Association between oral anticoagulants and COVID-19 related outcomes: two cohort studies

Abstract

ObjectivesWe investigated the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes, comparing current OAC use versus non-use in Study 1; and warfarin versus direct oral anticoagulants (DOACs) in Study 2.DesignTwo cohort studies, on behalf of NHS England.SettingPrimary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England.ParticipantsStudy 1: 70,464 people with atrial fibrillation (AF) and CHA□DS□-VASc score of 2. Study 2: 372,746 people with non-valvular AF.Main outcome measuresTime to test for SARS-CoV-2, testing positive for SARS-CoV-2, COVID-19 related hospital admission, COVID-19 deaths or non-COVID-19 deaths in Cox regression.ResultsIn Study 1, we included 52,416 current OAC users and 18,048 non-users. We observed no difference in risk of being tested for SARS-CoV-2 associated with current use (adjusted HR, 1.01, 95%CI, 0.96 to 1.05) versus non-use. We observed a lower risk of testing positive for SARS-CoV-2 (adjusted HR, 0.73, 95%CI, 0.60 to 0.90), and COVID-19 deaths (adjusted HR, 0.69, 95%CI, 0.49 to 0.97) associated with current use versus non-use. In Study 2, we included 92,339 warfarin users and 280,407 DOAC users. We observed a lower risk of COVID-19 deaths (adjusted HR, 0.79, 95%CI, 0.76 to 0.83) associated with warfarin versus DOACs. Similar associations were found for all other outcomes.ConclusionsAmong people with AF and a CHA□DS□-VASc score of 2, those receiving OACs had a lower risk of receiving a positive COVID-19 test and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or more cautious behaviours leading to reduced infection risk. There was no evidence of a higher risk of severe COVID-19 outcomes associated with warfarin versus DOACs in people with non-valvular AF regardless of CHA□DS□-VASc score.Key pointsWhat is already known on this topicCurrent studies suggest that prophylactic or therapeutic anticoagulant use, particularly low molecular weight heparin, lower the risk of pulmonary embolism and mortality during hospitalisation among patients with COVID-19.Reduced vitamin K status has been reported to be correlated with severity of COVID-19. This could mean that warfarin, as a vitamin K antagonist, is associated with more severe COVID-19 disease than non-vitamin K anticoagulants.What this study addsIn 70,464 people with atrial fibrillation, at the threshold of being treated with an OAC based on risk of stroke, we observed a lower risk of testing positive for SARS-CoV-2 and COVID-19 related deaths associated with routinely prescribed OACs, relative to non-use.This might be explained by OACs preventing severe COVID-19 outcomes, or more cautious behaviours and environmental factors reducing the risk of SARS-CoV-2 infection in those taking OACs.In 372,746 people with non-valvular atrial fibrillation, there was no evidence of a higher risk of severe COVID-19 outcomes associated with warfarin compared with DOACs.

Evaluation of antithrombotic use and COVID-19 outcomes in a nationwide atrial fibrillation cohort

“…Of the AF cohort analysed, 8% (n=77,364) had a recorded COVID-19 event of which 3.8% (n=37,418) had a COVID-19 related hospitalisation and 2.2% (n=21,116) died. A marginally lower risk of COVID-19 death was observed for those with pre-existing AT use which directionally aligns with the most comparable previous studies[9,11]. AT use was, however, associated with higher odds of COVID-19 hospitalisation.…”

“…For DOACs vs warfarin, no difference was observed between groups for COVID-19 death, but DOACs were associated with marginally reduced odds of COVID-19 hospitalisation. Our analysis did not directly investigate the previously reported observation that vitamin K depletion through warfarin is harmful[15] but, more generally, our findings suggest that it is unlikely that warfarin offers protection against severe COVID-19 outcomes compared with DOACs[11].…”

“…Lastly, exposure to AT medication was defined as one or more dispensed prescriptions (recorded in NHS BSA Dispensed Medicines) in the previous 6 months. Other studies have used different time periods and prescription frequency counts[9,11] and adherence was not measured[30]. We purposefully defined a liberal threshold to support evaluation of AT usage up to May 2021 that may have included unusual buying patterns (e.g.…”

“…However, evidence is discordant with a US study (n=3,772) observing no difference in mortality in groups on AC or AP[10]. In the UK, a larger study (n = 70,464 / 372,746) explored AC and AC sub-types (warfarin vs direct oral anticoagulants (DOACs)) in individuals with AF and observed that AC was associated with a lower COVID-19 specific mortality[11]. This observational evidence is promising, but it does not compare all sub-types of AT and only covered the period up to September 28 th 2020.…”

A nationwide deep learning pipeline to predict stroke and COVID-19 death in atrial fibrillation

“…The ability of CHA 2 DS 2 -VASc to discriminate an individual’s future stroke risk is also only moderate (pooled area under the receiver operating characteristics curve (AUC) of 0.67 across 27 studies 14 ) and potentially lower for predicting first ever stroke based on information at the point of AF diagnosis where available evidence is significantly limited. Recent research has also observed that pre-existing use of antithrombotics, particularly anticoagulants, is associated with lower odds of people with AF dying from COVID-19 15,16 . A model that could improve prediction of first stroke in people with AF and also identify those at greatest risk of COVID-19 death would be a potentially valuable new tool to inform anticoagulant prescribing decisions.…”