Valproic acid is one of the very few drugs whose discovery is credited to serendipity. A metabolically inert organic solvent, it was discovered in the 19th century and was found to have anti-seizure activity in the late 20th century. It is one of the oldest antiseizure medications (ASMs) and is still used regularly in the modern medical era. One of its unique characteristics is that it has an extremely broad spectrum of efficacy for different seizure types, making it a drug of choice for many hard-to-classify seizures and generalized-onset seizures.
In a previous post, we focused on the Standard and New Antiepileptic Drugs (SANAD) trial’s Arm A, which evaluated carbamazepine’s efficacy compared to new ASMs for focal epilepsy. The SANAD trial’s Arm B was similar in study design to Arm A, but instead compared valproate’s efficacy in patients with generalized epilepsy to newer ASMs.
The SANAD’s Arm B1 randomized 716 patients with generalized onset seizures or hard-to-classify seizures into 3 treatment groups; valproate, lamotrigine, and topiramate. To mimic the real-life clinical scenarios, the eligibility criteria were kept very relaxed. Dose selection was based on the clinician’s judgment. The primary outcomes included time to treatment failure (inadequate seizure control, severe adverse effects, need for an additional ASM), and time to 12 months of remission. Other studied outcomes were the time to a first seizure, time to achieve a 2-year remission, the incidence of clinically-important adverse events, quality of life, and cost-effectiveness. There was some reluctance to randomize young women of childbearing age, as evident from the gender ratios in different age groups, due to the associated risk of fetal malformations with valproate.
The time to treatment failure was significantly better for valproate when compared to topiramate but not when compared to lamotrigine. Despite this, lamotrigine had the highest incidence of treatment failure during the study interval due to inadequate seizure control. Lamotrigine was the best tolerated and topiramate was the worst tolerated. Considering quality-adjusted life years and the number of seizures avoided, valproate was concluded to remain the drug of choice for generalized onset as well as hard-to-classify seizures.
While SANAD’s Arm B asserted valproate as the most efficacious medication for generalized epilepsy in its study, it is important to note its significant risks with use in females of childbearing age and its long-term side effects (osteoporosis, polycystic ovarian syndrome, alopecia, hepatic dysfunction, etc.). Also note that all generalized seizures (absence, myoclonic, generalized tonic-clonic, etc.) are not pathophysiologically the same, and this study is therefore limited as it did not stratify by seizure type. Too, since this study, many new ASMs have hit the market and should be considered.
All in all, ASM selection for a patient should be individualized and well thought-out, including consideration of the patient’s type of epilepsy/seizures and comorbidities, as well as the medication’s efficacy, cost, and side effect profile.
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Learn more about valproic acid here!
References:
- Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26.
- Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15.
- Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet 2021; 397: 1375–86.
