Epilepsy & Behavior xxx (2013) xxx–xxx

YEBEH-03535; No. of pages: 8; 4C:

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Epilepsy & Behavior

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Control of seizures in different stages of partial epilepsy: LACO-EXP,a Spanish retrospective study of lacosamide

Vicente Villanueva a,⁎, Francisco Javier López b, José María Serratosa c, Beatriz González-Giraldez c,Dulce Campos d, Albert Molins e, Juan Rodriguez Uranga f, José Angel Mauri g, Javier Salas-Puig h,Manuel Toledo h, Juan Carlos Sánchez-Alvarez i, Antonio Moreno j, Pedro J. Serrano-Castro k,Rosa Ana Saiz-Diaz l, Jesús González de la Aleja l, Pilar de la Peña l, Montserrat Asensio m

a Hospital Universitario y Politécnico La Fe Valencia, Bulevard Sur, s/n, Carretera de Malilla, 46026 Valencia, Spainb Complejo Hospitalario Universitario Santiago, Travesía da Choupana, s/n, 15706 Santiago de Compostela, Spainc Hospital Universitario Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spaind Hospital Clínico Universitario Valladolid, Avda. Ramón y Cajal, s/n, Valladolid, Spaine Hospital Universitario Dr. Josep Trueta, Av. França, s/n, 17007 Girona, Spainf Instituto de Especialidades Neurológicas (IENSA), Clinica Sagrado Corazón, Av. Manuel Siurot, 49, 41013 Sevilla, Spaing Hospital Clínico Universitario Lozano Blesa, Av. San Juan Bosco, 15, 50009 Zaragoza, Spainh Hospital Universitario Vall d'Hebrón, P. de la Vall d'Hebron, 119–129, 08035 Barcelona, Spaini Hospital Clínico Universitario San Cecilio, Av. Dr. Olóriz, 16, 18012 Granada, Spainj Hospital Universitario Son Espases, Carretera de Valldemossa, 79, 07120 Palma de Mallorca, Spaink Complejo Hospitalario Torrecárdenas, Paraje de Torrecárdenas, s/n, 04009 Almeria, Spainl Hospital Universitario 12 de Octubre, Carretera de Andalucía km. 5400, 28041 Madrid, Spainm Hospital General Universitario Alicante, Av. Pintor Baeza, 12, 03010 Alicante, Spain

⁎ Corresponding author at: Multidisciplinary Epilepsy UUniversitario y Politécnico La Fe, Bulevard Sur, s/n, CarreSpain. Fax: +34 961244330.

E-mail addresses: villanueva_vichab@gva.es (V. Villan(F.J. López), joseserratosa@me.com (J.M. Serratosa), beagi(B. González-Giraldez), dm04cb@hotmail.com (D. Campo(A. Molins), juanuranga@telefonica.net (J. Rodriguez Uran(J.A. Mauri), jsalasp@meditex.es (J. Salas-Puig), mtoledo7jucasan9@gmail.com (J.C. Sánchez-Alvarez), antonio.morepedro.serrano.c@gmail.com (P.J. Serrano-Castro), rsaizdiajesus_goal@yahoo.es (J. González de la Aleja), pilar_pena@asensio_mon@gva.es (M. Asensio).

1525-5050/$ – see front matter © 2013 Elsevier Inc. All rihttp://dx.doi.org/10.1016/j.yebeh.2013.07.024

Please cite this article as: Villanueva V, et al,lacosamide, Epilepsy Behav (2013), http://d

a b s t r a c t

a r t i c l e i n f o

Article history:Received 14 May 2013Revised 25 July 2013Accepted 29 July 2013Available online xxxx

Keywords:Focal epilepsySeizure-freeLacosamideAntiepileptic drugsRetrospective study

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) triedis associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associat-ed with better efficacy/tolerability were analyzed. After 12 months, the responder rate (≥50% reduction inseizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide wasthe first or second add-on AED, although there was a small chance to be seizure-free even for patients whohad received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, butdifferences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage–titrationschedule was associated with a lower adverse event rate. Further investigation of the timing of initiation oflacosamide add-on therapy and ideal combinations of AEDs is required.

© 2013 Elsevier Inc. All rights reserved.

1. Introduction

Treatment response in patients with epilepsy who have never be-fore received an antiepileptic drug (AED) is high (64% of patients

nit/Neurology Service, Hospitaltera de Malilla, 46026 Valencia,

ueva), javieritol@yahoo.comraldez@yahoo.ess), amolinsalbanell@yahoo.esga), jamauri@telefonica.net5@hotmail.com (M. Toledo),no@ssib.es (A. Moreno),z@yahoo.com (R.A. Saiz-Diaz),yahoo.com (P. de la Peña),

ghts reserved.

Control of seizures in differentx.doi.org/10.1016/j.yebeh.201

became seizure-free) [1]. However, a notable proportion of patientsare considered to have epilepsy that is pharmacoresistant to AEDs(about 19–36%) and continue to experience seizures [1–3]. It has beensuggested that treatment response to initial monotherapy is prognosticof long-term treatment success and that few patients, after treatmentwith two AEDs, become seizure-free [1]. The International LeagueAgainst Epilepsy (ILAE) definition of drug-resistant epilepsy seems tosupport this pessimistic outlook: drug-resistant epilepsy is the failureof two appropriate and adequately trialed AED regimens that can beinterpreted as seizure freedom being less likely to be attained with fur-ther changes in the patient's AED regimens [4].

Recent studies have challenged this view; there is still a possibility offinding a combination that could achieve a seizure-free state in patientswhose epilepsy is refractory to AEDs [5–7]. The introduction of newAEDs over the past years has favored the possibility of identifying AED

stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of3.07.024

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combinations that will provide optimal seizure control with minimaladverse effects both in the early and late stages of treatment [1,5–9].

Lacosamide is anAED that selectively enhances sodium channel slowinactivation and is approved in theUS andEU for use in adolescent/adultpatients with epilepsy as adjunctive therapy in the treatment of focalepilepsies (partial-onset seizures). Its efficacy and tolerability wereestablished in three pivotal phase II/III trials in patients with refractoryfocal epilepsies [10–12]. Clinical trials do not provide information onoptimal AED combinations, AED dosing, or differences in response totreatment across different stages of epilepsy treatment; observationalstudies are therefore required to confirm this information in a “real-world” setting.

Several observational studies of the use of lacosamide in the clinicalpractice setting have been published, but some have been of limitedfollow-up duration and/or small sample size [13–20]. In the larger andmore recent of the observational studies in adult patients with refracto-ry focal epilepsies, one prospective (n = 158) [18], one retrospective(n = 403) [14], and one clinical practice audit (n = 113) [17], adjunc-tive lacosamide was associated with good treatment response and agenerally favorable tolerability profile. Study results raised questions,however, regarding the best combinations of AEDs in this patient pop-ulation and when best to initiate lacosamide therapy. The aim of thecurrent study was to analyze the efficacy and tolerability of lacosamideover 1 year in a large population of patients with focal epilepsies, to de-termine the best combinations of AEDs, and to examine treatment effi-cacy (seizure-free status) across different treatment stages. To the bestof our knowledge, this is one of the largest cohorts of patients with a12-month follow-up in a study of lacosamide in the real-world setting.

2. Methods

2.1. Study design and participants

The LACO-EXP study was a multicenter, retrospective, 1-year, ob-servational study. Thirteen tertiary hospital centers participated inthe study (the initials of study investigators at each hospital are shownin parentheses): Hospital Universitario Vall d'Hebron, Barcelona(JSP, MT); Hospital Universitario Son Espases, Mallorca (AM); HospitalUniversitario Fundación Jiménez Díaz, Madrid (JMS); HospitalUniversitario 12 de Octubre, Madrid (PP, RS, JG); Complejo HospitalarioTorrecárdenas, Almeria (PS); Complejo Hospitalario Universitario,Santiago (JL); Hospital General Universitario, Alicante (MA); Hospi-tal Clínico Universitario San Cecilio, Granada (JCS); Instituto deEspecialidades Neurológicas, Sevilla (JU); Hospital UniversitarioDr. Josep Trueta, Girona (AM); Hospital Clínico Universitario, Valladolid(DC); and Hospital Clínico Universitario Lozano Blesa, Zaragoza (JAM).The study investigator from the Hospital Universitario y PolitécnicoLa Fe (Valencia, Spain) [VV] acted as the principal investigator and pro-moter of the study. No patients from this center were eligible for partic-ipation in the current study because they had been included in a priorstudy at this center (RELACOVA study [18]). The study protocol was ap-proved by the ethics committee of Hospital Universitario y PolitécnicoLa Fe, and the study was conducted according to the code of ethics setout in the Declaration of Helsinki.

The inclusion criteria were as follows: 1) written informed con-sent by the patients or their legal representative; 2) patients olderthan 18 years; 3) diagnosis of focal epilepsy (partial-onset seizures);4) treatment with lacosamide initiated between September 2009 andNovember 2011 and according to usual clinical practice at the center;and 5) patients with at least 1 focal onset seizure in the year prior tostarting lacosamide. All patients were required to have a minimumfollow-up duration of one year at the closing of the database; thosewith shorter follow-up durations were excluded from the analysis.The exclusion criteria were as follows: 1) patients enrolled in otherstudies of AEDs or medical devices; 2) a history of alcoholism or drug

Please cite this article as: Villanueva V, et al, Control of seizures in differenlacosamide, Epilepsy Behav (2013), http://dx.doi.org/10.1016/j.yebeh.201

abuse in the prior year; and 3) inaccurate or unreliable clinical recordsaccording to participating physicians.

2.2. Data source and collection

The source of datawaspatient clinical records of information collect-ed according to usual clinical practice at each center by participatingphysicians, i.e., the number of seizures (efficacy), adverse events (AEs;safety), and changes in the concomitant AEDs at each clinic visit,and, when a new AED is initiated, results of vital signs and blood tests(i.e., hemogram and biochemistry at least once during follow-up).When a new AED is started, there is, as a minimum, a baseline visitand visits at 3, 6, and 12 months.

The following data were entered into a database: demographic data,seizure type (using the 1981 seizure classification standards [21]), typeof epilepsy according to the brain lobe of origin (participating physi-cians could also use results of a previous electroencephalogram [EEG],neuroimaging, and video-EEG monitoring if available in the clinicalchart for confirmation), etiology, age at onset, number of seizures permonth (mean of the last 3 months prior to initiation of lacosamide orthe last 12 months prior to initiation of lacosamide if they have nothad seizures in the prior 3 months), and previous and concomitantAEDs.

For the purposes of analysis, concomitant AEDs were groupedby mechanism of action (MOA): either as sodium channel blockers(SCBs; carbamazepine, phenytoin, lamotrigine, oxcarbazepine, andeslicarbazepine acetate) or as non-SCBs (any other AED). Patients inthe SCB group were those taking at least one SCB, while those in thenon-SCB group did not receive any SCBs. For the analysis of stages oftreatment, early add-on treatment was the addition of lacosamide inpatients who had tried up to two AEDs, and late add-on treatmentwas the addition of lacosamide in patientswhohad tried at least 3 AEDs.

2.3. Data analysis

The efficacy population included all patients who fulfilled the inclu-sion/exclusion criteria, started lacosamide treatment, and had at leastone efficacy measurement obtained during the 12 months after initiat-ing lacosamide. The safety population included all patients who fulfilledthe inclusion/exclusion criteria and had received at least one dosage oflacosamide. Intention-to-treat (ITT) analysis, according to the last ob-servation carried forward (LOCF), was conducted.

The primary study objective was to assess the efficacy of lacosamideover 12 months and the secondary objectivewas to assess the tolerabil-ity of lacosamide at 3, 6, and 12 months. The primary efficacy variablewas the responder rate at 3, 6, and 12 months. Responderswere definedas those patients with a reduction in seizure frequency of at least 50%compared to baseline. Secondary efficacy variables included seizure-free and retention rates of the patients that were included in the studyat 3, 6, and 12 months. Seizure freedom was defined as no seizuresfrom the beginning of starting lacosamide (up to time points earlierthan the 12-month visit), no seizures for the last 6 months (at the 12-month visit), or no seizures for 12 months if patients were seizure-free in the 3 months prior to starting lacosamide.

Only AEs considered to be related to lacosamide by participatingphysicians were included in the analysis. Adverse events were classifiedby study investigators as mild, moderate, or severe. Safety variables in-cluded the proportion of patientswith an AE and the proportionwith anAE that led to discontinuation at 3, 6, and 12 months.

A comparisonwasmade of thenumber of concomitant AEDs at base-line versus final visit. Analyses were conducted to determine the rela-tionship (if any) between efficacy and/or safety variables and selecteditems among the following: baseline characteristics, prior and concom-itant AED treatment (number and type), MOA of concomitant AEDs,lacosamide dosage and titration schedule, change in concomitant AEDregimens, and AED combination.

t stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of3.07.024

Table 1Characteristics of the study population. Data are n (%) unless stated otherwise.

Characteristic All patients (N = 500)

Female 232 (46.4)Age (years), mean (range) 42.4 (18–88)Age at epilepsy onset (years), mean (SD) 20.9 (17.3)Time since epilepsy onset (years), mean (SD) 21.5 (14.3)Epilepsy type

Frontal 126 (25.2)Temporal 266 (53.2)Parietal 15 (3.0)Occipital 10 (2.0)Lobe unknown 83 (16.6)

EtiologyCryptogenic (i.e., unknown) 174 (34.8)Mesial temporal sclerosis 76 (15.2)Cortical developmental malformation 43 (8.6)Perinatal hypoxia 42 (8.4)Tumor 41 (8.2)Vascular 34 (6.8)Trauma 33 (6.6)Brain infection 22 (4.4)Other 35 (7)

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2.4. Statistical analysis

Descriptive statistical analyses of all the variableswere conducted. Tocompare the characteristics of the SCB and non-SCB groups of patients,the following tests were used: Student's t-test for age and lacosamidedosage; the Mann–Whitney U test for time-to-disease onset, monthlyseizure frequency at baseline, and number of previous AEDs; and thechi-square test to compare sex, percentage of patients who reduce thedosage of concomitant AEDs, AEs, and withdrawals.

Other subgroups were analyzed: seizure-free and not seizure-free,patientswith andwithout adverse events, early add-on/late add-on, eti-ology of epilepsy, epilepsy type, and LCM as first SCB. For these sub-groups, the chi-square test was used to make comparisons regardingtitration schedule and efficacy, and the Student's t-test was used tocompare changes in LCMdosage. The number of AEDs between baselineand the final visit was compared using the Wilcoxon test. Adverseevents (isolated or in combination) that led to discontinuation wereanalyzed by the chi-square test. Statistical significance was defined asp b 0.05. The Statistical Package for Social Science version 17.0 (SPSSInc.) was used.

Monthly seizure frequencyMean (SD) 10.5 (24.2)Median 3.3

Number of previous AEDsMean (SD) 5.0 (2.9)Median 4

AED, antiepileptic drug; SD, standard deviation.

3. Results

3.1. Patient disposition

Five hundred patients met the criteria for inclusion in the study(51 patients were excluded). Fig. 1 shows patient disposition over the12-month study period. By the end of the 12-month follow-up, 45 pa-tients (9%) had withdrawn because of AEs, 28 patients (5.6%) becauseof lack of efficacy, and 1 patient (0.2%) because of both reasons [with-drawal rates are cumulative]. The retention rate was 96.6% at 3 months,89.4% at 6 months, and 84.4% at 12 months.

Patient demographics and disease characteristics are summarizedin Table 1. The majority of patients had temporal lobe epilepsy, andmost had epilepsy of cryptogenic (i.e., unknown) origin. The monthlyseizure frequency before starting lacosamide was about 11 seizures(median: 3.3); three patients had only one seizure during the12 months prior to inclusion in the study. One hundred two patients(20.4%) had received 1 or 2 AEDs before starting lacosamide (the earlyadd-on treatment group), and three hundred ninety-eight patients(79.6%) received lacosamide after having been treated previously withat least 3 AEDs (the late add-on treatment group). The mean numberof prior AEDs was 5. Thirty-seven patients (7.4%) added a new AED be-fore the 12-month visit; however, lacosamide was maintained in thesepatients, so they were not excluded from the study.

When the patient population was divided according to type of MOAof concomitant AED, there were no statistically significant differencesbetween the SCB group (n = 362; 72.4% of all patients) and the non-SCB group (n = 138; 27.6%) in patient or disease characteristics withthe exception of small but significant differences in mean ± standarddeviation (SD) disease duration (22.5 ± 13.8 vs 18.7 ± 15.3 years;p = 0.002), mean number of prior AEDs (5.3 ± 2.8 vs 4.3 ± 3.0;

Fig. 1. Patient disposition at the start of lacosamide treatment (‘basel

Please cite this article as: Villanueva V, et al, Control of seizures in differentlacosamide, Epilepsy Behav (2013), http://dx.doi.org/10.1016/j.yebeh.201

p b 0.001), and mean monthly seizures prior to initiating lacosamide(10.8 ± 24.5 vs 9.8 ± 23.4; p = 0.009).

3.2. Lacosamide treatment

The mean ± SD daily dosage of lacosamide at each visit was 253 ±84 mg (3 months), 311.7 ± 92 mg (6 months), and 338.5 ± 96.3 mg(12 months); median daily dosages at 3, 6, and 12 months were200 mg, 300 mg, and 400 mg, respectively. Only 35 patients receivedmore than 400 mg/day. There was no difference in final lacosamidedosage (i.e., at last visit) in the SCB and non-SCB subgroups (mean:326.6 vs 323.4 mg/day, median: 350 vs 325 mg/day).

One of four dosage–titration schedules were followed by most ofthe patients: a starting dosage of 100 mg/day in two divided dosagesfollowed by increases in the daily dosage by 100 mg each week(schedule 1 (as per the Spanish prescribing information [22])) ora starting dosage of 50 mg/day followed by increases of 50 mg eitherper week (schedule 2), every 10 days (schedule 3), or every 2 weeks(schedule 4), until the optimum dosage had been reached. The max-imum recommended dosage of lacosamide is 400 mg/day [22], buthigher dosages can be prescribed if necessary. The number of pa-tients on each schedule was 90 (schedule 1), 177 (2), 64 (3), and88 (4) [data were missing for 69 patients, and other titration sched-ules were used by 12 patients].

ine’) and at each follow-up visit. AE, adverse event; pts, patients.

stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of3.07.024

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The final lacosamide dosage was lower in patients who withdrew(for any reason) than in thosewho stayed on lacosamide for 12 months(mean ± SD dosage of 257.0 ± 90.9 vs 383.0 ± 96.1 mg/day).

3.3. Concomitant AED treatment

The most frequently used concomitant non-SCB AEDs werelevetiracetam (49.6%), clobazam (21.0%), valproate (21.0%), zonisamide(16.2%), and topiramate (10.4%). The most frequently used concom-itant SCBs were carbamazepine (36.6%), lamotrigine (18.2%), andoxcarbazepine (16.4%).

There was a small but statistically significant reduction in the num-ber of concomitant AEDs between the start of lacosamide adjunctivetherapy and the 12-month visit (2.2 vs 2.0; p b 0.001).

More than one-half of patients had a dosage reduction of at least oneof their concomitant AEDs (58.2%). Significantly more patients in theSCB group had such a dosage reduction compared to those in the non-SCB group (63.0% vs 45.7%; p b 0.001).

3.4. Efficacy

Initiation of adjunctive lacosamidewas associated with good clinicalresponse. The responder ratewas 44.0% at 3 months, 53.0% at 6 months,and 57.1% at 12 months (LOCF); respective seizure-free rates were16.0%, 15.5%, and 14.9%. Among the 420 patients who completed thestudy, 12-month responder and seizure-free rates were 62.6% and15.7%, respectively. Of the three patients with only one seizure in the12 months before inclusion, two were seizure-free, and the otherexperienced one seizure during the 12-month observation period.

There were no differences in efficacy between etiologies of epilepsy,although the seizure-free rate was higher in patients with vascular epi-lepsy (44.1%) than in those with other etiologies (cryptogenic epilepsy,12.2%; mesial temporal sclerosis, 4.1%; cortical developmental malfor-mation, 17.1%; perinatal damage, 12.2%; tumor, 17.5%; trauma, 18.8%;brain infection, 9.1%; and other etiologies, 20.0%). Responder rateswere 51.8%, 56.8%, 53.7%, 48.8%, 60.0%, 70.6%, 71.9%, 63.6%, and 62.9%,respectively, for patients with cryptogenic epilepsy, mesial temporalsclerosis, cortical developmental malformation, perinatal damage,tumor, vascular epilepsy, trauma, brain infection, and other etiologies.

Fig. 2 illustrates the influence of the number of prior AEDs (at initia-tion of adjunctive lacosamide) on treatment response, with responderrate shown in Fig. 2A and seizure-free rate in Fig. 2B. While both graphsdemonstrate that a better response is achieved when lacosamide isadded in early-stage treatment, response to treatment is still possibleeven when lacosamide is the 14th AED (i.e., 13 prior AEDs), and seizurefreedom (for at least six months) is still possible even when patientshad tried up to 10 AEDs before. Responder and seizure-free rates weresignificantly higher in the early add-on group than in the late add-ongroup and were 74.7% versus 52.6% and 41.4% versus 8.1%, respectively(both p b 0.001). Specifically, the response rate when lacosamide wasthe first add-on was 80.0% and 70.4% when it was the second add-on,and respective seizure-free rates were 57.8% and 27.8%.

Seizure-free rates were significantly higher in the non-SCB groupthan in the SCB group at each time point: 3 months: 22.8% vs 13.5%(p = 0.014), 6 months: 24.1% vs 12.3% (p = 0.001), and 12 months:27.1% vs 10.3% (p b 0.001). However, when MOAs were compared inthe early add-on and late add-on groups, differences in seizure-freerates between the non-SCB and SCB groups were statistically significantonly in the late add-on group (p = 0.023) (Table 2). However, some as-pects should be considered. First, the size of the early add-on group issmaller than the late add-on group (102 vs 398). Second, in the earlyadd-on group, the seizure-free rate was still higher in the non-SCBgroup than in the SCB group (52.1% vs 32.7%), and although differencesdid not reach significance, they were close to being so (p = 0.067)(Table 2).

Please cite this article as: Villanueva V, et al, Control of seizures in differenlacosamide, Epilepsy Behav (2013), http://dx.doi.org/10.1016/j.yebeh.201

Thefinal dosage of lacosamidewas lower in seizure-free patients thanin those whowere not seizure-free at 12 months (mean ± SD daily dos-age of 266.0 ± 97.1 vs 340.2 ± 94.2 mg). An analysis of seizure-free pa-tients found that when adjunctive lacosamide was introduced as a lateadd-on, the final mean dosage was higher than if lacosamide was addedat an early stage: 283.8 ± 103.7 vs 336.5 ± 95.7 mg/day (p b 0.001).

There was a significantly higher responder rate and seizure-free rateif adjunctive lacosamide was the first SCB to be used in a patient than ifanother SCB was used as the first SCB and lacosamide was added later(78.0% vs 54.4%; p = 0.001 and48.0% vs 11.2%; p b 0.001, respectively).When specific combinations of adjunctive lacosamide with otherAEDswere analyzed for an association with efficacy, there were no spe-cific combinations of AEDs significantly associated with responder orseizure-free rates. However, the highest seizure-free rates were ob-served with valproate (47.1%), levetiracetam (32.8%), and lamotrigine(27.3%).

3.5. Adverse events

Lacosamide-related AEs occurred in 29.9%, 35.4%, and 39.6% of pa-tients at 3, 6, and 12 months, respectively. Most were of mild ormoder-ate severity. Therewere fewer cumulative AEs at 12 months in the non-SCB subgroup than in the SCB subgroup (31.9% vs 42.5%; p = 0.029).Therewere no serious AEs or deaths. Therewere no clinically significantproblems in vital signs or blood tests. Lacosamide-related AEs are sum-marized in Table 3, with themost frequent being dizziness, occurring inone-fifth of patients. No unexpected AEs were observed.

A slower lacosamide dosage–titration schedule was associated witha numerically lower AE rate at 3 months (schedules 2, 3, and 4 vs 1:30.4% (100/329) vs 38.9% (35/90); p = 0.127), and when schedule 1was compared with each slower schedule individually, a significantlylower 3-month AE rate was found only for schedule 3 vs 1 (12.5% vs38.9%; p b 0.001). This difference was even more pronounced in thenon-SCB group,with none of the 12patients on schedule 3 experiencingan AE at 3 months compared with 33.3% (9/27) of those on schedule 1(p = 0.036). The rates of AEs according to titration schedule and theMOA of concomitant AEDs are summarized in Table 4.

3.6. Adverse event-related withdrawals

The cumulative number (proportion) of patients in the safety pop-ulation (n = 500) who discontinued lacosamide because of an AE was13 (2.6%), 36 (7.2%), and 46 (9.2%) at 3, 6, and 12 months, respectively(the 12-month value includes one patient who discontinued also be-cause of a lack of efficacy— see Fig. 1). In the analysis of timing of addi-tion of lacosamide (early vs late add-on treatment), there appeared tobe no significant difference in frequency of withdrawals because ofAEs (8.8% vs 9.3%, p = 0.88). The proportion of patients withdrawn be-cause of an AE was higher in the SCB than in the non-SCB group, al-though not statistically significantly so (10.9% vs 8.6%; p = 0.425).

When a possible relationship between lacosamide dosage and AEwithdrawal rate was examined, the final mean lacosamide dosage wassignificantly lower in patients who discontinued because of an AEthan in those who did not discontinue (mean ± SD of 224.5 ± 77.5vs 336.0 ± 95.8 mg/day; p b 0.001). Lacosamide titration schedulemay influence AEwithdrawal rate, at least in the initial months of treat-ment: there was a trend to lower AE withdrawal rate at 3 months withall slower titration schedules (schedules 2, 3, and 4, see Methods) ascompared with dosage–titration according to the manufacturer's pre-scribing information (schedule 1) [5.2% vs 10.0%; p = 0.092]. A similartrend was found regardless of the MOA of concomitant AEDs (SCB vsnon-SCB; data not shown). In fact, when schedule 1was compared indi-vidually with each slower dosage–titration schedule in the non-SCBsubgroup, no patients who had started lacosamide according to sched-ule 3 (n = 12) or 4 (n = 26) withdrew because of an AE at 3 months(i.e., 50-mg/day starting dosage for the first week followed by 50-mg

t stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of3.07.024

Fig. 2. Response curves after initiation of adjunctive lacosamide based on number of prior antiepileptic drugs (AEDs) received, where response is (A) responder rate and (B) seizure-freerate. Values under the x-axis represent the number and proportion of patients in the total baseline patient population (N = 500) in each number of prior AED category.

Table 2Difference in efficacy at 12 months between patients in the SCB and non-SCB groupsaccording to the stage of treatment.

% pts seizure-free

SCB Non-SCB p-Value

Early add-on 32.7 52.1 0.067Late add-on 6.4 14.0 0.023Total population 10.3 27.1 0.001

Non-SCB, non-sodium channel blocker; pts, patients; SCB, sodium channel blocker.

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Please cite this article as: Villanueva V, et al, Control of seizures in differentlacosamide, Epilepsy Behav (2013), http://dx.doi.org/10.1016/j.yebeh.201

increases every 10 days or 2 weeks). In comparison, the AEwithdrawalrate was 11.1% (3/27) of patients under schedule 1 and 10.6% (5/47)under schedule 2. However, differences were not statistically signifi-cant. The rates of withdrawal due to AEs according to titration scheduleand the MOA of concomitant AEDs are summarized in Table 4.

No specific combinations of AEDs with lacosamide were associatedsignificantly with withdrawal from lacosamide therapy during the12 months because of an AE. In an analysis of the influence of any onespecific AED (regardless of other concomitant AEDs) on AE withdrawalrates, topiramate (p = 0.03) and oxcarbazepine (p = 0.02) were each

stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of3.07.024

Table 3The tolerability of adjunctive lacosamide therapy in patients with focal epilepsies. Data aren (% pts).

Lacosamide-related adverse event Patients (N = 500)

Dizziness 97 (20)Drowsiness/weakness 57 (11.8)Blurred vision/diplopia 32 (6.6)Gait disturbance/ataxia 31 (6.4)Headache 17 (3.5)Irritability 12 (2.5)Gastrointestinal disturbances 11 (2.2)Mental slowness/memory disturbances 10 (2.1)Skin reaction 6 (1.2)Othera 18 (4.8)

a Tremor: n = 4 (0.8), paresthesias: 2 (0.4), weight loss: 1 (0.2), sexual dysfunction: 3(0.6), depression: 2 (0.4), leg stiffness: 1 (0.2), hallucinations: 1 (0.2), and unspecified: 4(0.8).

6 V. Villanueva et al. / Epilepsy & Behavior xxx (2013) xxx–xxx

associated with higher rates of withdrawal compared with patients notreceiving these AEDs. The presence of levetiracetam (regardless of otherconcomitant AEDs) was also associated with significantly (p = 0.004)fewer withdrawals from lacosamide treatment because of an AE thanwhen levetiracetam was absent.

4. Discussion

In this large retrospective study, the addition of lacosamide to thetreatment regimen for adult patients with focal epilepsies was associat-edwith a good response 12 months after starting treatment (responderrate of 57%). A sizable proportion of patients remained seizure-freewhile on treatmentwith adjunctive lacosamide (about 15% of patients).These results are particularly notable given that most patients had re-fractory disease (≈80% had tried more than two AEDS before addinglacosamide to their regimen). The addition of lacosamide was generallywell tolerated.

This study therefore confirms the favorable results of the use oflacosamide in the clinical practice setting as reported in a recent, large,observational, prospective study in Spain (RELACOVA) [18] and pre-liminary results from a prospective clinical practice audit in the UKby Stephen and colleagues [17]. Patients enrolled in the currentstudy were broadly similar to those in RELACOVA [18]. The 12-monthresponder rate was slightly higher in the current study than inRELACOVA (57% vs 47%), possibly because in the current study, 37 pa-tients added a new AED during the 12 months. The seizure-free ratein the current study was lower than in the RELACOVA study (15% vs24%). The difference in the seizure-free rate is probably due to theRELACOVA study having included some patients (5) that were not tak-ing other AEDs at inclusion (all of them had discontinued their priorAED treatment) and the different sizes of the populations of the twostudies. In the Stephen et al. study, the seizure-free rate was 26.2%(where patients had to be seizure-free for at least 6 months), and an ad-ditional 24.6% of patients had a 50% or greater seizure reduction, giving

Table 4Rate of adverse events and withdrawals due to adverse events at 3 months, according totitration schedule and mechanism of action of concomitant antiepileptic drugs.

Schedule 1(100 mg/week)

Schedule 2(50 mg/week)

Schedule 3(50 mg/10 days)

Schedule 4(50 mg/2 weeks)

Adverse events (%)Total 38.9 35.6 12.5 33SCB 41.3 39.2 15.4 33.9Non-SCB 33.3 25.5 0 30.8

Withdrawal (%)Total 10 6.2 4.7 3.4SCB 9.5 4.6 5.8 4.8Non-SCB 11.1 10.6 0 0

Non-SCB, non-sodium channel blocker; SCB, sodium channel blocker.

Please cite this article as: Villanueva V, et al, Control of seizures in differenlacosamide, Epilepsy Behav (2013), http://dx.doi.org/10.1016/j.yebeh.201

a responder rate of 50.8%. The patients from that study were similar tothose in the current study, i.e. they have treatment-refractory epilepsy.The higher seizure-free rate in the Stephen et al. study can be explainedby the difference in the size of the population from the current study.

Several other retrospective studies of add-on lacosamide, in adultpatients already receiving AED treatment mostly for focal epilepsies(some studies included a minority of patients with other types of epi-lepsy), have also reported encouraging efficacy results [14–16,23]. Inthe largest of these (n = 403), a chart review by Flores et al. in theUnited Kingdom, both the responder rate and seizure-free rate werelower than those in the current study (37.5% vs 57% and 9.8% vs 14.9%,respectively) [14]. Clinical responsewas seen in 47%, 69%, and 41%of pa-tients receiving lacosamide in the studies conducted by García-Moraleset al. [15], Harden et al. [16], and Kamel et al. [24], respectively.

It was found that even as a late add-on therapy, some patients wereresponders (≥50% seizure frequency reduction) to lacosamide evenafter 13 prior AEDs (Fig. 2A). Lacosamide also gave patients a smallchance to be seizure-free (for 6 months, by definition — see Methods),even for thosewho had tried 10 AEDs before (Fig. 2B), which is a highernumber than that previously reported by Schiller and Najjar [7]. Resultsof their prospective cohort study suggested that patients can be ren-dered seizure-free even when up to 5 AEDs have been used before, al-though their seizure-free definition was more restrictive than thecurrent study, requiring patients to be seizure-free for 1 year. Our re-sults support those of another study in patients with treatment-refrac-tory epilepsy: after 12 months of follow-up, the seizure-free rate wassimilar to ours (16%) [5]. In an extended follow-up of these patients(6.9 years), a seizure-free rate of 8% was reported [6]. Thus, our studyconfirms previous evidence that it is possible to be seizure-free (for6 months) even in the late stage of treatment. Of note, the final dosageof lacosamide in seizure-free patients was higher in patients who beganlacosamide add-on therapy at the late stage of treatment than in thosewho began it as an early add-on therapy in our study, so it seems appro-priate to increase the lacosamide dosage in these former patients inorder to achieve an improvement. In any case, we observed in the anal-ysis of thewhole group a lower lacosamide dosage in patientswhowereseizure-free, so it seems that a fast response can be observed in a sub-group of patients, but if there is no response, there is still a chance to ob-tain one by pushing up the dosage, especially in late add-on patients.

The response curves in Fig. 2 do illustrate, however, that the bestresponse to lacosamide add-on therapy is obtained in early-stage treat-ment (i.e., lacosamide asfirst or secondadd-on), and thiswas confirmedin an analysis of response and seizure-free rates in the subgroups ofpatients who had received lacosamide as their first or second add-ontreatment (e.g., response rate of 70–80% and seizure-free rate of28–58%). These results support results from other studies with differ-ent AEDs that also show that response is better in the early stages oftreatment [1,5–7,25]. They also confirm the findings by Stephen andcolleagues [17] where 41.7% of patients were seizure-free whenlacosamide was used as the first add-on treatment; if lacosamide wasthe first SCB to be used by the patient, responder and seizure-freerates were significantly higher compared to those of patients in whomanother SCB had been used before. Further investigation of the timingof addition of lacosamide to an AED regimen is required to confirmthese preliminary analyses.

Since patients with epilepsy require long-term therapy, long-termAEs or AEs that lead to treatment discontinuation become importantclinical concerns. It is not unexpected that in the clinical practice settingwhere patients have long-standing refractory disease and receive mul-tiple AEDs, the rate of AEs can be as high as 50%, as has been previouslyseen in lacosamide observational studies [14,18]. In the current study,lacosamide-related AEs occurred in 40% of patients by 12 months. Themost frequent AE, dizziness, is an expected finding; dizziness is amongthe AEs commonly observed with lacosamide, attributed to its effecton voltage-gated sodium channels, a MOA it shares with other SCBssuch as phenytoin, carbamazepine, lamotrigine, and oxcarbazepine

t stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of3.07.024

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[26]. There were no new or unexpected safety findings in our study.About 10% of patients had discontinued treatment with lacosamidebecause of an AE by 12 months; this falls within the range previously re-ported in other lacosamide observational studies (10–21%) [14–16,18,23].

Treatment withdrawal because of an AE may be influenced by thelacosamide dosage–titration schedule, and the current study may beone of the first to have analyzed results in terms of the lacosamide dos-age–titration schedule. Titration schedules slower than the one recom-mended by the manufacturer were associated with fewer AEs ordiscontinuations because of an AE. The ‘slower’ dosage–titration sched-ules beganwith a lower starting dosage of lacosamide and increased thedosage by a smaller quantity over similar or longer intervals. It has beennoted before, in clinical practice in the United Kingdom, that it is usualfor neurologists to titrate slowly and observe response, particularly inpatients receivingmultiple AEDs [14]. In our clinical experience, Spanishneurologists follow the same cautious approach.

Finally, we attempted to determine whether any specific AED com-bination with add-on lacosamide was associated with superior effec-tiveness versus other combinations. There is little clinical evidencefrom well-controlled clinical trials concerning which combinations aremore effective or preferable in patients with focal epilepsies. In thisstudy, an analysis of specific combinations of lacosamide with otherAEDs and therapeutic response was conducted but did not reveal asignificant association between any particular combination and treat-ment efficacy. However, the use of levetiracetam, valproate, orlamotrigine was associated with the highest seizure-free rates. Twoout of these three AEDS are non-SCBs, and this additional effectivenessmay be explained by the combination of lacosamide with a non-SCBagent, as has been proposed in prior studies [18,27], although not con-firmed in others [14,17]. However, such differences between combininglacosamide with an SCB versus a non-SCB may not be so apparent inearly-stage treatment. Neither our study nor the VITOBA study (wherelacosamide was used as add-on to a single drug and in an interim anal-ysis (109 patients), 50.1% had tried just one or two AEDs before), inwhich seizure rates for SCB versus non-SCB were 40% vs 46%, showedsignificant differences between the combination of lacosamide with anSCB and the combination of lacosamide plus a non-SCB in the earlystages of treatment [28]. However, limitations of statistical analysis inour study were mentioned in the Methods section. The presence oflevetiracetam (versus its absence) was associated with significantlyfewer withdrawals from treatment because of an AE, whereas the con-verse was true of topiramate and oxcarbazepine, i.e., there were moreAE-related withdrawals because of their presence. We consideredlevetiracetam and topiramate to be non-SCBs and oxcarbazepine anSCB. So, as with prior studies, data are contradictory regarding differ-ences in tolerability when lacosamide is given concomitantly withAEDs with the same or different MOA (for example, higher AE-relatedwithdrawals when combined with another SCB) [14–16,18,23,27]. Awell-controlled trial designed to assess the hypothesis of better efficacyand tolerabilitywhen an SCB plus a non-SCB is given in combination hasyet to be conducted.

The limitations of this study relate to its retrospective design. In ad-dition, several analyses used data captured at the start of treatment thatmay have changed during lacosamide treatment, for example, patientsdivided between the SCB and non-SCB groups and specific concomitantAEDs. Results may have been influenced by the small number ofpatients who added a new AED before the end of the follow-up period.Moreover, the SCB and non-SCB subgroups were not homogeneous insample size or degree of refractoriness to treatment (the SCB group ofpatients had more refractory disease). Some of the analyses includedvery small numbers of patients (for example, the dosage–titrationschedule analyses, the treatment response curves by number of priorAEDs). Finally, the sample size of the early add-on and late add-ongroups is different. Study strengths include the relatively long and ho-mogeneous follow-upperiod (12 months), the large patient population,the nature of the patient population (patients in different stages of

Please cite this article as: Villanueva V, et al, Control of seizures in differentlacosamide, Epilepsy Behav (2013), http://dx.doi.org/10.1016/j.yebeh.201

treatment were represented), and the usefulness of real-life efficacyand safety data.

5. Conclusions

The addition of lacosamide to an AED regimen in patients with focalepilepsies, most of whom had received at least two prior AEDs, was as-sociated with a clinically significant response to treatment inmore thanhalf of the patients after 12 months. Lacosamidewas generally well tol-erated and was not associated with any unexpected AEs. Treatment re-sponse curves suggested that even some patients at the late stage oftreatment, i.e., those who had received up to 10 prior AEDs, couldbecome seizure-free for 6 months with the addition of lacosamide.However, in general, treatment efficacy was better at the early stageof treatment when lacosamide was given as the first or second add-onAED. When combining LCM, it seems to work independently of theMOA, and although efficacy tends to be larger when combining with anon-SCB, this difference is not significant in the early stages.

Conflict of interest

Dr. Villanueva has participated in advisory boards and pharmaceuti-cal industry-sponsored symposia for Eisai Inc., UCB, Merck Sharp &Dohme, Bial, Pfizer, and GlaxoSmithKline (GSK). Dr. López has partici-pated in advisory boards and pharmaceutical industry-sponsored sym-posia for Eisai Inc., UCB, Bial, and GSK. Dr. Serratosa has receivedhonoraria from UCB, Eisai Inc., Bial, Merck Sharp & Dohme, and Johnsonand Johnson for participation in advisory boards or pharmaceuticalindustry-sponsored symposia. Dr. Campos has participated in advisoryboards and pharmaceutical industry-sponsored symposia for Eisai Inc.,UCB, Bial, and GSK. Dr. Molins has participated in advisory boards andpharmaceutical industry-sponsored symposia for Eisai Inc., UCB, Bial,Pfizer, and GSK. Dr. Rodriguez Uranga has received honoraria fromUCB, Bial, Eisai Inc., GSK, and Cyberonics. Dr. Mauri has received hono-raria from UCB, Bial, Eisai Inc., GSK, and Pfizer. Dr. Salas-Puig has partic-ipated in advisory boards and pharmaceutical industry-sponsoredsymposia for Eisai Inc., UCB, Bial, and GSK. Dr. Toledo has receivedhonoraria for activities organized by Eisai Inc., UCB, Bial, and GSK.Dr. Sánchez-Alvarez has participated in advisory boards and pharma-ceutical industry-sponsored symposia for Eisai Inc., UCB, Bial, Pfizer,Novartis, and GSK. Dr. Serrano-Castro has received honoraria fromUCB, Eisai Inc., Bial, GSK, Novartis, andMerck Sharp & Dohme for partic-ipation in advisory boards or pharmaceutical industry-sponsored sym-posia. Dr. González-Giraldez, Dr. Moreno, Dr. Saiz-Diaz, Dr. Gonzálezde la Aleja, Dr. de la Peña, and Dr. Asensio have no conflicts of interestto declare.

Acknowledgments

We thank Tracy Harrison of inScience Communications, SpringerHealthcare, for medical writing assistance. We also thank PatriciaSantagueda for conducting the statistical analyses. The promoter ofthis study was Instituto de Investigación Sanitaria La Fe. The study wasfunded by an unrestricted grant from UCB. UCB was not involved inthe study design, the collection, analysis and interpretation of the datagathered, the writing of the report, or the decision to submit the articlefor publication.

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