{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T03:23:12Z","timestamp":1789010592543,"version":"build-2803163510"},"reference-count":28,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n It is unclear whether the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase 2 (COX-2) in decreasing the risk of gastrointestinal (GI) bleeding are retained in patients with nonvalvular atrial fibrillation (NVAF) concomitantly treated with direct oral anticoagulants (DOACs).<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess whether concomitant use of DOACs and COX-2\u2013selective NSAIDs is associated with a decreased risk of GI bleeding vs concomitant use of DOACs and nonselective NSAIDs in patients with NVAF.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This multinational cohort study used electronic medical records from the UK and claims data from Quebec between January 1, 2011, and December 12, 2020. Adult patients (aged \u226518 years) with NVAF who initiated concomitant use of DOACs and NSAIDs during the study period were included. Cohort entry was the first day of concomitant use. Patient data were followed until a study outcome, death, or treatment discontinuation or switch. All analyses were conducted between November 19, 2024, and July 25, 2025.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Concomitant use of DOACs and COX-2\u2013selective NSAIDs or concomitant use of DOACs and nonselective NSAIDs.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was GI bleeding, and the secondary outcome was non-GI bleeding. Inverse probability of treatment weighting was used to control for confounding. Cox models were used to estimate site-specific hazard ratios (HRs) and 95% CIs, which were pooled using random-effects models. Further stratification was performed for potential effect modifiers.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The study cohort included 30 240 patients with NVAF who initiated concomitant use of DOACs and NSAIDs (mean [SD] age, 72.1 [9.2] years, 17 146 male [56.7%]). They contributed 37 833 episodes of concomitant use of DOACs and NSAIDs (45.2% COX-2\u2013selective NSAIDs, 54.8% nonselective NSAIDs). Concomitant use of DOACs and COX-2\u2013selective NSAIDs was associated with a decreased risk of GI bleeding (pooled weighted HR, 0.63 [95% CI, 0.46-0.87];\n I<\/jats:italic>\n 2<\/jats:sup>\n \u2009=\u200956%) and non-GI bleeding (pooled weighted HR, 0.54 [95% CI, 0.40-0.74];\n I<\/jats:italic>\n 2<\/jats:sup>\n \u2009=\u20090%) vs concomitant use of DOACs and nonselective NSAIDs. Female patients had a greater decreased risk of GI bleeding associated with concomitant use of DOACs and COX-2\u2013selective NSAIDs (pooled weighted HR, 0.50 [95% CI, 0.31-0.80];\n I<\/jats:italic>\n 2<\/jats:sup>\n \u2009=\u20090%) than male patients (HR, 0.85 [95% CI, 0.55-1.32];\n I<\/jats:italic>\n 2<\/jats:sup>\n \u2009=\u200978%). There was no major effect measure modification by age, order of drug initiation in concomitant use, baseline bleeding risk, or individual DOACs.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n These findings suggest that COX-2\u2013selective NSAIDs may retain their beneficial effects regarding GI bleeding during concomitant use with DOACs. Future studies should examine the association of COX-2 selectivity with stroke risk among patients treated with DOACs.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.13941","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T15:00:51Z","timestamp":1779807651000},"page":"e2613941","source":"Crossref","is-referenced-by-count":1,"title":["Direct Oral Anticoagulants, COX-2\u2013Selective NSAIDs, and Gastrointestinal Bleeding in Atrial Fibrillation"],"prefix":"10.1001","volume":"9","author":[{"given":"Fabian Maximilian","family":"Meinert","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Dimakos","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cui","sequence":"additional","affiliation":[{"name":"Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian B.","family":"Filion","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, Quebec, Canada"},{"name":"Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada"},{"name":"Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Renoux","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, Quebec, Canada"},{"name":"Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada"},{"name":"Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonios","family":"Douros","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"issue":"12","key":"zoi260411r1","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1136\/gut.2005.080754","article-title":"Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations.","volume":"55","author":"Lanas","year":"2006","journal-title":"Gut"},{"issue":"6","key":"zoi260411r2","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1002\/art.27412","article-title":"Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding.","volume":"62","author":"Mass\u00f3 Gonz\u00e1lez","year":"2010","journal-title":"Arthritis Rheum"},{"issue":"9149","key":"zoi260411r3","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/S0140-6736(98)12154-2","article-title":"COX-2 inhibitors.","volume":"353","author":"Hawkey","year":"1999","journal-title":"Lancet"},{"issue":"21","key":"zoi260411r4","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1056\/NEJM200011233432103","article-title":"Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.","volume":"343","author":"Bombardier","year":"2000","journal-title":"N Engl J Med"},{"issue":"26","key":"zoi260411r5","doi-asserted-by":"publisher","first-page":"2519","DOI":"10.1056\/NEJMoa1611593","article-title":"Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.","volume":"375","author":"Nissen","year":"2016","journal-title":"N Engl J Med"},{"issue":"10","key":"zoi260411r6","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1001\/jama.284.10.1247","article-title":"Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.","volume":"284","author":"Silverstein","year":"2000","journal-title":"JAMA"},{"issue":"1","key":"zoi260411r7","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1161\/CIR.0000000000001193","article-title":"2023 ACC\/AHA\/ACCP\/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines.","volume":"149","author":"Joglar","year":"2024","journal-title":"Circulation"},{"issue":"11","key":"zoi260411r8","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1056\/NEJMoa1107039","article-title":"Apixaban versus warfarin in patients with atrial fibrillation.","volume":"365","author":"Granger","year":"2011","journal-title":"N Engl J Med"},{"issue":"6","key":"zoi260411r10","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1093\/ije\/dyz034","article-title":"Data resource profile: Clinical Practice Research Datalink (CPRD) Aurum.","volume":"48","author":"Wolf","year":"2019","journal-title":"Int J Epidemiol"},{"issue":"11","key":"zoi260411r13","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1016\/j.cjca.2021.06.014","article-title":"Recategorization of non-aspirin nonsteroidal anti-inflammatory drugs according to clinical relevance: abandoning the traditional NSAID terminology.","volume":"37","author":"Bonnesen","year":"2021","journal-title":"Can J Cardiol"},{"issue":"1","key":"zoi260411r14","doi-asserted-by":"publisher","first-page":"2558","DOI":"10.1038\/s41598-020-59517-y","article-title":"Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells.","volume":"10","author":"Huang","year":"2020","journal-title":"Sci Rep"},{"issue":"5","key":"zoi260411r16","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/jcph.2003","article-title":"Risk of bleeding associated with nonsteroidal anti-inflammatory drug use in patients exposed to antithrombotic therapy: a case-crossover study.","volume":"62","author":"Paternoster","year":"2022","journal-title":"J Clin Pharmacol"},{"issue":"3","key":"zoi260411r17","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials.","volume":"7","author":"DerSimonian","year":"1986","journal-title":"Control Clin Trials"},{"issue":"5","key":"zoi260411r18","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1378\/chest.10-0134","article-title":"A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.","volume":"138","author":"Pisters","year":"2010","journal-title":"Chest"},{"issue":"7","key":"zoi260411r19","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1038\/sj.bjp.0703955","article-title":"Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge.","volume":"132","author":"Gretzer","year":"2001","journal-title":"Br J Pharmacol"},{"issue":"2","key":"zoi260411r20","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0928-4257(00)00145-5","article-title":"Expression of cyclooxygenase (COX)-1 and COX-2 in adaptive cytoprotection induced by mild stress.","volume":"94","author":"Brzozowski","year":"2000","journal-title":"J Physiol Paris"},{"issue":"21","key":"zoi260411r21","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1001\/jama.2018.17242","article-title":"Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding.","volume":"320","author":"Ray","year":"2018","journal-title":"JAMA"},{"key":"zoi260411r22","doi-asserted-by":"publisher","DOI":"10.1177\/10742484211054609","article-title":"Gender related differences in gastrointestinal bleeding with oral anticoagulation in atrial fibrillation.","author":"Ferroni","year":"2022","journal-title":"J Cardiovasc Pharmacol Ther"},{"issue":"3","key":"zoi260411r23","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.jacc.2018.04.066","article-title":"Sex-based differences in outcomes of oral anticoagulation in patients with atrial fibrillation.","volume":"72","author":"Law","year":"2018","journal-title":"J Am Coll Cardiol"},{"issue":"7","key":"zoi260411r24","doi-asserted-by":"publisher","first-page":"506","DOI":"10.7326\/0003-4819-142-7-200504050-00009","article-title":"Brief communication: duration of platelet dysfunction after a 7-day course of Ibuprofen.","volume":"142","author":"Goldenberg","year":"2005","journal-title":"Ann Intern Med"},{"key":"zoi260411r25","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/S0090-6980(02)00029-1","article-title":"Distinct functions of COX-1 and COX-2.","volume":"68-69","author":"Morita","year":"2002","journal-title":"Prostaglandins Other Lipid Mediat"},{"issue":"1","key":"zoi260411r26","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1161\/CIRCULATIONAHA.119.041296","article-title":"Patients with atrial fibrillation taking nonsteroidal anti-inflammatory drugs and oral anticoagulants in the ARISTOTLE trial.","volume":"141","author":"Dalgaard","year":"2020","journal-title":"Circulation"},{"issue":"3","key":"zoi260411r27","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.jacc.2018.04.063","article-title":"Concomitant oral anticoagulant and nonsteroidal anti-inflammatory drug therapy in patients with atrial fibrillation.","volume":"72","author":"Kent","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"zoi260411r28","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/6707985","article-title":"Time trends and treatment pathways in prescribing individual oral anticoagulants in patients with nonvalvular atrial fibrillation: an observational study of more than three million patients from Europe and the United States.","volume":"2022","author":"Vora","year":"2022","journal-title":"Int J Clin Pract"},{"key":"zoi260411r9","unstructured":"Clinical Practice Research Datalink. Medicines & Healthcare Products Regulatory Agency. Accessed July 15, 2025. https:\/\/cprd.com\/"},{"key":"zoi260411r11","unstructured":"About us. Optum. Accessed July 15, 2025. https:\/\/www.emishealth.com\/about-us"},{"key":"zoi260411r12","unstructured":"R\u00e9gie de l\u2019assurance maladie. Governement du Qu\u00e9bec. Accessed July 15, 2025. https:\/\/www.ramq.gouv.qc.ca\/en"},{"key":"zoi260411r15","unstructured":"Tiaprofenic acid. ScienceDirect. Accessed August 12, 2025. https:\/\/www.sciencedirect.com\/topics\/pharmacology-toxicology-and-pharmaceutical-science\/tiaprofenic-acid"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2849349\/meinert_2026_oi_260411_1779114217.08576.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T15:00:53Z","timestamp":1779807653000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2849349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":28,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2026.13941","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,26]]}}}