NSAID use and clinical outcomes in COVID-19 patients: a 38-center retrospective cohort study

Abstract

Background 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. Methods 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 19,746 COVID-19 inpatients was constructed by matching cases (treated with NSAIDs at the time of admission) and 19,746 controls (not treated) from 857,061 patients with COVID-19 available for analysis. 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. Results 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. Conclusions 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 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.

Ibuprofen in the Management of Viral Infections: The Lesson of COVID‐19 for Its Use in a Clinical Setting

“…Other studies, including a systematic review and meta‐analysis by Zhou et al., 7 and a retrospective study by Reese et al., 57 confirmed the safety of NSAIDs in COVID‐19.…”

“…103,104 A study by the EU Pharmacovigilance Risk Assessment Committee reported that ibuprofen, at a dose up to 1200 mg/day, is not associated with any cardiovascular risk. 105 Other studies, including a systematic review and meta-analysis by Zhou et al, 7 and a retrospective study by Reese et al, 57 confirmed the safety of NSAIDs in COVID-19.…”

Precision management of post‐COVID pain: An evidence and clinical‐based approach

“…ibuprofen, flurbiprofen, etoricoxib or paracetamol, had no effects on ACE2 expression or activity in vitro or in vivo (de Bruin et al, 2022). A human study also observed that NSAID use was not associated with increased COVID-19 severity (Reese et al, 2022). However, the effects of NSAIDs for managing post-COVID pain have not been investigated yet.…”

Hypothesis: Efficacy of early treatments with some NSAIDs in COVID‐19: Might it also depend on their direct and/or indirect zinc chelating ability?

“…Differences in COX‐independent mechanisms among these compounds have already been described (Tegeder et al, 2001 ). Because additional effects may affect either efficacy or toxicity, these may have therapeutic consequences depending on a specific disease and/or patient, possibly accounting for weak associations between NSAID use and COVID‐19 protection (Reese et al, 2022 ; Zhou et al, 2022 ). Therefore, the underlying mechanism(s) leading to different COVID‐19 outcomes depending on the NSAID used should be elucidated.…”