Pharmacoepidemiological Research on N-Nitrosodimethylamine-Contaminated Ranitidine Use and Long-Term Cancer Risk: A Population-Based Longitudinal Cohort Study

SIMPLE SUMMARY: There is a lack of published data regarding the association between N-nitrosodimethylamine and human cancer risks. Hence, this study answers several questions using propensity score matching with a large population size selected from a high-quality nationwide and population-based database with a long follow-up period to assess the relationship between the cumulative individual cancer incidence and long-term ranitidine use. ABSTRACT: N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and cancer emergence over time. Using the Taiwan National Health Insurance Research Database, a population-based cohort study was conducted. A total of 55,110 eligible patients who received ranitidine between January 2000 and December 2018 were enrolled in the treated cohort. We conducted a 1:1 propensity-score-matching procedure to match the ranitidine-treated group with the ranitidine-untreated group and famotidine controls for a longitudinal study. The association of ranitidine exposure with cancer outcomes was assessed. A multivariable Cox regression analysis that compared cancer risk with the untreated groups revealed that ranitidine increased the risk of liver (hazard ratio (HR): 1.22, 95% confidence interval (CI): 1.09–1.36, p < 0.001), lung (HR: 1.17, CI: 1.05–1.31, p = 0.005), gastric (HR: 1.26, CI: 1.05–1.52, p = 0.012), and pancreatic cancers (HR 1.35, CI: 1.03–1.77, p = 0.030). Our real-world observational study strongly supports the pathogenic role of NDMA contamination, given that long-term ranitidine use is associated with a higher likelihood of liver cancer development in ranitidine users compared with the control groups of non-ranitidine users treated with famotidine or proton-pump inhibitors.