Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: A Danish nationwide cohort study

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Abstract

Background

Concerns over the safety of non-steroidal anti-inflammatory drug (NSAID) use during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been raised. We studied whether use of NSAIDs was associated with adverse outcomes and mortality during SARS-CoV-2 infection.

Methods and findings

We conducted a population-based cohort study using Danish administrative and health registries. We included individuals who tested positive for SARS-CoV-2 during the period 27 February 2020 to 29 April 2020. NSAID users (defined as individuals having filled a prescription for NSAIDs up to 30 days before the SARS-CoV-2 test) were matched to up to 4 non-users on calendar week of the test date and propensity scores based on age, sex, relevant comorbidities, and use of selected prescription drugs. The main outcome was 30-day mortality, and NSAID users were compared to non-users using risk ratios (RRs) and risk differences (RDs). Secondary outcomes included hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and acute renal replacement therapy. A total of 9,236 SARS-CoV-2 PCR-positive individuals were eligible for inclusion. The median age in the study cohort was 50 years, and 58% were female. Of these, 248 (2.7%) had filled a prescription for NSAIDs, and 535 (5.8%) died within 30 days. In the matched analyses, treatment with NSAIDs was not associated with 30-day mortality (RR 1.02, 95% CI 0.57 to 1.82, p = 0.95; RD 0.1%, 95% CI −3.5% to 3.7%, p = 0.95), risk of hospitalization (RR 1.16, 95% CI 0.87 to 1.53, p = 0.31; RD 3.3%, 95% CI −3.4% to 10%, p = 0.33), ICU admission (RR 1.04, 95% CI 0.54 to 2.02, p = 0.90; RD 0.2%, 95% CI −3.0% to 3.4%, p = 0.90), mechanical ventilation (RR 1.14, 95% CI 0.56 to 2.30, p = 0.72; RD 0.5%, 95% CI −2.5% to 3.6%, p = 0.73), or renal replacement therapy (RR 0.86, 95% CI 0.24 to 3.09, p = 0.81; RD −0.2%, 95% CI −2.0% to 1.6%, p = 0.81). The main limitations of the study are possible exposure misclassification, as not all individuals who fill an NSAID prescription use the drug continuously, and possible residual confounding by indication, as NSAIDs may generally be prescribed to healthier individuals due to their side effects, but on the other hand may also be prescribed for early symptoms of severe COVID-19.

Conclusions

Use of NSAIDs was not associated with 30-day mortality, hospitalization, ICU admission, mechanical ventilation, or renal replacement therapy in Danish individuals who tested positive for SARS-CoV-2.

Trial registration

The European Union electronic Register of Post-Authorisation Studies EUPAS34734

Abstract

In a nationwide cohort study, Lars C. Lund, Kasper B. Kristensen, and colleagues investigate the association of NSAID use and outcomes in COVID-19 patients.

Author summary

Why was this study done?

During the early phases of the pandemic of coronavirus disease 2019 (COVID-19), concerns were raised that ibuprofen, a drug commonly used to treat weak pain and fevers, may lead to a more severe course of coronavirus disease.
If this risk is verified, it would be important to reduce the use of ibuprofen and ibuprofen-like drugs, commonly referred to as non-steroidal anti-inflammatory drugs (NSAIDs), among patients at risk of COVID-19.

What did the researchers do and find?

We identified all Danish residents who tested positive for the infectious agent of COVID-19 and grouped them into users and non-users of NSAIDs.
The risks of being hospitalized, admitted to the intensive care unit, or dying were compared between the 2 groups.
Overall, risks for all studied outcomes were similar between users and non-users of ibuprofen and other NSAIDs.

What do these findings mean?

NSAIDs do not lead to more severe coronavirus disease according to this study.

Related collections

Most cited references 22

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Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Lei Fang, George Karakiulakis, Michael Roth (2020)

The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues 1 were cerebrovascular diseases (22%) and diabetes (22%). Another study 2 included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, 3 of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study. Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. 4 The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). 4 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. 5 ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. If this hypothesis were to be confirmed, it could lead to a conflict regarding treatment because ACE2 reduces inflammation and has been suggested as a potential new therapy for inflammatory lung diseases, cancer, diabetes, and hypertension. A further aspect that should be investigated is the genetic predisposition for an increased risk of SARS-CoV-2 infection, which might be due to ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension, specifically in Asian populations. Summarising this information, the sensitivity of an individual might result from a combination of both therapy and ACE2 polymorphism. We suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs. Based on a PubMed search on Feb 28, 2020, we did not find any evidence to suggest that antihypertensive calcium channel blockers increased ACE2 expression or activity, therefore these could be a suitable alternative treatment in these patients. © 2020 Juan Gaertner/Science Photo Library 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19

Harmony Reynolds, Samrachana Adhikari, Claudia Pulgarin … (2020)

Abstract Background There is concern about the potential of an increased risk related to medications that act on the renin–angiotensin–aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). Methods We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. Results Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. Conclusions We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

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Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19

Giuseppe Mancia, Federico Rea, Monica Ludergnani … (2020)

Abstract Background A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. Methods We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. Results Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. Conclusions In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.

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Author and article information

Contributors

Lars Christian Lund:

ORCID: http://orcid.org/0000-0001-8651-6072

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Kasper Bruun Kristensen:

ORCID: http://orcid.org/0000-0001-6373-1386

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing – original draftRole: Writing – review & editing

Mette Reilev:

ORCID: http://orcid.org/0000-0003-1241-4385

Role: ConceptualizationRole: Writing – review & editing

Steffen Christensen: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing

Reimar Wernich Thomsen:

ORCID: http://orcid.org/0000-0001-9135-3474

Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Christian Fynbo Christiansen:

ORCID: http://orcid.org/0000-0002-0727-953X

Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Henrik Støvring:

ORCID: http://orcid.org/0000-0002-5821-2351

Role: SupervisionRole: Writing – review & editing

Nanna Borup Johansen:

ORCID: http://orcid.org/0000-0003-3764-8532

Role: ConceptualizationRole: MethodologyRole: Writing – review & editing

Nikolai Constantin Brun: Role: SupervisionRole: Writing – review & editing

Jesper Hallas:

ORCID: http://orcid.org/0000-0002-8097-8708

Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Anton Pottegård:

ORCID: http://orcid.org/0000-0001-9314-5679

Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Anne C. Cunningham: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Med

Journal ID (iso-abbrev): PLoS Med

Journal ID (publisher-id): plos

Journal ID (pmc): plosmed

Title: PLoS Medicine

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1549-1277

ISSN (Electronic): 1549-1676

Publication date (Electronic): 8 September 2020

Publication date Collection: September 2020

Volume: 17

Issue: 9

Electronic Location Identifier: e1003308

Affiliations

[1 ] Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark

[2 ] Department of Anaesthesia and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark

[3 ] Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

[4 ] Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark

[5 ] Department of Medical Evaluation and Biostatistics, Danish Medicines Agency, Copenhagen, Denmark

BRUNEI DARUSSALAM

Author notes

I have read the journal's policy and the authors of this manuscript have the following competing interests: KBK, NBJ, SC, NB, declare no conflicts of interest. RWT and CFC declare no personal conflicts of interest, yet the Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to and administered by Aarhus University. None of these studies are related to the current study. HS reports personal fees from Bristol-Myers Squibb, personal fees from Novartis, personal fees from Roche, outside the submitted work. AP and JH report participation in research funded by Alcon, Almirall, Astellas, AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Servier and LEO Pharma, all with funds paid to the institution where they were employed (no personal fees) and with no relation to the work reported in this paper. LCL reports participation in research projects funded by Menarini Pharmaceutical and LEO Pharma, with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. MR reports participation in research projects funded by LEO Pharma, with funds paid to the institution where she was employed (no personal fees) and with no relation to the work reported in this paper.

* E-mail: apottegaard@ 123456health.sdu.dk

Author information

Lars Christian Lund http://orcid.org/0000-0001-8651-6072

Kasper Bruun Kristensen http://orcid.org/0000-0001-6373-1386

Mette Reilev http://orcid.org/0000-0003-1241-4385

Reimar Wernich Thomsen http://orcid.org/0000-0001-9135-3474

Christian Fynbo Christiansen http://orcid.org/0000-0002-0727-953X

Henrik Støvring http://orcid.org/0000-0002-5821-2351

Nanna Borup Johansen http://orcid.org/0000-0003-3764-8532

Jesper Hallas http://orcid.org/0000-0002-8097-8708

Anton Pottegård http://orcid.org/0000-0001-9314-5679

Article

Publisher ID: PMEDICINE-D-20-02753

DOI: 10.1371/journal.pmed.1003308

PMC ID: 7478808

PubMed ID: 32898149

SO-VID: f0b82fe1-7f9c-4feb-bf28-bf4c898ae021

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 15 June 2020

Date accepted : 3 August 2020

Page count

Figures: 1, Tables: 4, Pages: 16

Funding

The authors received no specific funding for this work.

Custom metadata

Data Availability Due to data protection regulation, data cannot be shared directly by the authors. Data is accessible to authorized researchers after application to the Danish Health Data Authority. To apply for data and help with the application process, please see https://sundhedsdatastyrelsen.dk/da/forskerservice/ansog-om-data.

Outbreaks COVID-19

ScienceOpen disciplines: Medicine

Data availability:

ScienceOpen disciplines: Medicine

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Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: A Danish nationwide cohort study

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Abstract

Background

Methods and findings

Conclusions

Trial registration

Abstract

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Related collections

PLOS: COVID-19 pandemic

Most cited references 22

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19

Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19

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