Abstract
Abstract Background: The discovery that ranitidine is contaminated with N-nitrosodimethylamine, a suspected human carcinogen, raises the hypothesis of a gastrointestinal carcinogenic effect; however, evidence remains inconclusive. Methods: We used the nationwide Danish Prescription Registry to identify a cohort of incident ranitidine users and two active comparator cohorts comprising users of other histamine-2 receptor blockers (H2RB) and users of proton pump inhibitors (PPI). All Danish adults with a first prescription of ranitidine, other H2RBs, or PPIs in 1996 through 2008 were followed virtually completely through 2018 for incidence of esophageal, stomach, liver, and pancreatic cancers. We used Cox regression with propensity-score weighting to calculate hazard ratios and 10-year cumulative risk with 95% confidence intervals. Results: We ascertained 276 newly diagnosed esophageal, 342 stomach, 133 hepatocellular, and 517 pancreatic cancers among ranitidine users during follow-up (median 14 years). In comparison with use of other H2RBs or PPIs, we found no consistent evidence of increased HRs or excess 10-year cumulative risk of any upper gastrointestinal cancer following ranitidine use. We observed no association after restriction to subjects with at least 5 or 10 prescriptions or those with 10 prescriptions and at least 10 years of follow-up. Conclusions: Our large prospective study using high-quality prescription and cancer incidence data, with two active comparator groups, provides no compelling evidence that ranitidine increases the risk of upper gastrointestinal cancers. Impact: Our results, which do not support any carcinogenic effect on esophagus, stomach, liver or pancreas, should be reassuring for millions of concerned past users of ranitidine.
Highlights
In 2019, contamination with N-nitrosodimethylamine (NDMA) was reported in the acid-reducing histamine-2 receptor blocker (H2RB) ranitidine, but not in other histamine-2 receptor blockers (H2RBs) [1]
In the primary analyses, which included individuals with at least one prescription of interest during the entire follow-up period, all hazard ratios (HRs) except one were clustered around the null value of 1.0, whether ranitidine was compared with other H2RBs or with pump inhibitors (PPIs)
Population-based study using high-quality exposure and outcome data, we consistently observed HRs and risk differences close to unity when use of ranitidine was compared with use of either other H2RBs or PPIs
Summary
In 2019, contamination with N-nitrosodimethylamine (NDMA) was reported in the acid-reducing histamine-2 receptor blocker (H2RB) ranitidine, but not in other H2RBs (e.g., cimetidine and famotidine) [1]. While NDMA is an animal carcinogen, decades of research have not documented a causal association with any human cancer type or site [2], leaving unresolved questions about the impact of NDMA on human health, especially at concentrations reportedly detected in ranitidine. Given these uncertainties, analyses of cancer risk following ranitidine use per se – rather than studies based on debatable estimates of NDMA exposure – are more informative about possibly increased cancer risk from use of this drug. In several studies of ranitidine and cancer risk, additional limitations include self-reported drug use, incomplete confounder adjustment, limited sample size, short follow-up, and conflation of disparate cancer types
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