Sodium channel-inhibiting drugs and cancer-specific survival: a population-based study using the CPRD

Objectives: Antiepileptic and antiarrhythmic drugs inhibit voltage-gated sodium (Na+) channels (VGSCs), and preclinical studies show that these medications reduce tumour growth, invasion and metastasis. We investigated the association between VGSC inhibitor use and survival in breast, bowel and prostate cancer patients. Design: Retrospective cohort study. Setting: Individual primary care records extracted from the CPRD database. Participants: Records for 132,996 patients with a diagnosis of breast, bowel or prostate cancer. Primary and secondary outcome measures: Adjusted Cox proportional hazards regression was used to analyse cancer-specific survival associated with exposure to VGSC inhibitors. Exposure to non-VGSC-inhibiting antiepileptic medication and other non-VGSC blockers were also considered. Drug exposure was treated as a time-varying covariate to account for immortal time bias. Results: During 1,002,225 person-years of follow-up, there were 42,037 cancer-specific deaths. 53,724 (40.4%) cancer patients had at least one prescription for a VGSC inhibitor of interest. Increased risk of cancer-specific mortality was associated with exposure to this group of drugs (hazard ratio: 1.59, 95% CI 1.56 to 1.63, p<0.001). This risk applied to VGSC-inhibiting tricyclic antidepressants, local anaesthetics and anticonvulsants, and persisted in sensitivity analyses stratifying by index cancer diagnosis and for other mortality outcomes. In contrast, exposure to VGSC-inhibiting Class 1c and 1d antiarrhythmics was associated with significantly improved cancer-specific survival in exploratory analyses. Conclusions: Association between VGSC inhibitor use and mortality in cancer patients varies according to indication. Exposure to VGSC-inhibiting antiarrhythmics, but not anticonvulsants, supports findings from preclinical data, with improved survival. However, additional confounding factors may underlie these associations, highlighting the need for further study.