use of non steroidal anti inflammatory drugs and risk of death from covid 19 an opensafely CORD-Papers-2022-06-02 (Version 1)

Title: Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts
Abstract: OBJECTIVES: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY a secure analytical platform. METHODS: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England we used routine clinical data in England linked to death data. In study 1 we identified people with an NSAID prescription in the last 3 years from the general population. In study 2 we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs compared with those not currently prescribed NSAIDs accounting for age sex comorbidities other medications and geographical region. RESULTS: In study 1 we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2 we included 1 708 781 people with rheumatoid arthritis/osteoarthritis of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model we observed a lower risk of COVID-19 related death (HR 0.78 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. CONCLUSIONS: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.
Published: 2021-01-21
Journal: Ann Rheum Dis
DOI: 10.1136/annrheumdis-2020-219517
DOI_URL: http://doi.org/10.1136/annrheumdis-2020-219517
Author Name: Wong Angel YS
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wong_angel_ys
Author Name: MacKenna Brian
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mackenna_brian
Author Name: Morton Caroline E
Author link: https://covid19-data.nist.gov/pid/rest/local/author/morton_caroline_e
Author Name: Schultze Anna
Author link: https://covid19-data.nist.gov/pid/rest/local/author/schultze_anna
Author Name: Walker Alex J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/walker_alex_j
Author Name: Bhaskaran Krishnan
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bhaskaran_krishnan
Author Name: Brown Jeremy P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/brown_jeremy_p
Author Name: Rentsch Christopher T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/rentsch_christopher_t
Author Name: Williamson Elizabeth
Author link: https://covid19-data.nist.gov/pid/rest/local/author/williamson_elizabeth
Author Name: Drysdale Henry
Author link: https://covid19-data.nist.gov/pid/rest/local/author/drysdale_henry
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: 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: 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: Tomlinson Laurie
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tomlinson_laurie
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: Parry John
Author link: https://covid19-data.nist.gov/pid/rest/local/author/parry_john
Author Name: Hester Frank
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hester_frank
Author Name: Harper Sam
Author link: https://covid19-data.nist.gov/pid/rest/local/author/harper_sam
Author Name: Evans Stephen JW
Author link: https://covid19-data.nist.gov/pid/rest/local/author/evans_stephen_jw
Author Name: Smeeth Liam
Author link: https://covid19-data.nist.gov/pid/rest/local/author/smeeth_liam
Author Name: Douglas Ian J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/douglas_ian_j
Author Name: Goldacre Ben
Author link: https://covid19-data.nist.gov/pid/rest/local/author/goldacre_ben
sha: e279042623d8883cf43bfa477d7189176116eea6
license: cc-by
license_url: https://creativecommons.org/licenses/by/4.0/
source_x: Medline; PMC
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 33478953
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/33478953
pmcid: PMC7823433
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823433
url: https://doi.org/10.1136/annrheumdis-2020-219517 https://www.ncbi.nlm.nih.gov/pubmed/33478953/
has_full_text: TRUE
Keywords Extracted from Text Content: NSAIDs COVID-19 non-steroidal anti-inflammatory drugs people OpenSAFELY NSAID paracetamol kidney gastrointestinal PPI DAG OpenSAFELY infliximab Patients AYSW celecoxib/etoricoxib UKRI NHS IG statins S5-S10 recombinant ACE 2 non-steroidal anti-inflammatory GlaxoSmithKline. cancer women COVID-19 Mohn-Westlake ibuprofen indometacin people £ Office Non-steroidal anti-inflammatory drugs cells UK Health Service Aspirin immune cells SARS-CoV-2 Patient CIs ≥1 oral NSAID ISO centre HbA1c high-dose naproxen renin-angiotensinaldosterone system blockers ACE 2 NCT04382768 participants myocardial S14 patients JPB NSAIDs COVID-19 33-36 patient Royston-Parmar Indometacin V.16.1 NCT04344457 NIHR, London School of Hygiene individuals aspirin proton-pump lung NCT04334629 41 naproxen line cardiovascular antiplatelet low-dose RA/OA Sir Henry Wellcome NCT04325633 39 NHS France cellular People cell humans Python V.3.8 S15 RA NSAID adalimumab National Health Service (NHS UK BG's grants COX-2 SARS virus BM CB National Health Service England/NHSX.Contributors PI BG Competing interests BG UK AYSW AM Mohn-Westlake JP
Extracted Text Content in Record: First 5000 Characters:Objectives To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. Methods We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region. Results In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. Conclusions We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for relief of pain and inflammation with nearly 11 million NSAID prescriptions dispensed in primary care in England in the last 12 months. 2 Additionally, some NSAIDs (eg, ibuprofen and aspirin) are available for sale without a prescription with a single brand of ibuprofen alone having sales of approximately £100 million per annum. 3 Nine non-interventional studies have suggested that NSAIDs may be associated with increased risk of complications of lower respiratory tract infections [4] [5] [6] [7] [8] [9] [10] [11] [12] ; though there is evidence that indometacin may have protective antiviral effects reported from a single animal study. 13 There is now a debate over whether NSAIDs may worsen the prognosis of COVID-19. On 14 March, it was recommended in France that patients should avoid NSAID use due to an apparent worsening of COVID-19 in those taking ibuprofen, based on unpublished reports. 14 This gained worldwide attention and resulted in the National Health Service (NHS) England medical director issuing a directive that paracetamol should be used in preference to NSAIDs 14 for symptoms of COVID-19. Subsequent reviews by USA, UK and EU drug regulators [15] [16] [17] recommended that individuals currently using NSAIDs for the management of chronic diseases should continue the treatment while calling for more evidence of the impact of NSAIDs in patients with COVID-19. Two systematic reviews highlighted a lack of studies investigating the effect of NSAIDs on COVID-19, demonstrating the urgent need of new studies. 18 19 One cohort study was recently conducted to investigate such association, but individual NSAIDs were not specifically investigated. 20 We therefore investigated the association between NSAID use and deaths from COVID-19 using linked data from >17 million patients in England. We further examined whether the association varied by types of NSAID. We conducted two cohort studies using primary care electronic health record data linked to death data from the Office for National Statistics between 1 March 2020 and 14 June 2020. Primary care records managed by the software provider The Phoenix Partnership (TPP) were linked to Office for National Statistics death data through OpenSAFELY, a data analytics platform created by our team on behalf of NHS England. 21 The dataset analysed within OpenSAFELY is based on 24 million people currently registered with primary care practices using The Phoenix Partnership SystmOne software, representing 40% of the English population. It includes pseudonymised data such as coded diagnoses, prescribed medications and physiological parameters. We identified two cohorts, anticipating that underlying factors influencing NSAID use and therefore potential biases would differ between them. The first cohort was all people with ≥1 oral NSAID prescription within the 3 years before study start (1 March 2020), identified from the general population. It was chosen to minimise confounding by restricting to people who were currently prescribed NSAIDs and those who recently stopped NSAIDs as their characteristics were likely to be more comparable than never-users. The second cohort was all people with a diagnosis of rheumatoid arthritis (RA)/osteoarthritis (OA) before
Keywords Extracted from PMC Text: CIs indometacin COVID-19 RA S16–S21 Patient France SARS-CoV-2.20 Office celecoxib/etoricoxib RA/OA patients.44 participants paracetamol cardiovascular disease,22 ≥1 oral NSAID Aspirin S14 described.21 PPI cells NSAIDs14 NCT04344457).42 immune cells NHS NSAIDs.22 cancer S5–S10 NHS IG Toolkit compliant47 infliximab cellular COX-2 COVID-19 diagnosis.37 NSAID recombinant ACE 2 null).25 Table 1 58–76 £ V.16.1 high-dose Python V.3.8 generalisability.34 A naproxen line Partnerships,24 unavailable.23 Figure 1 kidney ibuprofen Patients lung NCT0432563339 UK DAG proton-pump renin–angiotensin–aldosterone system blockers statins adalimumab SARS-CoV-2 women NSAIDs https://github.com/opensafely/nsaids-covid-research antiplatelet people OpenSAFELY myocardial https://codelists.opensafely.org/. annum.3 cell gastrointestinal ACE S15 low-dose UK Health Service Royston-Parmar ISO patient National Health Service (NHS humans patients NHS England.21 aspirin route.30
Extracted PMC Text Content in Record: First 5000 Characters:COVID-19, caused by the SARS-CoV-2, has been diagnosed in approximately 18 million patients with >690 000 deaths in >200 countries as of 5 August 2020.1 Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for relief of pain and inflammation with nearly 11 million NSAID prescriptions dispensed in primary care in England in the last 12 months.2 Additionally, some NSAIDs (eg, ibuprofen and aspirin) are available for sale without a prescription with a single brand of ibuprofen alone having sales of approximately £100 million per annum.3 Nine non-interventional studies have suggested that NSAIDs may be associated with increased risk of complications of lower respiratory tract infections4–12; though there is evidence that indometacin may have protective antiviral effects reported from a single animal study.13 There is now a debate over whether NSAIDs may worsen the prognosis of COVID-19. On 14 March, it was recommended in France that patients should avoid NSAID use due to an apparent worsening of COVID-19 in those taking ibuprofen, based on unpublished reports.14 This gained worldwide attention and resulted in the National Health Service (NHS) England medical director issuing a directive that paracetamol should be used in preference to NSAIDs14 for symptoms of COVID-19. Subsequent reviews by USA, UK and EU drug regulators15–17 recommended that individuals currently using NSAIDs for the management of chronic diseases should continue the treatment while calling for more evidence of the impact of NSAIDs in patients with COVID-19. Two systematic reviews highlighted a lack of studies investigating the effect of NSAIDs on COVID-19, demonstrating the urgent need of new studies.18 19 One cohort study was recently conducted to investigate such association, but individual NSAIDs were not specifically investigated.20 We therefore investigated the association between NSAID use and deaths from COVID-19 using linked data from >17 million patients in England. We further examined whether the association varied by types of NSAID. We conducted two cohort studies using primary care electronic health record data linked to death data from the Office for National Statistics between 1 March 2020 and 14 June 2020. Primary care records managed by the software provider The Phoenix Partnership (TPP) were linked to Office for National Statistics death data through OpenSAFELY, a data analytics platform created by our team on behalf of NHS England.21 The dataset analysed within OpenSAFELY is based on 24 million people currently registered with primary care practices using The Phoenix Partnership SystmOne software, representing 40% of the English population. It includes pseudonymised data such as coded diagnoses, prescribed medications and physiological parameters. We identified two cohorts, anticipating that underlying factors influencing NSAID use and therefore potential biases would differ between them. The first cohort was all people with ≥1 oral NSAID prescription within the 3 years before study start (1 March 2020), identified from the general population. It was chosen to minimise confounding by restricting to people who were currently prescribed NSAIDs and those who recently stopped NSAIDs as their characteristics were likely to be more comparable than never-users. The second cohort was all people with a diagnosis of rheumatoid arthritis (RA)/osteoarthritis (OA) before study start. It was chosen because they were potential NSAID users with similar underlying diseases to reduce confounding by indication. A patient could be included in both cohorts. In both cohorts, people with missing data for gender, index of multiple deprivation, <1 year of primary care records or aged <18 or >110 years were excluded. Aspirin is used at lower doses as an antiplatelet to prevent cardiovascular disease,22 indicating aspirin users constitute a different population from other NSAID users. We therefore excluded people ever prescribed aspirin in the 10 years before study start or a record of either stroke or myocardial infarction before study start. We excluded people with a record of gastrointestinal bleeding or current asthma before the study start, as they are contraindications to NSAIDs.22 In the main analysis, we defined current NSAID users as those ever prescribed NSAID in the 4 months prior to study start, and non-users are those with no record of NSAID prescription in the same time period. We examined whether the association varied by types of NSAID, specifically: (1) naproxen dose (categorised as non-use, high-dose naproxen (500 mg), low-dose naproxen (250 mg) and other NSAIDs based on the strength of the formulation), (2) COX-2 specific NSAIDs (categorised as non-use, COX-2 specific (celecoxib/etoricoxib) and non-specific NSAIDs) and (3) ibuprofen (categorised as non-use, ibuprofen and other NSAIDs). Follow-up for each cohort began on the 1 March 2020 and ended either on date of death or study end date (14 June 2020). If people
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