Higher incidence of new atrial fibrillation in hospitalised COVID-19 patients compared to lower respiratory tract infection, however, less patients prescribed anticoagulants at discharge

Isuru Induruwa, Elizabeth Cattermole, Christopher Paisey, Colver Ken Howe Ne and Kayvan Khadjooi
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DOI: https://doi.org/10.7861/clinmed.2023-0188
Clin Med September 2023

Abstract

Infection contributes to developing cardiac arrhythmias, such as atrial fibrillation (AF), which causes over 25% of ischaemic stroke. We analysed a hospital coding database of patients hospitalised with Coronavirus 2019 (COVID-19) ± AF or a lower respiratory tract infection (LRTI) ± AF, to compare the incidence of first-diagnosed or ‘new’ AF (nAF) between COVID-19 and LRTI, as well as risk factors associated with developing nAF during COVID-19. In total, 2,243 patients with LRTI and 488 patients with COVID-19 were included. nAF was diagnosed in significantly more patients with COVID-19 compared with those with LRTI (7.0% vs 3.6%, p=0.003); however, significantly fewer patients with COVID-19 were discharged on anticoagulation medication (26.3% vs 56.4%, p=0.02). Patients who developed nAF during COVID-19 were older (p<0.001), had congestive cardiac failure (p=0.004), ischaemic heart disease (IHD) or peripheral vascular disease (PVD) (p<0.001) and a higher CHA2DS2-VASc score (p=0.02), compared with patients with COVID-19 patients who did not develop nAF. Older age (Odds ratio (OR) 1.03, p=0.007) and IHD/PVD (OR 2.87, p=0.01) increased the odds of developing nAF with COVID-19.

KEYWORDS:

Introduction

The global pandemic caused by Coronavirus 2019 (COVID-19) has identified new challenges to healthcare systems, and treating the medical complications that follow COVID-19 will remain an ongoing challenge facing healthcare providers.

Atrial fibrillation (AF) is a common cardiac arrhythmia, responsible for at least one-fifth of all ischaemic stroke in the UK;1 yet, an individual's stroke risk can be mitigated by ∼65% with anticoagulation treatment.2 A first diagnosis of AF or ‘new’ AF (nAF), discovered during admission to hospital with an infection, is common, with large studies associating a sixfold higher risk of developing AF in patients with severe sepsis.3 In particular, studies have shown that patients who develop nAF during pneumonia have an increased risk of thromboembolism or death at 3 years.4

The prevalence of AF in patients hospitalised with COVID-19 is reported to be 8–11%.5,6 A recent meta-analysis demonstrated that AF and COVID-19 are significantly associated with poor outcomes,7 particularly as they are both more common in older patients.6 Although only a few studies have investigated nAF in patients hospitalised with COVID-19, they consistently report a higher incidence of nAF during COVID-19 infection compared with other cohorts.8–10

We performed a database analysis to compare the incidence of nAF in patients admitted with a lower respiratory tract infection (LRTI) or COVID-19, and anticoagulation rates at discharge, as well as to determine factors associated with developing nAF in patients admitted with COVID-19.

Materials and methods

This single-centre analysis of coding data included adult patients (≥18 years) admitted between 1 March 2020 and 31 December 2020 to a large university hospital in the UK. Data were extracted from electronic patient records where diseases are coded using International Classification of Diseases (ICD-10) and attributed to the patient during their hospital admission. Further information on the codes used for this preliminary extraction are found in Table S1 in the supplementary material online. After excluding duplicate or incorrectly coded entries, patients with a discharge diagnosis of LRTI or COVID-19 ± AF were included in the final dataset for analysis. If there were multiple admissions to hospital during the study period, only details of the first admission were included.

For all LRTI and COVID-19 populations, basic data, such as age, sex, length of hospital stay and whether they were coded with AF, were collected.

Additionally, for patients with COVID-19 with AF, whether known or nAF, demographic variables, including age, sex and past medical history (hypertension, congestive cardiac failure (CCF), diabetes mellitus, hypercholesterolaemia, ischaemic heart disease (IHD) and/or peripheral vascular disease (PVD) or previous stroke) were also extracted from ICD-10 codes and used in CHA2DS2-VASc and ORBIT score calculations. Admission haemoglobin, white cell count, neutrophil count and C-reactive protein (CRP) were collected, as well as the admission National Early Warning Score 2 (NEWS),11 Quick COVID-19 Severity Index score (QCSI),12 admission to the intensive care unit, numbers of inpatient deaths, myocardial infarction, ischaemic or haemorrhagic stroke at 6 months and death at 1 year.

Hospital records were then manually accessed to determine patients' anticoagulation status on admission, proportion discharged on anticoagulation, as well as the reasons for non-prescription of anticoagulation in patients with LRTI or COVID-19 with nAF. For all patients with nAF within the LRTI and COVID-19 cohorts, as well as the all patients with known AF within the COVID-19 cohort, electronic records, including GP or medical records, telemetry reports and 12-lead electrocardiograms (ECG), were checked to confirm the diagnosis of AF during that admission. Atrial fibrillation was defined as;13

  • irregularly irregular R-R intervals (when atrioventricular conduction is not impaired)

  • absence of distinct repeating P waves

  • irregular atrial activations on a 12-lead ECG for inclusion.

This project was registered with Cambridge University Hospitals Quality Surveillance Team. Formal confirmation was received that ethical approval from an institutional review board was not required.

Statistical analysis

The cut-off for statistical significance was set at p<0.05. Continuous data were tested for normality using Shapiro–Wilk testing. Parametric data are reported as mean ± standard deviation (SD) and non-parametric data as median and interquartile range (Q1–Q3). Cohort comparisons between parametric data were carried out using Student's t-test, or the Mann–Whitney U test for non-parametric data. Comparisons of proportions between categorical data were carried out using Fisher's exact test.

Common population predictors of developing AF were used in a backward stepwise logistic regression model in the COVID-19 population, excluding those with known AF, to determine which variables are associated with developing nAF in COVID-19. The independent variables modelled were age, pre-existing hypertension, CCF, diabetes, stroke, IHD/PVD, as well as the CHA2DS2-VASc score, admission CRP, NEWS score and sex. At each stage in the regression model, the least significant variable was eliminated until only variables with p<0.10 remain. Unstandardised coefficient (B) and significance (p) are reported for each of the significantly associated variables. These variables were then used in a binary logistic regression model to report the strength of association in developing nAF in COVID-19 as an odds ratio (OR). Data were analysed using Prism v.9.4.1 (GraphPad, San Diego, CA, USA) and SPSS v.29 (IBM Corp, Armonk, NY, USA).

Results

The initial search returned 5,301 entries of which 2,570 entries were excluded as detailed below. Out of the remaining 2,731 patients, 2,243 patients (82.1%) had been coded as a LRTI and 488 (17.9%) as COVID-19. We then determined via manual patient record review which of these patients developed nAF. In total, 284 patients (12.6%) in the LRTI cohort were coded with AF, of which 73 were new diagnoses. In the COVID-19 cohort, 77 patients (15.8%) were coded with AF, of which 31 were nAF (Fig 1).

Fig 1.
Fig 1.

Flow diagram showing the number of cases included or excluded at each stage of the study and the final numbers analysed within each cohort. AF = atrial fibrillation; COVID-19 = Coronavirus 2019; LRTI = lower respiratory tract infection.

Incidence of nAF in COVID-19 compared with LRTI

Patients with COVID-19 were significantly younger than patients with LRTI (median age (Q1–Q3) COVID-19; 64 (48–79), LRTI 77 (64–86), p<0.001 (Table S2 in the supplementary material online). Patients with COVID-19 and nAF were also significantly younger compared with patients with LRTI and nAF (median age (Q1–Q3) COVID-19+nAF; 75 (64–84), LRTI+nAF 83 (74-90), p=0.02) and had significantly lower white cell (p=0.007) and neutrophil counts at admission (p=0.03) but similar haemoglobin, CRP and NEWS scores. The proportion of vascular risk factors, CHA2DS2-VASc scores and events since discharge; ischaemic stroke, myocardial infarction, or death at 1 year, were also not significantly different (Table 1).

View this table:
Table 1.

Incidence of nAF in patients with COVID-19 or LRTIa

However, despite patients with COVID-19 being younger, the incidence of nAF was significantly higher in patients admitted with COVID-19 compared with LRTI (COVID-19; 7.0%, LRTI; 3.6%, p=0.003) (Table 1).

Proportions of patients with COVID-19 or LRTI discharged on anticoagulants and reasons for non-prescription

Excluding those who were already taking anticoagulants for alternative diagnoses, inpatient deaths and those who had a low risk of ischaemic stroke as calculated by the CHA2DS2-VASc score, significantly fewer patients with nAF in the COVID-19 cohort were discharged on anticoagulants compared with those with LRTI (COVID-19+nAF; 26.3%, LRTI+nAF; 56.4%, p=0.02), despite similar ages and CHA2DS2-VASc scores between the two cohorts (Table 2). Patients with COVID-19+nAF also had a lower risk of bleeding as per ORBIT scores,14 compared with the patients with LRTI+nAF.

View this table:
Table 2.

Proportions of patients with nAF newly started or discharged on anticoagulants, and reasons provided in notes for non-prescription

Individual analysis of medical notes in patients not prescribed anticoagulation at discharge revealed that 13/24 (54.2%) LRTI with nAF patients had a clear contraindication not to be anticoagulated (9 limited life expectancy, 3 recent or current intracerebral haemorrhage, 1 end-stage renal failure), whereas this was only the case in 1/15 (6.6%) patients with COVID-19 and nAF (one with end-stage renal failure). In 10/26 (38.4%) patients with LRTI+nAF and 8/12 (66.7%) patients with COVID-19+nAF, a reason for non-prescription of anticoagulants was not documented in the notes (Table 2). Of those that were discharged on anticoagulants, apixaban was the choice in 69.2% of patients with LRTI and 80% of patients with COVID-19.

Variables and outcomes associated with nAF in COVID-19

Excluding those with already known AF, there were 411 (84.2%) patients admitted with COVID-19 who did not develop AF, and 31 patients (7.0%) who developed nAF. Patients who developed nAF during hospitalisation with COVID-19 were significantly older (median age (Q1–Q3) COVID-19+nAF; 75 (64–84), COVID-19 no AF; 62 (46–79), p<0.001). There was a significantly higher proportion of pre-existing CCF (p=0.004), IHD or PVD (p<0.001) within the COVID-19 and nAF cohort and a higher CHA2DS2-VASc score (median (Q1–Q3) COVID-19+nAF; 3 (1–5), COVID-19 no AF; 2 (1–3), p=0.02) (Table 3). There was no significant difference between the admission NEWS score, haemoglobin or CRP, but patients hospitalised with COVID-19 who developed nAF had a significantly longer length of stay in hospital (LOS) compared with patients with COVID-19 without AF (median LOS (Q1–Q3) COVID-19+nAF; 15 days (8–28), COVID-19 no AF; 5 days (1–12), p<0.001).

View this table:
Table 3.

Factors associated with developing first-diagnosed AF during hospitalisation with COVID-19a

Predictors of nAF in patients with COVID-19

Backward stepwise logistic regression revealed significant associations between age (p=0.007) and having a history of IHD/PVD (p=0.01) with developing nAF during hospitalisation with COVID-19. Sex demonstrated no significant association (p=0.09). When age, IHD/PVD and sex were modelled in a binary logistic regression with nAF as the dependent variable, the odds of nAF were significantly higher if patients were older (OR 1.03 (1.01–1.06), p=0.007) or had a previous diagnosis of IHD/PVD (OR 2.87 (1.23–6.66), p=0.01) (Table 4).

View this table:
Table 4.

Strength of association between age, IHD/ PVD and female sex and developing nAF during hospitalisation with COVID-19

Discussion

Anticoagulants have shown promise in preventing and treating COVID-19-associated thrombosis,15 but the link between nAF, COVID and ischaemic stroke has been poorly explored. This is important because AF and COVID-19 are both implicated as cardioinflammatory and thrombogenic disorders, highlighting the need for careful consideration of strategies to prevent thrombotic complications.

Our results demonstrated an incidence of 7% nAF in patients hospitalised with COVID-19, significantly higher than in those admitted with a LRTI (3.6%, p=0.003). What is striking is that patients who developed nAF with COVID-19 were significantly younger compared with the LRTI cohort but had a similar proportion of vascular risk factors and CHA2DS2-VASc scores. Anticoagulation rates also differed between the two groups. Patients with COVID and nAF who were not discharged on anticoagulants were of similar age, had similar CHA2DS2-VASc scores and lower ORBIT scores compared with patients with LRTI with nAF, conveying a similar future risk of ischaemic stroke and a reduced risk of possible haemorrhage associated with anticoagulation. Despite this, significantly fewer patients with nAF and COVID-19 were discharged on anticoagulants compared with patients with LRTI (26.3% vs 56.4%, p=0.02).

Further analysis of medical notes of those not discharged on anticoagulants revealed that 13/24 patients with LRTI had a clear contraindication not to be on anticoagulants, whereas this was only the case in 1/15 patients with COVID-19 and nAF. It is difficult to ascertain whether anticoagulation was considered in these cases because a reason for non-prescription was not documented but no characteristic within patients with COVID-19 appeared to be predictive of non-prescription. Paroxysmal AF was incorrectly noted as a reason not to start anticoagulation in two patients, suggesting that non-prescription appeared to be a mix of lack of physician education and reluctance to anticoagulate patients in this cohort; although these assumptions require assessment in larger, focussed studies.

This is important because studies investigating nAF during sepsis reported increased AF recurrence during the first year and a higher risk of ischaemic stroke.16,17 It is likely that many patients who develop nAF during sepsis have a pre-existing substrate for AF, often because of the burden of existing vascular risk factors, unmasked by infection, leading to AF. Studies do support this in patients hospitalised with COVID-19 who also develop nAF, reporting a higher incidence of thromboembolic events18 and ischaemic stroke.10 This suggests that, in patients identified as being high risk of ischaemic stroke in the setting of nAF and COVID-19, stroke preventative measures, including offering anticoagulants, should be considered. In our study, only five patients with nAF in both cohorts had a truly low risk of future stroke (CHA2DS2-VASc of 0 or 1 (for female sex)). In addition, further outpatient cardiac monitoring was organised in only one out of the 31 patients in the COVID-19 group; therefore, whether AF diagnosed after COVID-19 recurs in our population cannot be ascertained.

Within patients who were hospitalised with COVID-19, those who developed nAF were significantly older (p<0.001), with a higher proportion of pre-existing congestive cardiac failure (p=0.004), ischaemic heart disease or peripheral arterial disease (p<0.001) and a higher CHA2DS2-VASc score (P=0.02) compared with those who did not develop nAF, consistent with previously published data.19 This strengthens the need to consider stroke prevention in these patients because the risk factors identified here are commonly also shared with ischaemic stroke caused by AF, outside of infection. Although there were more patients with COVID-19 who developed nAF admitted to the intensive care unit (ITU) compared with patients with COVID-19 without AF (p=0.01), their admission NEWS and QCSI scores did not differ. This could explain why patients who developed nAF with COVID-19 had a significantly longer hospitalisation compared with patients with COVID-19 without AF (p<0.001), despite the LOS of patients with COVID-19 being significantly less than those with LRTI overall (Table S2 in the supplementary material online; p<0.001). Finally, in our population, patients who were older and those with a history of ischaemic heart disease or peripheral arterial disease had increased odds of developing nAF during a COVID-19 infection.

Although our dataset is representative of the wider population and has results from an appropriate control group, its reliance on accurate clinical coding of disease in electronic records could introduce information bias resulting from missing, misclassified or incorrectly entered data, although this was reduced through manual review of the data, as described in the Materials and methods section. The follow-up data relating to readmissions, myocardial infarction, and stroke within 6 months, could be incomplete because data on patients who are subsequently treated out of area, treated at another local hospital, or managed in primary care would not be captured in our hospital records. Another consideration is that the data were collected during the height of the COVID-19 pandemic in 2020. Therefore, we cannot comment on how nAF incidence might differ with vaccination, dexamethasone, other COVID-19 treatments or with the Omicron, Delta and other COVID-19 variants, because there is a paucity of literature that has reported this thus far. Although most COVID-19 infections now cause a very mild systemic illness not requiring hospital admission, clinicians should remain vigilant for cardiovascular complications of COVID-19 within hospital, particularly because long-term inflammatory conditions are reported after COVID-19,20 which could, in turn, increase the risk of cardiac arrhythmias, such as AF. Furthermore, although in our population the incidence of nAF in COVID-19 was higher than with LRTI, other large datasets have described a similar prevalence of nAF in patients hospitalised with LRTI (7.6%).21 Therefore, nAF in the setting of infection is a common complication and each patient who is at risk of future stroke should be holistically considered for stroke preventative treatment.

Conclusions

Given that COVID-19 will continue to remain endemic throughout the world, the true impact of nAF in the setting of COVID-19 could become apparent over the coming years. Our results demonstrate poorer anticoagulation rates in patients with COVID-19 with nAF, compared with those with LRTI, despite a similar ischaemic stroke risk between the cohorts. This reflects an uncertainty in clinical practice because research quantifying the recurrence rate of AF secondary to COVID-19 and its implication on thrombotic diseases, such as stroke, is lacking. However, until such evidence is available, clinicians should consider offering anticoagulants to patients who develop nAF with COVID-19 who have high ischaemic stroke risk, facilitating discussions between patients and specialists allowing informed and collaborative decision making in secondary care.

Summary

What is known?

Infections, such as COVID-19 or LRTI, can lead to cardiac arrythmias, such as AF, a major cause of ischaemic stroke.

What are the questions?

Is the incidence of nAF higher in COVID-19 compared with LRTI, and what factors within patients with COVID-19 could lead to the development of nAF?

What was found?

The incidence of nAF was significantly higher in patients hospitalised with COVID-19 compared with those hospitalised with LRTI, despite patients with COVID-19 being younger.

A significantly lower proportion of patients with COVID-19 and nAF were discharged on anticoagulants, compared with LRTI and nAF, even though both groups had a similar ischaemic stroke and bleeding risk.

Older age and a history of thrombotic disease conveyed a higher likelihood of developing nAF in patients with COVID-19.

What is the implication for practice now?

AF in the setting of infections carries a high recurrence rate and ischaemic stroke risk. Until more research on COVID-19, nAF and ischaemic stroke is available, clinicians should holistically consider anticoagulation in this patient cohort to reduce risk of future stroke.

Funding

This work was supported by an NIHR Academic Clinical Lectureship (RG85316) to II as well as support from the British Heart Foundation Cambridge Centre of Research Excellence and the Addenbrookes Charitable Trust. The funders had no role in the design, data collection, data analysis, data interpretation or writing of the manuscript.

This project was registered with Cambridge University Hospitals Quality Surveillance Team for service improvement in AF detection and anticoagulation rates. Formal confirmation from Cambridge University Hospitals was received that ethical approval from an Institutional Review Board was not required.

Declaration of interests

KK has received travel grants from Bayer, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer. The other authors declare no conflicts of interest.

Supplementary material

Additional supplementary material may be found in the online version of this article at www.rcpjournals.org/content/clinmedicine.

S1 – Supplementary tables

Acknowledgments

We would like to thank the Cambridge University Hospitals Clinical Coding Department for their assistance with this study.

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Higher incidence of new atrial fibrillation in hospitalised COVID-19 patients compared to lower respiratory tract infection, however, less patients prescribed anticoagulants at discharge
Isuru Induruwa, Elizabeth Cattermole, Christopher Paisey, Colver Ken Howe Ne, Kayvan Khadjooi
Clinical Medicine Sep 2023, 23 (5) 478-484; DOI: 10.7861/clinmed.2023-0188
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