ABSTRACT

Background and purpose A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore inhibiting HDAC9 might offer a novel secondary preventative treatment for ischaemic stroke. The antiepileptic drug (AED) sodium valproate (SVA) is a non-specific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate.

Methods Data was pooled from three prospective studies recruiting patients with previous stroke or TIA and long-term follow up: the South London Stroke Register, The Vitamins to Prevent Stroke Study and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received AEDs other than SVA using survival analysis and Cox Regression.

Results 11949 patients with confirmed ischaemic event were included. Recurrent stroke rate was lower in patient taking SVA (17/168) than other AEDs (105/530, log rank survival analysis p=.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (HR=.44, 95% CI: 0.3-0.7, p=.002). A similar result was obtained when patients taking SVA where compared with all cases not taking SVA. (Cox regression, HR=.47, 95% CI: 0.29-0.77, p=.003).

Conclusions These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischaemic stroke pathogenesis, and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischaemic stroke.