Ranitidine Use is Not Associated with an Increased Risk of Cancer, Finds Latest Multinational Study Involving Over 1.1 Million Patients

In this extensive study, conducted across 11 large databases spanning Europe, North America, and Asia, researchers explored whether the commonly prescribed histamine-2 receptor antagonist (H2RA), Ranitidine, was associated with a heightened risk of cancer when compared to other H2RAs.

This federated international network cohort study was conducted with the support of the Observational Health Data Sciences and Informatics open science collaboration. The study identified eligible individuals from electronic health records and health claim data in the US, the UK, Germany, France, Spain, South Korea, and Taiwan. Adult patients aged >20 years who had used Ranitidine for over 30 days, with a minimum of one year of exposure-free observation preceding cohort entry were included in the study. The study encompassed data from 1,183,999 individuals and primarily aimed to evaluate the potential cancer-related risks linked to Ranitidine usage.

The study employed propensity score matching to mitigate potential confounding factors arising from covariate imbalances at baseline. Multiple sensitivity analyses were conducted, varying the times of risk, population definitions, outcomes, and statistical approaches. Additionally, race and ethnicity were considered in the analysis, as they could influence treatment decisions.

In this study, the primary outcome was to assess the occurrence of various cancer types, excluding non-melanoma skin cancer. Secondary outcomes encompassed the occurrence of all cancer types, including non-melanoma skin cancer, while excluding thyroid cancer, along with an analysis of 16 specific cancer subtypes. These include breast cancer; prostate cancer; lung cancer; colorectal cancer; bladder cancer; liver cancer; leukemia; pancreatic cancer; stomach cancer; lip, oral cavity, and pharynx cancer; thyroid cancer; corpus uteri cancer; ovary cancer; esophageal cancer; gall bladder and biliary tract cancer; and cervix uteri cancer.

Association of Ranitidine Usage with Overall Cancer Risk (Excluding Non-Melanoma Skin Cancer)

The study revealed no differences in cancer risk between individuals using Ranitidine and those utilizing H2RA medications, as evidenced by the AmbEMR database (HR, 1.00; 95% CI: 0.97-1.03, mean follow-up of 2.6 years) and the CUIMC database (HR, 0.97; 95% CI, 0.87-1.08, mean follow-up of 3.6 years).

Association of Ranitidine Usage with Overall Cancer and Site-Specific Cancer Risk

No significant variations in cancer risk were observed between Ranitidine users and individuals employing other H2RA medications for all cancer types (excluding thyroid cancer) and the 16 specific cancer subtypes. (Listed above)

Sensitivity Analyses Comparing Ranitidine and Other H2RA Users

Nonetheless, the positive associations between Ranitidine use and cancer incidence did not exist after empirical calibration was done to address systematic bias or after diverse sensitivity analyses with diverse balancing methods or time windows.

Comparison of Risk of Primary Outcome Between Ranitidine and Individual H2RA Users

No significant difference was observed in the risk of the primary outcome between Ranitidine and famotidine users (HR, 1.02; 95% CI, 0.98-1.06) and between Ranitidine and nizatidine users (HR, 1.05; 95% CI, 0.94-1.17).

Abbreviations: HR- hazard ratio; PY- person year

^a HRs and 95% CI were empirically calibrated based on the results from the negative control outcome to address systemic bias.

^b P values were adjusted using the Bonferroni correction for multiple comparisons. The Bonferroni-corrected P value for multiple comparisons was not calculated for a single primary outcome.

^c If the number of outcomes was less than the prespecified minimum count (n=5), the exact number was masked before aggregation to minimize the reidentification risk of a patient.

AmbEMR- Ambulatory Electronic Medical Research

CUIMC- Columbia University Irving Medical Center data warehouse