The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19

In total, 24 relevant publications (covering 25 studies) reporting original research data were identified (Table 1). All of these were observational cohort studies, and eight were described as retrospective. No randomized controlled trials were identified. Nineteen of the studies were conducted in patients with COVID-19 or SARS-CoV-2 infection, and the number of participants ranged from 103 to 2.74 million. In addition, a meta-analysis that included 2414 patients from three studies was retrieved29.

Table 1 Summary of included studies.NSAIDs—general

A total of 17 publications (covering 18 studies) reported data on the effects of treatment with one or multiple NSAIDs, either prescribed or self-obtained OTC, on outcomes relating to COVID-19. Three of these compared the risks of contracting COVID-19 among individuals treated with NSAIDs with those not receiving NSAIDs. In a cross-sectional study of patients (n = 2102, n = 318 classified as chronic NSAID users) treated at the outpatient Rheumatology Service of Hospital del Mar, Barcelona, Spain, there was no association between the COVID-19 infection rate and chronic NSAID use30. Drew et al. analyzed data from 2.74 million users of the COVID Symptom Study smartphone application from the US, UK, and Sweden31. Initial analysis included 8966 COVID-19-positive test results documented over >60 million person-days of follow-up, and NSAID use was associated with a modest increase in the risk of testing positive for COVID-19 (hazard ratio [HR] 1.22 [95% confidence interval (CI) 1.13–1.32]). However, after adjusting for potential confounders (lifestyle factors, comorbidities, and baseline symptoms), NSAID use was not associated with any change in this risk (HR 1.02 [95% CI 0.94–1.10]). Chandan et al. used a large UK primary care data set (n ≥ 25,000 adults with osteoarthritis) to compare susceptibility to developing suspected or confirmed COVID-19 among patients prescribed NSAIDs vs. other common analgesics (either paracetamol/codeine or paracetamol/dihydrocodeine)32. They found no increase in the risk of suspected/confirmed COVID-19, and no increase in all-cause mortality, among those who were prescribed NSAIDs compared with those who received the comparator drugs.

Two large English cohort studies assessing NSAID use and deaths from COVID-19 (in the general population and patients with rheumatoid arthritis or osteoarthritis) were reported in a single publication33. In the general population (2.5 million participants), prescribed NSAID use did not affect the risk of COVID-related death. Among 1.7 million patients with rheumatoid arthritis or osteoarthritis, analysis with adjustment for confounders showed a lower risk of death from COVID-19 among users of prescribed NSAIDs (HR 0.78 [95% CI 0.64–0.94]). A small cohort study from South Korea (n = 103 adult patients with COVID-19) evaluated factors that increase the COVID-19 patient death rate and showed no statistically significant difference in NSAID use between the survivor and non-survivor COVID-19 patients34.

Three studies investigated the relationship between hospitalization for COVID-19 and NSAID use. In an analysis of the German national registry of patients with inflammatory rheumatic and musculoskeletal disease, NSAID treatment was not identified as a risk factor for COVID-19 related hospitalization35. NSAID therapy was reported in 19.1% of hospitalized patients and 25.4% of non-hospitalized population; univariate analysis indicated that NSAID use had no significant effect on the risk of COVID-19 related hospitalization. Similarly, a European international study of rheumatic disease patients with COVID-19 showed that NSAID therapy was less common in a hospitalized vs. non-hospitalized population (16% vs. 25%)36. A retrospective cohort study of electronic health records for >4500 US patients with COVID-19 did, however, find a statistically significant association between NSAID use and hospitalization37.

A prospective cohort study reported by Abu Esba et al. assessed the association between NSAID use and COVID-19 outcomes (including death, hospital admission, severity, time to clinical improvement, oxygen requirement, and length of hospital stay) in Saudi Arabian adult patients38. The study concluded that acute or chronic use of NSAIDs was not associated with worse COVID-19 outcomes compared to non-NSAID users. A Danish nationwide cohort study also assessed the association between NSAID use (defined as a filled prescription up to 30 days before the patient had a positive test for SARS-CoV-2) and various COVID-19 outcomes39. Treatment with NSAIDs was not associated with 30-day mortality, risk of hospitalization, intensive care unit (ICU) admission, mechanical ventilation, or renal replacement therapy. In addition, a retrospective, multi-center cohort study conducted in the US (n = 1305 patients with COVID-19) showed that NSAID use prior to admission was not associated with development of renal failure or increased mortality40. Indeed, patients using NSAIDs prior to hospitalization had lower odds of mortality (odds ratio [OR]: 0.55 [95% CI 0.39–0.78]), a finding which remained present on multivariate regression analysis (adjusted OR 0.56 [95% CI 0.40–0.82]). In a retrospective South Korean study, Park et al. conducted propensity score-matched analysis to compare outcomes in COVID-19 patients treated with NSAIDs vs. those receiving paracetamol41. No significant differences between the two groups were observed in all-cause mortality or the incidence of ventilator care.

The largest study of COVID-19 patients identified was a US retrospective cohort study using electronic health record data from >250,000 patients42. Potential associations between eight COX inhibitors (paracetamol, aspirin, celecoxib, diclofenac, ibuprofen, ketorolac, meloxicam, naproxen) and COVID-19 severity were assessed. The study reported an association with increased COVID-19 severity for five of the eight agents tested (aspirin, ibuprofen, ketorolac, naproxen, and paracetamol); no significant associations were found for diclofenac, meloxicam, and celecoxib, which display selectivity for inhibition of COX-2. Aspirin and paracetamol (the latter of which is not considered to be COX-selective) were also associated with increased mortality.

A multi-center, observational study conducted in the UK examined the association between use of NSAIDs and outcomes in hospitalized patients (n = 1222) with COVID-19 admitted to eight UK hospitals34,43,44,45. Univariate analysis suggested a modest benefit of prior NSAID use, while multivariable analyses indicated no association between prior NSAID use and time to mortality or length of hospital stay. Another UK study enrolled 78,674 patients across 255 healthcare facilities to assess whether pre-existing NSAID use (within the 2 weeks before hospital admission) was associated with increased severity of COVID-19 disease34,43,44,45. The primary outcome was in-hospital mortality, and secondary outcomes included disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. After adjusting for explanatory variables, NSAID use was not associated with worsening of any COVID-19 disease outcomes. A South Korean study of 1824 patients hospitalized with COVID-19 reported higher risk of two composite adverse outcomes among NSAID users (individuals prescribed NSAIDs during the 7 days before hospitalization)46. For the first outcome (in-hospital death, ICU admission, mechanical ventilation use, or sepsis), the adjusted OR was 1.54 (95% CI 1.11–2.15) and, for the second outcome (cardiovascular or renal complications), it was 2.64 (95% CI 1.67–4.16).

A meta-analysis by Kow and Hasan included data from 2414 patients across three studies that compared COVID-19 patients who were users or non-users of NSAIDs29. A pooled HR of 0.86 (95% CI 0.49–1.51) demonstrated no significant difference in the risk of fatality between NSAID users and non-NSAID users.

Ibuprofen

The two large cohort studies by Wong et al. also reported data specifically for ibuprofen33; in both, the general population and patients with rheumatoid arthritis or osteoarthritis, risk of death from COVID-19 was not significantly different between users of ibuprofen vs. other NSAIDs.

Several other studies have assessed the impact of ibuprofen use on the risk of severe COVID-19. A retrospective, single-center study from Israel assessed whether ibuprofen use in individuals with COVID-19 (n = 403) was associated with more severe disease, compared with use of paracetamol or no antipyretics47. Among the entire cohort, 44 patients (11%) needed respiratory support and 12 (3%) died; there was no significant difference in either outcome between the ibuprofen and non-ibuprofen groups, nor between ibuprofen users and exclusive paracetamol users. Kragholm et al. conducted a nationwide register-based study of patients in Denmark with COVID-19 to assess if prescription of ibuprofen affected the risk of severe disease48. The outcome assessed was a 30-day composite of severe COVID-19 diagnosis with acute respiratory syndrome, ICU admission, or death. The study found that there was no significant (p = 0.74) association between ibuprofen prescription claims and severe COVID-19; standardized absolute risks of the composite outcome for ibuprofen-prescribed vs. non-ibuprofen patients were 16.3% (95% CI 12.1–20.6) vs. 17.0% (95% CI 16.0–18.1). Similarly, in the Saudi Arabian study of COVID-19 patients reported by Abu Esba et al., acute use of ibuprofen was not associated with worse COVID-19 outcomes compared to non-NSAID users38.

Castro et al. used electronic health records to identify commonly prescribed medications that may be associated with a lower risk of morbidity among patients with COVID-1949. Records of 12,818 individuals from five US hospitals were assessed. Ibuprofen was associated with favorable outcomes, with users less likely to require hospitalization; among hospitalized patients, use of ibuprofen was associated with a lower risk of ICU admission and mortality.

A study of South Korean patients hospitalized with early-stage COVID-19 (n = 293) reported an increased likelihood of ibuprofen use among individuals with COVID-19 disease progression compared with those exhibiting improvement/stabilization50. However, after adjustment for confounding variables via propensity score matching, the authors found that ibuprofen was not a risk factor for progression. However, a study of 158 hospitalized patients from a single center in Iran reported a significant (p < 0.001) relationship between history of ibuprofen consumption before COVID-19 and the severity of the disease, as well as the mortality rate of patients with COVID-1951.

Aspirin

Several of the studies identified included data for aspirin, and these specific findings are summarized below. Studies assessing the anti-platelet effects of aspirin in patients with COVID-19 are beyond the focus of the current review.

The large study of smartphone application users from the US, UK, and Sweden also included analysis of aspirin users31. The risk of contracting COVID-19 in this group was not significantly different from that among individuals not taking any NSAIDs, either before or after adjustment for confounders (HR after adjustment: 1.03 [95% CI 0.83–1.28]). In a US study of COVID-19 patients admitted to hospital, Chow et al. showed that the use of aspirin was associated with a more favorable disease course52. After adjustment for confounding variables, the risk of ICU admission was reduced by 43% (HR 0.63 [95% CI 0.31–0.90]) in users of aspirin compared with non-users. Similar reductions in the risks of mechanical ventilation (HR 0.56 [95% CI 0.37–0.85]) and in-hospital mortality (HR 0.53 [95% CI 0.31–0.90]) were also observed.

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