The incidence and impact of atrial fibrillation on hospitalized Coronavirus disease‐2019 patients

Abstract Background Since 2019, Coronavirus disease‐2019 (COVID‐19) has raised unprecedented global health crisis. The incidence and impact of atrial fibrillation (AF) on patients with COVID‐19 remain unclearly defined. Methods We conducted a retrospective cohort study using ICD‐10 codes to identify patients with a primary diagnosis of COVID‐19 with or without AF in National Inpatient Sample Database 2020. We compared the outcome of COVID‐19 patients with a concurrent diagnosis of AF with those without. Hypothesis AF will adversely affect the prognosis of hospitalized COVID‐19 patients. Results A total of 211 619 patients with a primary diagnosis of COVID‐19 were identified. Among these patients, 31 923 (15.08%) had a secondary diagnosis of AF. Before propensity score matching, COVID‐AF cohort was older (75.8 vs. 62.2‐year‐old, p < .001) and had more men (57.5% vs. 52.0%, p < .001). It is associated with more comorbidities, mainly including diabetes mellitus (43.7% vs. 39.9%, p < .001), hyperlipidemia (54.6% vs. 39.8%, p < .001), chronic kidney disease (34.5% vs. 17.0%, p < .001), coronary artery disease (35.3% vs. 14.4%, p < .001), anemia (27.8% vs. 18.6%, p < .001), and cancer (4.8% vs. 3.4%, p < .001). After performing propensity score match, a total of 31 862 patients were matched within each group. COVID‐AF cohort had higher inpatient mortality (22.2% vs. 15.3%, p < .001) and more complications, mainly including cardiac arrest (3.9% vs. 2.3%, p < .001), cardiogenic shock (0.9% vs. 0.3%, p < .001), hemorrhagic stroke (0.4% vs. 0.3%, p = .025), and ischemic stroke (1.3% vs. 0.7%, p < .001). COVID‐AF cohort was more costly, with a longer length of stay, and a higher total charge. Conclusion AF is common in patients hospitalized for COVID‐19, and is associated with poorer in‐hospital mortality, immediate complications and increased healthcare resource utilization.

The Coronavirus disease-2019 (COVID-19) pandemic has posed a challenge to healthcare systems worldwide. 1,2As researchers continue to understand the intricate interactions between COVID-19 and various pre-existing medical conditions, emerging evidence suggests that cardiovascular comorbidities may play a significant role in the clinical course and outcomes of COVID-19 patients. 3,4ong these comorbidities, atrial fibrillation (AF), one of the most common cardiac arrhythmias, 5 has emerged as a topic of interest in COVID-19 research.An increasing body of evidence suggests that AF, may play a crucial role in shaping the clinical outcomes of COVID-19 patients. 6Several preliminary studies have hinted at a potential bidirectional link between COVID-19 and AF.
One study conducted by Daniel D et al. reported a higher prevalence of AF in severe COVID-19 cases compared to milder cases. 1 Additionally, recent evidence suggests that COVID-19 may lead to myocardial injury and contribute to AF initiation or exacerbation. 2wever, the mechanisms underlying this relationship remain largely elusive.
Understanding the impact of AF on COVID-19 patients is essential for optimizing clinical management strategies.The presence of AF may pose unique challenges for antiviral therapies, immunomodulatory drugs, and anticoagulant regimens used in COVID-19 treatment.This research paper aims to comprehensively investigate the implications of AF on hospitalized COVID-19 patients.

| Ethical statement
In our study, the National Inpatient Sample (NIS) 2020 database was used to examine the association of COVID-19 and AF inhospital outcomes.As NIS data is deidentified and publicly available, this study was exempt from institutional review board evaluation.

| Study population
Patients with a primary diagnosis of COVID-19 and with discharge status were included in the study.][10][11][12] The selected patients were divided into two groups: those with AF and those without.

| Outcomes
The primary endpoints of the studies were (1) in-hospital mortality, (2) in-hospital complications, which include, cardiac arrest, cardiogenic shock, ventricular arrhythmia, acute respiratory failure (ARF), acute kidney injury (AKI), hemorrhagic stroke, and ischemic stroke; (3) length of stay (LOS) and total cost during hospitalization.Of note, those outcomes were identified by ICD-10 codes within NIS database (Supporting Information: Table 1).

| Statistical analysis
Mean and standard deviation (SD) were used to characterize continuous variables.Percentage was used to describe categorical variables.T test was used to compare continuous variables, and χ2 was used for categorical variables.A p-value less than .05was considered statistically significant.Statistical analysis was conducted using the R statistical software (version 3.6.1;R Foundation for Statistical Computing).
We first analyzed the overall characteristics of the COVID-AF and COVID-non-AF cohort, and compared the in-hospital outcomes of two cohorts.We then used propensity score matching method to reduce selection bias with a 1:1 target ratio from the two cohorts.
Multivariate logistic regression model was used to adjust patient demographics (age, sex, race, geographic location, household income, and primary payer), hospital demographics (hospital type, region, and bed size), and common cardiovascular comorbidities as mentioned above.Finally, we compared in-hospital outcomes between the two cohorts before and after matching to demonstrate the impact of AF on in-hospital outcomes of COVID-19 patients.

| DISCUSSION
In this study, we conducted a real-world analysis to assess the prevalence and features of patients admitted for COVID-19 infection with concurrent diagnosis of AF, and described its correlation of COVID-AF group also utilized more health care resources, with longer LOS and higher total cost.
Demographically, patients in COVID-AF cohort are older with more comorbidities.This observation is consistent with prior research that AF is associated with increased age. 13The age correlation can be attributed to age-related changes in the atria.With aging, there are increased cardiac tissue fibrosis, and alterations in ion channel function that predispose older individuals to arrhythmia development. 14Older age is also associated with a higher burden of comorbidities, which further increase individuals' vulnerability to COVID infection and AF complications.Separately, COVID-AF cohort has a higher proportion of men.Being men is also associated with an increased risk of both AF 15 and severe COVID-19. 16Hormonal, genetic, and immunological factors are thought to play a role in this gender-specific difference in the disease susceptibility and progression. 17,18tients in COVID-AF cohort has a higher rate of cardiovascular comorbidities.For example, the association between AF and DM as well as hyperlipidemia has been extensively reported. 19 and hyperlipidemia contribute to atrial remodeling and NIU ET AL.
| 5 of 9 pro-inflammatory changes in the atrial tissue, fostering the development and persistence of AF. 20,21 Additionally, CKD has also been found related to a higher incidence of AF due to fluidelectrolyte imbalances, inflammation, and oxidative stress. 22CKD is an independent predictor of severe outcomes in COVID-19 patients, contributing to the higher rate of mortality and complications in COVID-AF group. 13AF is prevalent in COPD.
The systemic inflammation and oxidative stress in COPD, along with respiratory distress, can contribute to atrial remodeling, thereby increasing the likelihood for AF development. 23Overall, the presence of AF in COVID-19 patients may be an indicator of a patient's overall wellbeing and comorbidity burden.
It is therefore not surprising that we found that COVID-AF cohort has significantly higher in-hospital mortality and complication rate, longer LOS, and increased healthcare costs compared to COVID-non-AF cohort.The worse outcomes persist after propensity score matching, adjusting for the comorbidities and baseline characteristics of both groups.Our result indicates that AF poses an independent risk for adverse outcomes in COVID-19 patients.The mechanisms underlying this association are probably multifactorial.
8][29] In COVID patients with AF, the inflammation may be further intensified, leading to a dysregulated immune response, increased vascular permeability, and coagulopathy and contributing to the observed worse outcomes.Second, AF-related hemodynamic changes, including rapid ventricular rates and loss of atrial contraction, reduce cardiac output and impair cardiac reserve.1][32][33] Third, COVID-19 is associated with endothelial dysfunction and thrombosis, 34 which can cause microvascular and macrovascular complications.AF is also known to promote a prothrombotic state, 35 and the combination of COVID-19 and AF may result in a synergistic increase in thrombotic events 36 and adverse outcomes. 37Anticoagulation therapy had been suggested in AF patients with high risk of thrombosis. 38The current recommendation is also in favor of prophylactic-intensity anticoagulation for patients with COVID-19-related critical illness. 39The thrombotic state and the emphasis on anticoagulation therapy can perhaps explain the increased incidence of cerebrovascular events in COVID-AF cohort.
It is plausible that the coexistence of AF is a indicator of a state of increased physiological stress, potentially resulting in a more severe hospital course in patients admitted for COVID infection. 21The The NIS 2020 database was used to examine the association of COVID-19 and AF in-hospital outcomes.NIS is a large, publicly available, all-payer inpatient healthcare database maintained by the Agency for Healthcare Research and Quality in the United States, representing an approximately 20% stratified sample of discharges from community hospitals and approximately 95% of the US population. 7COVID-19 diagnosis was identified as code "U071 (2019 novel coronavirus disease)" by the International Classification of Diseases, 10th edition, Clinical Modification (ICD-10-CM).

[
DM], obstructive sleep apnea [OSA] syndrome, chronic obstructive pulmonary diseases [COPD], coronary artery disease [CAD], chronic kidney disease [CKD] higher mortality and worse outcomes.Among the 211 619 patients diagnosed with COVID-19, 15.1% had a secondary diagnosis of AF, indicating that AF is not a rare comorbidity in COVID-19 patients.The COVID-AF cohort also exhibited increased mortality and higher incidences of major cardiovascular and cerebral complications, including cardiac arrest, cardiogenic shock, ventricular arrhythmia, ARF, AKI, ischemic stroke, and hemorrhagic stroke.These findings suggest that AF may serve as an indicator of the severity of COVID-19, rather than merely being a concurrent condition.
Several limitations should be acknowledged.First, the study's retrospective nature introduces inherent biases and potential unaccounted confounders.Such can influence the observed associations between AF and COVID-19 outcomes.Second, the study focused on hospitalized patients, which may not fully represent the entire COVID-19 infected population in the community.Third, the study lacked data on the timing of AF onset in relation to the COVID-19 infection, which limits the ability to further understand the intricate relationship between the two conditions.Last, we did not note or compare the treatment strategies and their impact on outcome between two cohorts due to the nature of the NIS database.Further research is needed to assess the impact of therapies on COVID-19 outcomes in patients with AF.6 | CONCLUSIONOur study underscores the significant impact of AF on the outcomes of hospitalized COVID-19 patients.The findings of the study suggest that COVID-19 patients with AF constitute a vulnerable subgroup with worse clinical outcomes.Further research is warranted to enhance our understanding of the intricate relationship between AF and COVID-19 and develop evidence-based strategies to mitigate its adverse effects on this high-risk subgroup.AUTHOR CONTRIBUTIONS Haiming Niu, Pengyang Li, Jianwei Li, and Yong Yuan conceived the study.Haiming Niu, Jianwei Li, Pengyang Li, Catherine Teng, Xiaojia Lu, Chengyue Jin, Ao Shi, Miaolian Chen, Xiaoqing Shen, and Qiqi Chen were involved in the data collection process.Pengyang Li and Peng Cai analyzed and interpreted the data.Pengyang Li, Yong Yuan, Catherine Teng, Peng Cai, Miaolian Chen, Ao Shi, Xiaoqing Shen, and Qiqi Chen interpreted the results.Haiming Niu, Pengyang Li, Catherine Teng, Xiaojia Lu, Chengyue Jin, and Xiaoqing Shen wrote the manuscript.All authors revised the manuscript and approved the final manuscript for submission.

Table 1 .
T A B L E 1 Baseline characteristics.
cohort warrants further study to improve outcome and reduce complications.Identifying COVID-19 patients with a comorbidity of AF early in their hospitalization allows clinicians to recognize those at higher risk for severe outcomes.Efforts to optimize AF before and during COVID-19 infection might positively influence patient outcomes.T A B L E 2 Abbreviations: AF, atrial fibrillation; AKI, acute kidney failure; ARF, acute respiratory failure; COVID-19: Coronavirus disease-2019; LOS, length of stay.