Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack

Stroke. 2018 Jan;49(1):54-61. doi: 10.1161/STROKEAHA.117.016674. Epub 2017 Dec 15.

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 ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate.

Methods: Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack 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 antiepileptic drugs other than SVA using survival analysis and Cox Regression.

Results: A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P=0.003).

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 ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.

Keywords: genetics; histone deacetylase; secondary prevention; sodium valproate; stroke; survival analysis.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anticonvulsants / administration & dosage*
  • Brain Ischemia* / complications
  • Brain Ischemia* / drug therapy
  • Brain Ischemia* / mortality
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Histone Deacetylase Inhibitors / administration & dosage*
  • Histone Deacetylases
  • Humans
  • Male
  • Middle Aged
  • Registries*
  • Repressor Proteins / antagonists & inhibitors*
  • Risk Factors
  • Stroke* / etiology
  • Stroke* / mortality
  • Stroke* / prevention & control
  • Survival Rate
  • Valproic Acid / administration & dosage*

Substances

  • Anticonvulsants
  • Histone Deacetylase Inhibitors
  • Repressor Proteins
  • Valproic Acid
  • HDAC9 protein, human
  • Histone Deacetylases