Introduction

One third of epilepsy patients worldwide are resistant to anti-seizure medication (ASM). Higher rates of mortality, medical and psychiatric co-morbidities in these patients account for most of its global burden of disease. Brivaracetam is a novel anti-seizure medication (ASM) used in Australia as add-on therapy in patients with focal epilepsy refractory to at least one first-line and two second line ASM. Brivaracetam demonstrates 15- to 30-fold increased affinity for SV2A compared to levetiracetam and produces similar effects on synaptic transmission at 100-fold lower concentrations.

Aim

To evaluate the efficacy and tolerability of brivaracetam in adult epilepsy patients in a real-world setting.

Patient Profile

• 228 adult epilepsy patients prescribed add-on brivaracetam at any time.
• Patients were included in the study if BRV prescription was confirmed in the clinical notes, regardless of underlying epilepsy type, baseline seizure frequency, availability of follow-up data, and whether BRV was subsequently dispensed or taken.
• There was no limit on age, although all participating institutions were adult comprehensive epilepsy centres.

Method

Study Design

• Multicenter retrospective observational cohort study

  Endpoints

• Primary outcomes: seizure response (least one category-level decrease in seizure frequency for all seizure types at the specified time point compared to baseline, corresponding to >50% reduction in frequency) and seizure freedom 12 months post brivaracetam commencement and tolerability
• Secondary outcomes: durability of early brivaracetam response in early responders and continuous seizure freedom from brivaracetam initiation
• Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (>4 prior ASMs) and highly refractory (>7 prior ASMs) epilepsy

Results  

Efficacy

• Brivaracetam was commenced at total daily doses of 25 - 200 mg and prescribed alongside a median of 2 other ASMs.
• Bivaracetam achieved a twelve-month responder rate of 15.4 to 46.3% and seizure freedom rate of 7.9 to 24.6% (depending on the approach to missing data: complete case analysis, last observation carried forward or intention to treat)
• Most frequently observed adverse effects (35.5%) with bivaracetam were sedation or cognitive slowing (14.4%), irritability or aggression (7%), and low mood (6.1%).
• Early brivaracetam responses were highly durable, with 3-month response maintained at all subsequent time points at 83% and seizure freedom maintained at 85%.
• Within-patient brivaracetam response was consistent over time (60% of late responders had been responders at all prior time points)
• Bivaracetam had similar responder and seizure frequency rates as the overall cohort in non-responders to levetiracetam, which suggested that prior failure of levetiracetam is not a contraindication to use of bivaracetam in clinical practice.
• Bivaracetam improved the 12-month seizure freedom (3.2 to 8.3%) in the highly refractory subgroup of patients and 7% to 17.4% in refractory group
• Outcomes were similar in subgroups of focal, generalized and refractory patients and also while using continuous outcome definitions

Figure 1: Outcomes with bivaracetam at 12 months

Conclusion

Brivaracetam was effective and well tolerated in real world refractory epilepsy population, with response rates consistent over time and adverse effect profiles similar to those observed in other clinical trials. Early responses to brivaracetam were enduring and maintained at all later study time points in the majority of patients.