and risk of bias

Among the eight included studies, six [27,28,29, 31,32,33] were retrospective observational studies, and two [30, 34] were prospective observational studies. The number of patients per study ranged from 94 to 2311. Four studies [28, 29, 31, 34] were determined to be of good quality, and the other four studies [27, 30, 32, 33] were of acceptable quality (Supplementary eTable 2). Characteristics of eligible studies are summarized in Table 1.

Table 1 Descriptive characteristics of the included studies
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3-Month good clinical outcome

Seven studies [27,28,29,30,31,32, 34] compared the good clinical outcome of 6267 AIS-LVO patients with AF. Our data showed that IVT plus EVT was associated with good clinical outcomes at 3 months compared with EVT alone (OR, 1.27 [95% CI, 1.05–1.54]; P = 0.01) (Fig. 2). No significant heterogeneity was observed among studies (I2 = 43%; P = 0.10).

Fig. 2
figure 2

Forest plot of rates of good clinical outcome (defined as an mRS Score of 0-2)

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Successful reperfusion rate

Successful reperfusion rates were reported in 7 studies [27,28,29,30, 32, 34] involving 5,451 AIS-LVO patients with AF. The successful reperfusion rate was not significantly different between IVT plus EVT and direct EVT (OR, 0.98 [95% Cl, 0.83–1.17]; P = 0.84), and no heterogeneity was observed across studies (I2 = 0%, P = 0.91) (Fig. 3).

Fig. 3
figure 3

Forest plot of rates of successful reperfusion (defined as thrombolysis in cerebral infarction scores of 2b to 3)

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sICH

Six studies [27,28,29,30,31, 34] involving 3965 patients compared the incidence of sICH with and without IVT. The incidence of sICH showed no significant difference between the two groups (OR, 1.26 [95% CI, 0.91–1.75]; P = 0.17), and there was no between-study heterogeneity (I2 = 0%, P = 0.52) (Fig. 4).

Fig. 4
figure 4

Forest plot of rates of symptomatic intracerebral hemorrhage

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3-Month mortality

Eight studies involving 6798 patients [27,28,29,30,31,32,33,34] compared 3-month mortality with and without IVT. The IVT plus EVT group had a significantly lower mortality rate than the direct EVT group (OR, 0.78 [95% Cl, 0.68–0.88]; P = 0.0001), and no heterogeneity was observed among studies (I2 = 0%; P = 0.86) (Fig. 5).

Fig. 5
figure 5

Forest plot of rates of mortality

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Discussion

Our meta-analysis revealed that IVT plus EVT results in better clinical outcomes and lower mortality rates compared with direct EVT. The incidence of sICH and the rate of successful reperfusion were not significantly different between the two groups. In the absence of randomized data, this is the first study to systematically assess the efficacy and safety of IVT before EVT in AIS-LVO patients with AF.

For patients with AIS-LVO who are eligible for IVT and EVT, relevant guidelines recommend the initiation of combination therapy within 4.5 h of stroke onset [9,10,11]. Thrombolysis can enhance the efficiency of embolus dissolution, facilitate embolus removal, and reduce both the recanalization time and the rate of EVT. Furthermore, TICI 2C or 3 reperfusion has been shown to exhibit superior functional prognosis compared with TICI 2B reperfusion [35]. AF is associated with a decreased frequency of venous thrombosis recanalization [36, 37]. When managing AF, the impaired efficacy of venous thrombosis is believed to be caused by decreased collateralization, limiting the penetration of thrombolytic medications into the thrombus [38]. This, in turn, results in unfavorable clinical outcomes in AF patients who undergo bridging therapy. Our data demonstrated that IVT plus EVT led to a comparable successful reperfusion rate but greater good clinical outcomes and lower mortality rates than direct EVT. This is likely attributed to the increased density of blood clots due to the presence of red blood cells and interstitial fibrin. Both types of clots are dense, but they penetrate recombinant tissue plasminogen activators more easily than leukocyte-rich clots that contain densely packed platelets and cell debris. Since red blood cell clots typically occur in cardiac embolism and are more likely to lead to late spontaneous recanalisation [39], this may explain the lack of a significant association with successful reperfusion.

While we did not observe any advantage of IVT plus EVT in successful reperfusion rate compared with direct EVT, we found that pre-thrombolysis enhanced functional outcomes and reduced mortality. Cao et al. revealed that the rate of recanalization before intravascular therapy was notably higher in the bridging thrombolytic group than in the untreated group [29]. Consistent with our findings, Zhou et al. have reported that individuals who undergo early reperfusion show improved clinical outcomes, suggesting that a certain level of reperfusion should be achieved before EVT to optimize patient prognoses [40]. Furthermore, thrombolytic drugs are the most efficacious pharmacological therapy for AIS, greatly improving survival rates and reducing disabilities among cerebral infarction patients [41, 42].

Intracranial hemorrhage is the most serious complication of thrombolysis in stroke and an important obstacle in the wide application of thrombolytic therapy [43]. AF is an independent risk factor for hemorrhagic transformation following thrombolysis [44]. We found that prior IVT did not elevate the incidence of symptomatic bleeding in AF patients who subsequently underwent EVT. This evidence confirms the safety of IVT plus EVT.

The Stroke Guidelines in the USA, Europe, and China all recommend thrombolysis within 4.5 h of onset without impacting EVT [9,10,11]. Therefore, it is not justifiable to categorize AF patients based solely on the study by Akbik et al. [32], as this may limit the number of eligible patients for bridging thrombolysis therapy, subsequently hindering their chances of benefiting from the treatment. Our findings contribute to the redefinition of the clinical practices for bridging thrombolytic therapy in AIS-LVO patients with AF and lay the groundwork for future efforts. Nonetheless, the inconsistency in our results has undermined confidence in bridging thrombolytic therapy, and further RCTs are warranted to verify its efficacy.

Limitations

First, this is a post hoc analysis that solely relied on the retrospective analyses of prospective observational and retrospective observational. As a result, the results are susceptible to confounding factors. Second, due to limited available data, we were unable to further examine the differences between patients with and without AF. Third, treatment allocation was determined by treating neurologists, and functional outcomes were assessed by physicians blinded to treatment details, potentially introducing selection and confirmation biases, respectively. Last, we did not conduct an in-depth analysis of the effects of anticoagulants.

Conclusion

IVT plus EVT is a promising treatment for stroke patients with AF without raising the risk of sICH. Consequently, it is unjustified to dismiss thrombolytic treatment solely based on the presence of AF.