Data support the further study of HDAC9 inhibition as a treatment for secondary stroke prevention.
Neurology Reviews. 2018 February;26(2):71
The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.
The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.
An Analysis of Three Large Cohort Studies
Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.
Hugh S. Markus, DM
Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.
Valproate Halved Risk of Recurrent Stroke
In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.
Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.
For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.
Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).
“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”
Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.