Ranitidine Use and Incident Cancer in a Multinational Cohort

Abstract

Importance: Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020.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.

Figure 1.. Patient Selection Flowchart

AmbEMR indicates IQVIA US Ambulatory Electronic Medical Research; AUSOM, Ajou University School of Medicine; H₂RA, histamine-2 receptor antagonist; CUIMC, Columbia University Irving Medical Center data warehouse; HUMIC, Hanyang University Medical Center; IMRD, UK’s IQVIA Medical Research Data; IQVIA DA Ger, IQVIA Disease Analyzer Germany; KDH, Kandong Sacred Heart Hospital; NHIS-NSC, Korean National Health Insurance System-National Sample Cohort; SIDIAP, The Information System for Research in Primary Care; STARR, Stanford University database warehouse; TMUCRD, Taipei Medical University Clinical Research Database. ^aDiagnostic criteria indicate satisfaction of both empirical equipoise and balance after 1:1 propensity score (PS) matching; the study diagnostic criteria included empirical equipoise and sufficient balance of covariates after PS adjustment, and the empirical equipoise was satisfied when the preference scores of most patients (a transformation of the propensity score adjusting for different prevalence of treatments) in both groups were between 0.3 and 0.7. The balance between the target and comparator cohorts was considered sufficient if the absolute standardized mean difference of all covariates was not greater than 0.1.

Figure 2.. Kaplan-Meier Plots for the Risk of All Cancer Except Nonmelanoma Skin Cancer Associated With Ranitidine Users and Other Histamine-2 Receptor Antagonist (H₂RA) Users

P-values in survival curves were estimated using Cox proportional hazard regression models. Shading in the survival curves indicates 95% CIs. AmbEMR indicates IQVIA US Ambulatory Electronic Medical Research; CUIMC, Columbia University Irving Medical Center data warehouse; NHIS-NSC, Korean National Health Insurance System-National Sample Cohort; SIDIAP, The Information System for Research in Primary Care.

Figure 3.. Risk of All Cancer Except Nonmelanoma Skin Cancer Between Ranitidine and Other H₂ Receptor Antagonist (H₂RA) Users in Meta-Analysis

The summary hazard ratios were calculated using a random-effects model. A, Meta-analysis of results passing diagnostics (primary analysis). B, subgroup meta-analysis for primary outcome using results from all available data sources based on geographic region. Size of the data marker indicates the weight of the study; error bars, 95% CIs. AmbEMR indicates IQVIA US Ambulatory Electronic Medical Research; AUSOM, Ajou University School of Medicine; CUIMC, Columbia University Irving Medical Center data warehouse; DA Germany, IQVIA Disease Analyzer Germany; HUMIC, Hanyang University Medical Center; IMRD, UK’s IQVIA Medical Research Data; KDH, Kandong Sacred Heart Hospital; NHIS-NSC, Korean National Health Insurance System-National Sample Cohort; SIDIAP, The Information System for Research in Primary Care; STARR, Stanford University database warehouse; TMUCRD, Taipei Medical University Clinical Research Database.