COVID-19 significantly raises stroke risk

Researchers confirm a strong link between COVID-19 and stroke risk, emphasizing the urgency for further investigation into prevention and treatment strategies.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

In a recent research paper uploaded to the medRxiv preprint* server, researchers undertook a metaumbrella review comprising 34 systematic reviews and 70 primary studies to elucidate the risk associations between SARS-CoV-2 infections and stroke.

Odds ratio equivalents (eOR) analysis revealed a strong association between the severity of COVID-19 infections and subsequent risk of stroke (eOR = 2.48), with hemorrhagic stroke (eOR = 3.86) and ischemic stroke (eOR = 2.48) depicting the highest risk. However, significant heterogeneity was observed across many studies, suggesting variability in the results (I² values > 50% in some cases), which necessitates cautious interpretation of these associations.

The study identified that men and older individuals (mean age of 61.2 years) were predominantly affected, highlighting the demographic groups most at risk for COVID-19-associated stroke.

Furthermore, patients with preexisting cerebrovascular comorbidities or previous stroke incidence were observed to be at higher risk of stroke-associated mortality (eOR = 2.48 and 6.08, respectively). Together, these findings establish a significant association between SARS-CoV-2 and stroke.

Despite these findings, the evidence strength for some associations, such as stroke mortality and ischemic stroke risk, was classified as weak due to small sample sizes and potential publication bias (identified through Egger’s test). Unfortunately, despite extensive work in the field, methodological inadequacies in most works highlight the need for additional research into the mechanisms underpinning these risk associations.

Background

Colloquially called 'a brain attack' and medically 'a cerebrovascular accident (CVA),' strokes are conditions wherein blood flow to the brain is halted. The brain requires a constant supply of oxygenated blood to function. Consequently, even a temporary restriction of oxygen can result in permanent brain damage, disability, and frequently death.

Alarmingly, despite decades of research, stroke remains the second leading cause of human mortality (~5.5 million deaths) and the third leading cause of disability worldwide, necessitating the need for an improved understanding of the risk factors and mechanisms underpinning its manifestation.

Stroke is a multifactorial condition with combinations of environmental, modifiable, and non-modifiable risk factors affecting its incidence and outcomes. Recent studies suggest that the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pathogen, may increase the risk of stroke.

Despite being primarily recognized as a respiratory infection-causing pathogen, SARS-CoV-2 is increasingly implicated in systemic inflammations, immune complications, and nervous system damage, all of which may exacerbate stroke risk and severity. Unfortunately, the association between COVID-19 and stroke risk remains confounding.

About the study

The present study uses a metaumbrella review approach to verify the associations between SARS-CoV-2 and the subsequent risk of stroke. Umbrella reviews are broadscale, exhaustive examinations of primary publications, systematic reviews, and meta-analyses to address a specific question or topic.

The geographical scope of the study was extensive, with most research coming from countries like China, the United States, and Italy, providing a global perspective on COVID-19 and stroke associations​.

An important limitation of the present study is the overlap of studies, where certain primary research works were counted more than once across multiple reviews, potentially affecting the overall conclusions. Herein, four online scientific repositories (PubMed/MEDLINE, Scopus, Web of Science, and LILACS) databases were queried for any studies published between March 2020 and March 2023 exploring the associations between COVID-19 and any stroke subtype (ischemic or hemorrhagic). Non-clinical evaluations, letters, reports, opinion articles, and book chapters were excluded from the dataset.

Two independent reviewers screened the study over two stages – title and abstract, and full text. Cohen's Kappa coefficient was used to measure the agreement between reviewer choices. The Covidence software was used to compute Cohen's Kappa index and generate a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart.

The ROBIS tool was used to evaluate the methodological soundness of the included research, including the risk of bias. Two study subjects ("COVID-19 and stroke mortality" and "COVID-19 and ischemic stroke risk") showed evidence of statistical excess significance bias (ESB), where the number of positive findings exceeded what would normally be expected. Pooled effect sizes for factors evaluated across multiple studies were estimated using random-effects meta-analysis. These effect sizes were then used to compute odds ratio equivalents (eORs).

Finally, between-study heterogeneity was evaluated using the I² index, and the strength of evidence from each study was rated on a 4-class rating scale. Of the five study objects, only two demonstrated low heterogeneity (I² < 50%), indicating greater consistency, while three others showed higher variability, reducing confidence in the results.

Study findings

Initial database search results revealed 2,490 studies relevant to the current metaumbrella review. Title and abstract screening excluded 1,430 studies, and full-text screening excluded an additional 1,026, leaving 34 eligible studies for inclusion in the current work. Summary statistics of included studies revealed a mean age of 61.2 years (high stroke risk population) and a predominantly male sample population (59.9%). The geographical coverage of included studies was high, encapsulating the United States (US), Italy, India, Spain, Brazil, and, most extensively, China.

ROBIS risk of bias assessment revealed that most studies demonstrated minimal bias risk across study identification, eligibility, and selection. However, some studies showed high or uncertain bias risk, particularly in study selection and result synthesis, which further emphasizes the need for caution when interpreting the pooled results.

Metaumbrella analyses revealed that the incidence of stroke in COVID-19 survivors was significantly higher than that in individuals who never contracted SARS-CoV-2 infections, establishing a pathological association between SARS-CoV-2 and stroke predisposition. Among stroke subtypes, hemorrhagic (eOR = 3.86) and ischemic (eOR = 2.48) stroke were most strongly influenced by prior COVID-19 vaccination status.

Additionally, the overlap of certain key studies across multiple reviews, such as those by Qureshi and Merkler, suggests that these works were pivotal in influencing the final conclusions.

While the mechanisms underpinning these associations require more work before they are elucidated, the present study suggests that SARS-CoV-2 infections may trigger hypercoagulability in patients, increasing the blood clotting risk in blood vessels supplying oxygen to the brain and, in turn, causing a stroke.

Conclusions

The present review employs the relatively novel metaumbrella methodological approach to elucidate the potential associations between COVID-19 and the subsequent risk of stroke. Study findings revealed that SARS-CoV-2 infections substantially increase the risk of stroke, particularly hemorrhagic and ischemic subtypes.

However, the strength of evidence for some associations was rated as weak, particularly for stroke mortality and ischemic stroke risk, due to small sample sizes and potential publication bias. It further suggests that SARS-CoV-2 might influence stroke risk by causing a state of hypercoagulation in its patients, triggering a cascade culminating in stroke events.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

• Preliminary scientific report. Association between SARS-CoV-2 and Stroke: Perspectives from a metaumbrella-review. Andreza Maria Luzia Baldo de Souza, Enoque Fernandes de Araújo, Nelson Carvas Junior, Augusto César Raimundo, Antonio Carlos Pereira, Marcelo de Castro Meneghim. medRxiv, DOI – 10.1101/2024.10.01.24314742,  https://www.medrxiv.org/content/10.1101/2024.10.01.24314742v1