association between warfarin and covid 19 related outcomes compared with direct oral CORD-Papers-2022-06-02 (Version 1)

Title: Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study
Abstract: BACKGROUND: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant it acts by antagonising vitamin K which is low in patients with severe COVID-19. To date the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. METHODS: On behalf of NHS England we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. RESULTS: A total of 92339 warfarin users and 280407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2 HR 0.73 (95% CI 0.680.79); COVID-19-related hospital admission HR 0.75 (95% CI 0.680.83); COVID-19-related deaths HR 0.74 (95% CI 0.660.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2 HR 0.80 (95% CI 0.790.81); non-COVID-19 deaths HR 0.79 (95% CI 0.760.83)]. CONCLUSIONS: Overall this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01185-0.
Published: 2021-10-19
Journal: J Hematol Oncol
DOI: 10.1186/s13045-021-01185-0
DOI_URL: http://doi.org/10.1186/s13045-021-01185-0
Author Name: Wong Angel Y S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wong_angel_y_s
Author Name: Tomlinson Laurie A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tomlinson_laurie_a
Author Name: Brown Jeremy P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/brown_jeremy_p
Author Name: Elson William
Author link: https://covid19-data.nist.gov/pid/rest/local/author/elson_william
Author Name: Walker Alex J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/walker_alex_j
Author Name: Schultze Anna
Author link: https://covid19-data.nist.gov/pid/rest/local/author/schultze_anna
Author Name: Morton Caroline E
Author link: https://covid19-data.nist.gov/pid/rest/local/author/morton_caroline_e
Author Name: Evans David
Author link: https://covid19-data.nist.gov/pid/rest/local/author/evans_david
Author Name: Inglesby Peter
Author link: https://covid19-data.nist.gov/pid/rest/local/author/inglesby_peter
Author Name: MacKenna Brian
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mackenna_brian
Author Name: Bhaskaran Krishnan
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bhaskaran_krishnan
Author Name: Rentsch Christopher T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/rentsch_christopher_t
Author Name: Powell Emma
Author link: https://covid19-data.nist.gov/pid/rest/local/author/powell_emma
Author Name: Williamson Elizabeth
Author link: https://covid19-data.nist.gov/pid/rest/local/author/williamson_elizabeth
Author Name: Croker Richard
Author link: https://covid19-data.nist.gov/pid/rest/local/author/croker_richard
Author Name: Bacon Seb
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bacon_seb
Author Name: Hulme William
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hulme_william
Author Name: Bates Chris
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bates_chris
Author Name: Curtis Helen J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/curtis_helen_j
Author Name: Mehrkar Amir
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mehrkar_amir
Author Name: Cockburn Jonathan
Author link: https://covid19-data.nist.gov/pid/rest/local/author/cockburn_jonathan
Author Name: McDonald Helen I
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mcdonald_helen_i
Author Name: Mathur Rohini
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mathur_rohini
Author Name: Wing Kevin
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wing_kevin
Author Name: Forbes Harriet
Author link: https://covid19-data.nist.gov/pid/rest/local/author/forbes_harriet
Author Name: Eggo Rosalind M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/eggo_rosalind_m
Author Name: Evans Stephen J W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/evans_stephen_j_w
Author Name: Smeeth Liam
Author link: https://covid19-data.nist.gov/pid/rest/local/author/smeeth_liam
Author Name: Goldacre Ben
Author link: https://covid19-data.nist.gov/pid/rest/local/author/goldacre_ben
Author Name: Douglas Ian J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/douglas_ian_j
sha: b711e9e6c7d5ed232b8ea604aeba2e85f397823d
license: cc-by
license_url: https://creativecommons.org/licenses/by/4.0/
source_x: Medline; PMC; WHO
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/https://www.who.int/
pubmed_id: 34666811
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/34666811
pmcid: PMC8525065
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525065
url: https://www.ncbi.nlm.nih.gov/pubmed/34666811/ https://doi.org/10.1186/s13045-021-01185-0
has_full_text: TRUE
Keywords Extracted from Text Content: anticoagulant NHS COVID-19 Open-SAFELY thromboembolism patients atrial SARS-CoV-2 warfarin oral anticoagulants vitamin K people SARS-CoV-2 antigen DOACs [4] [5] [6] [7] People men atrial Office venous thromboembolism oral anticoagulants vitamin K UK anticoagulants myocardial DOACs Figure S2 blob/ DAG antiplatelets anticoagulant NHS [16] CEM Tables S2-S6 patients antiplatelet alcohol extrahepatic vitamin K non-anticoagulant heparin vitamin K antagonists Royston-Parmar riskprone people SARS-CoV-2 antigen non-COVID-19 UK's Pillar 1 OpenSAFELY Pillar 2 kidney mitral causespecific heart AJW glomerular prothrombin vitamin K. antiphospholipid antibody participants OAC DAGadjusted dp-ucMGP intracranial gastrointestinal COVID-19 patient oestrogen CIs SARS-CoV-2 Figure S1 warfarin Cornfield anticoagulants 4 peripheral arterial COVID-19 patients CB NHS England/NHSX ISO oral anticoagulants DOACs blob/ VPN antiplatelets anticoagulant NHS patients cell OpenSAFELY COPI NHS IG GSK COVID-19 patient oagul org/ coi_ oestrogen BG Mohn-Westlake oral anticoagulant warfarin GlaxoSmithKline (
Extracted Text Content in Record: First 5000 Characters:Background: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. Methods: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the Open-SAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. Results: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)]. Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease. The OpenSAFELY Collaborative et al. J Hematol Oncol (2021) 14:172 outcomes among patients with COVID-19 treated with warfarin, which works by antagonising vitamin K. Unlike warfarin, the mechanism of action of direct oral anticoagulants (DOACs) is independent of vitamin K. To date, there is limited evidence comparing outcomes from COVID-19 between patients treated with warfarin and those treated with DOACs. Current studies comparing the outcomes from COVID-19 between patients treated with warfarin and/or DOACs with non-anticoagulant users [4] [5] [6] [7] limit the understanding of risks and benefits of prescribing different types of oral anticoagulants specifically in the context of the COVID-19 pandemic. We therefore conducted a population-based cohort study to investigate the association between routinely prescribed warfarin and COVID-19-related outcomes, in comparison with those treated with DOACs. To minimise confounding by indication, we compared outcomes between patients treated for non-valvular atrial fibrillation (AF). We conducted a population-based cohort study between 1 March 2020 and 28 September 2020. Primary care records managed by the software provider TPP were linked to SARS-CoV-2 antigen testing data from the Second Generation Surveillance System, COVID-19-related hospital admissions from the secondary uses service, and Office for National Statistics death data through OpenSAFELY, a data analytics platform created by our team on behalf of NHS England [8] . The data set analysed within OpenSAFELY is based on 24 million people currently registered with primary care practices using TPP SystmOne software, representing 40% of the English population. It includes pseudonymised data such as coded diagnoses, prescribed medications and physiological parameters. We first identified all patients with a diagnosis of AF on or before study start (1 March 2020) (Fig. 1 ). People with missing data for sex, Index of Multiple Deprivation, < 1 year of primary care records, or aged < 18 or > 110 and prescribed injectable anticoagulants 4 months before study start date were excluded. In addition, people with a record of mitral stenosis or prosthetic mechanical valves, chronic kidney disease stage V (estimated glomerular filtration rate < 15 mL/min or on dialysis), or antiphospholipid antibody syndrome before study start were also excluded in this study because DOACs are not recommended for use in these patient groups. We defined participants as DOAC users if they were prescribed a DOAC as their latest OAC prescription in the 4 months before study start. The comparison group was people who were prescribed warfarin as the latest OAC prescription in the 4 months before study start date. If both warfarin and DOACs were prescribed on the same day as the latest prescription (n = 32), we classified them as warfarin users as a conservative estimate because warfarin is hypothesised to have a harmful effect on severe COVID-19 compared with DOACs. The outcomes were (1) testing positive for SARS-CoV-2, (2) COVID-19-related hospital admission, and (3) COVID-19-related death (defined as the presence of ICD-10 codes U071 (confirmed COVID-19) and U072 (suspected COVID-19) anywhere on the death certificate). Testing outcomes were obtained from the UK's Pillar 1 (NHS and Public Health England l
Keywords Extracted from PMC Text: patient COVID-19 UK's Pillar 1 alcohol peripheral arterial extrahepatic vitamin K oral anticoagulant anticoagulants 4 dp-ucMGP Figure S1 vitamin K antiplatelets venous thromboembolism non-anticoagulant SARS-CoV-2 oestrogen heart gastrointestinal participants Office glomerular thromboembolism [1, 2 anticoagulant CIs mitral Cornfield prothrombin kidney people DAG antiplatelet AJW CB COVID-19 patients atrial intracranial Pillar 2 myocardial anticoagulants vitamin K antagonists Figure S2 vitamin K. DOACs non-COVID-19 NHS warfarin OAC People CEM patients [16] UK oral anticoagulants SARS-CoV-2 antigen OpenSAFELY heparin antiphospholipid antibody
Extracted PMC Text Content in Record: First 5000 Characters:People with severe COVID-19 disease have a high risk of thromboembolism [1, 2], and it is also known that lower levels of vitamin K could lead to pro-thrombotic conditions [3]. This might also lead to poorer outcomes among patients with COVID-19 treated with warfarin, which works by antagonising vitamin K. Unlike warfarin, the mechanism of action of direct oral anticoagulants (DOACs) is independent of vitamin K. To date, there is limited evidence comparing outcomes from COVID-19 between patients treated with warfarin and those treated with DOACs. Current studies comparing the outcomes from COVID-19 between patients treated with warfarin and/or DOACs with non-anticoagulant users [4–7] limit the understanding of risks and benefits of prescribing different types of oral anticoagulants specifically in the context of the COVID-19 pandemic. We therefore conducted a population-based cohort study to investigate the association between routinely prescribed warfarin and COVID-19-related outcomes, in comparison with those treated with DOACs. To minimise confounding by indication, we compared outcomes between patients treated for non-valvular atrial fibrillation (AF). We conducted a population-based cohort study between 1 March 2020 and 28 September 2020. Primary care records managed by the software provider TPP were linked to SARS-CoV-2 antigen testing data from the Second Generation Surveillance System, COVID-19-related hospital admissions from the secondary uses service, and Office for National Statistics death data through OpenSAFELY, a data analytics platform created by our team on behalf of NHS England [8]. The data set analysed within OpenSAFELY is based on 24 million people currently registered with primary care practices using TPP SystmOne software, representing 40% of the English population. It includes pseudonymised data such as coded diagnoses, prescribed medications and physiological parameters. We first identified all patients with a diagnosis of AF on or before study start (1 March 2020) (Fig. 1). People with missing data for sex, Index of Multiple Deprivation, < 1 year of primary care records, or aged < 18 or > 110 and prescribed injectable anticoagulants 4 months before study start date were excluded. In addition, people with a record of mitral stenosis or prosthetic mechanical valves, chronic kidney disease stage V (estimated glomerular filtration rate < 15 mL/min or on dialysis), or antiphospholipid antibody syndrome before study start were also excluded in this study because DOACs are not recommended for use in these patient groups. We defined participants as DOAC users if they were prescribed a DOAC as their latest OAC prescription in the 4 months before study start. The comparison group was people who were prescribed warfarin as the latest OAC prescription in the 4 months before study start date. If both warfarin and DOACs were prescribed on the same day as the latest prescription (n = 32), we classified them as warfarin users as a conservative estimate because warfarin is hypothesised to have a harmful effect on severe COVID-19 compared with DOACs. The outcomes were (1) testing positive for SARS-CoV-2, (2) COVID-19-related hospital admission, and (3) COVID-19-related death (defined as the presence of ICD-10 codes U071 (confirmed COVID-19) and U072 (suspected COVID-19) anywhere on the death certificate). Testing outcomes were obtained from the UK's Pillar 1 (NHS and Public Health England laboratories) and Pillar 2 (commercial partners) testing strategies and included results from polymerase chain reaction swab tests used to identify symptomatic individuals [9]. As pre-specified analyses, we also conducted negative control outcome analyses to examine the presence of residual confounding between warfarin and DOAC users. First, we anticipated that, within our population of people with non-valvular AF, there were unlikely to be marked differences in the likelihood of being tested for SARS-CoV-2 infection in relation to drug treatment with warfarin or DOAC. Therefore, we included being tested for SARS-CoV-2 as a negative control outcome to test our assumption. Second, we also included non-COVID-19 death, as differences in this outcome between DOAC and warfarin users could imply that differences in health characteristics had not been successfully controlled for. We conducted additional post hoc analyses to include cause-specific deaths as outcomes (i.e. death due to myocardial infarction, ischaemic stroke, venous thromboembolism, gastrointestinal bleeding and intracranial bleeding) to aid the interpretation of our results. Follow-up for each cohort began on 1 March 2020 and ended at the latest of the outcome of interest in each analysis, deregistration from the TPP practice, death or study end date (28 September 2020) (Fig. 1). Covariates were pre-specified, identified from a directed acyclic graph (DAG) approach (Additional file 1: Figure S1), including age, sex, obesity, smoking status, hypertension,
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