The efficacy and tolerability of adjunctive brivaracetam for the treatment of adult epilepsy: An Australian multi-center retrospective real-world observational cohort study

Objective: Assess the efficacy and tolerability of add-on therapy brivaracetam (BRV) in adult patients with epilepsy in a real-world setting. Methods: This multi-center retrospective observational cohort study examined all adult patients who commenced on BRV at 11 Australian epilepsy centers between 2017 and 2020. Primary outcomes were seizure response (≥50% reduction in frequency) and seizure freedom 12 months post BRV commencement, and tolerability. We report three approaches to missing data (complete case analysis, CCA; last observation carried forward, LOCF; and intention to treat, ITT). Secondary outcomes included the durability of early BRV response and continuous seizure freedom from BRV initiation. Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (≥4 prior ASMs) and highly refractory (≥7 prior ASMs) epilepsy. Outcomes were also assessed at ‘personalized’ seizure outcome time points based on baseline seizure frequency. Results: Baseline and follow-up data were available for 228 patients. The mean age was 41.5 years (IQR 30, 50). Most had focal epilepsy (188/228, 82.5%). Median number of previous ASMs was 4 (2, 7), and concomitant ASMs 2 (2, 3). Twelve-month responder rate was: 46.3% using CCA (95% CI 34.0, 58.9); 39.5% using LOCF (33.1, 46.1); and 15.4% using ITT (10.9, 20.7). Twelve-month seizure freedom was: 23.9% using CCA (14.3, 35.9); 24.6% using LOCF (19.1, 30.7); and 7.9% using ITT (4.7, 12.1). The most frequent adverse effects were sedation or cognitive slowing (33/228, 14.5%), irritability or aggression (16/228, 7.0%), and low mood (14/228, 6.1%). Outcomes were similar using continuous outcome definitions and ‘personalized’ outcome assessment time points. Early responses were highly durable, with 3-month response maintained at all subsequent time points at 83%, and seizure freedom maintained at 85%. Outcomes were similar in focal (n = 187) and generalizsed (n = 25) subgroups. Outcomes were similar in refractory patients (n = 129), but lower in the highly refractory group (n = 62), however improvement with BRV was still observed with 12-month seizure freedom of 8.3% using CCA (1.0, 27), 6.5% using LOCF (1.8, 15.7); and 3.2% using ITT (0.4, 11.2). Conclusions: Meaningful real-world responder and seizure freedom rates can be still observed in a refractory epilepsy population. Brivaracetam response can occur early and appears to be maintained with minimal later relapse. The results should be interpreted with caution given the retrospective nature of the study and the quantities of missing data at later time points.