{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:39:38Z","timestamp":1791725978386,"version":"4.3.4"},"reference-count":36,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n \n Ranitidine, the most widely used histamine-2 receptor antagonist (H\n 2<\/jats:sub>\n RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To examine the comparative risk of cancer associated with the use of ranitidine vs other H\n 2<\/jats:sub>\n RAs.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H\n 2<\/jats:sub>\n RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021.\n <\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n \n The main exposure was use of ranitidine vs other H\n 2<\/jats:sub>\n RAs (famotidine, lafutidine, nizatidine, and roxatidine).\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 1\u202f183\u202f999 individuals in 11 databases, 909\u202f168 individuals (mean age, 56.1 years; 507\u202f316 [55.8%] women) were identified as new users of ranitidine, and 274\u202f831 individuals (mean age, 58.0 years; 145\u202f935 [53.1%] women) were identified as new users of other H\n 2<\/jats:sub>\n RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H\n 2<\/jats:sub>\n RA users. After PS matching, cancer risk was similar in ranitidine compared with other H\n 2<\/jats:sub>\n RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H\n 2<\/jats:sub>\n RAs. Further research is needed on the long-term association of ranitidine with cancer development.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.33495","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T12:43:24Z","timestamp":1695127404000},"page":"e2333495","source":"Crossref","is-referenced-by-count":23,"title":["Ranitidine Use and Incident Cancer in a Multinational Cohort"],"prefix":"10.1001","volume":"6","author":[{"given":"Seng Chan","family":"You","sequence":"first","affiliation":[{"name":"Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea"},{"name":"Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung In","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Falconer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yanover","sequence":"additional","affiliation":[{"name":"KI Research Institute, Kfar Malal, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talita","family":"Duarte-Salles","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3 Institut Universitari per a la recerca a l\u2019Atenci\u00f3 Prim\u00e0ria de Salut Jordi Gol i Gurina, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Seager","sequence":"additional","affiliation":[{"name":"IQVIA, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose D.","family":"Posada","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stanford University School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigam H.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stanford University School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phung-Anh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeesuk","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, College of Medicine, Hanyang University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason C.","family":"Hsu","sequence":"additional","affiliation":[{"name":"International PhD Program in Biotech and Healthcare Management, College of Management, Taipei Medical University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mui","family":"Van Zandt","sequence":"additional","affiliation":[{"name":"IQVIA, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Huei","family":"Hsu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang Lak","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heejoo","family":"Ko","sequence":"additional","affiliation":[{"name":"College of Medicine, The Catholic University of Korea, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woon Geon","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea"},{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Pratt","sequence":"additional","affiliation":[{"name":"Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rae Woong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea"},{"name":"Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin G.","family":"Reich","sequence":"additional","affiliation":[{"name":"IQVIA, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc A.","family":"Suchard","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles"},{"name":"VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Salt Lake City, Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Hripcsak","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Columbia University, New York, New York"},{"name":"Medical Informatics Services, New York-Presbyterian Hospital, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Hyuk","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Prieto-Alhambra","sequence":"additional","affiliation":[{"name":"Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom"},{"name":"Department of Medical Informatics, Erasmus Medical Center University, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,9,19]]},"reference":[{"issue":"4","key":"zoi230968r1","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1001\/archinte.1990.00390160023006","article-title":"Clinical review of histamine2 receptor antagonists.","volume":"150","author":"Lipsy","year":"1990","journal-title":"Arch Intern Med"},{"issue":"6","key":"zoi230968r8","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1136\/bmj.k3851","article-title":"Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study.","volume":"70","author":"Potteg\u00e5rd","year":"2018","journal-title":"BMJ"},{"issue":"5","key":"zoi230968r9","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1053\/j.gastro.2020.12.037","article-title":"Ranitidine use and cancer risk: results from UK Biobank.","volume":"160","author":"Kantor","year":"2021","journal-title":"Gastroenterology"},{"issue":"1","key":"zoi230968r10","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3390\/jcm10010153","article-title":"Risk of cancer following the use of N-nitrosodimethylamine (NDMA) contaminated ranitidine products: a nationwide cohort study in South Korea.","volume":"10","author":"Yoon","year":"2021","journal-title":"J Clin Med"},{"key":"zoi230968r11","first-page":"574","article-title":"Observational Health Data Sciences and Informatics (OHDSI): opportunities for observational researchers.","volume":"216","author":"Hripcsak","year":"2015","journal-title":"Stud Health Technol Inform"},{"issue":"1","key":"zoi230968r12","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1136\/amiajnl-2011-000376","article-title":"Validation of a common data model for active safety surveillance research.","volume":"19","author":"Overhage","year":"2012","journal-title":"J Am Med Inform Assoc"},{"issue":"16","key":"zoi230968r13","doi-asserted-by":"publisher","first-page":"1640","DOI":"10.1001\/jama.2020.16167","article-title":"Association of ticagrelor vs clopidogrel with net adverse clinical events in patients with acute coronary syndrome undergoing percutaneous coronary intervention.","volume":"324","author":"You","year":"2020","journal-title":"JAMA"},{"issue":"10211","key":"zoi230968r14","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.1016\/S0140-6736(19)32317-7","article-title":"Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis.","volume":"394","author":"Suchard","year":"2019","journal-title":"Lancet"},{"issue":"5","key":"zoi230968r16","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.ejps.2011.02.004","article-title":"Cimetidine: an anticancer drug?","volume":"42","author":"Kubecova","year":"2011","journal-title":"Eur J Pharm Sci"},{"issue":"3","key":"zoi230968r17","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s40264-020-01024-0","article-title":"Risk of cancer in association with ranitidine and nizatidine vs other h2 blockers: analysis of the Japan medical data center claims database 2005\u20132018.","volume":"44","author":"Iwagami","year":"2021","journal-title":"Drug Saf"},{"issue":"1","key":"zoi230968r19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1145\/2414416.2414791","article-title":"Massive parallelization of serial inference algorithms for a complex generalized linear model.","volume":"23","author":"Suchard","year":"2013","journal-title":"ACM Trans Model Comput Simul"},{"issue":"6","key":"zoi230968r20","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1093\/ije\/dyy120","article-title":"Evaluating large-scale propensity score performance through real-world and synthetic data experiments.","volume":"47","author":"Tian","year":"2018","journal-title":"Int J Epidemiol"},{"issue":"3","key":"zoi230968r22","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":"3","key":"zoi230968r23","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1097\/EDE.0b013e3181d61eeb","article-title":"Negative controls: a tool for detecting confounding and bias in observational studies.","volume":"21","author":"Lipsitch","year":"2010","journal-title":"Epidemiology"},{"issue":"11","key":"zoi230968r24","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.1073\/pnas.1708282114","article-title":"Empirical confidence interval calibration for population-level effect estimation studies in observational healthcare data.","volume":"115","author":"Schuemie","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"zoi230968r25","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.3945\/ajcn.111.012377","article-title":"N-nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)\u2013Norfolk Study.","volume":"93","author":"Loh","year":"2011","journal-title":"Am J Clin Nutr"},{"issue":"6","key":"zoi230968r26","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.18253","article-title":"In vitro analysis of N-nitrosodimethylamine (NDMA) formation from ranitidine under simulated gastrointestinal conditions.","volume":"4","author":"Gao","year":"2021","journal-title":"JAMA Netw Open"},{"issue":"3","key":"zoi230968r27","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1001\/jama.2021.9199","article-title":"Effect of oral ranitidine on urinary excretion of N-nitrosodimethylamine (NDMA): a randomized clinical trial.","volume":"326","author":"Florian","year":"2021","journal-title":"JAMA"},{"key":"zoi230968r28","doi-asserted-by":"publisher","DOI":"10.1177\/2042098618823458","article-title":"Valsartan recall: global regulatory overview and future challenges.","author":"Farrukh","year":"2019","journal-title":"Ther Adv Drug Saf"},{"issue":"4","key":"zoi230968r29","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1093\/aje\/kwm324","article-title":"Immortal time bias in pharmaco-epidemiology.","volume":"167","author":"Suissa","year":"2008","journal-title":"Am J Epidemiol"},{"issue":"6","key":"zoi230968r30","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1007\/s00228-014-1677-y","article-title":"Primary non-adherence in general practice: a Danish register study.","volume":"70","author":"Potteg\u00e5rd","year":"2014","journal-title":"Eur J Clin Pharmacol"},{"issue":"3-4","key":"zoi230968r32","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/0165-1218(91)90123-4","article-title":"Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential.","volume":"259","author":"Tricker","year":"1991","journal-title":"Mutat Res"},{"issue":"10","key":"zoi230968r35","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1002\/pds.4267","article-title":"Validity of cancer diagnosis in the National Health Insurance database compared with the linked National Cancer Registry in Taiwan.","volume":"27","author":"Kao","year":"2018","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"5","key":"zoi230968r36","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.canep.2012.05.013","article-title":"Validity of cancer diagnosis in a primary care database compared with linked cancer registrations in England. Population-based cohort study.","volume":"36","author":"Dregan","year":"2012","journal-title":"Cancer Epidemiol"},{"key":"zoi230968r5","volume-title":"Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42","author":"International Agency for Research on Cancer","year":"1987"},{"key":"zoi230968r2","unstructured":"ClinCalc. Ranitidine: drug usage statistics, United States, 2013-2020. Accessed December 18, 2022. https:\/\/clincalc.com\/DrugStats\/Drugs\/Ranitidine"},{"key":"zoi230968r3","unstructured":"ClinCalc. The top 300 drugs of 2021. Accessed December 18, 2022. https:\/\/clincalc.com\/DrugStats\/Top300Drugs.aspx"},{"key":"zoi230968r4","unstructured":"US Food and Drug Administration. Statement alerting patients and health care professionals of NDMA found in samples of ranitidine. News release. September 13, 2019. Accessed December 18, 2022. https:\/\/www.fda.gov\/news-events\/press-announcements\/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine"},{"key":"zoi230968r6","unstructured":"US Food and Drug Administration. FDA requests removal of all ranitidine products (Zantac) from the market. News release. April 1, 2020. Accessed December 18, 2022. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-requests-removal-all-ranitidine-products-zantac-market"},{"key":"zoi230968r7","unstructured":"European Medicines Agency. Nitrosamine impurities. Accessed December 18, 2022. https:\/\/www.ema.europa.eu\/en\/human-regulatory\/post-authorisation\/referral-procedures\/nitrosamine-impurities"},{"key":"zoi230968r15","unstructured":"You? SC, Seo? SI, Park? CH. Ranitidine Cancer Risk. Accessed August 15, 2023. https:\/\/github.com\/ohdsi-studies\/RanitidineCancerRisk"},{"key":"zoi230968r18","unstructured":"US Food and Drug Administration. Laboratory tests\u2014ranitidine. Accessed December 18, 2022. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/laboratory-tests-ranitidine"},{"key":"zoi230968r21","unstructured":"CohortMethod. Accessed August 15, 2023. https:\/\/github.com\/OHDSI\/CohortMethod"},{"key":"zoi230968r31","unstructured":"European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ENCePP guide on methodological standards in pharmacoepidemiology. Accessed December 18, 2022. https:\/\/www.encepp.eu\/standards_and_guidances\/methodologicalGuide.shtml"},{"key":"zoi230968r33","unstructured":"European Medicines Agency. Update on review of recalled valsartan medicines: preliminary assessment of possible risk to patients. News release. February 8, 2018. Accessed December 18, 2022. https:\/\/www.ema.europa.eu\/en\/news\/update-review-recalled-valsartan-medicines-preliminary-assessment-possible-risk-patients"},{"key":"zoi230968r34","unstructured":"US Food and Drug Administration. Laboratory analysis of valsartan products. Accessed December 18, 2022. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/laboratory-analysis-valsartan-products"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2809671\/you_2023_oi_230968_1694461256.53093.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T12:43:31Z","timestamp":1695127411000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2809671"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,19]]},"references-count":36,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,9,5]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.33495","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,19]]}}}