Economic Aspects of Epilepsy and Antiepileptic Treatment

Demetris K. Pillas

Caroline E. Selai

John T. Langfitt

Marc R. Nuwer

Introduction

Significance of Economic Evaluation of Epilepsy and Its Treatment Modalities

Over the last 15 years there has been a dramatic increase in the therapeutic options available for the treatment of epilepsy. Epilepsy can now be treated with 13 different U.S. Food and Drug Administration (FDA)-approved antiepileptic drugs (AEDs);³⁷ surgery has now been established as an effective treatment for reducing or eliminating seizures in patients with medically intractable epilepsy.⁶¹ Furthermore, vagal nerve stimulation (VNS), which includes the first implantable device with antiseizure properties, is now considered a safe therapeutic procedure, with clinically useful and sustained benefits.⁵³

Many of these developments for treating epilepsy have a higher initial cost than the older treatments they replace. On the other hand, they may offer long-term savings if an increasing number of patients undergoing the new treatments become seizure-free. Therefore, it has become necessary to evaluate the economic burden of health care alternatives as well as their therapeutic efficacy. It is no longer sufficient merely to demonstrate a satisfactory degree of efficacy for a particular treatment if the cost of such therapy would cause the health care system to deny an equivalently efficacious yet cheaper remedy to a wider group of the target population.¹⁰

In addition, with the growing emphasis on cost containment and managed care in health care delivery, evaluations of the cost of epilepsy and its treatment are increasingly required by government agencies, advocacy groups, and health care payers concerned with the allocation of research and treatment resources among disease conditions.

In such a context, it is of interest to review critically the recently published literature on the economic aspects of epilepsy and its treatment in order to:

Compare the variance and distribution of costs between and within various countries
Identify and discuss methodologic issues and limitations in calculating the cost of epilepsy
Evaluate the cost-effectiveness of the different treatments available

In this chapter, we explore these issues by systematically reviewing all the recent epilepsy-related cost-evaluation studies, analyzing their results, comparing their findings and, discussing their implications.

Types of Economics Studies

We identified studies via Medline and hand-searching English-language, epilepsy-related, and health economics journals. To have been included, studies had to have (a) been published between January 1998 and January 2006, (b) followed one of the standard methods of health economics evaluation (cost of illness [COI], cost-minimization analysis [CMA], cost-effectiveness analysis [CEA], cost-benefit analysis [CBA], cost-utility analysis [CUA]) (Table 1), and (c) aimed to provide estimations on the cost of epilepsy alone, not including comorbidities.

We identified 31 studies: 17 COI studies,¹^,³^,⁸^,⁹^,¹¹^,¹⁷^,¹⁹^,²¹^,²³^,²⁴^,³¹^,³⁴^,³⁵^,⁴¹^,⁴⁵^,⁶³^,⁶⁴ four studies using a CMA,²⁹^,³⁰^,⁴⁸^,⁵⁸ 10 studies performing a CEA,¹⁶^,³²^,⁴⁰^,⁴²^,⁴⁷^,⁴⁹^,⁵⁵^,⁵⁶^,⁵⁹^,⁶⁵ two studies using a CBA,¹²^,¹³ and five studies performing a CUA.¹⁸^,²⁵^,⁴⁴^,⁵⁰^,⁵¹ All studies were classified based on how the primary outcome was reported.

The general, transnational comparative, approach presented here takes into account not only the differences in the studies’ methods, but the epidemiologic features (incidence and prevalence of epilepsy), stage of economic development, and organization of health care sector in the countries studied.

Table 1 Types of economic evaluation

Type of study	Description
Cost-of-illness studies (COI)	To itemize, value, and sum the costs of a particular problem with the aim of giving an idea of its economic burden
Cost-minimization analysis (CMA)	If the interventions have the same consequences, the economic analysis can concentrate on inputs only. This analysis is concerned with the identification of the intervention with the lowest possible costs
Cost-effectiveness analysis (CEA)	If the outcome of interest is the same in two programs, but they have different success in achieving the outcome
Cost-benefit analysis (CBA)	If neither the consequences nor the outcomes of two programs are the same; cost-benefit analysis aims to compare all social costs and consequences across different interventions or against a do-nothing option
Cost-utility analysis (CUA)	This analysis is preferred by analysts who have reservations about valuing benefits in dollar terms; utility refers to the preferences individuals or society may have for any particular set of health outcomes—this approach incorporates quality of life adjustments to treatment outcomes

Transnational Comparison of Cost-of-illness Studies

COI studies enumerate all costs attributable to a disease to arrive at a total cost of that disease. A COI study can follow a variety of perspectives.²^,⁵^,⁷^,¹⁴^,²⁸^,³³^,³⁶^,³⁸ From an epidemiologic point of view, COI studies can be conducted using either a prevalence- or incidence-based approach, depending on whether an annual or longitudinal horizon is adopted. Also, COI evaluations vary in their study design (i.e., prospective or retrospective study design) and method of data collection (e.g., questionnaire, medical database, case report). The sampling strategy is also a significant parameter when evaluating the cost of a disease. This ranges from collecting data from a general practitioner or a hospital, to estimating costs based on administrative databases or national samples. COI studies also vary as to whether the direct or indirect costs of a disease are calculated. Direct costs are the monetary value of resources consumed in the prevention, treatment, or rehabilitation of people with the disorder. Indirect costs represent the loss of productivity to society due to a disease and its treatment.⁷^,¹⁴

To achieve a comprehensive transnational comparison of all recent COI studies, these study perspectives were taken into consideration when analyzing, categorizing, and tabulating the studies and their results. The results appear in Tables, 2, 3, and 4.

Comparison of COI Prevalence-based Studies

Table 2 includes only prevalence-based studies, stating the country of the study, data source, method of data collection, direct or indirect costs estimated by the study, and any additional general information in the study that is of significance.

Comparison of COI Incidence-based Studies

Incidence-based studies are shown in Table 3, with an emphasis on the evolution of costs over time. Only the first 4 years after onset were included, because most studies estimated costs up to the fourth year.

Direct Cost Distribution

Table 4 depicts the breakdown of the direct costs of epilepsy treatment. Three categories are included:

Hospital costs: In- and outpatient visits, admissions, emergency room visits, and emergency transportation (ambulance) costs
Drug costs: Prescribed antiepileptic drugs (AEDs), as well as costs attributable to adverse drug reactions from the AEDs
Other costs: Diagnostic procedures, such as laboratory tests, electroencephalography, computed tomography, and magnetic resonance imaging scans as well as medical consultations that are part of the diagnostic procedures.

Six studies that did not categorize direct costs in this way were excluded from the table.¹⁹^,²³^,³⁴^,³⁵^,⁴¹^,⁶³

Cost-minimization Analysis

CMA provides the simplest economic evaluation when the alternate treatments, in this case AEDs, have equivalent clinical efficacy. To be equivalent, the comparators should be of the same efficacy in all patients, under all conditions, with similar risks of adverse events.¹⁰

Table 5 displays study duration, the configuration of the treatment pathways followed, and the nature of the direct costs included during the cost estimation procedure for four CMA studies, along with the mean cost per patient for each of the four AEDs that were examined.

Cost-effectiveness Analysis

CEA assesses how efficiently a specific health intervention influences health, compared with the next best alternative. Thus, CEAs specifically account for the costs to health of a disease and treatment that are typically excluded from COI studies (i.e., premature mortality, morbidity, disability, as well as pain and suffering).³⁶

Tables 6 and 7 include ten CEA studies. Table 6 focuses on CEA studies on AEDs; Table 7 presents CEA studies of alternative treatments which, in this case, only incorporate surgical treatment of epilepsy. The information included relates to the AEDs/treatments compared, patient population, cost and outcome measures, as well as the general findings/results of each specific study.

Cost-benefit Analysis

CBA primarily attempts to reduce outcome measures to monetary terms. Hence, when costs and benefits are expressed in the same unit of measurement, it is possible to judge whether a specific therapeutic modality is desirable from a societal viewpoint.²⁶ The two published CBA studies were conducted by the same author. Therefore, a tabulation of the CBA studies is not presented.

Table 2 Main characteristics of cost-of-illness studies: prevalence-based studies

Country	Data sources	Data collection		Annual cost per patient (US$)		Comments (costs in US$)	Ref.
Country	Data sources	Data collection		Direct	Indirect	Comments (costs in US$)	Ref.
U.S.	National sample	Retrospective	Database	1,758	—	2,053 for children	24
U.S.	Multiple MCOs	Retrospective	Database	3,007	—	Adults taking CBZ formulation (n = 1,767)	22
U.S.	MCO and medical center	Retrospective	Database	935	5,994	Total cost from 1,031–12,612 in different severity groups	8
U.S.	MCO	Retrospective	Database	1,575/3,449	—	1,575 (epilepsy-attributable cost) and 3,449 (case-control estimate)	19
U.K.	GP	Retrospective	Provider and population surveys	3,065	—	866–6,855 depending on seizure frequency	31
Italy	EC	Prospective	Questionnaire	1,098	—	547–3,530 in different prognostic categories (aged 18+)	3
Italy	EC	Prospective	Provider and population surveys	1,055	—	371–3,551 in different severity groups	63
Italy	UH, hospital and outpatient service	Prospective	Case report	1,590	—	760–2,941 in different severity groups (childhood epilepsy)	23
Italy	Referral centers	Retrospective	Case report	1,588	224	Total cost from 1,569 for adults to 2,412 for children	11
Italy	Referral centers	Retrospective	Questionnaire	1,290		411–2,941 in different severity groups	21
The Netherlands	GP, UH and EC	Prospective	Questionnaire and cost diary	2,444	—	808 cost at GP, 2,790 cost at UH, and 4,298 cost at EC	34
India	EC	Retrospective	Case report	55	128	117 cost of annual productivity loss	35
India	Medical centers	Retrospective	Questionnaire	105	283	Cost of travel included in direct cost	64
Hong Kong	EC	Retrospective	Database	433	582	Costs derived from dividing the 4-year total cost by 4	41
Burundi	National sample	Retrospective	Questionnaire	1.8	10.5	12 (epileptics), 7.7 (control group)	45
Oman	UH	Prospective	Case report	1,524	—	Only patients aged 13 and over	1
EC, epilepsy center; GP, general practitioner (physician); MCO, managed care organization; UH: University hospital.

Cost-utility Analysis

In CUA, an attempt is made to directly assess the impact of the treatments on patient well being by using a utility indicator. This approach shifts the focus from clinical indicators to the patients themselves and assesses the treatment effects, via various parameters, to determine the quality of life (QoL).³⁹ Although an increasing number of published studies focus on the QoL of epileptic patients, only five studies, referring to AED treatment of epilepsy, can be considered to be cost-utility studies.¹⁸^,²⁵^,⁴⁴^,⁵⁰^,⁵¹

Table 3 Main characteristics of cost-of-illness studies: incidence-based studies

Country	Data sources	Data collection		Annual cost (US$) per patient (direct cost)				Comments (costs US$)	Ref.
Country	Data sources	Data collection		Year 1	Year 2	Year 3	Year 4	Comments (costs US$)	Ref.
U.S.	Medical center plus HMO	Retrospective	Database	3,813	848	569	496	3,749 to 7,671 depending on seizure frequency (in 4 years)	9
U.S.	National sample	Retrospective	Database	1,317	892	892	892	Top-down analysis	24
U.S.	Expert panel	Retrospective	Questionnaire	6,506	2,282	2,282	2,282	Bottom-up analysis	24
France	Specialists	Prospective	Cohort	2,379	626	—	—	Second year costs were more sensitive to seizure frequency	17

Conversion of the Results of Cost-of-epilepsy Studies

In transnational comparisons of health economics evaluations, several monetary issues must be considered, such as fluctuating exchange rates and the rate of inflation.

For purposes of comparison, the estimates from different countries were converted into 2003 US$. The rate of inflation was calculated using the Consumer Price Index. The exchange rate used was the mean exchange rate for the US$ for the year 2003.

Table 4 Distribution of direct costs

Country	Hospital costs (%)	Drug costs costs (%)	Others (%)	Ref.
U.S.	51	24	25	24
U.S.	39	31	30	8
U.K.	32	10	58	31
Italy	23	60	17	3
Italy	82	12	6	11
Italy	34	48	18	21
India	17	58	25	64
Burundi	22	71	7	45
Oman	68	23	9	1

Findings Among Economics Studies

Cost-of-illness Studies

The literature identified 17 studies performing a COI analysis. Tables 2, 3, and 4 show the results in US$ at the 2003 exchange

rate. A total of 15 of these studies were included in Table 2, as prevalence-based studies. The vast majority of the studies were conducted in the United States or Europe (three in the United States, one in the United Kingdom, five in Italy, and one in The Netherlands). Only four other countries conducted COI studies (India, Hong Kong, Burundi, and Oman). Table 3 shows that only three studies followed an incidence-based approach (one of which calculated the costs in two different ways). Two of these were based in the United States, and the other in France.

Prevalence Based-studies

Direct Costs of Epilepsy.

The estimated annual direct costs of epilepsy vary significantly from study to study and range from US$1.8 to US$3,449 (Table 2). However, a closer look reveals that a smaller disparity of costs tends to exist if they are grouped based on the degree of development of the country in which the studies were conducted. Estimated direct costs vary from US$935 to US$3,449 in the United States, US$3,065 in the United Kingdom, and US$1,055 to US$1,590 in Italy. In the less developed countries, the costs of epilepsy range from US$55 to US$105 in India, to US$1.8 in Burundi (Table 2). Nevertheless, the variation between the costs is large. Heaney et al. found that prices for medical services and AEDs vary widely even between developed countries.²⁷ In a comparison among eight economically developed European countries, similar medical services were found to vary by as much as 24 times, whereas the prices of similar AEDs varied up to 4.4 times. Previous reviews have speculated on the difficulty of comparing results from COI studies.²^,⁵^,⁷^,¹⁴^,²⁸^,³³^,³⁶^,³⁸ Methodologic issues give rise to such disparities in cost-of-epilepsy estimations. Perhaps future studies could normalize or reduce international disparities; for example, they might be normalized using per capita income, gross domestic product, or some other standard economic indicator.

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