Cyclooxygenase inhibitor use is associated with increased COVID-19 severity
Justin T Reese, Ben Coleman2, Lauren Chan3, Hannah Blau4, Tiffany J Callahan5, Luca Cappelletti7, Tommaso Fontana8, Katie Rebecca Bradwell9, Nomi L Harris1, Elena Casiraghi7, Giorgio Valentini7, Guy Karlebach4, Rachel Deer11, Julie A Mcmurry6, Melissa A Haendel6, Christopher G Chute12, Emily Pfaff13, Richard Moffitt14, Heidi Spratt11, Jasvinder Singh15, Christopher J Mungall1, Andrew E Williams17, Peter N Robinson
doi:10.1101/2021.04.13.21255438
BACKGROUND Cyclooxygenase (COX) inhibitors including non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community acquired pneumonia and other respiratory tract infections (RTIs). Conclusive data are not available about potential beneficial or adverse effects of COX inhibitors on COVID-19 patients.
METHODS We conducted a retrospective, multi-center observational study by leveraging the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative (N3C). Potential associations of eight COX inhibitors with COVID-19 severity were assessed using ordinal logistic regression (OLR) on treatment with the medication in question after matching by treatment propensity as predicted by age, race, ethnicity, gender, smoking status, comorbidities, and BMI. Cox proportional hazards analysis was used to estimate the correlation of medication use with morbidity for eight subcohorts defined by common indications for COX inhibitors.
RESULTS OLR revealed statistically significant associations between use of any of five COX inhibitors and increased severity of COVID-19. For instance, the odds ratio of aspirin use in the osteoarthritis cohort (n=2266 patients) was 3.25 (95% CI 2.76 -3.83). Aspirin and acetaminophen were associated with increased mortality.
CONCLUSIONS The association between use of COX inhibitors and COVID-19 severity was consistent across five COX inhibitors and multiple indication subcohorts. Our results align with earlier reports associating NSAID use with complications in RTI patients. Further research is needed to characterize the precise risk of individual COX inhibitors in COVID-19 patients. .
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'group-title': 'Infectious Diseases (except HIV/AIDS)',
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Non-steroidal '
'anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation '
'but have been associated with complications in community-acquired pneumonia. Observations '
'shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was '
'associated with an increased risk of adverse events in COVID-19 patients, but subsequent '
'observational studies failed to demonstrate increased risk and in one case showed reduced '
'risk associated with NSAID '
'use.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A 38-center '
'retrospective cohort study was performed that leveraged the harmonized, high-granularity '
'electronic health record data of the National COVID Cohort Collaborative. A '
'propensity-matched cohort of COVID-19 inpatients was constructed by matching cases (treated '
'with NSAIDs) and controls (not treated) from 857,061 patients with COVID-19. The primary '
'outcome of interest was COVID-19 severity in hospitalized patients, which was classified as: '
'moderate, severe, or mortality/hospice. Secondary outcomes were acute kidney injury (AKI), '
'extracorporeal membrane oxygenation (ECMO), invasive ventilation, and all-cause mortality at '
'any time following COVID-19 '
'diagnosis.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Logistic '
'regression showed that NSAID use was not associated with increased COVID-19 severity (OR: '
'0.57 95% CI: 0.53-0.61). Analysis of secondary outcomes using logistic regression showed that '
'NSAID use was not associated with increased risk of all-cause mortality (OR 0.51 95% CI: '
'0.47-0.56), invasive ventilation (OR: 0.59 95% CI: 0.55-0.64), AKI (OR: 0.67 95% CI: '
'0.63-0.72), or ECMO (OR: 0.51 95% CI: 0.36-0.7). In contrast, the odds ratios indicate '
'reduced risk of these outcomes, but our quantitative bias analysis showed E-values of between '
'1.9 and 3.3 for these associations, indicating that comparatively weak or moderate confounder '
'associations could explain away the observed '
'associations.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Study '
'interpretation is limited by the observational design. Recording of NSAID use may have been '
'incomplete. Our study demonstrates that NSAID use is not associated with increased COVID-19 '
'severity, all-cause mortality, invasive ventilation, AKI, or ECMO in COVID-19 inpatients. A '
'conservative interpretation in light of the quantitative bias analysis is that there is no '
'evidence that NSAID use is associated with risk of increased severity or the other measured '
'outcomes. Our findings are the largest EHR-based analysis of the effect of NSAIDs on outcome '
'in COVID-19 patients to date. Our results confirm and extend analogous findings in previous '
'observational studies using a large cohort of patients drawn from 38 centers in a nationally '
'representative multicenter database.</jats:p></jats:sec>',
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