Seng Chan You, MD1,2; Seung In Seo, MD3,4; Thomas Falconer, MSc5; Chen Yanover, PhD6; Talita Duarte-Salles, PhD7; Sarah Seager, BA8; Jose D. Posada, PhD9; Nigam H. Shah, PhD9; Phung-Anh Nguyen, PhD10; Yeesuk Kim, MD11; Jason C. Hsu, PhD12; Mui Van Zandt, BS8; Min-Huei Hsu, MD10; Hang Lak Lee, MD13; Heejoo Ko, MD14; Woon Geon Shin, MD3,4; Nicole Pratt, PhD15; Rae Woong Park, MD16,17; Christin G. Reich, MD8; Marc A. Suchard, MD18,19; George Hripcsak, MD5,20; Chan Hyuk Park, MD21; Daniel Prieto-Alhambra, MD22,23
1Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
2Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, Korea
3Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
4Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
5Department of Biomedical Informatics, Columbia University, New York, New York
6KI Research Institute, Kfar Malal, Israel
7Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina, Barcelona, Spain
8IQVIA, Cambridge, Massachusetts
9Department of Medicine, Stanford University School of Medicine, Stanford, California
10Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan
11Department of Orthopaedic Surgery, College of Medicine, Hanyang University, Seoul, Korea
12International PhD Program in Biotech and Healthcare Management, College of Management, Taipei Medical University, Taipei, Taiwan
13Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
14College of Medicine, The Catholic University of Korea, Seoul, Korea
15Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, Australia
16Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea
17Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
18Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles
19VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Salt Lake City, Utah
20Medical Informatics Services, New York-Presbyterian Hospital, New York, New York
21Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
22Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
23Department of Medical Informatics, Erasmus Medical Center University, Rotterdam, Netherlands
Drs You and Seo contributed equally.
Drs C. H. Park and Prieto-Alhambra are co–senior authors.
Corresponding Author: Chan Hyuk Park, MD, PhD
Importance: Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), 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.
Objective: To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs.
Design, setting, and participants: 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 H2RAs 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.
Exposure: The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine).
Main outcomes and measures: 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.
Results: Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. 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 H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA 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.
Conclusions and relevance: In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.