Interference of New Antiseizure Agents with Hospital Transfer of Stroke Patients in Japan: A Retrospective Cohort Study

Abstract

Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients’ hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital. The main outcome measures were the length of hospital stay and days from the last seizure to hospital transfer.Ninety-four eligible patients were divided into those treated with perampanel or lacosamide (n = 18) and those treated with other agents (n = 76). The mean length of hospital stay and days from the last seizure to hospital transfer were 52.9 and 45.4 d in the perampanel and lacosamide group, and 32.7 and 28.6 d in the other medication group (p < 0.001). The mean antiseizure medication costs and total drug costs were U.S. $4.88 and $6.85 in the perampanel/lacosamide group and U.S. $1.94 and $4.41 in the other medication group (p < 0.001, p = 0.007), respectively. Considering antiseizure medication availability and cost in the transfer destination hospital is important when choosing medications for patients requiring hospital transfer from an acute-care hospital.

INTRODUCTION

The prevalence of epilepsy is 6.38 per 1000 people in the general population, with an annual incidence rate of 61.44 per 100000 people.¹⁾ The incidence of epilepsy is higher in infants and the elderly.²⁾ Stroke accounts for 30–40% of cases of epilepsy in the elderly.³⁾ Post-stroke epilepsy occurs in 3–12% of patients with stroke⁴⁾ and is expected to increase in the future as Japan’s population ages. Epilepsy complicated with stroke should be treated with anti-seizure medications (ASMs) according to the epilepsy classification, while the underlying disease should also be treated. Rehabilitation is recommended to improve the physical function of patients with stroke.⁵⁾ In Japan, each hospital has particular medical functions: after treatment in an acute-care hospital, patients are transferred to recovery-phase rehabilitation or convalescence hospitals.⁶⁾

Shorter intervals between stroke onset and admission to convalescent rehabilitation wards contribute to improved outcomes, such improved activities of daily living, dysphagia, and discharge rates to home, in patients with ischemic stroke, regardless of stroke severity.⁷⁾ Interestingly, the factors associated with a longer hospital stay after stroke include the National Institutes of Health Stroke Scale score, ischemic or hemorrhagic stroke, lower level of consciousness on admission, history of congestive heart failure, and history of atrial fibrillation.⁸⁾ Hemorrhagic stroke, cortical stroke, pneumonia, urinary tract infection, and onset at a young age also reportedly interfere with the transition to rehabilitation.⁹⁾

Newer ASMs have fewer interactions and adverse effects than traditional ASMs,^10,11) thereby making them useful for older patients in acute care hospitals. Nonetheless, new ASMs have the disadvantage of being expensive.¹²⁾ Chronic care hospitals in Japan often use a case-based payment system, which may not be available owing to the high cost of new ASMs. Therefore, patients with high cost medication often have difficulty in selecting and screening chronic-care and rehabilitation hospitals to transfer because of the high costs and unavailability of the newest ASMs. Seizure occurring within 7 d of stroke is defined as acute symptomatic seizures,^2,13) and ASM treatments are often completed within 7 d at our hospital. In contrast, late post-stroke epilepsy requires long-term continuation of ASMs. Nevertheless, no previous study has examined ASMs and their impact on hospital transfer in patients with stroke. Specifically, perampanel and lacosamide are the newest ASMs and generic drugs are not available in Japan. The impact of these medications on hospital transfers remains unknown.

We compared the number of days to hospital transfer between patients with epilepsy after stroke receiving perampanel or lacosamide and those receiving other ASMs. This study aimed to clarify the impact of new ASMs in clinical practice on hospital transfer coordination, thereby supporting shorter hospital stays and smoother hospital transfer for patients with epilepsy after stroke.

MATERIALS AND METHODS

Patients

This study was conducted at Tokyo Medical University Hachioji Medical Center, which provides acute treatment for stroke, including thrombolysis, mechanical thrombectomy, and surgery. Patients diagnosed with acute intracerebral hemorrhage or acute cerebral infarction between April 1, 2016, and March 31, 2021, were selected. Among these patients, those who received ASMs and were transferred to another hospital were included. We excluded patients (1) who did not receive ASMs for more than 7 d, (2) who received ASMs for a diagnosis other than epilepsy, (3) who were hospitalized for non-acute stroke, (4) who were transferred to a hospital for highly advanced medical treatment, and (5) whose data were unavailable for analysis.

We report cases of patients in whom new ASM prescriptions interfered with the coordination of hospital transfer.

Study Design

This was a single-center, retrospective cohort study. One investigator examined the medical records of the patients to obtain their medication history. Length of hospital stay and days from the last seizure to hospital transfer (DSHT) were compared between the group of participants that were prescribed perampanel or lacosamide (perampanel/lacosamide group) and other ASMs (other ASM groups). If no seizures occurred during hospitalization, they were excluded from the calculation of DSHT. Multiple regression analysis was performed using factors, other than perampanel or lacosamide medications, which are associated with a longer hospital stay, in order to reduce the effects of confounding bias. The correlation between the daily cost of medications for patients in both groups using ASMs at the time of hospital transfer and the number of DSHT were examined to determine whether the cost of medications affected hospital transfer coordination. Drug costs were based on official drug prices set by the Ministry of Health, Labor, and Welfare of Japan as of April 1, 2022. Japanese yen (¥) was converted to U.S. dollars ($). The exchange rate was set at ¥138.7 to $1. Furthermore, we report cases (1) where patients required a change in ASM upon transfer; (2) where the patient’s destination hospital was changed from the scheduled hospital to another hospital due to the prescription of perampanel or lacosamide medication; and (3) where the patient required other adjustments or modifications for hospital transfer that were related to ASMs.

Evaluation Criteria and Data Collection

Data on age, sex, stroke classification, Glasgow Coma scale (GCS) score at admission, co-morbidity, records of ASM use, the daily cost of medications at the time of hospital transfer, records of seizures, concomitant pneumonia, concomitant urinary tract infections, and length of hospital stay were collected. The primary endpoints were the length of hospital stay and the number of DSHT.

Statistical Analysis

The calculated sample size was 147 using the average length of hospital stay of 30 d, with a 10-d increase in the perampanel or lacosamide medication group, a power of 80%, and a significant difference of 5%. Statistical analysis was performed using the Mann–Whitney U test for comparison of quantitative data, the chi-square test and Fisher’s exact test for comparison of categorical data, and Spearman’s rank correlation coefficient for analyzing the correlation level between variables. To eliminate the effects of confounding factors, multiple regression analysis with a forced input method was performed; with length of hospital stay or number of DSHT as target variables; and the use of perampanel and/or lacosamide medication, age, stroke classification, GCS score at admission, concomitant pneumonia and/or urinary tract infections, number of concomitant ASMs at hospital transfer, additional administration of ASM treatment during hospitalization, and increase in the ASM dose over that taken prior to hospitalization as descriptive variables. Furthermore, ANOVA was used to discern the significance of the relationship obtained by multiple linear regression analysis. The significance level was set at 5%.

Ethics Approval

This study was performed in accordance with the Declaration of Helsinki and was approved by the Tokyo Medical University Medical Ethics Committee (Approval No. T2022-0007). The requirement for obtaining informed consent from patients was waived due to the retrospective nature of the study. Information concerning this study was made available on our website to ensure that patients could refuse to have their information used in the study.

RESULTS

Patient Characteristics

We extracted the data of 118 patients who were diagnosed with intracerebral hemorrhage or cerebral infarction, treated with ASMs, and transferred to another hospital during the study period. Of these, 24 patients were excluded from the analysis based on the exclusion criteria. Thus, 94 patients were finally included in the study (Fig. 1). Twelve neurosurgeons, four neurologists, and seven emergency medicine physicians prescribed ASMs to the patients enrolled in this study. The mean patient age was 67.6 years, and 58.5% were men. All patients were diagnosed with focal epilepsy based on electroencephalographic findings or the clinical course, and all patients were prescribed ASMs. These patients were divided into two groups: those treated with perampanel or lacosamide (n = 18) and those who were treated with other ASMs (n = 76). One patient was prescribed both lacosamide and perampanel. The patient characteristics in the two groups are presented in Table 1. Analysis of patient data showed significant differences between the two groups in the number of concomitant ASMs at hospital transfer (p = 0.001) and in the proportion of patients for whom ASMs were added during hospitalization (100 vs. 81.6%, p = 0.048).

Fig. 1. Number and Grouping of Patients

PER, perampanel; LCM, lacosamide; ASM, antiseizure medication.

Table 1. Patient Characteristics

		Perampanel or lacosamide (n = 18)	Other antiseizure medications (n = 76)	p-Value
Age (years)a)		68.6 ± 13.4	67.3 ± 13.3	0.377
Sex (%)	Male	61.1	57.9	0.803
	Female	38.9	42.1
Disease (%)	Cerebral infarction	33.3	27.6	0.631
	Intracerebral haemorrhage	66.7	72.4
Glasgow Coma Scale score at admissionb)		8.5	10	0.420
Number of concomitant antiseizure medications at hospital transferb)		1.5	1	0.001
Complications during hospitalization (%)	Pneumonia	50.0	43.4	0.614
	Urinary tract infection	33.3	21.1	0.269
Additional administration of antiseizure medications during hospitalization (%)		100	81.6	0.048
Dose increase of antiseizure medications used before admission (%)		5.6	1.3	0.262
Antiseizure medications (%)c) [dosage/d]d)	Perampanel	44.4 [4.66 mg]	0	NA
	Lacosamide	61.1 [128.57 mg]	0	NA
	Levetiracetam	88.9 [1575 mg]	85.5 [1160 mg]	0.710
	Carbamazepine	5.6 [−]	9.2 [300 mg]	0.617
	Valproic acid	0 [−]	5.3 [350 mg]	0.320
	Clonazepam	0 [−]	5.3 [0.9 mg]	0.320
	Zonisamide	0 [−]	3.9 [200 mg]	0.392
	Phenytoin	0 [−]	2.6 [175 mg]	0.487
	Lamotrigine	0 [−]	1.3 [200 mg]	0.625

NA, not analyzed. a) Mean ± standard division, b) Median, c) Antiseizure medications administered for more than 7 d during hospitalization, including those that were discontinued at hospital transfer, d) Mean dosage in patients who received each drug at hospital transfer.

Length of Hospital Stay and the Number of DSHT

The mean length of hospital stay was 52.9 and 32.7 d in the perampanel or lacosamide and other ASM groups, respectively (Fig. 2). The mean DSHT was 48.6 d in the perampanel or lacosamide group and 28.3 d in the other ASM group (Fig. 3). Patients who did not have seizures during hospitalization were excluded from this analysis: three and 44 patients in the perampanel or lacosamide group and in the other ASM group, respectively. Both the length of hospital stay and the number of DSHT were significantly longer in the perampanel or lacosamide group (p < 0.001). Multiple regression analysis was performed to determine if the number of DSHT was affected by perampanel or lacosamide medication prescriptions, even after eliminating the effects of confounding factors (Table 2). After controlling for confounding factors, perampanel or lacosamide medication prescriptions still significantly affected the number of DSHT (p < 0.001).

Fig. 2. Length of Hospital Stay

The statistical significance between the PER or LCM group (n = 18) and the other ASM group (n = 76) was evaluated using the Mann–Whitney U test (*** p < 0.001). Data are presented as median and interquartile range. PER, perampanel; LCM, lacosamide; ASM, antiseizure medication.

Fig. 3. Days from Last Seizure to Hospital Transfer

The statistical significance between the PER or LCM group (n = 15) and the other ASM group (n = 32) was evaluated using the Mann–Whitney U test (*** p < 0.001). Data are presented as median and interquartile range. PER, perampanel; LCM, lacosamide; ASM, antiseizure medication.

Table 2. Multiple Linear Regression for Variables Predicting the Number of DSHT

Coefficient	Estimates	Standard error	95% Confidence interval	p-Value
(Intercept)	57.32	18.79	19.37–95.27	0.004
Perampanel or lacosamide medication	19.26	5.22	8.73–29.80	<0.001
Age	−0.20	0.18	−0.57–0.17	0.283
Cerebral infarction	−7.76	5.99	−19.85–4.32	0.202
Complications of pneumonia	−3.31	4.83	−13.07–6.44	0.497
Complications of urinary tract infection	−1.46	4.83	−11.53–8.61	0.771
Observations	48
R2/adjusted R2	0.320/0.237

Drug Costs and Their Impact on the Number of DSHT

The mean cost of ASMs and total drug costs were U.S. $4.88 and 6.85, respectively, in the perampanel/lacosamide group, and U.S. $1.94 and 4.41 in the other ASM group, respectively (p < 0.001 and p = 0.007, respectively; Fig. 4). A mild correlation was observed between total drug costs and the number of DSHT (R = 0.356, p = 0.014, Fig. 5).

Fig. 4. The Mean ASM and Total Drug Costs

The statistical significance between the PER or LCM group (n = 15) and the other ASM group (n = 32) was evaluated using the Mann–Whitney U test (** p < 0.01, *** p < 0.001). Data are presented as means and standard errors. PER, perampanel; LCM, lacosamide; ASM, antiseizure medication.

Fig. 5. Correlation between the Daily Drug Cost and Days from Last Seizure to Hospital Transfer

Between daily drug cost and days from last seizure to hospital transfer were analyzed by Spearman’s rank correlation coefficient. A mild correlation was observed between total drug costs and the number of days from last seizure to hospital transfer (R = 0.356, p = 0.014) ASM, antiseizure medication.

Case Reports

In Table 3, we report cases where perampanel or lacosamide prescription interfered with hospital transfer of patients. In Cases 1–3, perampanel or lacosamide was unavailable at the transfer destination hospital. Therefore, these new ASMs were discontinued, and the patients were switched to other ASMs, or the dosage of existing ASMs increased. In Case 4, since lacosamide was not available at the transfer destination hospital, the destination hospital was changed. In Case 5, the patient was scheduled for transfer at the time of ASM initiation. As it was considered that lacosamide would prevent hospital transfer, carbamazepine was initiated instead. However, carbamazepine was discontinued due to hyponatremia, and the patient was switched to lacosamide. Eventually, the patient was transferred to a hospital where lacosamide was available. In Case 6, perampanel was newly started in addition to levetiracetam and carbamazepine. However, perampanel was discontinued as it interfered with the transfer and, therefore, the dosage of the other ASMs increased.

Table 3. Cases of New Antiseizure Medications (ASMs) Interfering with Hospital Transfer

No.	Age (years)	Sex	ASMs that required adjustment	Reasons	Adjustment of ASMs and clinical course	Length of hospital stay (d)
1	73	F	Perampanel	Not available	Discontinuation of perampanel	73
2	91	F	Perampanel	Not available	Discontinuation of perampanel (Levetiracetam dose increased instead)	27
3	60	F	Lacosamide	Not available	Replaced with levetiracetam	49
4	87	M	Lacosamide	Not available	Patient was transferred to another hospital	19
5	81	F	Lacosamide	Unavailability predicted	Carbamazepine was initiated in consideration of transfer; however, due to adverse effects, it was switched to lacosamide.	50
6	83	M	Perampanel	Unavailability predicted	Discontinuation of perampanel (levetiracetam and carbamazepine doses were increased in consideration of transfer)	49

M, male; F, female.

DISCUSSION

Statement of Key Findings

We conducted a retrospective cohort study to investigate whether perampanel and lacosamide prescription interfered with hospital transfer in patients with stroke, by comparing the number of days required for hospital transfer. Patients with stroke who received perampanel or lacosamide at our institution and who were, then, transferred to chronic-care and rehabilitation hospitals had significantly longer hospital stays and a greater number of DSHT than patients who received other ASMs. ASM costs were significantly higher, and total drug costs tended to be higher for patients who received perampanel or lacosamide than for those who received other ASMs. A mild correlation was observed between total drug costs and the number of DSHT. We further report the clinical course of six cases where perampanel or lacosamide prescription interfered with hospital transfer. The hospitals, for which data were collected, were located in the Minamitama medical region, and the numbers of hospitals and hospital beds were 5.2 and 1172.5 per 100000 population, respectively.¹⁴⁾ The corresponding numbers in Japan are 6.6 and 1195.2 per 100000 population, respectively.¹⁵⁾ Therefore, the data in this study appeared to be collected from medical areas with average numbers of hospitals and beds per population in Japan.

To the best of our knowledge, no previous study has shown the interference of ASM prescriptions with hospital transfer of patients with stroke who were transferred to chronic-care and rehabilitation hospitals. In the case of other medications, warfarin was often chosen over direct oral anticoagulants for cardiogenic cerebral embolism in critically ill patients, partly because these patients were transferred to facilities or convalescence wards where expensive drugs were not available.¹⁶⁾ Reportedly, nursing homes offer a comprehensive payment system for routine nursing care services, which includes the cost of drug therapy. Therefore, patients taking high-cost medications may be less likely to be accepted.¹⁷⁾ For the same reason, nursing homes have reported that high-cost medications tend to be discontinued or changed to other drugs upon admission.¹⁸⁾

Post-stroke epilepsy is characterized by prolonged hospitalization, increased mortality, prolonged ventilator management, and delayed initiation of physical and occupational therapy.^19,20) Older patients with epilepsy are usually on multiple medications due to their comorbidities,²¹⁾ and adverse effects are more likely to occur as a result of decreased metabolism and excretion capacity.²²⁾ Consequently, for these patients, new ASMs are often selected²³⁾ because of their few drug interactions¹⁰⁾ and high tolerability.¹¹⁾ Conversely, in terms of drug economics, new ASMs tend to be more expensive than conventional ASMs, which may prevent their use in treatment.¹²⁾ Among patients transferred from our institution to the hospital with case-based payment systems, the newer ASMs also tended not to be used. Thus, in the case of perampanel and lacosamide, the high cost of the drugs may have delayed hospital transfer coordination. The cases we present here suggest that patients receiving perampanel or lacosamide had longer hospital stays because of the long time needed to discontinue, change, or adjust ASMs. Japan has lagged behind European countries and the United States in terms of drug development for neurological diseases.²⁴⁾ Table 4 shows the current drug prices and approval status of ASMs in Japan. Lacosamide is available in its generic formulation in several countries; however, it is the newest ASM in Japan and the generic formulation is currently unavailable. Lacosamide and perampanel are useful drugs, although their prices are still high in Japan. They may not be suitable for prescription to patients in chronic-care hospitals, where high drug costs are particularly burdensome.

Table 4. Current Drug Prices and Approval Status of Antiseizure Medications (ASMs) in Japan

ASM (Brand name)	Cost with minimum maintenance dose (U.S. Dollar)	Availability of GE drugs in Japan	Year of approval in Japan	Year of approval in FDA
Lacosamide (Vimpat®)	5.13	Not available	2016	2008
Perampanel (Fycompa®)	2.31	Not available	2016	2012
Levetiracetam (E Keppra®)	2.18 GE: 0.86	Available	2010	1999
Lamotrigine (Lamictal®)	0.92 GE: 0.32	Available	2008	1994
Valproic acid (Depakene® R)	0.18 GE: 0.15	Available	1975	1978
Carbamazepine (Tegretol®)	0.06 GE: 0.04	Available	1969	1974

FDA, The United States Food and Drug Administration GE drugs, generic drugs.

The present study has some limitations. This was a single-center, retrospective study; therefore, data collection was limited, and selection bias could not be ruled out. Moreover, perampanel and lacosamide have only been approved in Japan fairly recently; thus, we were unable to obtain adequate sample sizes for analysis. In addition, we did not systematically assess other factors that might have affected the length of hospital stay, such as the National Institutes of Health Stroke Scale score on admission. Furthermore, patients using new ASMs (perampanel or lacosamide), which have fewer interactions, might have had poorer physical conditions than those treated with existing drugs. The influence of this factor on the length of hospital stay could not be ruled out. Finally, we could not investigate whether medication affected transfers for all patients except six cases, as the reasons for refusal of transfers were not always clear. Therefore, prospective studies are needed to clarify whether drugs are truly related to transfer coordination.

To the best of our knowledge, this is the first study to examine the use of ASM and its impact on transfer days in stroke patients with epilepsy. Based on the findings of this study, the cost of drugs should be considered for patients with stroke who are expected to be transferred to another hospital after acute treatment in Japan. Even if ASMs are newly approved in the future, drug cost and availability in many hospitals should be considered before administering them. Furthermore, according to the individual patient’s situation, ASMs should be selected based on an overall assessment of drug efficacy, adverse effects, and cost.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and data analysis were performed by Satoru Matsunuma. The first draft of the manuscript was written by Satoru Matsunuma and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Conflict of Interest

The authors declare no conflict of interest. The authors declare that no funds, Grants, or other support were received during the preparation of this manuscript.

Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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