Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study

Abstract

Background Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were 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. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. 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, 0·87–1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80–1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96–1·32; p=0·14), requirement for oxygen (1·00, 0·89–1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92–1·26; p=0·33). Interpretation NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity. Funding National Institute for Health Research and Medical Research Council.

NSAIDs and COVID-19: A Systematic Review and Meta-analysis

“…Ten papers described death in NSAID users [ 12 , 14 , 17 – 24 ], with various exposure periods, including current or acute exposure [ 12 , 14 , 25 ], or within 30 days [ 17 ] or 4 months [ 23 ].…”

“…Four papers studied death in ibuprofen users, for current exposures [ 14 , 24 ], exposures of < 7 days [ 26 ] or exposures of < 4 months, in rheumatoid arthritis, or in the general population [ 23 ] (Table 2 d). The paper by Wong et al, in either the general population or the rheumatoid arthritis population, was considered as two different studies [ 23 ].…”

“…Study authors were contacted to check the status of NCT04325633 (from ClinicalTrials.gov), a clinical trial of naproxen. Furthermore, an attempt was made to obtain data from Jeong regarding the number of patients receiving ibuprofen alone but this was unsuccessful [ 27 ], and to verify an apparent inversion of columns in the study by Drake et al [ 24 ], and the number of cases in the study by Sahai et al [ 30 ].…”

A HOME-TREATMENT ALGORITHM BASED ON ANTI-INFLAMMATORY DRUGS TO PREVENT HOSPITALIZATION OF PATIENTS WITH EARLY COVID-19: A MATCHED-COHORT STUDY (COVER 2)

“…Physicians may be reluctant to use NSAIDs, including relatively selective COX-2 inhibitors, due to the known risk of cardiovascular events (33) and the hepatotoxicity of nimesulide, which is admittedly very low when the drug is prescribed at the recommended daily dose and time of administration (34). On the other hand, in a large cohort of over 4200 patients admitted to the hospital who had taken NSAIDs within the 2 weeks preceding hospital admission, the use of these drugs was not associated with higher mortality or increased severity of COVID-19, as compared to a matched group of NSAID non-users (35). Moreover, another study provided no indication that harm was induced by NSAIDs, as demonstrated by the lack of increased risk of poorer outcomes in COVID-19 patients given NSAIDs compared with those treated with paracetamol, or NSAID non-users (36).…”

Nonsteroidal anti-inflammatory drugs and glucocorticoids in COVID-19

“…Consistently, a recent large prospective, multicentre cohort study based on the ISARIC Clinical Characterisation Protocol UK dataset (>78,000 patients) failed to identify an association between pre-existing NSAID use (within two weeks before hospitalization) with higher in-hospital mortality or worse outcome (critical care admission, need for invasive ventilation, need for oxygen, and acute kidney injury) in hospitalized COVID-19 patients. In a subgroup analysis, ibuprofen use was not associated with an increased risk of mortality compared to other NSAIDs or no NSAIDs ( Drake et al, 2021 ). Similarly, an Israeli retrospective cohort study reported that the use of ibuprofen before SARS-CoV-2 infection was not associated to increased mortality or the need for respiratory support (oxygen administration and mechanical ventilation) compared to non-NSAID users or acetaminophen users ( Rinott et al, 2020 ).…”