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

English version

Autoři: Lars Christian Lund ^aff001; Kasper Bruun Kristensen ^aff001; Mette Reilev ^aff001; Steffen Christensen ^aff002; Reimar Wernich Thomsen ^aff003; Christian Fynbo Christiansen ^aff003; Henrik Støvring ^aff001; Nanna Borup Johansen ^aff005; Nikolai Constantin Brun ^aff005; Jesper Hallas ^aff001; Anton Pottegård ^aff001
Působiště autorů: Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark ^aff001; Department of Anaesthesia and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark ^aff002; Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark ^aff003; Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark ^aff004; Department of Medical Evaluation and Biostatistics, Danish Medicines Agency, Copenhagen, Denmark ^aff005
Vyšlo v časopise: Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: A Danish nationwide cohort study. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003308
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003308

Souhrn

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

Klíčová slova:

COVID 19 – Danish people – Intensive care units – Medical risk factors – NSAIDs – Renal analysis – SARS CoV 2 – Virus testing

Zdroje

1. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8:e21. doi: 10.1016/S2213-2600(20)30116-8 32171062

2. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020;368:m1086. doi: 10.1136/bmj.m1086 32184201

3. European Medicines Agency. EMA gives advice on the use of non-steroidal anti-inflammatories for COVID-19. EMA/136850/2020. Amsterdam: European Medicines Agency; 2020 [cited 2020 Aug 3]. Available from: https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19.

4. Basille D, Thomsen RW, Madsen M, Duhaut P, Andrejak C, Jounieaux V, et al. Nonsteroidal antiinflammatory drug use and clinical outcomes of community-acquired pneumonia. Am J Respir Crit Care Med. 2018;198 : 128–31. doi: 10.1164/rccm.201802-0229LE 29461860

5. Voiriot G, Philippot Q, Elabbadi A, Elbim C, Chalumeau M, Fartoukh M. Risks related to the use of non-steroidal anti-inflammatory drugs in community-acquired pneumonia in adult and pediatric patients. J Clin Med. 2019;8 : 786. doi: 10.3390/jcm8060786 31163625

6. Meganathan P, Awasthi S. Predicting complicated parapneumonic effusion in community acquired pneumonia: hospital based case-control study. Indian J Pediatr. 2019;86 : 140–7. doi: 10.1007/s12098-018-2769-y 30182278

7. Messika J, Sztrymf B, Bertrand F, Billard-Pomares T, Barnaud G, Branger C, et al. Risks of nonsteroidal antiinflammatory drugs in undiagnosed intensive care unit pneumococcal pneumonia: younger and more severely affected patients. J Crit Care. 2014;29 : 733–8. doi: 10.1016/j.jcrc.2014.05.021 24997726

8. Epperly H, Vaughn FL, Mosholder AD, Maloney EM, Rubinson L. Nonsteroidal anti-inflammatory drug and aspirin use, and mortality among critically ill pandemic H1N1 influenza patients: an exploratory analysis. Jpn J Infect Dis. 2016;69 : 248–51. doi: 10.7883/yoken.JJID.2014.577 26255728

9. Lund LC, Reilev M, Hallas J, Kristensen KB, Thomsen RW, Christiansen CF, et al. Association of nonsteroidal anti-inflammatory drug use and adverse outcomes among patients hospitalized with influenza. JAMA Netw Open. 2020;3:e2013880. doi: 10.1001/jamanetworkopen.2020.13880 32609352

10. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. Use of non-steroidal anti-inflammatory drugs and clinical outcome of COVID-19: a Danish nationwide cohort study. EUPAS34734. Amsterdam: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance; 2020 [cited 2020 Aug 3]. Available from: http://www.encepp.eu/encepp/viewResource.htm?id=34735.

11. Thygesen LC, Daasnes C, Thaulow I, Brønnum-Hansen H. Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving. Scand J Public Health. 2011;39 : 12–6. doi: 10.1177/1403494811399956 21898916

12. Pottegård A, Kristensen KB, Reilev M, Lund LC, Ernst MT, Hallas J, et al. Existing data sources in clinical epidemiology: the Danish COVID-19 cohort. Clin Epidemiol. In press.

13. Voldstedlund M, Haarh M, Mølbak K, MiBa Board of Representatives. The Danish Microbiology Database (MiBa) 2010 to 2013. Euro Surveill. 2014;19 : 20667. doi: 10.2807/1560-7917.es2014.19.1.20667 24434175

14. Schmidt M, Schmidt SAJ, Adelborg K, Sundbøll J, Laugesen K, Ehrenstein V, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11 : 563–91. doi: 10.2147/CLEP.S179083 31372058

15. Pottegård A, Schmidt SAJ, Wallach-Kildemoes H, Sørensen HT, Hallas J, Schmidt M. Data resource profile: the Danish National Prescription Registry. Int J Epidemiol. 2017;46 : 798–798f. doi: 10.1093/ije/dyw213 27789670

16. Schmidt M, Schmidt SAJ, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7 : 449–90. doi: 10.2147/CLEP.S91125 26604824

17. Helweg-Larsen K. The Danish Register of Causes of Death. Scand J Public Health. 2011;39 : 26–9. doi: 10.1177/1403494811399958 21775346

18. Blichert-Hansen L, Nielsson MS, Nielsen RB, Christiansen CF, Nørgaard M. Validity of the coding for intensive care admission, mechanical ventilation, and acute dialysis in the Danish National Patient Registry: a short report. Clin Epidemiol. 2013;5 : 9–12. doi: 10.2147/CLEP.S37763 23359787

19. Schmidt M, Hallas J, Friis S. Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999–2012. Clin Epidemiol. 2014;6 : 155–68. doi: 10.2147/CLEP.S59156 24872722

20. Schmidt M, Hallas J, Laursen M, Friis S. Data resource profile: Danish online drug use statistics (MEDSTAT). Int J Epidemiol. 2016;45 : 1401–1402g. doi: 10.1093/ije/dyw116 27892409

21. Kristensen KB, Karlstad Ø, Martikainen JE, Pottegård A, Wastesson JW, Zoega H, et al. Nonaspirin nonsteroidal antiinflammatory drug use in the Nordic countries from a cardiovascular risk perspective, 2000–2016: a drug utilization study. Pharmacotherapy. 2019;39 : 150–60. doi: 10.1002/phar.2217 30636337

22. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70 : 41–55. doi: 10.1093/biomet/70.1.41

23. Sturmer T, Rothman KJ, Avorn J, Glynn RJ. Treatment effects in the presence of unmeasured confounding: dealing with observations in the tails of the propensity score distribution—a simulation study. Am J Epidemiol. 2010;172 : 843–54. doi: 10.1093/aje/kwq198 20716704

24. Leuven E, Sianesi B. PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing. Boston: Boston College Department of Economics; 2018 [cited 2020 Aug 3]. Available from: https://ideas.repec.org/c/boc/bocode/s432001.html.

25. Pottegård A, Kurz X, Moore N, Christiansen CF, Klungel O. Considerations for pharmacoepidemiological analyses in the SARS-CoV-2 pandemic. Pharmacoepidemiol Drug Saf. 2020 May 5. doi: 10.1002/pds.5029 32369865

26. Franklin JM, Rassen JA, Ackermann D, Bartels DB, Schneeweiss S. Metrics for covariate balance in cohort studies of causal effects: metrics for covariate balance in cohort studies of causal effects. Stat Med. 2014;33 : 1685–99. doi: 10.1002/sim.6058 24323618

27. Rassen JA, Glynn RJ, Rothman KJ, Setoguchi S, Schneeweiss S. Applying propensity scores estimated in a full cohort to adjust for confounding in subgroup analyses. Pharmacoepidemiol Drug Saf. 2012;21 : 697–709. doi: 10.1002/pds.2256 22162077

28. Gribsholt SB, Pedersen L, Richelsen B, Thomsen RW. Validity of ICD-10 diagnoses of overweight and obesity in Danish hospitals. Clin Epidemiol. 2019;11 : 845–54. doi: 10.2147/CLEP.S214909 31572015

29. Glynn RJ, Knight EL, Levin R, Avorn J. Paradoxical relations of drug treatment with mortality in older persons. Epidemiol. 2001;12 : 682–9. doi: 10.1097/00001648-200111000-00017 11679797

30. Schmidt M, Lamberts M, Olsen A-MS, Fosbøll E, Niessner A, Tamargo J, et al. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. Eur Heart J Cardiovasc Pharmacother. 2016;2 : 108–18. doi: 10.1093/ehjcvp/pvv054 27533522

31. Qiao W, Wang C, Chen B, Zhang F, Liu Y, Lu Q, et al. Ibuprofen attenuates cardiac fibrosis in streptozotocin-induced diabetic rats. Cardiology. 2015;131 : 97–106. doi: 10.1159/000375362 25896805

32. Mehta N, Kalra A, Nowacki AS, Anjewierden S, Han Z, Bhat P, et al. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020 May 5. doi: 10.1001/jamacardio.2020.1855 32369097

33. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med. 2020;382 : 2431–40. doi: 10.1056/NEJMoa2006923 32356627

34. Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, et al. Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382 : 2441–8. doi: 10.1056/NEJMoa2008975 32356628

Článek Patterns of beverage purchases amongst British households: A latent class analysis

Článek COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

Článek Social capital, social cohesion, and health of Syrian refugee working children living in informal tented settlements in Lebanon: A cross-sectional study

Článek Economic influences on population health in the United States: Toward policymaking driven by data and evidence

Článek Gabapentin in pregnancy and the risk of adverse neonatal and maternal outcomes: A population-based cohort study nested in the US Medicaid Analytic eXtract dataset

Článek Gestational age and the risk of autism spectrum disorder in Sweden, Finland, and Norway: A cohort study

Článek Providing TB and HIV outreach services to internally displaced populations in Northeast Nigeria: Results of a controlled intervention study

Článek Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study

Článek Reassessment of the risk of narcolepsy in children in England 8 years after receipt of the AS03-adjuvanted H1N1 pandemic vaccine: A case-coverage study

Článek How to make your research jump off the page: Co-creation to broaden public engagement in medical research

Článek Comparative functional survival and equivalent annual cost of 3 long-lasting insecticidal net (LLIN) products in Tanzania: A randomised trial with 3-year follow up

Článek Quality of clinical management of children diagnosed with malaria: A cross-sectional assessment in 9 sub-Saharan African countries between 2007–2018