Clinical and economic implications of epilepsy management across treatment lines in Spain: a real-life database analysis

Epilepsy is a chronic brain disease characterized by recurrent seizures and is one of the most common neurologic diseases, with approximately 50 million people affected worldwide [1, 2]. The annual incidence rate of epilepsy has been estimated at 50.4 to 81.7 cases per 100,000 individuals [1, 3], and according to the Global Burden of Disease Study, epilepsy constitutes a significant cause of disability and mortality [4]. In Spain, the mortality rate of patients with epilepsy is estimated to be two to three times higher than that of the general population [5]. In addition, patients with epilepsy present with many comorbidities, such as depression, anxiety, dementia, and migraine [6].

The ultimate epilepsy treatment goals are to achieve seizure freedom without clinically significant adverse effects and to improve quality of life [5, 7, 8]. Epilepsy guidelines recommend a first-line treatment based on monotherapy, followed by a second monotherapy or a first adjuvant treatment if seizures persist [5]. Nonetheless, existing guidelines do not contain therapeutic algorithms recommending the use of specific pharmacological alternatives for each treatment line [5, 8, 10].

Drug-resistant epilepsy (DRE) is defined by the International League Against Epilepsy (ILAE) as the failure of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [6, 11]. In recent decades, the number of antiseizure medications (ASMs) has increased and many therapeutic alternatives are now available [5], but studies suggest that 30–40% of patients can still be defined as drug-resistant based on the ILAE definition [12‐14]. Poor medication adherence and comorbidities are key predictors of lack of seizure control [15].

The costs associated with epilepsy management depend on disease duration and severity, response to treatment, and healthcare setting [16‐18]. Consequently, patients with poor control and more severe forms of epilepsy, such as DRE, use more healthcare resources, resulting in substantial costs for healthcare systems [17‐19]. In addition, epilepsy causes significant productivity losses derived from the higher frequency of unemployment and precariousness among patients [16, 20]. Despite the existing evidence regarding the clinical and economic implications of epilepsy, data on the management of patients across treatment lines is limited [21]. In Spain, real-life studies regarding epilepsy management, healthcare resource use, and associated costs for the Spanish National Health System (SNHS) and society are scarce. This 6-year, retrospective study aimed to analyze the clinical and economic consequences of the current management of adult patients with epilepsy across treatment lines in Spain using clinical practice data from a large administrative database collected between January 2016 and December 2021. To that end, we studied: the demographic characteristics and comorbidities of patients with epilepsy across treatment lines; the epilepsy treatments and concomitant medications used in clinical practice; and the use of healthcare resources and associated costs.

This study provides real-world evidence on the characteristics, comorbidities and most frequently used treatments of patients with epilepsy in Spain. We also evaluated the duration of the therapy lines, and the progression of healthcare resource use and associated costs across epilepsy treatment lines.

Study cohorts were defined according to treatment line and our results show that the patients’ characteristics were comparable among them. Comorbidities were similar among cohorts when individually compared, except that depressive syndrome was more prevalent in cohort 4. However, when the Charlson Index, a weighted index to predict risk of death for patients with specific comorbid conditions was calculated, a trend towards a higher comorbidity burden was observed with treatment line progression, with a significantly higher score in cohort 4. This agrees with the previously described higher comorbidity burden in patients with medically refractory epilepsy [30].

Previous studies reported that approximately a third of patients remain uncontrolled after treatment with at least two antiepileptic drugs [12‐14]. In our study, the proportion of patients in the ≥ 3rd line of treatment was 13.3%. However, in cohorts 1 and 2 of our study, a high proportion of patients had a follow up that was shorter than the average time to progress to the next line of treatment. Therefore, DRE could not be ruled out in these patients.

Patients with newly diagnosed focal epilepsy have been shown to have a higher prevalence of mood disorders, anxiety disorders and suicidality than the general population [31]. In addition, studies have shown an association between DRE and depressive disorders [32, 33]. In agreement, our results showed that 30.8% of the patients in the 4th + treatment line, in which 93.2% of the patients were prescribed ≥ 3 antiepileptic drugs, were diagnosed with depressive disorder as compared with 22.6%, 21.3% and 23.4% in the 1st, 2nd and 3rd treatment lines, respectively. For patients with DRE, depression is a significant predictor of reduced quality of life [34]. Therefore, special attention must be given to prevent depressive disorder during the management of patients with epilepsy, not only in those with DRE but also in patients with newly diagnosed disease.

Analysis of the main ASMs prescribed during the study period revealed a broad heterogeneity in drug combinations used from the second line onwards, in line with a lack of a specific therapeutic algorithm. Many patients were treated with levetiracetam, in accordance with a previous study [35]. We also observed widespread use of the first-generation drug valproic acid. This might be due to its high effectiveness against generalized seizure and related epileptic syndromes [36], despite the restrictions in women with childbearing potential [37]. For third-generation drugs such as brivaracetam, which have only become available in Spain more recently, prescriptions recorded in our study may be lower than current usage based on the time period of the study. We also observed scarce use of valproate + lamotrigine in the 3rd and ≥4th lines of therapy compared with other polytherapies, despite this combination being shown to be effective in the management of patients with refractory epilepsy based on the synergistic effect of the two agents [38].

Our data show a decrease in treatment duration as treatment lines progressed. This could be due to the perception of poor disease control by the physician, whose alternative might be moving the patient to the following treatment line. This reduction in treatment line duration was accompanied by an increase in HRU use and associated costs. Our results corroborate that poor control of epilepsy involves substantial costs; the incremental cost between lines 1 and 2 was smaller than between lines 2 and 3, which in turn was smaller than between lines 3 and 4, thus indicating that costs progressively increased across treatment lines. Moreover, the cost difference widened with each line (the difference between lines 3 and 4 was bigger than between lines 1 and 2). In this regard, other studies found that DRE was associated with increased expenditure. Villanueva et al. described that the patients diagnosed with DRE had higher direct epilepsy-related costs than non-DRE patients [18]. Similarly, Willems et al. found that, compared with non-DRE, DRE entailed higher expenditure in terms of total, direct, and indirect costs of illness [39]. Furthermore, Zelicourt et al. reported that the use of almost all healthcare resources was higher in patients with DRE; consequently, the direct epilepsy-related costs were more than double that in non-DRE patients [40]. Similarly, DRE costs in Spanish daily clinical practice have been shown to be associated with lower patient-reported outcome scores, highlighting how the increasing negative impact of DRE on the patient leads to higher costs [41].

The mean annual direct cost per patient of €2803 found in our study is consistent with that reported by other authors (range €1698–5432 per patient and year) [20, 39, 42, 43]. In addition, the estimated mean annual direct cost per patient was €3829 and €4903 for patients receiving 3rd and ≥4th lines of treatment, respectively, which are in line with those found in other studies (range €3777–6304 per patient and year) [18, 40, 44]. Direct medical costs increased with the treatment line and the main component of these direct costs was pharmacological treatment. This agrees with previously published data showing that the number of antiepileptic drugs, seizure frequency, and disease duration are significantly associated with the cost of illness of epilepsy [45]. In contrast with the recommendations of epilepsy guidelines [5, 9, 10], our data shows that 533 out of 662 patients in 3rd and ≥4th line therapy (85.7%) were treated with 3–4 antiepileptic medications, increasing the direct costs associated with the management of the disease. In addition, the number and duration of hospitalizations also increased with treatment line, which also explains the increase in economic burden in subsequent treatment lines.

The potential confounding effect of age, sex, and comorbidities on direct and indirect costs was addressed with an adjusted analysis. The difference in total and direct costs among cohorts remained statistically significant after adjustment, but the difference in indirect costs did not. In this regard, our analysis of indirect costs did not include unemployment or early retirement, which have been described as major contributors to indirect costs [39, 43, 46, 47]. Furthermore, indirect costs among cohorts were adjusted for comorbidities, including depression, even though depressive disorders are known to be associated with DRE [32, 33] and with an increased risk of sick leave [48], which in turn has an impact on epilepsy-associated indirect costs. In our study, the prevalence of depressive syndrome increased significantly in patients with more complex disease and associated advanced lines of treatment. Even after adjusting for depression, there was a noticeable trend toward increased indirect costs with later lines of therapy. Together, our direct and indirect cost data indicate that delaying epilepsy control increases the burden of epilepsy for the healthcare system and society. While little progress has been made to improve seizure-free rates among patients in the last few decades, use of new ASMs at earlier lines of therapy may provide an opportunity to improve seizure control [49], thereby reducing costs. Notably, new ASMs such as cenomabate (for focal seizures) and fenfluramine (for developmental and epileptic encephalopathy) were not commercialized in Spain at the time of database closure (December 2021) and are not therefore factored into our analysis.

This study has some limitations. First, the BIG-PAC^® database is administrative and may lack some data about the study population, especially if patients have been treated in private healthcare centers or in public healthcare centers that are out of the scope of BIG-PAC^®. The missing data may lead to classification bias and errors in categorizing diseases and the operational extent of costs. Another limitation is that the classification of patients by pathology in the BIG-PAC^® database is based on the ICD-9-CM coding system and not on the ILAE classification. Moreover, our study did not include direct non-healthcare costs (i.e., out-of-pocket costs or those paid for by the patient/family) as they are not registered in the database and the study design does not provide direct access to patients. Another significant limitation is the lack of information about the reasons for treatment change, which has prevented us from discriminating treatment failures from other reasons for treatment change and, therefore, calculating the proportion of DRE patients. Moreover, we have no information on how many patients are treated in epilepsy referral centers, which might impact on clinical practice. However, there are several strengths as this study included a large sample of patients with epilepsy, allowing us to capture valuable data on the public Spanish National Health System and to analyze the use of resources and costs by treatment line. In addition, we assessed not only direct, healthcare-related costs but also indirect costs associated with productivity loss. Although the differences between healthcare systems may hinder the application of our results to other settings, this analysis highlights the importance of early control of epilepsy to reduce the use of resources and the costs associated with this disease.

In conclusion, this study confirmed the substantial expenditure and use of resources derived from managing patients with epilepsy and found a progressive increase in the use of resources and costs across subsequent treatment lines. Consequently, the early control of epilepsy may not only benefit patients but also reduce the economic burden for healthcare providers.