Abstract
Objective
This study aimed to understand how people living with drug‐resistant focal epilepsy (DRE) navigate through lines of antiseizure medications (ASM) and experience adverse events (AEs) in the real‐world setting in the United States.
Methods
A retrospective study was conducted with medical chart data from clinical practices in the United States. Eligible adults had a confirmed diagnosis of DRE and initiated a third‐line ASM therapy between January 2013 and January 2020 (i.e., the index date). Subjects must have medical history data available for ≥1 year prior to (the baseline) and ≥2 years after the index date (the follow‐up). Treatment patterns were captured from first to fourth lines. After the emergence of drug resistance, time to ASM discontinuation, reasons for discontinuation, AE experience and AE management were reported separately during third and fourth lines of treatment and beyond.
Results
The study included a total of 345 individuals, with an average (standard deviation) age of 23.9 (11.9) years at first diagnosis. All individuals had at least three lines of ASMs with first and second lines during baseline, and third line during follow‐up. The first line for most individuals was monotherapy. As individuals progressed through additional lines of ASM therapy, they were more likely to receive polytherapy. The regimens were more individualized after meeting drug resistance criteria. The top reasons for discontinuing were uncontrolled seizure and/or intolerance/AEs for both third and subsequent lines. More than a third of individuals experienced at least one AE. Among those with at least one AE, many individuals had to manage these AEs with dose adjustment (39.4%), discontinuation of offending ASM (37.9%), de novo pharmacotherapy (25.8%), emergency room visit (13.6%), and hospitalization (12.1%).
Significance
This study demonstrated that individuals living with DRE experience significant AEs, and many of these AEs lead to treatment disruption and significant healthcare resource utilization.
Plain Language Summary
This study examined how individuals with focal epilepsy are treated across various clinics in United States and reported the adverse events these individuals experienced during treatment, along with the consequence associated with these adverse events. We found that as individuals progressed through additional treatments, they were more and more likely to receive more than one antiseizure medication, and a significant portion of individuals experienced at least one adverse event, often manifested as headache, somnolence, dizziness, and fatigue.
Keywords: adverse events, antiseizure medication, drug‐resistant focal epilepsy
Key points.
Most individuals with drug‐resistant focal onset epilepsy (DRE) initiated first‐line monotherapy with levetiracetam as the top agent of choice. As lines of antiseizure medications (ASM) therapy progressed, individuals were more likely to receive polytherapy, and regimens were more likely to be individualized.
A significant proportion of individuals discontinued at least one ASM after acquiring drug resistance. The top reasons for discontinuation were uncontrolled seizure and intolerance/adverse events (AEs).
Among those with AEs, 39.4% had dose adjustment, 37.9% discontinued the offending ASM, 25.8% initiated de novo pharmacotherapy, 13.6% had emergency room visit, and 12.1% were hospitalized.
1. INTRODUCTION
In the United States, it is estimated that approximately 3.4 million people have seizure disorders, affecting 1 in 26 people 1 , 2 with approximately 61% of individuals with epilepsy having focal seizures. 3
Anti‐seizure medications (ASMs) are the most crucial means to prevent recurrent seizures. Currently, there are more than 30 ASMs available in the United States, and these ASMs can be grouped into first, second, and third generation based on the timing of commercial availability. In general, the newer generation of ASMs was better tolerated than the older ones. However, new generation ASMs are not necessarily more efficacious in seizure control than the older generations thus leaving many people living with epilepsy under the torment of frequent seizures. 4 A cohort study on 470 individuals who started first‐line ASM between 1982 and 1998 showed that 36% of individuals experienced seizures despite treatment. 5 Using data from the same center, a follow‐up study with a 30‐year follow‐up on individuals who started ASM between 1982 and 2012 found that the rate of failure to achieve 1‐year seizure freedom was 36.3%, nearly identical to the prior study. 6 These two studies demonstrated that even though individual patients may have benefited from the availability of new ASMs, the prognosis for the overall population living with epilepsy is far from satisfactory. The current consensus is that nearly 30–40% of adult individuals with epilepsy remain drug resistant to therapies, 7 , 8 which is defined by the International League Against Epilepsy (ILAE) as failure to achieve sustained seizure freedom after two adequate trials of tolerated and appropriately chosen anti‐epileptic drug schedules. 9
One potential reason for the lack of true progress in achieving seizure control may be due to the difficulty in matching an individual's needs with the side effect/tolerability/drug–drug interaction profile of available ASMs. Although generally better in safety profile than the first‐generation ASMs, the second‐ and third‐generation ASMs still cause considerable adverse events (AEs), which impose significant burden on people living with epilepsy and their care givers when lifelong treatment is required.
Much of the evidence regarding AE profiles of each ASM originates from clinical trials that have highly restrictive study population and a relatively short follow‐up period. There is a limited understanding of the treatment journey, AE experiences and management in the real‐world setting among people living with drug‐resistant focal onset epilepsy (DRE) in the United States. The current study aimed to fill this evidence gap with a cohort of individuals receiving routine treatment across clinical practices in the United States.
2. METHODS
2.1. Study design and participating physician recruitment
This retrospective, non‐interventional chart review study was conducted using individual‐level data provided by 189 neurologists or epileptologists across the United States via an online case report form. Data were collected between April 6th and July 11th, 2022. Physicians from a neurologist/epileptologist specialty panel were invited to participate in this study via email by a third party that holds a database of physicians consented to participate in research activities. To be eligible, the physicians were required to have had practiced for a minimum of 3 years as a neurologist or epileptologist and had treated at least three patients with drug‐resistant focal or generalized epilepsy in the prior year to ensure physicians are actively engaged in clinical practice. Each participating physician was instructed to select up to four eligible individuals using a semi‐randomized process. Participating physicians were asked to review a patient chart with last name corresponding to a randomly generated letter prompted via an electronic case report form. This individual was selected if all eligibility criteria were met. If no eligible individuals were identified, another random letter was generated, and the process was repeated. Data completeness and quality from these physicians were routinely monitored across multiple studies, where underperformers were removed from the panel. Data quality of completed patient charts was monitored throughout the data collection period. Charts with a high level of missing data or were completed under 10 minutes were removed, and this scrutiny resulted in one participant chart being removed due to missing third‐line starting date.
Individuals were eligible if they were age 18 years or older, had confirmed diagnosis of focal onset epilepsy, initiated a third‐line ASM therapy between January 2013 and January 2020 after failing of two trials of adequate, appropriate, and tolerated ASM regimens (thus meeting the drug‐resistant criteria per ILAE definition 9 ). In addition, individual must had medical history data available for at least 12 months prior to and at least 24 months after the initiation of third‐line ASM. To maximize data captured for the recently launched cenobamate, neither minimum nor maximum follow‐up period was required for individuals who initiated cenobamate in third line. Individuals were excluded if they had a confirmed diagnosis of combined focal and generalized epilepsy, or if they had participated in a clinical trial during 12 months prior to or 24 months after the initiation of third‐line therapy.
For all subjects, the index date was defined as the date of initiation of third‐line ASM therapy (either monotherapy or polytherapy). The baseline period was defined as the 12‐month period prior to the index date and the follow‐up period as the 24‐month period starting on and following the index date with the exception that individuals receiving cenobamate in third line had variable follow‐up length.
ASM regimens from baseline to follow‐up were captured for first, second, third, and fourth lines (benzodiazepine as a pro re nata [PRN] rescue treatment was separately captured and thus ASM hereafter excludes rescue agents). The duration of a line of therapy was defined as the number of months between the initiation of the first ASM in that regimen and the last discontinuation of the ASMs in that regimen or the initiation of a new ASM (whichever is earlier). Treatment duration, monotherapy versus polytherapy, and ASM regimen were reported by clinicians separately for all four lines. Number of subjects who discontinued any ASM in third or fourth lines, along with reasons of discontinuation, was separately reported for third and fourth lines. AEs experienced, and the management of these AEs were recorded separately for two discrete periods during the follow‐up: (1) during third line; and (2) starting on fourth line till end of follow‐up.
2.2. Statistical analysis
All variables captured during the baseline and follow‐up periods were analyzed descriptively. Means, standard deviations (SDs), and/or interquartile ranges (IQRs) were reported for continuous variables and counts and proportions were reported for categorical variables. Time from the index date to the discontinuation of third‐line therapy was described using Kaplan–Meier analysis.
All statistical analyses were conducted using SAS Enterprise Guide 7.1 software (SAS Institute, Cary, NC, USA) and R Statistical Software (version 3.6.3; R Foundation for Statistical Computing, Vienna, Austria).
3. RESULTS
3.1. Study population
A total of 345 individuals with DRE were included in the study. The average (SD) age at the index date was 32.4 (11.2) years old and 23.9 (11.9) years at first diagnosis, with 65.5% being male, 78.3% being White/Caucasian, and nearly equally distributed across the four regions of the US (Table 1).
TABLE 1.
Study population.
| N = 345 | |
|---|---|
| Age of first epilepsy diagnosis (years), mean (SD) | 23.9 (11.9) |
| Age at index date (years), mean (SD) | 32.4 (11.2) |
| Length of follow‐up (months), mean (SD) | 25.0 (11.3) |
| Male, n (%) | 226 (65.5%) |
| Race/ethnicity, n (%) a | |
| White/Caucasian | 270 (78.3%) |
| Black/African American | 47 (13.6%) |
| Hispanic/Latino | 16 (4.6%) |
| Asian/Asian American | 14 (4.1%) |
| Other/Unknown | 3 (0.9%) |
| Geographic region, n (%) | |
| South | 100 (29.0%) |
| Northeast | 85 (24.6%) |
| West | 80 (23.2%) |
| Midwest | 80 (23.2%) |
Abbreviation: SD, standard deviation.
Multiple responses were allowed, so counts and percentages may not sum to the total N or 100%.
3.2. ASM treatment characteristics and duration of treatment
By study design, all individuals had at least three lines of ASMs with first and second lines during baseline and third line during follow‐up. Individuals could continue to further lines of ASM treatment post third line during the follow‐up. Treatment duration, monotherapy versus polytherapy, and top ASM agents used from first through fourth lines are shown in Table 2. Figure 1 shows that individuals who received polytherapy in the prior line were most likely to receive polytherapy in the next line. Most individuals (84.1%) started their first line as monotherapy with two‐thirds of individuals (67.2%) receiving one of six ASMs: levetiracetam, carbamazepine, phenytoin/fosphenytoin, oxcarbazepine, lamotrigine, and divalproex sodium in decreasing share. Polytherapy was sparsely used (15.9%) as first‐line option and each ASM combination was distinct (data not shown). In the second line, there was an approximately 50/50 split between monotherapy and polytherapy, and the ASM regimens were less concentrated with 52.2% individuals receiving one of the 10 most used ASM regimens. Notably, among individuals receiving these top 10 regimens as second‐line options, 51.1% (comment: this % was incorrect, now corrected) had either levetiracetam monotherapy or a levetiracetam‐containing polytherapy. In the third line (where individuals met the definition for drug resistance), about two‐thirds of individuals had polytherapy. The nine most used ASM regimens (many ties for the 10th position) only constituted 30.4% of individuals. The remaining individuals received various ASM combinations. A total of 187 individuals (54.2%) initiated a fourth‐line therapy, and 88.7% of them did so with widely dispersed polytherapy. The eight most used regimens (many ties for the 9th position) constituted only 15.5% of the individuals among those started fourth‐line ASMs.
TABLE 2.
Treatment duration, anti‐seizure medication regimens, treatment discontinuation, and associated reasons.
| Baseline | Follow‐up | |||
|---|---|---|---|---|
| First line (N = 345) | Second line (N = 345) | Third line (N = 345) | Fourth line (N = 187) | |
| Treatment duration (months) | ||||
| Mean (SD) | 30.7 (47.3) | 40.4 (74.3) | 15.4 (11.9) | 14.6 (12.2) |
| Median (IQR) | 12.1 [5.4–31.0] | 14.8 [7.5–43.3] | 15.0 [5.8–24.0] | 13.0 [8.0–20.1] |
| Treatment, n (%)2 | ||||
| Monotherapy | 290 (84.1%) | 170 (49.3%) | 112 (32.5%) | 21 (11.2%) |
| Polytherapy | 55 (15.9%) | 175 (50.7%) | 233 (67.5%) | 166 (88.8%) |
| Commonly used regimens (n) |
LEV (87) CBZ (46) PHT (43) OXC (22) LTG (18) DVP (16) TPM (8) |
LEV (39) LTG (29) CBZ (20) LTG/LEV (18) DVP (16) LCM/LEV (12) CBZ/LEV (12) OXC (12) TPM (11) LEV/OXC (11) |
LEV (19) LTG (16) OXC (14) TPM (12) LCM (11) LCM/LEV (11) LTG/LEV (8) CNB (8) LEV/OXC/TPM (6) |
TPM (5) GBP/LTG (4) LCM (4) LCM/LTG/LEV (4) BRV/LCM (3) LCM/LEV/TPM (3) ESL (3) CNB (3) |
| Individuals discontinued any medication in the regimen, n (%) | — | 64 (18.6%) | 52 (27.8%) | |
| Reasons for medication discontinuation, n (%) | ||||
| Uncontrolled seizure | 39 (60.9%) | 27 (51.9%) | ||
| Treatment tolerance or adverse events | 27 (42.2%) | 30 (57.7%) | ||
| Patient preference | 7 (10.9%) | 12 (23.1%) | ||
| Cost to patient | 6 (9.4%) | 9 (17.3%) | ||
| Planned treatment completion | 2 (3.1%) | 3 (5.8%) | ||
| Planned pregnancy | 1 (1.6%) | 1 (1.9%) | ||
| Unknown | 0 (0.0%) | 5 (9.6%) | ||
Note: First generation ASMs (underlined): CBZ, carbamazepine; PHT, phenytoin/fosphenytoin. Second generation ASMs (plain text): GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; TPM, topiramate. Third generation ASMs (bolded): BRV, brivaracetam; CNB, cenobamate; DVP, divalproex sodium; ESL, eslicarbazepine acetate; LCM, lacosamide.
Abbreviations: IQR, interquartile range; SD, standard deviation.
FIGURE 1.
Distribution of monotherapy and polytherapy from first to fourth lines of therapy
Although most of individuals have a fixed 24 months of follow‐up, those individuals (n = 51) whose third line contained cenobamate (either monotherapy or polytherapy) were allowed to vary; thus, the average follow‐up duration was 25.0 (SD 11.3) months and ranged from 0.1 to 114.4 months for all individuals. The treatment duration tended to be longer in earlier lines than in latter ones, with an average (SD) of 30.7 (47.3), 40.4 (74.3), 15.4 (11.9), and 14.6 (12.2) months for first to fourth lines, respectively.
Discontinuation of any ASM within a regimen and reasons for discontinuation for third and fourth lines are presented in Table 2. A total of 18.6% of individuals discontinued at least one ASM from the third‐line regimen, with uncontrolled seizure as the most common reason of discontinuation (60.9%) and intolerance/AEs as the second most common reason (42.2%). During the fourth line, 27.8% individuals discontinued at least one ASM, with the top reasons being intolerance/AEs (57.7%) and uncontrolled seizure (51.9%).
Figure 2 shows the Kaplan–Meier survival curve for individuals during third line. A total of 190 (55%) individuals discontinued all ASMs in their third‐line regimen and the median time to discontinuation was 17.2 (95% CI: 15.0, 23.9) months.
FIGURE 2.
Time to discontinuation of all antiseizure medications in the third line.
Among the 254 individuals who experienced seizure events, 125 (49.2%) used benzodiazepines as a rescue treatment for seizure events during the follow‐up. Other procedures for epilepsy treatment such as epileptic surgery or vagal nerve stimulation were not commonly used (data not shown) among this study population.
3.3. Adverse events during the follow‐up period
Table 3 shows various AEs reported during third line and the period from fourth line to the end of the follow‐up. During the third line, a total of 132 (38.3%) individuals reported at least one AE with an average of 3.9 (SD: 4.1) AEs reported per individual. The most prevalent AEs were related to central nervous system such as headache, somnolence, dizziness, and fatigue. From fourth line to the end of the follow‐up, a total of 85 individuals (45.5%) reported at least one AE with an average of 4.1 (SD: 4.0) AEs per individual. The most prevalent AEs reported were also related to the central nervous system such as headache, asthenia, fatigue, and somnolence, while conditions in gastrointestinal system such as diarrhea and vomiting were also commonly reported.
TABLE 3.
Adverse events (AE) during the follow‐up period.
| 3rd line (N = 345) | Fourth line till end of follow‐up (N = 187) | ||
|---|---|---|---|
| Individuals with ≥1 AEs, n (%) | 132 (38.3%) | Individuals with ≥1 AEs, n (%) | 85 (45.5%) |
| Numbers of AEs reported | Numbers of AEs reported | ||
| Mean (standard deviation) | 3.9 (4.1) | Mean (standard deviation) | 4.1 (4.0) |
| Median (interquartile range) | 2.0 [1.0–4.5] | Median (interquartile range) | 2.0 [1.0–5.0] |
| Nervous system AE | 123 (35.7%) | Nervous system AE | 75 (40.1%) |
| Headache | 51 (14.8%) | Headache | 35 (18.7%) |
| Somnolence | 43 (12.5%) | Asthenia | 28 (15.0%) |
| Dizziness | 38 (11.0%) | Fatigue | 21 (11.2%) |
| Fatigue | 38 (11.0%) | Somnolence | 21 (11.2%) |
| Asthenia | 24 (7.0%) | Dizziness | 18 (9.6%) |
| Tremor | 21 (6.1%) | Tremor | 17 (9.1%) |
| Irritability | 20 (5.8%) | Blurred vision | 16 (8.6%) |
| Cognitive dysfunction | 16 (4.6%) | Diplopia | 13 (7.0%) |
| Diplopia | 15 (4.3%) | Cognitive dysfunction | 8 (4.3%) |
| Ataxia | 11 (3.2%) | Irritability | 8 (4.3%) |
| Blurred vision | 9 (2.6%) | Ataxia | 7 (3.7%) |
| Aggression | 5 (1.4%) | Aggression | 4 (2.1%) |
| Motor incoordination | 2 (0.6%) | Motor incoordination | 2 (1.1%) |
| Worsened depression/suicidal ideation | 1 (0.3%) | Worsened depression/suicidal ideation | 0 (0.0%) |
| Gastrointestinal system AE | 73 (21.2%) | Gastrointestinal system AE | 48 (25.7%) |
| Nausea | 31 (9.0%) | Diarrhea | 22 (11.8%) |
| Diarrhea | 29 (8.4%) | Vomiting | 21 (11.2%) |
| Abdominal pain | 27 (7.8%) | Abdominal pain | 19 (10.2%) |
| Anorexia | 25 (7.2%) | Anorexia | 16 (8.6%) |
| Vomiting | 23 (6.7%) | Nausea | 16 (8.6%) |
| Weight gain | 13 (3.8%) | Weight gain | 10 (5.3%) |
| Respiratory system AE | 26 (7.5%) | Respiratory system AE | 19 (10.2%) |
| Flu syndrome | 19 (5.5%) | Flu syndrome | 11 (5.9%) |
| Rhinitis | 14 (4.1%) | Rhinitis | 9 (4.8%) |
| Infection | 8 (2.3%) | Infection | 5 (2.7%) |
| Pharyngitis | 3 (0.9%) | Pharyngitis | 3 (1.6%) |
| Other AE | 25 (7.2%) | Other AE | 15 (8.0%) |
| Lab abnormalities | 11 (3.2%) | Lab abnormalities | 7 (3.7%) |
| Renal dysfunction | 10 (2.9%) | Rash | 6 (3.2%) |
| Rash | 9 (2.6%) | Renal dysfunction | 5 (2.7%) |
| Tremor, hyponatremia, and insomnia | 3 (0.9%) | Hyponatremia and insomnia | 2 (1.1%) |
3.4. Adverse events management/consequence during the follow‐up period
Among individuals with at least one AE during third line, 39.4%, 37.9%, 25.8%, 13.6%, and 12.1% managed AEs through dose adjustment, discontinuation of offending ASM, de novo pharmacotherapy to deal with AEs, emergency room (ER) visit, and hospitalization, respectively. Among individuals reporting at least one AE during fourth line to the end of follow‐up, 48.2%, 32.9%, 31.8%, 22.4%, and 10.6% had discontinuation of offending ASM, dose adjustment, de novo pharmacotherapy to deal with AEs, ER visit, and hospitalization, respectively.
4. DISCUSSION
This non‐interventional real‐world study examined individuals with DRE who received care across clinical practices in the United States. The utilization of a physician panel enabled efficient collection of individual‐level data including treatment patterns before and after the emergence of drug resistance. To our knowledge, this is the first study to report treatment discontinuation, AEs, and their corresponding management/consequence for individuals with DRE in the United States.
We found that most individuals started first‐line ASM as monotherapy using one of six common ASMs, of which levetiracetam was the most frequently used ASM and phenytoin as the third most common agent despite its common side effects. Levetiracetam was also the leading agent in second‐line treatment either as monotherapy or as polytherapy. Despite the availability of many new ASMs, the predominant players in first‐line ASMs were largely unchanged with only one third‐generation ASM (divalproex) used in first line: In 2013, Chen et al. showed that the exact same five ASMS (levetiracetam, phenytoin, carbamazepine, oxcarbazepine, and lamotrigine) were the most used ones among individuals on first‐line monotherapy 10 ; in 2018, Faught et al. showed very similar makeup of first‐line ASMs. 11 Our findings are in line with the ILAE guideline where levetiracetam has level A evidence as initial therapy for adults with focal onset epilepsy 12 and is suggested to have, along with lamotrigine, better efficacy than all other ASMs in a recent review. 13 After individuals met the drug‐resistant definition, use of polytherapy increased dramatically and the ASM regimen became more and more individualized. While levetiracetam was still the most used ASM after the emergence of drug resistance, lacosamide and cenobamate were the two most frequently used third‐generation ASMs in the third line. The general lack of preferred regimens after drug resistance somewhat follows the two practice guidelines (2004 and 2018) jointly provided by the American Academy of Neurology and the America Epilepsy Society, where a variety of ASMs were recommended with varying level of evidence. 14 , 15 This study highlights the challenges presented by DRE in the clinical practices, as it is a multifactorial and extremely intricate condition where many diverse underpinnings of drug resistance may “coexist and interact in the same individual.” 16
For individuals with DRE, the rate of discontinuing certain ASMs increased with lines of therapy, as did the frequency of reported AEs: 19% and 28% of individuals discontinued at least one ASM, 38% and 45% experienced at least one AE during third‐ and during or after fourth‐line ASM, respectively. Breakthrough seizure and intolerance/AEs were most frequently reported as the reasons for discontinuation. In another real‐world study using Columbia and Yale antiepileptic drug database, Chen et al. 17 reported 17.2% of individuals who newly initiated an ASM experienced at least one psychiatric and behavioral AE. The SANAD study authors reported the rate of intolerable adverse events at 8%–32% depending on the ASM used; however, most study participants (at least 81%) were receiving 1st line ASM. 18
Discontinuation and real‐world AE rates for individuals living with DRE were harder to locate because most AE data on ASMs are reported from clinical trials with very constricted study population and a relatively short follow‐up, and real‐world studies either focused on one or two ASMs or used data from a single practice, often with unclear number of prior lines of ASM therapy. For example, a real‐world study on Italians taking brivaracetam as an add‐on therapy for focal epilepsy found that 26% individuals discontinued their ASM treatment during the 1‐year follow‐up, and 30% individuals reported at least 1 AE. 19 An European study on real‐world use of eslicarbazepine as adjunctive treatment found that discontinuation rate was 14%, and 34% reported AEs. 20 A single‐center study on individuals from Beaumont Hospital, Dublin, Ireland who received cenobamate via early access program showed that 12% of discontinuation within 3 months and 77% reported at least 1 AE. 21 One exception is the recently published COMPARE study where the authors examined four third‐generation ASMs from multiple centers in Italy and found that all four ASMs had 21% patients discontinued with 1–36 months of follow‐up. 22 However, the study population had exclusively focused on four third‐generation ASMs and included a mix of seizure types with only approximately 70% of the study population having focal epilepsy alone, the rest having generalized epilepsy or a mix of both focal and generalized epilepsy. While the exact proportions vary across studies, it is clear a significant fraction of individuals with DRE had discontinued their ASMs and/or experiencing significant AEs, which would negatively impact their treatment outcomes and decrease their quality of life.
4.1. Limitations
One limitation of the current study lies with the reliance on participating physicians to determine whether and when an individual met drug‐resistant criteria. However, definition for drug‐resistant epilepsy (according to ILAE) and line of therapy, and instructions to identify eligible individuals were provided to the physicians within the online case report form to minimize misclassification. Nevertheless, it is still possible that what constituted a line of therapy and/or treatment failure may vary across physicians; therefore, some individuals included in this study may not be truly treatment resistant. Unfortunately, the ILAE definition of drug resistance does not address the possibility of individuals receiving a line of ASM that was not titrated to the optimal therapeutic dose, nor accounts for suboptimal adherence unreported to treating physicians. In addition, it was not feasible to compare discontinuation and AE rates across different ASMs because each regimen in third line had fewer than 20 individuals. Because of its retrospective nature, the generalizability of this study findings needs to be considered along with the possibility of reporting bias, recall bias, selection bias, and potential non‐randomness of missing data. For example, individuals who can afford to receive treatments from neurologists/epileptologists and make frequent visits to hospital/medical center were more likely to be included in this study. Although a randomization scheme was implemented to minimize the probability of most memorable individuals being selected into the study, selection bias is still probable, and physicians who participated in this study may differ from non‐participating physicians. It is also possible that participating clinical sites may not be representative of the clinical sites in the United States and/or other countries with different reimbursement or practice patterns. For example, the literature suggests perampanel as a suitable add‐on therapy in DRE. 23 However, this study did not identify perampanel as a commonly used ASM in later lines of therapy, which may not be reflective of all practices in the United States. Similarly, other studies have indicated the potential utility of newer generation ASMs such as lacosamide 24 and eslicarbazapine, 20 but determining efficacy for these potential third line ASMs was not the goal of the current study.
5. CONCLUSIONS
Findings from this study suggest significant unmet needs exist among individuals living with DRE in the United States, as evidenced by highly individualized ASM regimen used after reaching drug‐resistant status, high prevalence of AEs observed, and the presence of resource‐intensive management/consequence of these AEs. Strategies to optimize the best ASM regimen for everyone early in their treatment journey to prevent the emergence of drug resistance and treatment options with better efficacy and safety are needed to bring seizure freedom without significant sacrifice in quality of life for individuals with focal onset epilepsy.
FUNDING INFORMATION
Cerevel Therapeutics, Cambridge, MA 02141.
CONFLICT OF INTEREST STATEMENT
JM and KT are employees of Cerevel Therapeutics and may hold Cerevel stock and/or equity. Ann Dandurand was an employee of Cerevel Therapeutics at the time of the study. MC, CX, AB, and YS are employees of Analysis Group, Inc., which received research funding from Cerevel Therapeutics. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ETHICS STATEMENT
This study was approved by Western Institutional Review Board (approval no. 20216977). In addition, the participating physicians did not know the study sponsor and the study sponsor was blinded to the participating physicians.
Supporting information
Figure S1.
ACKNOWLEDGMENTS
The authors thank Dr. Steve Arcona, an employee of Cerevel Therapeutics, for his participation in the early phases of this study.
Mao J, Takahashi K, Cheng M, Xu C, Boca A, Song Y, et al. Real‐world anti‐seizure treatment and adverse events among individuals living with drug‐resistant focal epilepsy in the United States. Epilepsia Open. 2024;9:1311–1320. 10.1002/epi4.12967
DATA AVAILABILITY STATEMENT
The data used in this study are not publicly available due to their proprietary nature.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1.
Data Availability Statement
The data used in this study are not publicly available due to their proprietary nature.