Table 1.
Summary of included studies.
| Reference | Country/region | Number of participants | Setting/participant type | Study type | Study objective | Key findings |
|---|---|---|---|---|---|---|
| NSAIDS—general | ||||||
| Blanch-Rubió et al. (2020)30 | Spain | 2102 | Patients with non-inflammatory rheumatic conditions attending an outpatient service | Cross-sectional | To investigate the influence of treatments for osteoporosis, OA, and fibromyalgia on COVID-19 incidence and clinical expression | No association between COVID-19 and chronic NSAID use identified. Values for aRR of COVID-19 among chronic NSAID users vs. controls, calculated using two different statistical models, were 0.94 (95% CI 0.57–1.56) and 0.95 (95% CI 0.58–1.55) |
|
Drew et al. (2021)31 Pre-print |
US, UK, Sweden | 2.74 million | General public | Prospective survey | To investigate whether NSAIDs are associated with incident COVID-19 outcomes | No evidence to support increased risk for COVID-19 in those that regularly use aspirin or non-aspirin NSAIDs. After adjustment for lifestyle factors, comorbidities, and baseline symptoms, any NSAID use was not associated with risk for testing COVID-19 positive (HR 1.02 [95% CI 0.94, 1.10]). Results were similar for those seeking healthcare for COVID-19 and were not substantially different according to lifestyle and sociodemographic factors |
| Chandan et al. (2021)32 | UK | 25,659 | Primary care patients with OA | Propensity score-matched cohort study with active comparators | To identify whether active use of NSAIDs increases susceptibility to developing COVID-19 compared to other common analgesics |
No increase in the risk of suspected or confirmed COVID-19 or mortality was observed among patients with OA in a primary care setting who were prescribed NSAIDs as compared to those who received comparator drugs Adjusted HRs for suspected or confirmed COVID-19 among the unmatched and propensity score-matched OA cohorts, using data from clinical consultations in primary care settings, were 0.82 (95% CI 0.62–1.10) and 0.79 (95% CI 0.57–1.11), respectively. Adjusted HRs for the risk of all-cause mortality were 0.97 (95% CI 0.75–1.27) and 0.85 (95% CI 0.61–1.20), respectively. There was no effect modification by age or sex |
| Wong et al. (2021)33 | England |
Study 1: 2.5 million Study 2: 1.7 million |
Study 1: General population with at least one NSAID prescription in the last 3 years Study 2: individuals with RA/OA |
Cohort studies | To assess the association between routinely prescribed NSAIDs and deaths from COVID-19 |
No evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths Study 1: no evidence of difference in risk of COVID-19 related death associated with current NSAID use (HR 0.96 [95% CI 0.80–1.14]) Study 2: a lower risk of COVID-19 related death (HR 0.78 [95% CI 0.64–0.94]) associated with current use of NSAID vs. non-use |
| Hwang et al. (2020)34 | South Korea | 103 | Adult in-patients diagnosed with COVID-19 | Retrospective cohort study | To identify differences in demographic data between COVID-19 survivors and non-survivors | NSAID use not significantly associated with death of COVID-19 patients. Numbers of patients with a history of taking NSAIDs were 3/77 (4%) among survivors and 2/26 (8%) among non-survivors (p = 0.436) |
| Hasseli et al. (2021)35 | Germany | 468 | Patients with inflammatory rheumatic diseases infected with SARS-CoV-2 | National registry | To describe patients with rheumatic and musculoskeletal diseases according to their COVID-19 severity and to identify risk factors for hospitalization | Univariate analyses indicated that NSAID use did not significantly affect the risk of COVID-19 related hospitalization |
| Gianfrancesco et al. (2020)36 | Europe | 600 | Individuals with rheumatic disease and COVID-19 | International registry | To describe the demographic and clinical characteristics associated with COVID-19 hospitalization status in people with rheumatic disease | NSAIDs use for pre-existing chronic conditions is not associated with increased risk of severe outcome in COVID-19 infection. NSAID use was reported less frequently among hospitalized patients than non-hospitalized patients (16% vs. 25%, p = 0.02; aOR 0.64 [95% CI 0.39–1.06]) |
| Jehi et al. (2020)37 | US | 4536 |
Single healthcare system in Ohio and Florida COVID-19-positive patients |
Retrospective cohort study | To characterize patients hospitalized with COVID-19 and their outcomes, and develop a statistical model for prediction of hospitalization risk in newly diagnosed patients |
4536 patients tested positive for SARS-CoV-2 during the study period. Of those, 958 (21.1%) required hospitalization Hospitalization risk increased with use of certain medications, including NSAIDs |
| Abu Esba et al. (2021)38 | Saudi Arabia | 503 | Adult patients diagnosed with COVID-19 | Prospective cohort study | To assess the association of acute and chronic use of NSAIDs with worse COVID-19 outcomes |
Acute or chronic NSAID use was not associated with a greater risk of mortality (aHR 0.492 [95% CI 0.178–1.362; p = 0.1721]) NSAID users did not have a significantly longer time to clinical improvement or length of stay |
| Lund et al. (2020)39 | Denmark | 9236 | Individuals who tested positive for SARS-CoV-2 | Population-based cohort study | To study whether use of NSAIDs is associated with adverse outcomes and mortality during SARS-CoV-2 infection |
Primary outcome: NSAID treatment was not associated with 30-day mortality in the crude unmatched analyses or adjusted analyses; for the adjusted analyses, the 30-day mortality RR was 1.02 (95% CI 0.57–1.82) Secondary outcomes: after adjustment, NSAID use was not associated with hospitalization (RR 1.16 [95% CI 0.87–1.53]), ICU admission (RR 1.04 [95% CI 0.54–2.02]), mechanical ventilation (RR 1.14 [95% CI 0.56–2.30]), or renal replacement therapy (RR 0.86 [95% CI 0.24–3.09]) |
| Park et al. (2021)41 | South Korea | 2763 (794 participants included in propensity score-matched analysis) | Patients diagnosed with COVID-19 | Retrospective review of insurance benefit claims | To investigate the association between NSAID use before diagnosis of COVID-19 and mortality afterwards |
Use of NSAIDs before COVID-19 diagnosis was not associated with increased mortality or need for ventilator care In the propensity score-matched analysis, all-cause mortality in the NSAIDs group was not significantly different from that in the paracetamol group (4.0% vs. 3.0%; HR 1.33 [95% CI 0.63–2.88]). The rate of ventilator care also showed no significant difference between the two groups (2.0% vs. 1.3%; HR 1.60 [95% CI 0.53–5.30]) |
|
Reese et al. (2021)42 Pre-print |
US | 250,533 | Individuals testing positive for COVID-19 | Retrospective observational study of electronic health record data | To assess associations of eight COX inhibitors with clinical severity and mortality of COVID-19 patients | This study found an association with increased COVID-19 severity for five COX inhibitors (aspirin, ibuprofen, ketorolac, naproxen, and paracetamol). The OR relating to aspirin use in the OA cohort (n = 2266 patients) was 3.25 (95% CI 2.76–3.83). Aspirin and paracetamol were also associated with increased mortality. There was no evidence of an association with increased COVID-19 severity or mortality for diclofenac, meloxicam, or celecoxib |
| Imam et al. (2020)40 | US | 1305 | Inpatients diagnosed with COVID-19 | Retrospective review of hospital records | To study patient demographics and their impact on in-hospital mortality in a large cohort of COVID-19 patients | Patients using NSAIDs prior to hospitalization had lower odds of mortality (OR 0.55 [95% CI 0.39–0.78], p = 0.001), a finding which remained present on multivariate regression analysis (aOR 0.56 [95% CI 0.40–0.82]) |
| Bruce et al. (2020)43 | UK | 1222 | Adult patients with COVID-19 admitted to hospital | Prospective observational study | To examine the association between prior use of NSAIDs and mortality and length of hospital stay in patients with COVID-19 |
No significant negative effect of NSAID use on mortality or time to discharge In-hospital mortality was 25.9% (n = 14) in NSAID users and 29.5% (n = 344) among non-users (p = 0.578). In multivariable analysis, no association between pre-admission NSAID use and time to mortality, aHR = 0.89 (95% CI 0.52–1.53, p = 0.67) No association between pre-admission NSAID use and day-7 mortality (aOR = 0.79, p = 0.60) or time to discharge (aHR = 0.89, p = 0.58) |
| Drake et al. (2021)44 | UK | 78,674 | Hospitalized patients with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 | Prospective cohort study | To characterize the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease | After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0.95 [95% CI 0.84–1.07]; p = 0.35), critical care admission (1.01 [95% CI 0.87–1.17]; p = 0.89), requirement for invasive ventilation (0.96 [95% CI 0.80–1.17]; p = 0.69), requirement for non-invasive ventilation (1.12 [95% CI 0.96–1.32]; p = 0.14), requirement for oxygen (1.00 [95% CI 0.89–1.12]; p = 0.97), or occurrence of acute kidney injury (1.08 [95% CI 0.92–1.26]; p = 0.33) |
| Jeong et al. (2020)46 | South Korea | 1824 | Patients hospitalized with COVID-19 | Cohort study | To examine the association between NSAIDs use compared to non-use and worsened clinical outcomes | NSAID use (prescription of NSAIDs during the 7 days before hospitalization; n = 285) was associated with increased risk of primary outcome (death, ICU admission, mechanical ventilation, or sepsis; aOR 1.54 [95% CI 1.11–2.15]), and secondary outcome (risk of cardiovascular or renal complications; aOR 2.64 [95% CI 1.67–4.16]) |
| Ibuprofen | ||||||
| Wong et al. (2021)33 | England |
Study 1: 2.5 million Study 2: 1.7 million |
Study 1: General population with at least one NSAID prescription in the last 3 years Study 2: individuals with RA/OA |
Cohort studies | To assess the association between routinely prescribed NSAIDs and deaths from COVID-19 |
Study 1: aHR for COVID-19 related death among current users of ibuprofen vs. non-NSAID users was 1.23 (95% CI 0.90–1.68) Study 2: aHR for COVID-19 related death among current users of ibuprofen vs. non-NSAID users was 0.83 (95% CI 0.56–1.25) |
| Rinott et al. (2020)47 | Israel | 403 | Individuals with COVID-19 | Retrospective cohort study | To evaluate whether ibuprofen use in individuals with COVID-19 is associated with more severe disease, compared with individuals using paracetamol or no antipyretics | In the ibuprofen group, three (3.4%) patients died, whereas in the non-ibuprofen group, nine (2.8%) patients died (p = 0.95). Nine (10.3%) patients from the ibuprofen group needed respiratory support, compared with 35 (11%) from the non-ibuprofen group (p = 1). When compared with exclusive paracetamol users, no differences were observed in mortality rates or the need for respiratory support among patients using ibuprofen |
| Kragholm et al. (2020)48 | Denmark | 1872 | Individuals with COVID-19 | Nationwide registry study | To determine the association between recent ibuprofen exposure in COVID-19 patients and severe infection | 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) |
| Abu Esba et al. (2021)38 | Saudi Arabia | 503 | Adult patients diagnosed with COVID-19 | Prospective cohort study | To assess the association of acute and chronic use of NSAIDs with worse COVID-19 outcomes |
Acute use of ibuprofen was not associated with a greater risk of mortality relative to non-use of NSAIDs (aHR 0.632 [95% CI 0.073–5.441; p = 0.6758]) Acute ibuprofen use was not associated with a higher risk of hospital admission compared to non-NSAID users |
|
Castro et al. (2020)49 Pre-print |
US | 12,818 | Patients with COVID-19 | Cohort study using electronic health records | To identify commonly prescribed medications that may be associated with lesser risk of morbidity with COVID-19 |
Ibuprofen was significantly associated with diminished risk for hospitalization (OR 0.73 [95% CI 0.64–0.84]). Among hospitalized patients, ibuprofen was significantly associated with decreased odds of requiring ICU (OR 0.70 [95% CI 0.56–0.86]) and mortality (0.73 [95% CI 0.56–0.96]) |
| Choi et al. (2020)50 | South Korea | 293 | Individuals hospitalized with early-stage COVID-19 | Cohort study | To evaluate risk factors for disease severity in early stages of COVID-19 |
Before propensity-score matching, there was an increased likelihood (p = 0.003) of ibuprofen use among individuals with COVID-19 disease progression compared with those exhibiting improvement or stabilization. After propensity-score matching, ibuprofen use was not a risk factor for progression |
| Samimagham et al. (2020)51 | Iran | 158 | Hospitalized adult patients with COVID-19 | Cross-sectional | To investigate the effect of ibuprofen on the severity of COVID-19 and mortality caused by the disease | A significant (p < 0.001) relationship was identified between history of ibuprofen consumption before COVID-19 and the severity of the disease, as well as the mortality rate of patients with COVID-19 |
| Aspirin | ||||||
|
Drew et al. (2021)31 Pre-print |
US, UK, Sweden | 2.74 million | General public | Prospective survey | To investigate whether NSAIDs are associated with incident COVID-19 outcomes | No evidence to support increased risk for COVID-19 in those that regularly use aspirin. 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]) |
| Chow et al. (2021)52 | US | 412 | Hospitalized adult patients with COVID-19 | Retrospective, observational cohort study | To evaluate if aspirin use is associated with the need for mechanical ventilation in adult patients hospitalized with COVID-19 |
Aspirin use was independently associated with a lower risk of mechanical ventilation, ICU admission, and in-hospital mortality After adjustment for confounding variables, the risk of ICU admission was reduced by 43% (HR 0.57 [95% CI 0.38–0.85]) 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 |
aHR adjusted hazard ratio, aOR adjusted odds ratio, aRR adjusted relative risk, CI confidence interval, COVID-19 coronavirus disease 19, COX cyclooxygenase, HR hazard ratio, ICU intensive care unit, NSAIDs non-steroidal anti-inflammatory drugs, OA osteoarthritis, OR odds ratio, RA rheumatoid arthritis, RR risk ratio, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.