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Long-Term Observational Study of Eslicarbazepine Acetate Monotherapy

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Long-Term Observational Study of Eslicarbazepine Acetate Monotherapy Epilepsy & Behavior 97 (2019) 51–59 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh MONOZEB: Long-term observational study of eslicarbazepine acetate monotherapy Vicente Villanueva a,⁎, Pedro Bermejo b,JavierMontoyac, Andreu Massot-Tarrús d, Maria Luisa Galiano d, Manuel Toledo e, Juan José Rodriguez-Uranga f, Vicente Bertol g, José Ángel Mauri h, Juan José Poza i, Macarena Bonet j, M. Dolores Castro-Vilanova k, Jesús Ruiz-Giménez l, Francisco Javier López-González m, Xiana Rodríguez-Osorio m, Diego Tortosa-Conesa n, Joaquín Ojeda o,PauGinerp, Mercedes Garcés a, Blanca Mercedes Alvarez f, Pablo Quiroga-Subirana q,PatriciaEstever, Joan Josep Baiges r, Kevin Hampel a a Hospital Universitario y Politécnico La Fe, Valencia, Spain b Hospital Universitario Puerta de Hierro, Madrid, Spain c Hospital General Universitario, Valencia, Spain d Hospital Universitario Gregorio Marañón, Madrid, Spain e Hospital Universitari Vall d'Hebrón, Barcelona, Spain f Centro Neurologia Avanzada, Sevilla, Spain g Hospital Universitario Miguel Servet, Zaragoza, Spain h Hospital Universitari Lozano Blesa, Zaragoza, Spain i Hospital Universitario Donostia, San Sebastian, Spain j Hospital Arnau de Vilanova, Valencia, Spain k Hospital Universitario Alvaro Cunqueiro, Vigo, Spain l Hospital Universitari Virgen de las Nieves, Granada, Spain m Complejo Hospitalario Universitario Santiago, Santiago, Spain n Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain o Hospital Universitario Infanta Sofia, Madrid, Spain p Hospital Universitario Doctor Peset, Valencia, Spain q Complejo Hospitalario Torrecárdenas, Almeria, Spain r Hospital Verge de la Cinta, Tortosa, Spain article info abstract Article history: Aim: The aim of the study was to evaluate the effectiveness and tolerability of eslicarbazepine acetate (ESL) when Received 26 March 2019 used as monotherapy for 1 year or more in routine clinical use in patients with focal seizures in epilepsy clinics in Revised 26 April 2019 Spain. Accepted 8 May 2019 Methods: This is a retrospective, observational, noninterventional study. Eligible patients were aged ≥18 years, Available online xxxx had focal seizures, and started on ESL ≥1 year before database closure. Primary endpoint was the following: pro- portion seizure-free for ≥6 months at 1 and 2 years. Secondary endpoints included retention on ESL monother- Keywords: Epilepsy apy at 1 and 2 years, seizure frequency change, seizure worsening, and side effects. Other analyses included Seizures seizure freedom from baseline to 1 and 2 years and outcomes in special populations. Antiepileptic drug Results: Four hundred thirty-five patients were included (127 on first-line monotherapy and 308 converting to Monotherapy ESL monotherapy): median daily dose was 800 mg at all time points; 63.2% were seizure-free at 1 year, 65.1% Sodium channel blocker at 2 years, and 50.3% for the entire follow-up. Mean duration of ESL monotherapy was 66.7 months; retention was 88.0% at 1 year and 81.9% at 2 years. Mean reduction in seizure frequency was 75.5% at last visit. Over the entire follow-up, seizure worsening was seen in 22 patients (5.1%), side effects in 28.0%, considered severe in 1.8%, and leading to discontinuation in 5.7%. Dizziness, hyponatremia (sodium b135 mEq/l), and somnolence were the most frequent side effects. Outcomes in special populations (patients aged ≥65 years and those with psychiatric history or learning difficulty) were consistent with the overall population. Conclusions: Patients with focal seizures taking ESL monotherapy had excellent retention, high seizure-free rates, and good tolerability up to 2 years. © 2019 Elsevier Inc. All rights reserved. ⁎ Corresponding author at: Hospital Universitario y Politécnico La Fe, Refractory Epilepsy Unit - Neurology, Valencia, Spain. E-mail address: [email protected] (V. Villanueva). https://doi.org/10.1016/j.yebeh.2019.05.003 1525-5050/© 2019 Elsevier Inc. All rights reserved. 52 V. Villanueva et al. / Epilepsy & Behavior 97 (2019) 51–59 1. Introduction All patients who were started on monotherapy or converted to monotherapy with ESL at least one year before database closure (August Epilepsy is one of the most common neurological disorders, with an 2018) were included. Other inclusion criteria were the following: writ- estimated risk of 3% to age 80 years [1]. Despite many new antiepileptic ten informed consent by the patient or legal representative according to drug (AED) approvals, successful treatment is still hampered by prob- study protocol; age ≥18 years; and diagnosis of focal epilepsy. Exclusion lems like persistent drug resistance [2], poor adherence to treatment, criteria were unreliable clinical records and enrolment in other studies and side effects that impact quality of life and can impair adherence with AEDs or medical devices. Eslicarbazepine acetate was prescribed and long-term retention [3]. The cost of poor adherence is high, both on an individual basis, at the discretion of the prescribing physician. in monetary terms for payers [4], and in risk of early mortality for pa- tients [5]. Simplifying dosage regimens can help to increase adherence 2.2. Data collection [6], and therefore, the potential for once-daily administration should be an important consideration in treatment selection, particularly for Patients completed seizure diaries, and seizure counts were tran- patients on AED monotherapy. scribed from these into patient clinical charts, according to usual clinical Eslicarbazepine acetate (ESL) is a dibenz[b,f]azepine derivative like practice at each center. At each visit, patients were also asked to report carbamazepine and oxcarbazepine. Eslicarbazepine acetate is rapidly any side effects, and any changes in AEDs were recorded. As part of de-esterified at the acetate functional group to produce the primary usual clinical practice in these centers, visits included baseline, 3 pharmacologically active metabolite S-licarbazepine, which accounts months, 6 months, and 12 months during the first year, 18 months for around 95% of the circulating active metabolites [7]. and 24 months for the second year, and the last visit available for longer Eslicarbazepine inhibits voltage-gated sodium channels but differ- follow-up. All patients had at least one blood test over the minimum ently from carbamazepine and oxcarbazepine. The affinity of one-year follow-up period, and vital signs were tested when considered eslicarbazepine for voltage-gated sodium channels in the resting state necessary by physicians. is about 15- to 5-fold lower than that of carbamazepine, oxcarbazepine, Data for this analysis were collected from patients' individual charts and R-licarbazepine [8], instead of having a predominant effect on chan- and kept according to usual clinical practice at each center. We recorded nel slow inactivation [9]. demographic data, seizure type (using 1981 and 2017 International Eslicarbazepine acetate is approved in the USA for the treatment of League Against Epilepsy (ILAE) terminology), etiology, age at epilepsy focal (partial-onset) seizures in patients aged ≥4 years [10].InEurope, onset, and previous AEDs. Mean seizure frequency was calculated at ESL is approved as monotherapy in the treatment of focal or focal-to-bi- baseline (mean of the last 3 months or, if no seizures, over the previous lateral seizures (partial-onset seizures, with or without secondary gen- year) and at each visit (as the mean monthly frequency since the prior eralization) in adults with newly diagnosed epilepsy and as adjunctive visit). therapy in adults, adolescents, and children aged N6 years with focal or focal-to-bilateral seizures (partial-onset seizures with or without sec- 2.3. Data analysis and endpoints ondary generalization) [11]. The program included four pivotal, phase III, multicenter, randomized, double-blind, placebo-controlled clinical The efficacy population included all patients who fulfilled eligibility trials of adjunctive ESL [12–15]. More recently, the efficacy and safety criteria, started ESL monotherapy treatment, and for whom at least of converting to ESL monotherapy has been reported [15], and ESL one efficacy measurement was obtained after ESL initiation. The safety monotherapy has been compared with carbamazepine controlled-re- population included all patients who had received at least one dose of lease monotherapy in a randomized, double-blind, parallel-group ESL and fulfilled eligibility criteria. The analysis was performed using study [16]. last observation carried forward (LOCF) procedure for missing data. Clinical trials are essential to meet regulatory requirements; how- Data are reported for the whole population and separately for two pop- ever, because they often use unrealistic dosing regimens and exclude ulations: (1) first-line ESL monotherapy (patients who were taking no patients with common comorbidities, they leave many practical ques- AEDs at the time of ESL initiation but who may have taken one or tions unanswered [17]. Observational studies of routine clinical use more AEDs at some point in the past) and (2) conversion to ESL mono- are necessary to fill these gaps and provide information that is relevant therapy (patients who were previously taking 1 or more other AED(s) to real-life clinical practice. Eslicarbazepine acetate, with its once-daily and switched to ESL monotherapy). administration, is a good option for long-term monotherapy for many The primary effectiveness endpoint was the percentage of seizure-
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