| 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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document_parses/pmc_json/PMC7823433.xml.json |
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use_of_non_steroidal_anti_inflammatory_drugs_and_risk_of_death_from_covid_19_an_opensafely |
