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. 2026 Feb;15(1):213-235.
doi: 10.1007/s40120-025-00860-5. Epub 2025 Nov 20.

Lacosamide is Associated with a Higher Treatment Persistence at 12 Months than Brivaracetam and Perampanel Despite Similar Efficacy

Roberta Roberti  1 , Cristina Politi  1   2 , Francesca Anzellotti  3 , Vincenzo Belcastro  4 , Simone Beretta  5 , Giovanni Boero  6 , Paolo Bonanni  7 , Laura Canafoglia  8 , Alfredo D'Aniello  9 , Filippo Dainese  10 , Carmen De Caro  1   11 , Giancarlo Di Gennaro  9 , Roberta Di Giacomo  12 , Jacopo C DiFrancesco  5 , Fedele Dono  3   13 , Giovanni Falcicchio  14 , Edoardo Ferlazzo  15   16 , Nicoletta Foschi  17 , Antonio Gambardella  18 , Alfonso Giordano  19 , Angelo Labate  20 , Angela La Neve  14 , Simona Lattanzi  17 , Ugo Leggio  21 , Claudio Liguori  22   23 , Marta Maschio  24 , Pietro Mattioli  25   26 , Annacarmen Nilo  27 , Francesca Felicia Operto  1   18 , Angelo Pascarella  15   16 , Giada Pauletto  28 , Luciano Pellegrino  10 , Rosaria Renna  29 , Gionata Strigaro  30 ; COMPARE Study Group; Emilio Russo  31 , Gianfranco Di Gennaro  1
Collaborators, Affiliations

Lacosamide is Associated with a Higher Treatment Persistence at 12 Months than Brivaracetam and Perampanel Despite Similar Efficacy

Roberta Roberti et al. Neurol Ther. 2026 Feb.

Abstract

Introduction: Evidence directly comparing newer antiseizure medications (ASMs) is limited but crucial for guiding treatment decisions. This study compared the real-world effectiveness and tolerability of brivaracetam (BRV), lacosamide (LCM) and perampanel (PER) as add-on therapy in adults with epilepsy, applying a causal-inference extension of the COMPARE study. The aim of this approach was to overcome the limitations of standard multivariable analyses, better approximate causal effects, and reinforce the credibility of the results.

Methods: Data were retrospectively collected in the Italian multicentre COMPARE study. To emulate a randomized setting, we estimated multinomial propensity scores and applied stabilized inverse probability weights. The primary analysis used a log-logistic accelerated failure time model to estimate time-to-treatment discontinuation, adjusting for adverse events (AEs), clinical response and follow-up duration. Secondary analyses evaluated changes in total and concomitant drug load and tolerability over time.

Results: Among the 850 subjects included in this analysis (259, 240 and 351 receiving LCM, BRV and PER, respectively; 53.4% female; median age 43 years), the estimated probability of 12-month retention was highest for LCM (86.1%), followed by BRV (79.1%) and PER (75.4%). Long-term trends suggested convergence of PER and LCM retention, whereas BRV discontinuation remained higher. In the adjusted analyses, BRV and PER were associated with shorter time-to-treatment discontinuation than LCM, but this negative effect decreased over time, while the beneficial effect of clinical response strengthened. Total drug load increased across all groups but remained lowest for LCM; concomitant ASM load decreased, particularly among responders. AEs were mostly mild, with dizziness, irritability and somnolence the most common AEs. AE rates were initially higher for PER and BRV, but differences diminished over time.

Conclusion: Treatment discontinuation in epilepsy emerges as a dynamic process shaped by both tolerability and clinical response. Early persistence was higher for LCM, whereas long-term retention was improved for BRV and PER. These results support a personalized approach to ASM selection that integrates early tolerability with sustained effectiveness.

Keywords: Antiseizure medications; Comparative analysis; Drug load; Epilepsy; Real world study; Retention rate; Safety.

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Conflict of interest statement

Declarations. Conflict of Interest: Roberta Roberti has received speaker’s or consultancy fees from Eisai, UCB Pharma and Jazz Pharmaceuticals. Francesca Anzellotti has received travel support from Eisai, UCB and Angelini Pharma; and has speaker honoraria from Eisai and Angelini Pharma. Giovanni Boero has received speaker’s or consultancy fees from Eisai, Angelini Pharma and UCB Pharma. Paolo Bonanni has received speaker’s or consultancy fees from Bial, Eisai, GW, LivaNova, Lusofarmaco, Proveca and Roche. Laura Canafoglia has participated in pharmaceutical industry-sponsored clinical trials for UCB Pharma and other pharmaceutical industries; and has received speaker honoraria from Eisai. Alfredo D’Aniello has participated in pharmaceutical industry-sponsored clinical trials for UCB Pharma; has received speaker honoraria and consultancy fees from Eisai, UCB Pharma, Angelini Pharma and Neuraxpharm; and has served on advisory boards for Angelini Pharma. Filippo Dainese has received speaker’s or consultancy fees from UCB Pharma, Eisai and Bial. Giancarlo Di Gennaro has received speaker honoraria from UCB Pharma, Eisai, Lusofarmaco, Livanova, Angelini Pharma and Jazz Pharmaceuticals; and has served on advisory board for Bial, Arvelle, Angelini Pharma, Livanova, Neuraxpharma and UCB Pharma. Fedele Dono has received travel support from Eisai, UCB Pharma and Angelini Pharma; and has received speaker honoraria from Eisai. Giovanni Falcicchio has received speaker fees from Angelini Pharma. Edoardo Ferlazzo has received speaker honoraria from UCB Pharma, Eisai and Angelini Pharma. Antonio Gambardella has received speaker honoraria from UCB Pharma, Eisai, Angelini Pharma, Jazz, Bial and Zambon. Angela La Neve has received speaker’s or consultancy fees from Eisai, Mylan, Sanofi, Bial, GW, Arvelle, Angelini Pharma and UCB Pharma; and has served on scientific advisory boards for GW Pharma, Jazz Pharmaceuticals and Angelini Pharma. Simona Lattanzi has received speaker’s or consultancy fees from Angelini Pharma, Eisai, GW Pharmaceuticals, Medscape and UCB Pharma; and has served on advisory boards for Angelini Pharma, Arvelle Therapeutics, BIAL, Eisai and GW Pharmaceuticals outside the submitted work. Simona Lattanzi received research grant support from the Ministry of Health and the Ministry of University and Research outside the submitted work. Pietro Mattioli has received speaker honoraria from Angelini Pharma. Emilio Russo has received speaker fees or funding from and has participated on advisory boards for Angelini Pharma, Eisai, Ethypharm, GW Pharmaceuticals, Jazz Pharmaceuticals, Kolfarma and UCB Pharma. Simona Lattanzi is an Editorial Board member of Neurology and Therapy, but was not involved in the selection of peer reviewers for the manuscript or in any of the subsequent editorial decisions. Cristina Politi, Vincenzo Belcastro, Simone Beretta, Carmen De Caro, Roberta Di Giacomo, Jacopo C DiFrancesco, Nicoletta Foschi, Alfonso Giordano, Angelo Labate, Ugo Leggio, Claudio Liguori, Marta Maschio, Annacarmen Nilo, Francesca Felicia Operto, Angelo Pascarella, Giada Pauletto, Luciano Pellegrino, Rosaria Renna and Gionata Strigaro and Gianfranco Di Gennaro have no conflicts of interest. Ethical Approval: The overall, anonymized data collection was approved by the Ethics Committee of Calabria Region, Italy (protocol number 115/19) and conducted in accordance with the Declaration of Helsinki. As the study was based on retrospective and fully anonymized data, written informed consent was not required.

Figures

Fig. 1
Fig. 1
Kaplan–Meier estimates of treatment retention over time by antiseizure medication. The survival curves represent time-to-treatment discontinuation for patients treated with lacosamide (blue), brivaracetam (red) and perampanel (orange). ASM Antiseizure medication
Fig. 2
Fig. 2
Distribution of estimated propensity scores across treatment groups. Kernel density estimates show the distribution of propensity scores for patients treated with lacosamide (blue), brivaracetam (red), and perampanel (orange). Propensity scores were estimated by multinomial regression model
Fig. 3
Fig. 3
Percentage change in drug load from baseline to 12 months, shown as percentage changes in drug load across the three treatment groups, both in the overall cohort and stratified by clinical response (defined as a ≥ 50% reduction in seizure frequency from baseline). a Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in the overall cohort treated with BRV (n = 149). b Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in responders treated with BRV (n = 68). c Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in non-responders treated with BRV (n = 81). d Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in the overall cohort treated with LCM (n = 184). e Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in responders treated with LCM (n = 121). f Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in non-responders treated with LCM (n = 63). g Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in the overall cohort treated with PER (n = 217). h Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in responders treated with PER (n = 133). i Percentage change from baseline to 12 months in total drug load and in the load of all concomitant ASMs in non-responders treated with PER (n = 84). Box limits indicate the first (Q1) and third (Q3) quartiles, with the central line representing the median. Whiskers extend to show the 2.5th and 97.5th percentile interval, while individual points represent values outside this range. In panels g, h, one data point falls above the upper axis limit and is not shown to improve graph readability (the change from a drug load of 0.06 to 0.75 corresponds to an increase of 1100%, although the clinical significance of such a percentage change is less relevant). Asterisks indicate significance at *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001 from the Wilcoxon matched-pairs signed-rank test comparing absolute values at 12 months to baseline (see Figs. 4a, b, 5a, b, 6a, b and ESM Figs. S2–S4). ASMs Antiseizure medications, BRV brivaracetam, LCM lacosamide, PER perampanel, ns not significant
Fig. 4
Fig. 4
Changes in total and stratified drug load (absolute values) from baseline to 12 months in the BRV group. Graphs illustrate scatter plots with bars showing the median and interquartile range of absolute ASM load values in the cohort treated with BRV (n = 149), including total ASM load and ASM load stratified by mechanism of action (MoA) and enzyme-inducing properties. Asterisks indicate significance at *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001 from the Wilcoxon matched-pairs signed-rank tests comparing 12-month values with baseline for: a Total ASM load (including BRV), b load of all concomitant ASMs (excluding BRV), c load of SCBs (carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, oxcarbazepine, phenytoin, rufinamide), d ASMs with MoAs other than SCBs (including BRV), e ASMs with MoAs other than SCBs (excluding BRV), f strong EIs (carbamazepine, phenobarbital, phenytoin, primidone), g nEIs (including BRV), h nEIs (excluding BRV). ASMs Antiseizure medications, BRV brivaracetam, EIs strong enzyme inducers, nEIs non-enzyme inducers, ns not significant, SCBs sodium channel blockers
Fig. 5
Fig. 5
Changes in total and stratified drug load (absolute values) from baseline to 12 months in the LCM group. Graphs illustrate scatter plots with bars showing the median and interquartile range of absolute ASM load values in the cohort treated with LCM (n = 184), including total ASM load and ASM load stratified by mechanism of action (MoA) and enzyme-inducing properties. Asterisks indicate significance at *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001 from the Wilcoxon matched-pairs signed-rank tests comparing 12-month values with baseline for: a Total ASM load (including LCM), b load of all concomitant ASMs (excluding LCM), c load of SCBs (carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, oxcarbazepine, phenytoin, rufinamide), d SCBs (excluding LCM), e ASMs with MoAs other than SCBs, f strong EIs (carbamazepine, phenobarbital, phenytoin, primidone), g nEIs (including LCM), h nEIs (excluding LCM). ASMs Antiseizure medications, EIs strong enzyme inducers, LCM lacosamide, nEIs non-enzyme inducers, ns not significant, SCBs sodium channel blockers
Fig. 6
Fig. 6
Changes in total and stratified drug load (absolute values) from baseline to 12 months in the PER group. Graphs illustrate scatter plots with bars showing the median and interquartile range of absolute ASM load values in the cohort treated with PER (n = 149), including total ASM load and ASM load stratified by mechanism of action (MoA) and enzyme-inducing properties. Asterisks indicate significance at *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001 from the Wilcoxon matched-pairs signed-rank tests comparing 12-month values with baseline for: a Total ASM load (including PER), b load of all concomitant ASMs (excluding PER), c load of SCBs (carbamazepine, eslicarbazepine acetate, lacosamide, lamotrigine, oxcarbazepine, phenytoin, rufinamide), d ASMs with MoAs other than SCBs (including PER), e ASMs with MoAs other than SCBs (excluding PER), f strong EIs (carbamazepine, phenobarbital, phenytoin, primidone), g nEIs (including PER), h nEIs (excluding PER). ASMs Antiseizure medications, EIs strong enzyme inducers, nEIs non-enzyme inducers, ns not significant, PER perampanel, SCBs sodium channel blockers
Fig. 7
Fig. 7
Tolerability and most common adverse events over time. a Proportion of subjects experiencing AEs within each observation interval (0–6, 6–12, 12–24 and 24–36 months). b Temporal trend in the absolute number of dizziness reports. c Temporal trend in the absolute number of irritability reports. d Temporal trend in the absolute number of somnolence reports. AE Adverse event
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