Introduction: This meta-analysis assessed the predictors of symptomatic intracranial hemorrhage (sICH) after endovascular thrombectomy (EVT) for patients with acute ischemic stroke. Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for studies published from inception to February 16, 2021. We included studies that evaluated the predictors of sICH after EVT. The random-effect model or fixed-effect model was used to pool the estimates according to the heterogeneity. Results: A total of 25 cohort studies, involving 15,324 patients, were included in this meta-analysis. The total incidence of sICH was 6.72 percent. Age (MD = 2.57, 95% CI: 1.53–3.61; p < 0.00001), higher initial NIHSS score (MD = 1.71, 95% CI: 1.35–2.08, p < 0.00001), higher initial systolic blood pressure (MD = 7.40, 95% CI: 5.11–9.69, p < 0.00001), diabetes mellitus (OR = 1.36, 95% CI: 1.10–1.69, p = 0.005), poor collaterals (OR = 3.26, 95% CI: 2.35–4.51; p < 0.0001), internal carotid artery occlusion (OR = 1.55, 95% CI: 1.26–1.90; p < 0.0001), longer procedure time (MD = 18.92, 95% CI: 11.49–26.35; p < 0.0001), and passes of retriever >3 (OR = 3.39, 95% CI: 2.45–4.71; p < 0.0001) were predictors of sICH, while modified thrombolysis in cerebral infarction score ≥2b (OR = 0.61, 95% CI: 0.46–0.79; p = 0.0002) was associated with a decreased risk of sICH. There were no significant differences in the female gender, initial serum glucose, initial ASPECT score, atrial fibrillation, oral anticoagulants, antiplatelet therapy, intravenous thrombolysis, general anesthesia, neutrophil-to-lymphocyte ratio, and emergent stenting. Conclusions: This study identified many predictors of sICH. Some of the results lack robust evidence given the limitations of the study. Therefore, larger cohort studies are needed to confirm these predictors.

© 2022 S. Karger AG, Basel

Introduction

Globally, stroke remained the second-leading level 3 cause of death (11.6%, 10.8–12.2 of total deaths) and the third-leading level 3 cause of death and disability combined in 2019 (5.7%, 5.1–6.2 of total disability-adjusted life-years), and its burden (in terms of the absolute number of cases) increased substantially from 1990 to 2019 [1]. In 2015, multiple landmark trials (MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, and EXTEND IA) established the superiority of endovascular thrombectomy (EVT) in combination with medical management over medical management alone for the treatment of anterior circulation large vessel occlusion stroke. In 2017, the DAWN and DEFUSE-3 trials successfully extended the time window up to 24 h in appropriately selected patients. Societal and national thrombectomy guidelines have incorporated these findings and offer class 1A recommendation to a subset of well-selected patients [2].

While the procedure is relatively safe, EVT is by no means entirely free of complications, with intracranial hemorrhage (ICH) the most feared [3]. Hemorrhagic complications after EVT include a broad spectrum of severity between small petechial hemorrhagic infarcts and parenchymal hematomas [4-6]. ICH, especially symptomatic ICH (sICH), strongly correlates with early neurological deterioration and poor clinical outcome [7]. This explains why sICH are mandatory safety outcomes of most acute ischemic stroke (AIS) randomized controlled trials (RCTs). Therefore, identifying predictors of sICH after EVT in patients with AIS and intervening in advance on the controllable risk factors are of great significance for clinicians to improve clinical prognosis. Previous reports have reported several risk factors for sICH in patients with AIS treated with MT [8-10]. Unfortunately, definitions of sICH varied widely among their studies, and each addressed their own potential predictors. Hence, the present systematic review and meta-analysis aimed to assess the most consistent predictors associated with sICH after EVT available for the management of patients with AIS.

MethodsLiterature Search

Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were performed in this study (online suppl. eTable 1; for all online suppl. material, see www.karger.com/doi/10.1159/000527193) [11]. One of the authors (Shuyang Dong) searched several databases (PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and Web of Science) from the inception date to February 1, 2022 to identify relevant articles evaluating the predictors of sICH after EVT for patients with AIS. The search terms were (1) Thrombectomy; (2) Thrombectomies; (3) Mechanical thrombectomy; (4) Endovascular treatment; (5) Endovascular therapy; (6) Revascularization; (7) Aspiration; (8) Stent retriever; (9) 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8; (10) Intracranial hemorrhage; (11) Symptomatic intracranial hemorrhage; (12) Hemorrhagic transformation; (13) Haemorrhagic transformation; (14) Parenchymal hematoma; (15) Brain hemorrhages; (16) 10 or 11 or 12 or 13 or 14 or 15; (17) Ischemic stroke; (18) Brain infarction; (19) Cerebral infarction; (20) Cerebral ischemia; (21) Cerebrovascular accident; (22) Cerebrovascular ischemia; (23) Cerebrovascular apoplexy; (24) 17 or 18 or 19 or 20 or 21 or 22 or 23; and (25) 9 and 16 and 24. Reference to reviews and eligible articles were also screened for additional articles. There were no language or publication-type restrictions. All the data used were secondary summary data; thus, our research required no ethical approval.

Inclusion Criteria and Exclusion Criteria

The studies were screened independently by two reviewers (Shuyang Dong, Qinbin Wu). Consensus or the help of a senior investigator (Chuanqing Yu) resolved disagreements. Study eligibility was based on if the following inclusion criteria were met: (1) patients had AIS and underwent EVT; EVT included aspiration, stent retriever, and rescue therapy (permanent intracranial stenting, balloon angioplasty, and intra-arterial thrombolysis); (2) follow-up CT or MRI (including gradient-echo T2-weighted imaging) to detect sICH within 30 days after EVT was completed; and (3) there were sufficient information for the reconstruction of two-by-two tables for the determination of the predictors of sICH after EVT.

Article exclusion was based on any of the following: (1) conference abstracts, reviews, letters, editorial, case reports including fewer than 10 patients, or animal studies; (2) reports just defining a study protocol, (3) studies not written in English, (4) non-comparative study or inappropriate groupings; and (5) insufficient data to reconstruct two-by-two tables even after attempting to contact the corresponding author.

Data Extraction

Two authors (Shuyang Dong and Tao Wang) independently extracted information on the lead author, publication year, country of origin, participant characteristics (number of patients, mean age, and gender), therapeutic drug doses, types of outcomes assessed, and trial duration. Consensus was resolved disagreements, and consulting a third author (Kun Gong) was necessary when a disagreement persisted. Information and data of interest reported were extracted from the original articles if the trials had more than 2 groups or factorial designs and permitted multiple comparisons. We extracted those fracture data from forest plots of the meta-analysis and reviewed original articles to confirm whether the trials met our inclusion criteria if a meta-analysis noted that the primary authors provided unpublished data. We pooled them with the data from primary trials.

Quality Assessment

The Newcastle-Ottawa scale was used to assess the methodological quality for the included trials independently by two researchers (Jialong Xu and Henglei Xia) based on the following three aspects: (1) participants selection, (2) study groups comparability, and (3) outcome [12]. The highest quality score is nine stars.

Data Analysis

This meta-analysis used the Cochrane Collaboration’s Review Manager Software Package (RevMan 5.4) and Stata 17. In our meta-analysis, we calculated the relative odds ratios (OR) and their corresponding 95% confidence intervals (CI) to measure the effect size of all the outcomes. The I2 statistic was used to test study heterogeneity [13]. If I2 ≤ 50%, this indicated no significant heterogeneity among studies, and a fixed-effect model was selected for further analysis. If I2 >50%, this indicated significant heterogeneity among studies, and a random-effects model was used for statistical analysis. If heterogeneity could not be ignored, we conducted a sensitivity analysis to determine heterogeneity source. Meta-analysis was conducted again after removing one or two studies at a time to investigate whether the results changed for the sensitivity. Publication bias was assessed by inspecting funnel plots for asymmetry and applying the Egger test for small study effects.

ResultsStudy Selection

Our search strategy retrieved 1,297 potentially relevant articles, 267 of which were duplicates. A total of 56 full-text articles were selected for further appraisal in the present study after removing duplicates and screening the titles and abstracts of all remaining unique articles. We excluded 30 citations because not all the patients underwent EVT (n = 10); outcomes did not include sICH (n = 8); studies lacked data or incomplete data (n = 7); partially overlapping cohorts (n = 5); and sICH was detected more than 30 days after EVT (n = 1). Eventually, 25 studies met our eligibility criteria [14-38]. The detailed selection process is shown in Figure 1.

Fig. 1.

Flow diagram of the study selection process.

Study Characteristics

The characteristics of the studies included for analysis are listed in Table 1. Studies were published between 2013 and 2021; nine were retrospective studies [18, 19, 22-25, 30, 34, 36, 38], eight were prospective registries [14-17, 20, 26, 27, 29, 31-33, 37], and two were prospective randomized studies [28, 35]. The sample size ranged from 59 to 4,180, with a total size of 15,324. Assessment of sICH varied across studies. The total sICH incidence was 6.72 (1,031/15,324). The European Cooperative Acute Stroke Study criteria (ECASS) defined sICH in 13 studies [14, 17-19, 21-23, 25, 26, 28, 30, 31, 37], whereas six used the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria [14, 16, 17, 23, 34, 35]. The Heidelberg Bleeding Classification was used in eight studies [20, 24, 29, 31-33, 36, 38]. The NINDS criteria were used to define sICH in two studies [26, 35]. The time from EVT to imaging sICH detection ranged from within 24 h to 7 days, with 48% of studies reporting the time of sICH evaluation as within 24 h after treatment. The general study quality was good, with NOS scores ranging from 6 to 9 stars. Specific items assessed for each study are presented in the online supplementary eTable 2.

Table 1.

Summary of studies included in meta-analysis

Predictors for sICH after EVTClinical Characteristics Related Predictors

The present study also showed that clinical characteristics, such as higher age (MD = 2.57, 95% CI: 1.53–3.61; p < 0.00001), higher initial NIHSS score (MD = 1.71, 95% CI: 1.35–2.08, p < 0.00001), higher initial systolic blood pressure (SBP) (MD = 7.40, 95% CI: 5.11–9.69, p < 0.00001), and diabetes mellitus (OR = 1.36, 95% CI: 1.10–1.69, p = 0.005), were predictors of sICH (Fig. 2). No significant heterogeneity was observed among age (I2 = 35%) and diabetes mellitus (I2 = 4%). Publication bias was not seen on funnel plots, and this outcome was confirmed on the Egger test (online suppl. eFig. 1a–c). However, significant heterogeneity was observed in the initial NIHSS score (I2 = 74%) and SBP (I2 = 99%), and an asymmetric state was seen on the funnel plot. The study by Sugiura et al. [21] and Desai et al. [27] was the main source of heterogeneity based on the sensitivity analysis of the initial NIHSS score. The heterogeneity was reduced significantly (I2 = 46%), and the funnel plot became more symmetrical after excluding the two studies (online suppl. eFig. 1b). The study by Neuberger et al. [24] and Zhang et al. [32] was the main heterogeneity source based on the sensitivity analysis of SBP. The heterogeneity was reduced significantly (I2 = 33%), and the funnel plot became more symmetrical after excluding the two studies (online suppl. eFig. 1d).

Fig. 2.

Forest plot of clinical characteristic-related predictors for sICH after EVT in patients with AIS: age (a), the initial NIHSS Score (b), diabetes mellitus (c), and systolic blood pressure (d). sICH, Symptomatic intracranial hemorrhage; EVT, endovascular thrombectomy; AIS, acute ischemic stroke; ICA, internal carotid artery; NIHSS, National Institute of Health Stroke Scale.

EVT-Related Predictors

Collateral scores were investigated in four studies, and the corresponding forest plot is shown in Figure 3a. Patients with poor collaterals were more prone to sICH after EVT (OR = 3.26, 95% CI: 2.35–4.51; p < 0.0001), as suggested by the pooled results using the fixed-effects model. Significant heterogeneity (I2 = 72%) was detected between studies. The sensitivity analysis of poor collaterals revealed that the main source of heterogeneity was the study by Semerano et al. [25]. Heterogeneity was reduced significantly (I2 = 0%), and the funnel plot became more symmetrical after excluding the study (online suppl. eFig. 1e).

Fig. 3.

Forest plot of EVT-related predictors for sICH in patients with AIS: pool collaterals (a), ICA occlusion (b), passes of retriever >3 (c), procedure time (d), and mTICI ≥2b (e). EVT, endovascular thrombectomy; sICH, symptomatic intracranial hemorrhage; AIS, acute ischemic stroke; ICA, internal carotid artery; mTICI, modified thrombolysis in cerebral infarction.

The proportion of internal carotid artery (ICA) occlusion was evaluated in 12 studies, and the forest plot was shown in Figure 3b. Patients with ICA occlusion were more likely to have sICH after mechanical thrombectomy based on the pooled results (OR = 1.55, 95% CI: 1.26–1.90; p < 0.0001). No significant heterogeneity bias was observed between the eight included studies (I2 = 26%). Funnel plots did not show publication bias, and the Egger test confirmed this outcome (online suppl. eFig. 1f).

The association of passes of retriever >3 and sICH after EVT and the forest plot shown in Figure 3c was evaluated in three studies. The pooled results revealed that passes of retriever >3 were more likely to have sICH after mechanical thrombectomy (OR = 3.39, 95% CI: 2.45–4.71; p < 0.0001). No significant heterogeneity bias was observed between the eight included studies (I2 = 0%). Funnel plots did not show publication bias, and the Egger test confirmed this outcome (online suppl. eFig. 1g).

Procedure time was a continuous variable. The association between time of puncture to reperfusion and sICH after EVT was revealed in all the included trials, and the forest plot was shown in Figure 3d. Pooled results showed that procedure time was significantly longer in patients with sICH after thrombectomy than in the non-sICH group (MD = 18.92, 95% CI: 11.49–26.35; p < 0.0001). Significant heterogeneity was observed (I2 = 76%). The sensitivity analysis of procedure time revealed that the main source of heterogeneity was the study by Zhang et al. [32] and Shen et al. [36]. Heterogeneity was reduced significantly (I2 = 0%), and the funnel plot became more symmetrical after excluding the two studies (online suppl. eFig. 1h).

Modified thrombolysis in cerebral infarction (mTICI) ≥2b was reported in nine studies and was shown in Figure 3e. The pooled results suggested that mTICI≥2b was a protective factor for the sICH risk (OR = 0.61, 95% CI: 0.46–0.79; p = 0.0002). Significant heterogeneity was observed (I2 = 55%). The sensitivity analysis of mTICI≥2b revealed that the main source of heterogeneity was the study by Semerano et al. [25] and Neuberger et al. [24]. The heterogeneity was reduced significantly (I2 = 12%), and the funnel plot became more symmetrical after excluding the two studies (online suppl. eFig. 1i).

Meta-analysis showed trends for associations of sICH risk with female gender, initial serum glucose, atrial fibrillation, the initial Alberta Stroke Program Early Computed Tomography (ASPECT) score, oral anticoagulants, antiplatelet therapy, intravenous thrombolysis, general anesthesia, neutrophil-to-lymphocyte ratio (NLR), and emergent stenting, but these were not statistically significant (online suppl. eFig. 2).

Discussion

This meta-analysis (twenty-five cohort studies with 15,324 cases) evaluated the predictors of sICH after EVT in patients with AIS and showed that higher age, a higher initial NIHSS score, diabetes mellitus, higher SBP, poor collaterals, ICA occlusion, passes of the retriever >3, mTICI ≥2b, and longer procedure time were predictors of sICH. There were no significant differences in the female gender, initial serum glucose, initial ASPECT score, atrial fibrillation, oral anticoagulants, antiplatelet therapy, intravenous thrombolysis, general anesthesia, neutrophil-to-lymphocyte ratio, and emergent stenting.

The total incidence of sICH was 6.72% in the present study. Any amount of blood detected on CT of a patient with neurological deterioration qualified as sICH in the NINDS rt-PA trial [39], whereas the ECASS-II investigators required an increase of more than 4 points on the NIHSS score and blood at any site on CT for this qualification [40]. These differences in the sICH definition make data comparisons between trials inexact. Still, they emphasize the importance of distinguishing symptomatic from asymptomatic ICH as a clinically relevant issue and a useful method in clinical trials of therapeutic agents in patients with AIS. The data from Berger and colleagues further suggested that only instances of sICH resulted in neurological deterioration in the acute phase and in worse outcomes at 3 months compared with asymptomatic ICH (aICH). Therefore, this meta-analysis defined sICH as the primary endpoint and attempted to evaluate the potential sICH predictors after EVT in patients with AIS.

In this study, 19 predictors from 25 clinical studies were enrolled for analysis. Clinical characteristics were identical for predicting sICH, such as higher age, a higher initial NIHSS score, diabetes mellitus, and a higher SBP. However, the meta-analysis of female gender, initial serum glucose, initial ASPECT score, atrial fibrillation, oral anticoagulants, antiplatelet therapy, intravenous thrombolysis, NLR for sICH were not significant. Therefore, hemorrhagic transformation should be closely monitored after thrombectomy for elderly patients, patients with diabetes mellitus, or patients with a higher initial NIHSS score or SBP. Dysglycemia has been shown to increase blood-brain barrier (BBB) damage, which increases the sICH risk and aggravates the degree of hemorrhage after reperfusion [41]. Notably, diabetes mellitus was associated with increased sICH risk but not initial serum glucose in this meta-analysis. The reason may be due to fluctuating glucose in diabetic patients have a more deleterious effect on endothelial function and oxidative stress in the brain tissues compared to those with constantly elevated glucose levels. This may lead to metabolic dysregulation and secondary brain injury by accelerating microvascular injury. Therefore, it is more necessary to routinely detect serum glucose levels before mechanical thrombectomy for patients with a previous history of diabetes.

Previous studies suggested atrial fibrillation was a strong risk factor for HT in AIS patients treated with endovascular therapy [42]. However, the present study indicates that atrial fibrillation was not associated with sICH risk. In recent years, this may be related to clinicians’ more scientific and rational oral anticoagulant use under the guidance of guidelines and RCTs [43, 44]. This study did not consider oral anticoagulants and antiplatelet therapy as the risk factors for sICH, which may partially support this hypothesis. NLR was not associated with sICH risk. Indeed, lymphopenia has been associated with increased HT in experimental severe stroke models, and T cells have been demonstrated to prevent HT from exerting a hemostatic function by their capacity to bind platelets through P-selectin [45]. Nonetheless, the lack of a significant association between sICH and admission leukocyte counts or NLR in the entire cohort suggests that the overall predictive value of lymphocyte counts on hemorrhagic risk is limited to certain conditions [25]. Further study will be required to verify this due to the limited sample size.

ICA occlusion, poor collaterals, passes of retriever>3, mTICI ≥2b, and procedure time were the predictors associated with increased risk of sICH when it comes to EVT-related factors. In contrast, in this meta-analysis, general anesthesia and emergent stenting were not associated with sICH risk in this meta-analysis. Previous studies have shown that intracranial hemorrhage may occur in high-grade atherosclerotic carotid artery stenosis by the rupture of dilated fragile compensatory pial vessels [46]. In addition, AIS caused by ICA occlusion is often accompanied by a large core infarct, which is one of the reasons why it is prone to hemorrhagic transformation. The above results are consistent with the results of this study.

This study found that the sICH risk was higher in patients with poor collaterals. The possible reasons are as follows: The penumbra cannot tolerate ischemia, and this intolerance leads to a massive cerebral infarction in the case of poor collateral circulation. The small vessels in the area surrounding the massive cerebral infarction will be compressed when cerebral edema occurs. The BBB integrity will be damaged with the ischemic and hypoxic time extensions. The BBB integrity depends on the tight junctions of the endothelial cells and the basal lamina. Thus, the BBB destruction will further induce endothelial cell damage and increase micro-vessel permeability, which leads to the leakage of red blood cells and other substances from the blood vessels and even HT, despite the vessels being recanalized within the treatment window [47].

Endovascular reperfusion therapy has limited existing data about time metrics. Kass-Hout et al. [19] supported an association between the sICH risk and a longer procedure time. In contrast, another data from Maros et al. [48] reported that more than three retrieval attempts were associated with a significant increase in sICH risk, regardless of procedure time. Our analysis demonstrated that both longer procedure times and passes of retriever >3 increased the risk of sICH after EVT. The longer procedure time may lead to the progression of ischemia, which may diminish the recanalization benefits and increase sICH risk. In addition, retriever pass may damage arterial intima and disrupt the BBB and subsequently increase the likelihood of sICH [49]. Therefore, it is a challenge for neuro-interventional physicians to choose the best approaches based on patient- and treatment-related factors to reduce the retriever pass number and procedure time to achieve recanalization as soon as possible.

Previous studies that assessed the recanalization effects on the sICH risk after EVT have inconsistent results [50, 51]. Unsuccessful reperfusion was reported to be an independent contributor to sICH in the Italian Registry of Endovascular Stroke Treatment in Acute Stroke [50]. Successful recanalization was also proven to be a protective factor for sICH risk in the present study. However, Bang et al. [51] performed a multicenter study. They showed that successful therapeutic recanalization with poor baseline collaterals might result in clinically significant hemorrhagic complications after endovascular therapy. The blind pursuit of successful recanalization may lead to prolonged procedure time, which may also increase the sICH risk after EVT. Therefore, relevant studies are still needed to further explore the effect of procedure time and collateral score on sICH in patients with successful recanalization.

There are several limitations to our study. First, there were four definitions of sICH in the included studies. Still, we had not unified the definition of sICH due to the limited number of studies included for each predictor, which may lead to some bias in the results. Second, we could not conduct a meta-analysis of all reported predictors because many were identified in only one study, such as CD4+CD25+ Treg-cell reductions in thrombi [8], low cerebral blood volume-ASPECTS [9], and early venous filling on angiographic imaging [52]. Third, the meta-analysis revealed that patients with ICA occlusion were more likely to have sICH after EVT. However, it is unclear whether ICA occlusion includes only atherothrombotic occlusion or also (cardiac) embolic ICA occlusion, which may occur with large emboli. This makes a difference concerning the procedure and periprocedural medication. Unfortunately, we could not further perform subgroup analysis on the association between different etiologies of ICA occlusion and sICH after thrombectomy because the included studies did not classify the etiology of ICA occlusion. Therefore, further high-quality RCTs are needed to investigate the effects of ICA occlusion caused by different etiologies on sICH after thrombectomy. Lastly, it was an independent predictor in the included studies for each variable. We could not assess the interaction between different variables in a systematic review. Whether these predictors have interacting effects should be investigated in further single studies.

Conclusion

Age, initial NIHSS score, diabetes mellitus, SBP, poor collaterals, ICA occlusion, passes of retriever >3, mTICI ≥2b, and longer procedure time were confirmed as a predictor of sICH after EVT in patients with AIS in this meta-analysis based on 25 cohort clinical trials. In addition, there were no significant differences in the female gender, initial serum glucose, initial ASPECT score, atrial fibrillation, oral anticoagulants, antiplatelet therapy, intravenous thrombolysis, general anesthesia, neutrophil-to-lymphocyte ratio, and emergent stenting. However, more evidence from high-quality RCTs is warranted to support our findings, considering these limitations in the study.

Acknowledgments

We would like to thank all the authors who helped in providing us with the data required for the analysis and for their valuable suggestions.

Statement of Ethics

An ethics statement is not applicable because this study is based exclusively on the published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported by the Natural Science Research Projects of Universities in Anhui Province (KJ2020A0337) and Anhui University of Science and Technology Youth Fund (FSYYYB2021-02).

Author Contributions

Shuyang Dong, Chuanqing Yu, and Tao Wang conceived and designed the study; Shuyang Dong performed search of the data; Qingbin Wu and Kun Gong conducted the systematic review and meta-analysis; Jialong Xu and Henglei Xia drafted and critically revised the manuscript. Final approval of the version to be published was given by Shuyang Dong, Chuanqing Yu, and Tao Wang.

Data Availability Statement

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

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