Intravenous thrombolysis and endovascular therapy for acute ischemic stroke in COVID-19: a systematic review and meta-analysis

Background The impact of COVID-19 on clinical outcomes in acute ischemic stroke patients receiving reperfusion therapy remains unclear. We therefore aimed to synthesize the available evidence to investigate the safety and short-term efficacy of reperfusion therapy in this patient population. Methods We searched the electronic databases MEDLINE, Embase and Cochrane Library Reviews for randomized controlled trials and observational studies that investigated the use of intravenous thrombolysis, endovascular therapy, or a combination of both in acute ischemic stroke patients with laboratory-confirmed COVID-19, compared to controls. Our primary safety outcomes included any intracerebral hemorrhage (ICH), symptomatic ICH and all-cause in-hospital mortality. Short-term favorable functional outcomes were assessed at discharge and at 3 months. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using DerSimonian and Laird random-effects model. Heterogeneity was evaluated using Cochran’s Q test and I2 statistics. Results We included 11 studies with a total of 477 COVID-19 positive and 8,092 COVID-19 negative ischemic stroke patients who underwent reperfusion therapy. COVID-19 positive patients exhibited a significantly higher risk of experiencing any ICH (RR 1.54, 95% CI 1.16–2.05, p < 0.001), while the nominally increased risk of symptomatic ICH in these patients did not reach statistical significance (RR 2.04, 95% CI 0.97–4.31; p = 0.06). COVID-19 positive stroke patients also had a significantly higher in-hospital mortality compared to COVID-19 negative stroke patients (RR 2.78, 95% CI 2.15–3.59, p < 0.001). Moreover, COVID-19 positive stroke patients were less likely to achieve a favorable functional outcome at discharge (RR 0.66, 95% CI 0.51–0.86, p < 0.001) compared to COVID-19 negative patients, but this difference was not observed at 3-month follow-up (RR 0.64, 95% CI 0.14–2.91, p = 0.56). Conclusion COVID-19 appears to have an adverse impact on acute ischemic stroke patients who undergo reperfusion therapy, leading to an elevated risk of any ICH, higher mortality and lower likelihood of favorable functional outcome. Systematic review registration PROSPERO, identifier CRD42022309785.

Intravenous thrombolysis and endovascular therapy for acute ischemic stroke in COVID-19: a systematic review and meta-analysis Introduction Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused a global pandemic of Coronavirus Disease 2019 (COVID-19) since its emergence in December 2019.By the time the World Health Organization declared the end to the COVID-19 global health emergency in May 2023, over 765 million confirmed cases of COVID-19 and more than 6.9 million reported deaths had been recorded worldwide (1).COVID-19 has been linked to a higher incidence of acute ischemic stroke, possibly due to disease-associated complications such as endothelial inflammation, hypercoagulopathy and cardiac thromboembolism (2)(3)(4)(5)(6).
Acute ischemic stroke is a leading cause of permanent disability in adults and death in the Western countries (7).COVID-19 patients with coincident acute ischemic stroke have been found to have worse outcomes, including higher mortality, compared to those without COVID-19 (6).Reperfusion therapies including intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA) and endovascular therapy (EVT) are effective and approved treatments for mitigating the risk of long-term disability and death in acute ischemic stroke patients (8).However, COVID-19 patients are generally at a higher risk of systemic bleeding complications due to coagulation disorders, which might be exacerbated by these reperfusion therapies (9).Moreover, COVID-19 patients are frequently treated in designated COVID-19 units, which may not provide the same level of stroke care as stroke units, leading to suboptimal neurological and hemodynamic monitoring and potentially increasing the risk of early bleeding complications from reperfusion therapies (4).
As literature on the utilization of reperfusion therapies in COVID-19 positive ischemic stroke patients is limited, we conducted a systematic review and meta-analysis of available literature to explore the safety and short-term efficacy of reperfusion therapies in this patient population.

Protocol registration
The pre-specified protocol for this systematic review and metaanalysis was registered with the international prospective register of systematic reviews (PROSPERO; Registration No. CRD42022309785) and the methodology adhered to updated preferred reporting items for systematic reviews and meta-analyzes (PRISMA) guidelines (10).The PRISMA checklist is provided in the Supplementary material.

Literature search and study eligibility
A systematic literature search using the electronic databases MEDLINE accessed by PubMed, Embase and Cochrane Library was performed from February 14 to March 8, 2022.The study eligibility criteria were defined in terms of: (1) Participants, which included acute ischemic stroke patients with concurrent laboratory-confirmed SARS-CoV-2 infection or COVID-19; (2) Intervention, involving reperfusion therapy by means of IVT, EVT or a combination of both; (3) Controls, consisting of a comparator group of acute ischemic stroke patients without SARS-CoV-2 infection or COVID-19 who were concurrently recruited; (4) Outcomes, which encompassed safety outcomes such as any intracerebral hemorrhage (ICH), symptomatic ICH, and all-cause in-hospital mortality, as well as short-term functional outcomes as indicated by the modified Rankin Scale (mRS) score at discharge or at 3 months; and (5) Study design, which included randomized controlled trials, observational cohort or case-control studies, or case series including at least 10 patients.
The search strategy was pre-defined without language restrictions and encompassed all publications from December 01, 2019 until our last search date March 8, 2022.Two reviewers (IS and AK) conducted the literature search independently and assessed all identified articles by screening of titles, abstracts and full texts using citation manager software to remove duplicates.In case of any discrepancies, a third investigator (JB) was consulted and disagreement was resolved by consensus.The search strings included various relevant terms and their combinations related to stroke and COVID-19 including "stroke, " "cerebrovascular disease, " "ischemic stroke," "ischaemic stroke," "brain ischemia," "cerebral ischemia," "embolic stroke," "cerebrovascular disorders," "coronavirus, " "COVID, " "COVID-19, " "2019-nCoV, " "severe acute respiratory syndrome coronavirus 2," and "SARS-CoV-2."No additional limits or filters were applied.The complete search algorithm is provided in the Supplementary materials.A snowball search in bibliographies of identified full-text articles and relevant review articles was also performed.If aforementioned outcomes of interest were not reported in eligible studies, the corresponding authors were asked to provide these data.Failure to provide at least one outcome of interest resulted in study exclusion.Furthermore, studies that did not confirm SARS-CoV-2 or COVID-19 cases by laboratory criteria (i.e., positive rapid antigen/PCR test) were considered unsuitable and excluded.

Data collection and data items
The extracted information from full text articles included first authors names, publication year, study design, sample size, total number of acute ischemic stroke patients with SARS-CoV-

Risk of bias assessment
We employed the Risk Of Bias In Non-randomized Studies -of Exposures (ROBINS-E) tool for quality control and bias assessment of included studies (11).Details of bias assessment for each study are listed in the Supplementary materials.

Statistical analysis
Categorical variables were reported as percentages, while continuous variables were presented as either mean ± standard deviation (SD) or median and interquartile range (IQR).The modified Wald method was used for computation of corresponding 95% confidence intervals (95%CI).To determine the pooled relative risks (RR) and their 95%CI for each categorial outcome of interest, we used a DerSimonian and Laird random-effects model (12).In addition, weighted mean differences (WMD) were calculated for continuous data such as time metrics.In studies where only the IQR was provided, we estimated the SD by dividing the range by 1.35 (13).Continuity correction of 0.5 was applied to studies with a zero cell.Sensitivity analyzes were performed on studies with consistent definitions for corresponding outcomes.We assessed the heterogeneity across the included studies using Cochran Q and the Higgins I 2 test.Specifically, I 2 values of 0 to 40% indicated absent or low heterogeneity, 30 to 60% indicated moderate heterogeneity, 50 to 90% indicated substantial heterogeneity, and 75 to 100% indicated considerable heterogeneity (14).Significance level of heterogeneity was set at p < 0.1.To examine the possibility of publication bias, we utilized Egger's test.We also visually inspected the corresponding funnel plots for the presence of small study effects.All statistical analyzes were conducted using STATA (version 16, StataCorp, College Station, TX).Statistical significance was set at p < 0.05.

Systematic literature review
Out of 1,279 titles retrieved from the electronic databases and the bibliographies from published articles, 160 were excluded due to duplication.After screening 1,119 abstracts, 186 full articles were evaluated for eligibility.Ultimately, 11 studies with a total of 8,569 acute ischemic stroke patients with (n = 477) and without (n = 8,092) concurrent SARS-CoV-2 infection or COVID-19 were included for quantitative synthesis (15-25).Two corresponding authors provided necessary outcome data upon request (24,25).The systematic screening and selection process is shown in Figure 1.Of the included studies, eight were retrospective observational studies and three were prospective.The majority of the included studies (n = 7) provided data on a combination of IVT and EVT (15, 19-22, 24, 25), while three studies provided data on EVT (16)(17)(18).One study focused on IVT only (23).Table 1 summarizes the characteristics of the included studies.

Additional analysis
Synthesis of data provided by three studies on the necessity of mechanical ventilation revealed that stroke patients who tested positive for COVID-19 had a significantly higher risk of ventilation dependency compared to ischemic stroke patients without COVID-19 (RR 1.58, 95%CI 1.03-2.44,p = 0.037) (15, 17, 19).However, this association exhibited substantial heterogeneity (I 2 = 73.7%,p = 0.02).

Bias and quality control assessment
Publication bias assessment was only conducted for in-hospital mortality due to a limited number of studies meeting the eligibility criteria for other outcome variables.This decision aligns with the Cochrane Handbook for Systematic Reviews of Interventions, which recommends a minimum of 10 studies for appropriate bias assessment (27).The findings indicated no presence of publication bias, supported

Discussion
This systematic review and meta-analysis highlights a higher risk of any ICH and in-hospital death following reperfusion therapy in acute ischemic stroke patients with COVID-19 compared to those without COVID-19.However, there was no significant increase in the risk of symptomatic ICH among COVID-19 positive stroke patients.These findings might indicate that the increased mortality in these patients is likely attributable to COVID-19 and its associated complications rather than bleeding complications arising from reperfusion therapies.
Intracerebral hemorrhage is a significant complication that can occur after acute reperfusion therapy in acute ischemic stroke (26,28).Current understanding indicates that ICH primarily results from tPA-related coagulopathy, blood-brain barrier disruption and hyperperfusion injury (29,30).Nevertheless, hemorrhagic transformation of infarcted brain tissue, frequently detected through routine neuroimaging following reperfusion therapy, does not always have a negative impact on clinical outcomes (26, 30).Clinical significance becomes apparent when larger hematomas occur within the infarcted brain tissue and are accompanied by neurological deterioration, as indicated by an increase in the NIHSS score.Symptomatic intracerebral hemorrhages are strongly associated with unfavorable functional outcomes and increased mortality (28,29).In our meta-analysis, COVID-19 positive patients with acute ischemic stroke displayed a heightened risk of any ICH following reperfusion therapy.Although the risk of symptomatic ICH was nearly doubled compared to COVID-19 negative patients, this association did not reach statistical significance and thus should be cautiously interpreted as potential indication of harm.In a recent multicenter study involving 853 COVID-19 positive ischemic stroke patients who received intravenous thrombolysis and/or EVT, a statistically significant 1.5-fold increased rate of sICH was observed compared to non-COVID-19 controls (9).This finding, which aligns with our analysis showing a nominally increased risk of sICH, could be attributed to the larger sample size utilized in the multicenter study compared to our data synthesis.Several factors have been identified as contributing to bleeding complications in ischemic stroke patients undergoing reperfusion therapy, including higher age, higher baseline NIHSS scores, elevated glucose levels, low platelet count and increased thrombin time at admission as well as inadequate blood pressure control (28,29).Abstracted data from the included studies suggest that COVID-19 positive ischemic stroke patients had more severe strokes than COVID-19 negative patients (15, [20][21][22][23]25).The risk of ICH in COVID-19 positive patients might be further enhanced due to pathophysiological mechanisms associated with COVID-19 including dysfunction of the reninangiotensin system leading to reduced ACE2 expression, hypertension, elevated D-dimer and tPA plasma levels, as well as cerebral endothelial dysfunction caused by inflammatory factors (25,31).Our data synthesis indicates that COVID-19 can lead to unfavorable outcomes in patients with acute ischemic stroke.COVID-19 is associated with common complications such as severe pneumonia, respiratory failure, kidney and hepatic dysfunction, dysregulated inflammatory response resulting in septic shock, and cardiac arrest (32).These complications may significantly contribute to poor outcomes following reperfusion therapy.Previous studies have consistently identified COVID-19 as a significant predictor of mortality in acute ischemic stroke patients, regardless of the treatment method (33).Moreover, in COVID-19 positive ischemic stroke patients who underwent reperfusion therapy, there is a higher likelihood of experiencing acute respiratory and kidney failure, septic shock, cardiac arrest, and requiring mechanical ventilation compared to COVID-19 negative patients (19,34).Consistently, our pooled analysis of three studies showed an increased risk of ventilation dependency in COVID-19 positive ischemic stroke patients compared to COVID-19 negative patients.It is worth noting that COVID-19 positive stroke patients often have more severe strokes, as indicated by higher baseline NIHSS scores, which may have contributed to worse functional outcomes in this pooled patient population (35,36).Lastly, cardiovascular risk factors commonly observed in patients with ischemic stroke have been shown to be associated with a higher risk of severe COVID-19 (37).This association may further diminish the chances of favorable outcomes in patients with ischemic stroke and COVID-19.
Based on the available data from the studies included in our metaanalysis, it appears that COVID-19 did not lead to a significant delay in starting reperfusion therapy.However, there was a notable finding in one study where a significant delay was observed in both door-toneedle and door-to-groin time for COVID-19 positive stroke patients when COVID-19 was suspected and confirmed with chest CT (24).These findings are surprising because one might expect treatment delays due to pre-clinical hygienic measures, prolonged intra-hospital processes through preventive measures, and swabbing for COVID-19 testing, which could potentially result in a missed therapeutic window, fewer implemented reperfusion therapies, and worse outcomes, as suggested by some studies (4,19,33,35).Therefore, it is possible that the worse outcomes observed in COVID-19 positive ischemic stroke patients could be associated with pathophysiological aspects of COVID-19 disease itself rather than delays in reperfusion therapy.
Our meta-analysis demonstrates several strengths including an comprehensive literature review involving two independent reviewers, strict adherence to standardized methodological criteria guided by the PRISMA statement and the ROBINS-E tool for risk of bias assessment, and prior registration with PROSPERO.A significant contribution of our study is the inclusion of four studies that were not encompassed in a recently published meta-analysis on the same topic (38).This inclusion expands the existing body of knowledge regarding the safety and short-term efficacy of reperfusion therapies in acute ischemic stroke patients with COVID-19.Importantly, we implemented rigorous measures to prevent potential overlap in patient samples within our analysis, addressing limitations identified in the previous meta-analysis where an overlap between two studies was observed (38)(39)(40).Furthermore, we excluded historical controls from our study considering that stroke outcomes during the pandemic could have been influenced by various factors, not only COVID-19 but also in-hospital cohorting and isolation strategies (4).Despite the differences in study selection, it is noteworthy that both meta-analyzes yielded comparable outcomes, underscoring the robustness of our findings.Nevertheless, it is essential to acknowledge the limitations of our study.Firstly, the small sample size, particularly among ischemic stroke patients with COVID-19, restricts the generalizability of our findings to a broader population.Secondly, the absence of patientlevel data on common confounding variables, such as age, baseline stroke severity, and the presence and location of large vessel occlusion, prevented us from performing meta-regression analysis.Additionally, the unavailability of patient-level data on COVID-19 severity hindered our ability to differentiate between unfavorable outcomes caused by the disease itself or complications arising from reperfusion therapy.Thirdly, due to possible impairment of consciousness in patients with severe COVID-19, it remains unclear how many patients eventually experienced asymptomatic or symptomatic ICH.Consequently, the actual symptomatic ICH rate could potentially be higher than reported.Fourthly, it is important to note that the majority of studies included in our meta-analysis recruited patients within the first year of the pandemic, aligning with the emergence of various SARS-CoV-2 variants, increasing vaccination rates and the availability of specific COVID-19 treatments.Our findings therefore may be prone to time-varying bias and may not necessarily be generalizable to current stroke patients with COVID-19.Lastly, the possibility of selection bias cannot be ignored, as patients may have been eligible for reperfusion therapy only if their treating physicians deemed the risk of bleeding complications to be low.

Conclusion
Our meta-analysis indicates that acute ischemic stroke patients tested positive for COVID-19 and undergo reperfusion therapy might be at higher risk of unfavorable outcomes compared to stroke patients without COVID-19.To optimize treatment strategies for COVID-19 positive stroke patients, further studies are necessary to explore the underlying mechanisms that contribute to these potential worse outcomes.

FIGURE 1 Flow
FIGURE 1Flow chart of study selection.

FIGURE 2
FIGURE 2Pairwise meta-analysis of all available studies on (A) symptomatic intracerebral hemorrhage, (B) any intracerebral hemorrhage and (C) in-hospital mortality between COVID-positive and COVID-negative stroke patients receiving intravenous or endovascular therapy.

FIGURE 3
FIGURE 3Pairwise meta-analysis of all available studies on favorable functional outcome (A) at discharge and (B) at 3 months between COVID-positive and COVID-negative stroke patients receiving intravenous or endovascular therapy.

FIGURE 4
FIGURE 4Pairwise meta-analysis comparing (A) door-to-needle times and (B) onset-to-groin or door-to-groin times among stroke patients with COVID-19 compared to those without COVID-19 who underwent intravenous or endovascular therapy.WMD indicates weighted mean difference.

TABLE 1
Characteristics of the studies included in the quantitative data synthesis.Numbers of patients correspond to available outcome data in the included studies (and do not account for missing data); # onset-to-needle time; $ number corresponds to mean, standard deviation not available; ‡ onset-to-groin time. *