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 (2–6).

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.

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, 20–23, 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 renin-angiotensin 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 meta-analysis, 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-to-needle 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 (38–40). 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 patient-level 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.

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.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

IS, AK, and JB: conceptualization of study design and supervision. IS, AK, JB, and KB: data acquisition, analysis and interpretation, manuscript writing and revision. TS: supervision and manuscript revision. All authors have read and agreed to the published version of the manuscript.

This work is the publication of a Master’s thesis of the Master’s program in Clinical Research provided by Dresden International University, Dresden, Germany. The Article Processing Charges (APC) were funded by the joint publication funds of the TU Dresden, including Carl Gustav Carus Faculty of Medicine, and the SLUB Dresden as well as the Open Access Publication Funding of the DFG.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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