Risk of COVID-19 Diagnosis and Hospitalisation in Patients with Osteoarthritis or Back Pain Treated with Ibuprofen Compared to Other NSAIDs or Paracetamol: A Network Cohort Study.

OBJECTIVE: We aimed to investigate whether ibuprofen use, compared with other non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), cyclooxygenase-2 inhibitors (COX-2i) or paracetamol, increases the risk of coronavirus disease 2019 (COVID-19) diagnosis or hospitalisation. DESIGN: A prevalent user and active comparator cohort study. SETTING: Two US claims databases (Open Claims and PharMetrics Plus) mapped to the Observational Medical Outcomes Partnership Common Data Model. PARTICIPANTS: Insured patients with a history of osteoarthritis or back pain and receiving ibuprofen, other ns-NSAIDs, COX-2i or paracetamol between 1 November, 2019 and 31 January, 2020 (study enrolment window 1) or between 1 February, 2020 and 31 October, 2020 (study enrolment window 2). MAIN OUTCOME MEASURES: Large-scale propensity score matching and empirical calibration were used to minimise confounding. Incidence and hazard ratios of COVID-19 diagnosis and hospitalisation according to drug/s use were estimated and pooled in the same study period across data sources using a fixed-effects meta-analysis. Index treatment episode was the primary risk evaluation window, censored at the time of discontinuation. RESULTS: A total of 633,562 and 1,063,960 participants were included in periods 1 and 2, respectively, for the ibuprofen versus ns-NSAIDs comparison, 311,669 and 524,470 for ibuprofen versus COX-2i, and 492,002 and 878,598 for ibuprofen versus paracetamol. Meta-analyses of empirically calibrated hazard ratios revealed no significantly differential risk of COVID-19 outcomes in users of ibuprofen versus any of the other studied analgesic classes: hazard ratios were 1.13 (0.96-1.33) for the ibuprofen-ns-NSAIDs comparison, 1.03 (0.83-1.28) for the ibuprofen-COX-2i comparison and 1.13 (0.74-1.73) for ibuprofen-paracetamol comparison on COVID-19 diagnosis in the February 2020-October 2020 window. Similar hazard ratios were found on COVID-19 hospitalisation and across both study periods. CONCLUSIONS: In patients with osteoarthritis or back pain, we found no differential risks of incident COVID-19 diagnosis or COVID-19 hospitalisation for ibuprofen users compared with other ns-NSAIDs, COX-2i or paracetamol. Our findings support regulatory recommendations that NSAIDs, including ibuprofen, should be prescribed as indicated in the same way as before the COVID-19 pandemic, especially for those who rely on ibuprofen or NSAIDs to manage chronic arthritis or musculoskeletal pain symptoms.

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

BACKGROUND: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. METHODS: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. FINDINGS: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). INTERPRETATION: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.