Ranitidine Use and Incident Cancer in a Multinational Cohort

• Published in: JAMA network open Vol. 6; no. 9; p. e2333495
• Main Authors: You, Seng Chan, Seo, Seung In, Falconer, Thomas, Yanover, Chen, Duarte-Salles, Talita, Seager, Sarah, Posada, Jose D., Shah, Nigam H., Nguyen, Phung-Anh, Kim, Yeesuk, Hsu, Jason C., Van Zandt, Mui, Hsu, Min-Huei, Lee, Hang Lak, Ko, Heejoo, Shin, Woon Geon, Pratt, Nicole, Park, Rae Woong, Reich, Christin G., Suchard, Marc A., Hripcsak, George, Park, Chan Hyuk, Prieto-Alhambra, Daniel
• Format: Journal Article
• Language: English
• Published: Chicago American Medical Association 05-09-2023
• Subjects: Cancer; Cohort analysis; Online Only; Original Investigation; Pharmacy and Clinical Pharmacology
• ISSN: 2574-3805; 2574-3805
• DOI: 10.1001/jamanetworkopen.2023.33495

Importance
Ranitidine, the most widely used histamine-2 receptor antagonist (H
2
RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020.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.
Objective
To examine the comparative risk of cancer associated with the use of ranitidine vs other H
2
RAs.
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 H
2
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.
Exposure
The main exposure was use of ranitidine vs other H
2
RAs (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 H
2
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
2
RA users. After PS matching, cancer risk was similar in ranitidine compared with other H
2
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.
Conclusions and Relevance
In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H
2
RAs. Further research is needed on the long-term association of ranitidine with cancer development.