Is sodium valproate, an HDAC inhibitor, associated with reduced risk of stroke and myocardial infarction? A nested case-control study

Abstract

Background: This study aimed to evaluate whether treatment with sodium valproate (SV) was associated with reduced risk of stroke or myocardial infarction (MI).

Methods: Electronic health records data were extracted from Clinical Practice Research Database for participants ever diagnosed with epilepsy and prescribed antiepileptic drugs. A nested case-control study was implemented with cases diagnosed with incident non-haemorrhagic stroke and controls matched for sex, year of birth, and study start date (ratio of 1:6). A second nested study was implemented with MI as outcome. The main exposure variable was SV therapy assessed as: ever prescribed, pre-stroke year treatment, number of SV prescriptions, and cumulative time on SV drug therapy. Odds ratios were estimated using conditional logistic regression.

Results: Data were analysed for 2002 stroke cases and 13,098 controls. MI analyses included 1153 cases and 7109 controls. Pre-year stroke SV treatment (28%) was associated with increased stroke risk (odds ratio 1.22, 95% confidence interval (CI): 1.09 to 1.38, p < 0.001). No association was observed between ever being prescribed SV with ischemic stroke (OR = 1.01, 95% CI: 0.91 to 1.12, p = 0.875). A significant association was observed between ever being prescribed SV with MI (OR = 0.78, 95% CI: 0.67 to 0.90, p < 0.001). Patients in the highest quarter of SV treatment duration had lower odds of ischemic stroke (OR = 0.57, 95% CI: 0.44 to 0.72, p < 0.001) and MI (OR = 0.29, 95% CI: 0.20 to 0.44, p < 0.001).

Conclusion: Sodium valproate exposure was associated with the risk of MI, but not ischemic stroke. However, longer exposure to SV was associated with lower odds of stroke, but this might be explained by survivor bias.

Keywords: antiepileptic drugs; epilepsy; histone deacetylase (HDAC) inhibitors; ischemic stroke; myocardial infarction; pharmacoepidemiology; sodium valproate.

Figure 1

Flow diagram for the selection of nested case–control patients. ^aSome patients could be controls for more than one case. Abbreviations: UTS, up-to-standard; CRD, current registration date; CPRD, Clinical Research Practice Datalink. Event refers to the date of a first ischemic stroke diagnosis