Standard drugs remain the best first-line treatments for epilepsy, according to the results of two UK clinical trials led by the University of Liverpool.

The Standard and New Antiepileptic Drugs (SANAD II) studies compared a range of antiepileptic drugs for how well they control seizures, their general tolerability and their cost, to assess whether newer drugs should be recommended as first-line treatments.

The findings, published in The Lancet, conclude that valproate is still the best first choice for generalised epilepsy, while lamotrigine remains the best first-line drug for focal epilepsy. Despite its growing popularity, the studies found no evidence to support the use of newer drug levetiracetam as a first-line drug for either type of epilepsy.

Valproate is a first-line treatment for newly diagnosed generalised epilepsy, but not for women of child-bearing age as it can cause birth defects and problems with a child’s development and learning. Levetiracetam has therefore been increasingly used as an alternative first-line drug, despite little head-to-head comparative data being available.

The SANAD II study looked at the clinical effectiveness and cost-effectiveness of valproate versus levetiracetam in patients (adults and children over 5 years) with newly diagnosed generalised epilepsy.

The randomised controlled trial recruited 520 participants between April 2013 and August 2016 and followed up for a further two to six years. Compared to valproate, levetiracetam was found to be neither clinically nor cost effective. After 2 years of treatment 15% more people had failed on levetiracetam due to worse seizure control, and after 1 year of follow up 19% more people with convulsive seizures had their seizures controlled with valproate.

Lead researcher Professor Tony Marson, Head of the Epilepsy Research Group at the University of Liverpool and a consultant neurologist at The Walton Centre NHS Trust, said: “The available evidence now identifies valproate as more clinically and cost effective than both lamotrigine and levetiracetam. Unfortunately, this means that female patients of childbearing age with generalised epilepsy are being denied the most effective treatment, while males are not. There should now be further debate to inform practice and policy to make sure we are getting the balance right, ensuring we are minimising the risk to women from seizure whilst also minimising the potential risk of harm in future pregnancies.”

The other SANAD II study assessed the longer term clinical and cost effectiveness of levetiracetam and zonisamide against the standard drug lamotrigine as first-line treatments for newly diagnosed focal epilepsy.

The randomised controlled trial recruited 990 participants between April 2013 and June 2017 and followed up for a further two to seven years. Participants were randomly allocated 1:1:1 to lamotrigine, levetiracetam or zonisamide.

Lamotrigine was found to be superior against both levetiracetam and zonisamide in a range of outcomes. People starting treatment with levetiracetam or zonisamide were significantly less likely to have their seizures controlled than people starting with lamotrigine unless they were changed to another medication. Levetiracetam and zonisamide were also found to be poor value for money for the NHS when used as first-line treatments.

Professor Marson, Director of Research Programmes for Liverpool Health Partners, said: “Levetiracetam has been widely adopted in the UK and worldwide as a first-line treatment for focal epilepsy, but this should no longer be the case as it is neither clinically nor cost effective compared to lamotrigine.

“Our findings have important implications for clinical practice and research. Although levetiracetam and zonisamide are licensed for used as monotherapy in focal epilepsy in Europe and elsewhere, our results do not support their use as first-line monotherapy.

“It is essential that we continue to provide evidence about which drugs are the most effective and safe for the patient, as well as identify those that are good value for the NHS.”

The SANAD II trial was co-sponsored by the University of Liverpool and The Walton Centre NHS foundation Trust, funded by the National Institute for Health Research Health Technology Assessment Programme (NIHR HTA) and coordinated by the Liverpool Clinical Trials Centre.

Research references:

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial, Lancet, https://doi.org/10.1016/S0140-6736(21)00247-6 

 The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: An un-blinded randomised controlled trial, Lancet, https://doi.org/10.1016/S0140-6736(21)00246-4