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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

Our take —

Despite early concern that ibuprofen may influence COVID-19 outcomes, population-based epidemiologic studies have not confirmed those results. Results from this study suggest that use of NSAIDs does not contribute to increased mortality among individuals with COVID-19. However, NSAID users appeared slightly more likely to be hospitalized than non-users. For either conclusion, confounding is possible, but these preliminary results provide support that well-indicated NSAID use could continue during the current COVID-19 pandemic.

Study design

Retrospective Cohort

Study population and setting

This nationwide registry-based study, included all Danish residents diagnosed with PCR-confirmed SARS-CoV-2 from February 27 to April 29, 2020. Authors aimed to evaluate the association between NSAID use and 30-day mortality; secondary outcomes included hospitalization, ICU admission, mechanical ventilation, and acute renal replacement therapy within 14 days of testing positive. Data were collected from several Danish health and administrative registries based on unique personal identifies that are assigned to all Danish residents at birth or immigration to Denmark, and individuals who lived in Denmark less than 1 year prior to their positive SARS-CoV-2 test were excluded. Current NSAID use was defined as having a prescription filled for any NSAID within 30 days of their positive SARS-CoV-2. Propensity score matching based on age, sex, comorbidities, other prescription drug use, and phase of the outbreak were used to decrease potential confounding between NSAID users and non-users.

Summary of Main Findings

Of 9,236 individuals included in the study (median age 50 years, 58% female), 6% (N=535) died within 30 days, 16% (N=1512) were hospitalized within 14 days, 3% (N=290) were admitted to the ICU, 2.5% (N=235) received mechanical ventilation, and <1% (N=61) received acute renal replacement therapy. Under 3% of the study population (N=248) were defined as current NSAID users; propensity score matched analyses included 224 NSAID users and 896 non-users. In unmatched and matched analysis, NSAID use was not associated with 30-day mortality. In the unmatched analysis, risk of hospitalization was higher among NSAID users (24.6% vs. 17.3%), but the risk difference decreased in matched analysis (24.5% vs. 21.2%). None of the other secondary outcomes were different between NSAID users and non-users in unmatched or matched analyses.

Study Strengths

This study used national registry data to characterize the association between NSAID use and COVID-19 outcomes, allowing for inclusion of individuals with COVID-19 who were managed in all settings (hospitals, community, etc). Subgroup analyses by age, sex, occupation, and history of cardiovascular disease, along with sensitivity analyses using different exposure and outcome assessment windows, support the findings of the main analysis that NSAID use was not associated with 30-day mortality.

Limitations

The main outcome of interest in the study was 30-day mortality, so these findings must be considered in light of that time frame, and not extrapolated to longer term outcomes. The definition of NSAID use was based on information available in the Danish National Prescription Registry, which does not include NSAIDs that are sold over the counter. Though only low-dose (200 mg) ibuprofen is sold over the counter and accounts for about 15% of all ibuprofen sales, misclassification due to this definition is likely with people who use low-dose ibuprofen classified as non-users. Limited data regarding dose and duration of use may also result in misclassification if those classified as users based on filling a prescription did not actually use the NSAIDs continuously. It is unclear how the authors handled missing data. Twenty four NSAID users were not included in the matched analyses, but the reason for this decision is not stated. There may be residual confounding due to unmeasured factors such as body weight, and potential confounding by indication due to prescription of NSAIDs in response to early COVID-19 symptoms cannot be ruled out.

Value added

This was one of the largest studies to date examining the association between NSAID use and COVID-19 outcomes in the general population.

This review was posted on: 3 October 2020