Abstract
Objective
We evaluated adherence to and 1-year persistence of two third-generation anti-seizure medications (ASMs), lacosamide and perampanel, in adult patients with focal epilepsy, compared with lamotrigine and levetiracetam.
Methods
A cohort study was conducted using a Japanese health insurance claims database (JMDC Inc.). We identified patients with adult-onset focal epilepsy who initiated any of the four ASMs between August 31, 2016, and October 31, 2019. Patients were further classified into ASM-naïve patients initiating any of the four ASMs as first-line treatment, and ASM-experienced patients initiating any of the four ASMs as second- or later-line treatment. Outcomes included adherence (proportion of days covered [PDC], defined as the total number of days covered by ASMs divided by the total number of days in the follow-up period) and 1-year persistence for the four ASMs.
Results
We identified 141 lacosamide, 75 perampanel, 80 lamotrigine, and 530 levetiracetam initiators. Among these, the proportion of ASM-naïve patients was highest in the levetiracetam group (60.8%), followed by the lamotrigine (25.0%), lacosamide (20.6%), and perampanel groups (1.3%). Mean PDC (standard deviation) was similar across the four groups, at 0.95 (0.08) for lacosamide, 0.93 (0.12) for perampanel, 0.92 (0.10) for lamotrigine and 0.94 (0.11) for levetiracetam. The proportion of patients persisting with treatment for 1 year was highest in the lacosamide group (73.0%), followed by the levetiracetam (58.3%), lamotrigine (57.5%), and perampanel groups (54.7%). In ASM-naïve patients, adherence and 1-year persistence were almost identical in the lacosamide, lamotrigine, and levetiracetam groups. Results for ASM-experienced patients did not significantly differ from those of all patients.
Significance
With regard to adherence and 1-year persistence, lacosamide may be equal to or better than lamotrigine and levetiracetam, especially in patients with experienced ASM, while perampanel may be comparable to lamotrigine and levetiracetam in patients with experienced ASM.
Keywords: Pharmacoepidemiology, Proportion of days covered, Real-world evidence, Third-generation anti-seizure medication
1. Introduction
Epilepsy is one of the most common neurologic disorders, affecting over 70 million people globally [1]. Focal epilepsy is the predominant type in adults [2]. The goal of treatment in patients with focal epilepsy is to achieve long-term seizure-free status. It is necessary to select an appropriate anti-seizure medication (ASM) that is most likely to control seizures while minimizing the risk of side effects [3]. Most patients with newly diagnosed epilepsy achieve seizure control with the first or second ASM [4]. However, the probability that a patient will become seizure-free declines sharply with each failed ASM, and more than a third of epilepsy patients have drug-resistant disease [4].
In 2016, two third-generation ASMs, lacosamide and perampanel, were approved in Japan as concomitant therapy with other ASMs for focal drug-resistant epilepsy. Lacosamide was approved in August 2017 for monotherapy. This agent selectively enhances slow inactivation of voltage-gated sodium channels [5]. It is non-inferior to carbamazepine in different types of epilepsy [6], and has a favorable safety profile [5]. In contrast, perampanel is a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist [7]. The efficacy of perampanel monotherapy for focal epilepsy was recently confirmed in Japan and South Korea and the drug was approved for this indication in January 2020 [8]. First-line use of both lacosamide and perampanel for focal epilepsy is expected to increase.
Medication adherence and persistence are key factors in effective management of chronic conditions and strongly associated with clinical outcome [[9], [10], [11]]. However, to our knowledge, no studies have compared adherence to lacosamide to that with other ASMs in real-world populations, and only one study has compared persistence [12]. Moreover, only one study has compared the adherence and persistence of perampanel with that of other ASMs [13].
Here, we assessed adherence and persistence among adult patients with focal epilepsy who initiated lacosamide or perampanel in routine clinical practice. As active comparator drugs, we selected lamotrigine and levetiracetam for two reasons: (1) lamotrigine and levetiracetam are newer ASMs, and are commonly used in the treatment of focal epilepsy in Japan [14]; and (2) lamotrigine is similar to lacosamide in blocking sodium channels, while levetiracetam exerts a mechanism different from both lacosamide and perampanel [15].
2. Materials and methods
2.1. Study design and data source
This retrospective cohort study was conducted using a health insurance claims database provided by JMDC Inc. (Tokyo, Japan) [16]. As of September 2021, the JMDC database included claims data of over 12 million employees and their dependents aged <75 years who were covered by employment-based health insurance. The database provides individual-level data on demographic information, both inpatient and outpatient diagnoses, procedures, and pharmacy dispensing records. An anonymous personal identifier allows tracking individuals longitudinally across medical institutions [16]. The JMDC database has often been used to investigate ASMs [14,17,18]. Our dataset included data from January 1, 2005, to October 31, 2020.
This study was approved by the ethics committee of Kyoto University Graduate School and Faculty of Medicine (approval number: R1685-2). The requirement for informed consent was waived because the data used were anonymous.
2.2. Study population and exposure
We identified patients with adult-onset focal epilepsy aged 20 years or older who were diagnosed between January 1, 2006, and October 31, 2019. For a more specific definition (Table S1), patients were required to meet the following three inclusion criteria: (1) ≥2 medical claims for focal epilepsy ≥30 days apart; (2) ≥1 year of continuous enrollment before the initial diagnosis date; and (3) a combination of claim records for electroencephalography (EEG) and either magnetic resonance imaging (MRI) or computed tomography (CT) performed within 180 days after the initial diagnosis date [14].
Among patients with focal epilepsy who were eligible for the study, we identified patients who had initiated lacosamide, perampanel, lamotrigine, or levetiracetam regardless of prior use of any ASMs. The index date was defined as the first dispensing date of the index ASM. Because these four ASMs entered the market at different times, we reduced confounding [19] by limiting the index dates to between August 31, 2016 (launch date for lacosamide, the most recently marketed ASM), and October 31, 2019. Patients were excluded if they did not have a diagnosis of focal epilepsy made on or before the index date. Patients were additionally required to have ≥1 year of continuous enrolment after the index date. Patients were assigned to cohorts based on their index ASM. Patients who had received two or more qualifying ASMs were entered into all corresponding cohorts.
2.3. Follow-up and study outcomes
Patients were followed from the index date until treatment discontinuation or 1 year after the index date, whichever came first. We defined treatment discontinuation as a 90-day gap between the end of supply of the index ASM and the next dispensing [9,20]. The date of discontinuation was the scheduled end date of drug supply before the 90-day gap. Stockpiling from the previous dispensing was considered when calculating the follow-up period.
The primary outcome was adherence to ASMs, measured by the prescription-based proportion of days covered (PDC) [21]. The PDC was defined as the total number of days covered by ASMs during the follow-up period divided by the total number of days in the follow-up period. Patients with a PDC ≥0.80 were considered adherent to their index ASM [22]. Another measure of medication adherence is the medication possession ratio (MPR); in this study, however, MPR was not used because MPR may overestimate true adherence [23]. The secondary outcome was persistence to ASMs, measured by the time in consecutive days from the index date to the end of follow-up. The median dose of ASMs was recorded at day 0 (baseline), day 180, and day 365.
2.4. Patient characteristics
We captured the following patient characteristics based on previous studies and clinical expert opinion: demographics (age, sex); comorbidities (mood affective disorders, schizophrenia spectrum disorders, arrhythmia, drug eruption, renal failure, and liver disease); and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors or UDP-glucuronosyltransferase (UGT) inhibitors. We also measured time from initial diagnosis of focal epilepsy to study drug initiation, features of study drug initiation (i.e., ASM-naïve or ASM-experienced, and at least one sodium channel blocker [SCB]-experienced or only non-SCB-experienced), and prior and concomitant use of ASMs. ASM-experienced patients were defined as those with prior or concomitant use of any ASM. Prior and concomitant use of ASMs was distinguished by whether the index ASM was initiated during the prescription period of other ASMs, with consideration to a 90-day gap after the preceding drug as a grace period. The list of definitions of patient characteristics and each assessment window for these characteristics are shown in Table S2.
2.5. Statistical analysis
For each ASM cohort, descriptive statistics were used to summarize patient characteristics and treatment patterns (i.e., adherence to ASMs, and the time-course of changes in the median dose of ASMs). Treatment persistence was assessed by Kaplan–Meier analysis. Because of the descriptive nature of the study, no statistical tests were performed, consistent with previous studies using the same methodology [24,25].
We performed subgroup analyses stratified by features of study drug initiation (ASM-naïve and ASM-experienced; and at least one SCB-experienced and only non-SCB-experienced) to assess whether treatment patterns were impacted by previous ASM experience. As a sensitivity analysis to assess potential exposure misclassification, we used a gap of 60 days to define the continued use of the ASMs [9].
All analyses were performed using commercial (SAS version 9.4, SAS Institute Inc., Cary, NC, USA) and open-source (R version 4.1.0, R Foundation for Statistical Computing, Vienna, Austria) software.
3. Results
3.1. Baseline characteristics
Of the 111,704 patients with an initial diagnosis of focal epilepsy in the JMDC database between January 1, 2006, and October 31, 2019, a total of 2,513 patients with adult-onset focal epilepsy were qualified (Fig. 1). After applying inclusion and exclusion criteria, we identified 141 patients initiating lacosamide, 75 initiating perampanel, 80 initiating lamotrigine, and 530 initiating levetiracetam. Baseline characteristics differed substantially among the four ASM groups (Table 1). Mean age (SD) of the lamotrigine group was 37.4 (13.9), which was younger than the other three ASMs groups. Lamotrigine was the only ASM prescribed for more female patients (53.8%), which may be attributable to females of childbearing age accounting for 45% of the total, which was more than twice that of other groups. With regard to comorbidities, the most common were mood (affective) disorders (22.0% and 14.3%, respectively) and liver disease (17.0% and 15.3%, respectively) in patients receiving lacosamide and levetiracetam; liver disease (22.7%) in those receiving perampanel; and mood (affective) disorders (28.8%), schizophrenia spectrum disorders (20.0%), and liver disease (18.8%) in those receiving lamotrigine.
Fig. 1.
Flow chart of eligible patients. Abbreviations: ASM, anti-seizure medication; CT, computed tomography; EEG, electroencephalography; MRI, magnetic resonance imaging.
Table 1.
Baseline characteristics of the study population.
| Baseline characteristic | Lacosamide (n = 141) | Perampanel (n = 75) | Lamotrigine (n = 80) | Levetiracetam (n = 530) | ||||
|---|---|---|---|---|---|---|---|---|
| Demographics | ||||||||
| Age, mean (SD) | 44.1 | (13.4) | 44.7 | (12.2) | 37.4 | (13.9) | 43.3 | (14.3) |
| Female, n (%) | 53 | (37.6) | 30 | (40.0) | 43 | (53.8) | 197 | (37.2) |
| Female of childbearing age (20–44 years old), n (%) | 27 | (19.1) | 17 | (22.7) | 36 | (45.0) | 112 | (21.1) |
| Type of epilepsy, n (%) | ||||||||
| Focal epilepsy (ICD-10 code: G40.1, G40.2) | 52 | (36.9) | 22 | (29.3) | 25 | (31.3) | 134 | (25.3) |
| Unclassifiable epilepsy (ICD-10 code: G40.9) | 89 | (63.1) | 53 | (70.7) | 55 | (68.8) | 396 | (74.7) |
| Comorbidities, n (%) | ||||||||
| Mood (affective) disorders | 31 | (22.0) | 9 | (12.0) | 23 | (28.8) | 76 | (14.3) |
| Schizophrenia spectrum disorders | 15 | (10.6) | 7 | (9.3) | 16 | (20.0) | 43 | (8.1) |
| Arrhythmia | 9 | (6.4) | 5 | (6.7) | 8 | (10.0) | 45 | (8.5) |
| Drug rash | 3 | (2.1) | 3 | (4.0) | 1 | (1.3) | 5 | (0.9) |
| Renal failure | 4 | (2.8) | 1 | (1.3) | 1 | (1.3) | 13 | (2.5) |
| Liver disease | 24 | (17.0) | 17 | (22.7) | 15 | (18.8) | 81 | (15.3) |
| Time from initial diagnosis of focal epilepsy to study drug initiation, median days (IQR) | 95.0 | (13.0–413.0) | 210.0 | (56.0–609.0) | 53.0 | (11.0–242.5) | 2.0 | (0–30.0) |
| Features of study drug initiation | ||||||||
| ASM-naïve, n (%) | 29 | (20.6) | 1 | (1.3) | 20 | (25.0) | 322 | (60.8) |
| ASM-experienced, n (%) | 112 | (79.4) | 74 | (98.7) | 60 | (75.0) | 208 | (39.2) |
| At least one SCB-experienced, n (%) | 67 | (47.5) | 53 | (70.7) | 36 | (45.0) | 190 | (35.8) |
| Only non-SCB-experienced, n (%) | 45 | (31.9) | 21 | (28.0) | 24 | (30.0) | 18 | (3.4) |
| Prior use of ASMs | ||||||||
| No. prior ASMs, mean (SD) | 1.45 | (1.5) | 1.01 | (1.3) | 1.33 | (1.2) | 0.49 | (0.7) |
| Any drug, n (%) | 104 | (73.8) | 40 | (53.3) | 60 | (75.0) | 201 | (37.9) |
| SCBs, n (%) | 65 | (46.1) | 35 | (46.7) | 36 | (45.0) | 187 | (35.3) |
| Carbamazepine, n (%) | 25 | (17.7) | 8 | (10.7) | 11 | (13.8) | 30 | (5.7) |
| Lacosamide, n (%) | 0 | 2 | (2.7) | 4 | (5.0) | 9 | (1.7) | |
| Lamotrigine, n (%) | 16 | (11.3) | 5 | (6.7) | 0 | 13 | (2.5) | |
| Phenobarbital, n (%) | 8 | (5.7) | 6 | (8.0) | 5 | (6.3) | 28 | (5.3) |
| Phenytoin, n (%) | 24 | (17.0) | 23 | (30.7) | 9 | (11.3) | 81 | (15.3) |
| Topiramate, n (%) | 7 | (5.0) | 3 | (4.0) | 2 | (2.5) | 4 | (0.8) |
| Valproate, n (%) | 28 | (19.9) | 11 | (14.7) | 22 | (27.5) | 65 | (12.3) |
| Clobazam, n (%) | 4 | (2.8) | 0 | 1 | (1.3) | 3 | (0.6) | |
| Clonazepam, n (%) | 16 | (11.3) | 6 | (8.0) | 13 | (16.3) | 27 | (5.1) |
| Gabapentin, n (%) | 3 | (2.1) | 2 | (2.7) | 2 | (2.5) | 1 | (0.2) |
| Levetiracetam, n (%) | 73 | (51.8) | 10 | (13.3) | 37 | (46.3) | 0 | |
| Perampanel, n (%) | 0 | 0 | 0 | 0 | ||||
| Concomitant use of ASMs | ||||||||
| No. concomitant ASMs, mean (SD) | 0.28 | (0.8) | 1.39 | (0.9) | 0.08 | (0.4) | 0.02 | (0.2) |
| Any drug, n (%) | 19 | (13.5) | 68 | (90.7) | 3 | (3.8) | 8 | (1.5) |
| SCBs, n (%) | 6 | (4.3) | 35 | (46.7) | 2 | (2.5) | 3 | (0.57) |
| Carbamazepine, n (%) | 2 | (1.4) | 8 | (10.7) | 1 | (1.3) | 0 | |
| Lacosamide, n (%) | 0 | 13 | (17.3) | 1 | (1.3) | 0 | ||
| Lamotrigine, n (%) | 0 | 3 | (4.0) | 0 | 1 | (0.2) | ||
| Phenobarbital, n (%) | 4 | (2.8) | 7 | (9.3) | 0 | 1 | (0.2) | |
| Phenytoin, n (%) | 1 | (0.7) | 4 | (5.3) | 0 | 2 | (0.4) | |
| Topiramate, n (%) | 1 | (0.7) | 2 | (2.7) | 0 | 0 | ||
| Valproate, n (%) | 1 | (0.7) | 11 | (14.7) | 0 | 0 | ||
| Clobazam, n (%) | 1 | (0.7) | 2 | (2.7) | 0 | 0 | ||
| Clonazepam, n (%) | 1 | (0.7) | 5 | (6.7) | 0 | 1 | (0.2) | |
| Gabapentin, n (%) | 0 | 0 | 0 | 0 | ||||
| Levetiracetam, n (%) | 17 | (12.1) | 49 | (65.3) | 2 | (2.5) | 0 | |
| Perampanel, n (%) | 12 | (8.5) | 0 | 2 | (2.5) | 6 | (1.1) | |
| Concomitant use of other medications, n (%) | ||||||||
| CYP3A4 inhibitors | 2 | (1.4) | 5 | (6.7) | 2 | (2.5) | 14 | (2.6) |
| UGT inhibitors | 32 | (22.7) | 25 | (33.3) | 32 | (40.0) | 156 | (29.4) |
Abbreviations: ASM, anti-seizure medication; CYP3A4, cytochrome P450 3A4; ICD-10, International Classification of Diseases, Tenth Revision; IQR, interquartile range; SCB, sodium channel blocker; SD, standard deviation; UGT, UDP-glucuronosyltransferase.
The median number of days from initial diagnosis of focal epilepsy to study drug initiation was shortest in the levetiracetam group (2.0; interquartile range [IQR], 0–30.0), followed by the lamotrigine (53.0; IQR, 11.0–242.5), lacosamide (95.0; IQR, 13.0–413.0), and perampanel groups (210.0; IQR, 56.0–609.0). The proportion of ASM-naïve patients among those who initiated ASMs was in the same order, namely highest in the levetiracetam group (60.8%, 322/530 patients), followed by the lamotrigine (25.0%, 20/80 patients), lacosamide (20.6%, 29/141 patients), and perampanel groups (1.3%, 1/75 patients). As for prior use of ASMs among ASM-experienced patients, approximately half of those who initiated lacosamide or lamotrigine had used levetiracetam, while those who initiated levetiracetam (38.9%, 81/208 patients) and perampanel (31%, 23/74 patients) had most often used phenytoin. Almost all patients who initiated lacosamide, lamotrigine, or levetiracetam took them as monotherapy while 90.7% of patients who initiated perampanel took it as part of polytherapy, in most cases concomitantly with levetiracetam (66.2%, 49/74 patients).
3.2. Main analysis
Adherence was similar across the four groups: mean PDC (SD) was 0.95 (0.08) in the lacosamide group, 0.94 (0.11) in the levetiracetam group, 0.93 (0.12) in the perampanel group, and 0.92 (0.10) in the lamotrigine group (Table 2). The proportion of patients who adhered to treatment (PDC ≥0.80) was 92.9% in the lacosamide group, 89.3% in the perampanel group, 91.3% in the lamotrigine group, and 88.3% in the levetiracetam group.
Table 2.
Adherence to index anti-seizure medication.
| Lacosamide | Perampanel | Lamotrigine | Levetiracetam | |||||
|---|---|---|---|---|---|---|---|---|
| Total population | ||||||||
| Patients, n | 141 | 75 | 80 | 530 | ||||
| PDC, mean (SD) | 0.95 | (0.08) | 0.93 | (0.12) | 0.92 | (0.10) | 0.94 | (0.11) |
| Adherent, n (%)a | 131 | (92.9) | 67 | (89.3) | 73 | (91.3) | 468 | (88.3) |
| ASM-naïve | ||||||||
| Patients, n | 29 | 1 | 20 | 322 | ||||
| PDC, mean (SD) | 0.94 | (0.08) | 1.00 | NA | 0.95 | (0.06) | 0.93 | (0.12) |
| Adherent, n (%)a | 27 | (93.1) | 1 | (100) | 20 | (100) | 282 | (87.6) |
| ASM-experienced | ||||||||
| Patients, n | 112 | 74 | 60 | 208 | ||||
| PDC, mean (SD) | 0.95 | (0.08) | 0.93 | (0.12) | 0.91 | (0.10) | 0.95 | (0.08) |
| Adherent, n (%)a | 104 | (92.9) | 66 | (89.2) | 53 | (88.3) | 186 | (89.4) |
| At least one SCB-experienced | ||||||||
| Patients, n | 67 | 53 | 36 | 190 | ||||
| PDC, mean (SD) | 0.96 | (0.08) | 0.91 | (0.14) | 0.92 | (0.11) | 0.95 | (0.08) |
| Adherent, n (%)a | 62 | (92.5) | 46 | (86.8) | 32 | (88.9) | 171 | (90.0) |
| Only non-SCB-experienced | ||||||||
| Patients, n | 45 | 21 | 24 | 18 | ||||
| PDC, mean (SD) | 0.94 | (0.07) | 0.95 | (0.06) | 0.91 | (0.09) | 0.91 | (0.13) |
| Adherent, n (%)a | 42 | (93.3) | 20 | (95.2) | 21 | (87.5) | 15 | (83.3) |
Abbreviations: ASM, anti-seizure medication; PDC, proportion of days covered; SCB, sodium channel blocker; SD, standard deviation.
Patients with a PDC ≥0.80 were considered adherent to their index ASM.
Persistence was consistently higher with lacosamide than with the other ASMs (Fig. 2), which all had closely similar persistence. The proportion of patients who persisted with therapy for ≥1 year was highest in the lacosamide group (73.0%, 103/141 patients), followed by the levetiracetam (58.3%, 309/530 patients), lamotrigine (57.5%, 46/80 patients) and perampanel groups (54.7%, 41/75 patients).
Fig. 2.
Kaplan–Meier curves of persistence with index anti-seizure medications in all patients.
Time-course changes were seen in the median doses of lacosamide, lamotrigine, and perampanel; in patients who persistently used them, doses increased over the study period. In contrast, the median dose of levetiracetam (1000 mg) did not change, albeit that the did IQR increase (Table S3).
3.3. Subgroup analyses
Only one patient in the perampanel group was ASM-naïve. Among other ASM-naïve patients, mean PDC (SD) was 0.95 (0.06) in the lamotrigine group, 0.94 (0.08) in the lacosamide group, and 0.93 (0.12) in the levetiracetam group (Table 2). The proportion of patients who were adherent to treatment (PDC ≥0.80) was 100% in the perampanel and lamotrigine groups, 93.1% in the lacosamide group, and 87.6% in the levetiracetam group. Persistence was higher for lacosamide until day 270, after which it was almost the same as for lacosamide, lamotrigine, and levetiracetam (Fig. 3).
Fig. 3.
Kaplan–Meier curves of persistence with index anti-seizure medications in treatment-naïve patients.
In the ASM-experienced patients, adherence and persistence were closely consistent with the results of the main analysis (Table 2 and Fig. 4).
Fig. 4.
Kaplan–Meier curves of persistence with index anti-seizure medications in treatment-experienced patients.
Results for the analysis stratified by SCB experience were similar to those for total ASM-experienced patients, except that persistence was greatly reduced among levetiracetam users with only non-SCB experience (Table 2 and Figs. S1 and S2).
Changes in the median dose of lacosamide, lamotrigine, and levetiracetam were the same between ASM-naïve and ASM-experienced patients; in both groups, doses tended to increase over time. In contrast, levetiracetam showed a stable median dose, albeit with an increasing IQR (Table S3).
3.4. Sensitivity analysis
In the sensitivity analysis, in which the grace period was changed from 90 days to 60 days, the results of treatment patterns (i.e., adherence to and persistence with ASMs, and time-course changes in the median dose of ASMs) were closely similar to those of the main analysis (Table S4, Table S5, and Figs. S3–S5).
4. Discussion
In this cohort study, we investigated treatment adherence and persistence among adult patients with focal epilepsy who initiated lacosamide, perampanel, lamotrigine, or levetiracetam, and further analyzed these features among ASM-naïve and ASM-experienced patients. In all patients, adherence was similar across the four groups. Persistence was highest among patients treated with lacosamide, while that with perampanel was similar to those with lamotrigine and levetiracetam. In ASM-naïve patients, adherence and 1-year persistence were closely similar in the lacosamide, lamotrigine, and levetiracetam groups. In ASM-experienced patients, results were similar to those of all patients.
Although our lack of adjustment for confounders hampers direct comparison of the four ASMs, it is worthwhile to note the characteristics of patients who received different ASMs. For lacosamide, adherence was similar in both ASM-naïve and ASM-experienced patients, whereas persistence was higher in ASM-experienced than ASM-naïve patients. Thus, switching to or adding lacosamide might be an effective strategy for some experienced patients, and is supported by previous findings. Most patients whose seizures are not controlled by existing therapy improve when switched to lacosamide monotherapy [26]. Adjunctive lacosamide is also effective regardless of the type of ASM taken before its addition, especially in combination with non-sodium channel blockers (non-SCBs) [27]. Switching from traditional SCBs to lacosamide has been successful in patients in whom traditional SCBs are ineffective or not tolerated. Lacosamide slowly inactivates voltage-gated sodium channels, unlike traditional SCBs [5], and causes fewer drug rashes and drug-drug interactions than traditional SCBs, including lamotrigine [28,29]. This may also explain why lacosamide showed comparable adherence and better persistence than lamotrigine in ASM-experienced patients.
For perampanel, patient baseline characteristics differed substantially from those of the other three ASM groups, raising the possibility that these characteristics could have contributed to the differences in adherence and persistence. Notably, almost all patients who started perampanel were ASM-experienced (98.7%) and had used it with other ASMs (90.7%), possibly because it is the most recently approved of the four ASMs for monotherapy (January 2020). As perampanel has a different mechanism of action from existing ASMs, it may be effective against seizures that do not respond well to existing ASMs. In this study, the perampanel group may have included more patients with refractory epilepsy, but it still had similar adherence and persistence as lamotrigine and levetiracetam.
For lamotrigine, several factors may have influenced adherence and persistence. First, the risk of drug rash means that dose titration of lamotrigine is likely to be done slowly and cautiously, especially in newly-diagnosed patients [30]. Nearly half of the women in the lamotrigine group were of childbearing age, more than twice as many as in the other groups, which may suggest a higher discontinuation rate because of pregnancy [31]. Two reasons may explain why ASM-naïve patients had better persistence with lamotrigine than ASM-experienced patients. First, lamotrigine has fewer side effects, potentially leading to better persistence in first-line use. Second, the ASM-naïve population had fewer patients with refractory epilepsy than the ASM-experienced population, which may have resulted in superior effectiveness of lamotrigine.
For levetiracetam, adherence was similar in ASM-naïve and ASM-experienced patients, while persistence was slightly higher in ASM-experienced than ASM-naïve patients, possibly reflecting levetiracetam's status as a first-line treatment for focal epilepsy and a higher rate of refractory epilepsy among ASM-naïve than ASM-experienced patients. The analysis stratified by SCB experience showed a significant reduction in persistence among levetiracetam users with only non-SCB experience. Of the total of 18 levetiracetam users with only non-SCB experience, 15 had experienced clonazepam and 3 had experienced perampanel, suggesting that their refractory epilepsy may have influenced their lower persistence.
To our knowledge, no studies have assessed adherence to lacosamide, and few studies have evaluated that to perampanel, lamotrigine, or levetiracetam. For perampanel, the only previous study used a Korean national claims database and reported an MPR of 0.92 [13]. Although that study used a different measure of adherence, adherence was nevertheless comparable to our present results. Three retrospective analyses from the US Veterans Health Administration, the German Disease Analyzer database, and the Korean national claims database reported proportions of patients with high treatment adherence (MPR ≥0.80) of 59.5%, 71.4%, and 85.1% for lamotrigine, and of 62.7%, 78.8%, and 84.1% for levetiracetam, respectively [13,32,33]. Although differences in adherence measures preclude simple comparisons, we found that lamotrigine had higher adherence than levetiracetam, whereas the US and German studies found that lamotrigine had lower adherence. Dose titration is more difficult for lamotrigine than levetiracetam, and the Japanese regulatory authorities have issued warnings regarding lamotrigine compliance [34]; these factors may have contributed to the better adherence to lamotrigine.
Although several studies have evaluated the persistence of lacosamide, perampanel, lamotrigine, and levetiracetam in routine clinical practice, their findings cannot be directly compared to our findings because of the different patient populations. For lacosamide, a retrospective study at specialized epilepsy centers in Italy showed 1-year persistence of 81.2% and 91.4% for first-line and conversion to monotherapy, respectively [35]. Persistence was higher than in our study, probably due to lower disease severity since the Italian study only analyzed monotherapy patients, but was consistent with our finding that ASM-naïve patients had shorter persistence than ASM-experienced patients (62.1% vs. 75.9%). Also consistent with our findings, a study at a single center in Finland showed higher 3-year persistence with lacosamide (77.1%) than lamotrigine (68.3%) and levetiracetam (66.7%) [12]. For perampanel, three retrospective single-center studies in the UK, Thailand, and Korea and one multicenter US retrospective study reported 1-year persistence of 51.0%, 61.0%, 61.0%, and 58.0%, respectively, which are comparable with our study (54.7%) [[36], [37], [38], [39]]. However, a Korean study using a national claims database reported a higher 1-year persistence of 70.3% [13]. Because the Korean study was limited to epilepsy patients who received perampanel as their first add-on to monotherapy, it had fewer patients with refractory epilepsy than our study, which may have resulted in its higher persistence [3]. For lamotrigine, compared with our study, studies conducted at a single center in the US and using the Korean national claims database showed higher 1-year persistence (74.5%, 67.7% vs. 57.5%) [13,40]. One study reported that the incidence of lamotrigine-induced severe drug rash was significantly higher in Japanese than other Asian and European populations, which may have lowered persistence [41]. For levetiracetam, compared with our study, 1-year persistence was comparable to the US study (56.6% vs. 58.3%) but lower than the Korean study (70.3% vs. 58.3%) [13,40]. The Korean study was limited to ASM-experienced patients only, which possibly explains the higher persistence; similarly, we observed higher 1-year persistence in our ASM-experienced (60.6%) than ASM-naïve patients (56.8%).
Our study confirmed that patients who used lamotrigine and levetiracetam more persistently tended to use them at a higher dose (Tables S3 and S5), which has been reported [40], but also revealed that patients who used lacosamide and perampanel followed the same pattern.
Several limitations of our study warrant consideration. First, in common with any study using claims databases, we did not capture reasons for treatment discontinuation. Generally, most patients likely discontinued ASMs because of adverse events or inadequate seizure control [42,43]. Second, because of the limited sample size, we could not adjust potential confounders introduced by the nonrandomized nature of the study. Imbalances in baseline characteristics between ASM groups, such as disease duration and ASM treatment history, could affect adherence to and persistence with study drugs. However, compared with randomized controlled trials, our study has the advantage of a heterogeneous population that is more representative of patients in routine clinical practice [39,44]. Third, again because of our small sample size, we limited assessment of treatment patterns to 1 year. Fourth, dispensing records did not guarantee the actual use of ASMs and may further overestimate adherence and persistence. Fifth, to identify patients with focal epilepsy, we used the International Classification of Diseases, Tenth Revision (ICD-10) code for unclassifiable epilepsy (G40.9) as well as ICD-10 codes for focal epilepsy (G40.1 and G40.2), in accordance with previous studies [12,14,45]; however, this may have resulted in the inclusion of other epilepsy types. Nevertheless, since focal epilepsy is predominant in adults [2], the majority of patients with unclassifiable epilepsy are expected to have focal epilepsy. Sixth, baseline comorbidities were identified using ICD-10 codes, but their accuracy is unknown. The high proportion we found of patients with comorbid liver disease, ranging from 12.3% to 27.5%, may be 1) an overestimation due to the use of ICD-10 codes, or 2) because many patients used ASMs at baseline that could cause liver dysfunction, such as carbamazepine, phenytoin, valproate, and clonazepam. Finally, our findings may have limited generalizability to older or less-wealthy patients because patients in the JMDC database are covered by company health insurance societies and are therefore younger and wealthier than the general population of epilepsy patients.
5. Conclusion
This real-world cohort study documented adherence and persistence among adult patients with focal epilepsy who initiated lacosamide, perampanel, lamotrigine, or levetiracetam. Adherence was similar across the four groups, but persistence with lacosamide might be highest, and lower but similar among perampanel, lamotrigine, and levetiracetam. Lacosamide may have adherence and persistence equal to or better than lamotrigine and levetiracetam, while perampanel may be comparable to lamotrigine and levetiracetam, especially in patients with a history of ASM use. These findings provide neurologists with insight into patients who initiate lacosamide or perampanel in real-world practice.
Author contribution statement
Siming Chen and Toshiki Fukasawa: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Akio Ikeda, Masato Takeuchi, Akihiro Shimotake, and Satomi Yoshida: Conceived and designed the experiments; Wrote the paper.
Koji Kawakami: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Funding
This work was partly supported by Support for Pioneering Research Initiated by the Next Generation (SPRING) from the Japan Science and Technology Agency (JPMJSP2110) to Siming Chen.
Data availability statement
The data cannot be shared publicly due to the privacy policy of JMDC Inc.
Declaration of interest's statement
The authors declare the following conflict of interests: Toshiki Fukasawa and Satomi Yoshida have been employed by the Department of Digital Health and Epidemiology, an Industry-Academia Collaboration Course, supported by Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Real World Data Co., Ltd., and Mitsubishi Corporation; and have received consulting fees from Real World Data Co., Ltd. Akio Ikeda has been employed by the Department of Epilepsy, Movement Disorders and Physiology, an Industry-Academia Collaboration Course supported by Eisai Co., Ltd., Nihon Kohden Corporation, Otsuka Pharmaceutical Co., Ltd., and UCB Japan Co. Ltd. Masato Takeuchi has received consulting fees from Eisai Co., Ltd. Koji Kawakami has received funds from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Pfizer Inc., Stella Pharma Corporation, CMIC Co., Ltd., Suntory Beverage & Food Ltd., Mitsubishi Corporation, and Real World Data Co., Ltd.; consulting fees from LEBER Inc., JMDC Inc., Shin Nippon Biomedical Laboratories Ltd., Kaken Pharmaceutical Co., Ltd., and Advanced Medical Care Inc.; executive compensation from Cancer Intelligence Care Systems, Inc.; and honoraria from Mitsubishi Chemical Holdings Corporation, Mitsubishi Corporation, Pharma Business Academy, and Toppan Inc.; and holds stock in Real World Data Co., Ltd. The remaining authors have no conflict of interest to disclose.
Acknowledgments
The authors thank Libby Cone, MD, MA of DMC Corp. (www.dmed.co.jp) for her support with the writing of the manuscript.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2023.e15017.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Associated Data
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Supplementary Materials
Data Availability Statement
The data cannot be shared publicly due to the privacy policy of JMDC Inc.