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ORIGINAL ARTICLE
Year : 2017  |  Volume : 8  |  Issue : 1  |  Page : 25-29

Comparative analysis of cost and efficacy for mono and dual therapy of antiepileptics among children


1 Department of Pharmacy Practice, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, Andhra Pradesh, India; Department of Clinical Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia, Kingdom of Saudi Arabia
2 Department of Pharmacy Practice, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, Andhra Pradesh, India
3 Department of Clinical Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia

Date of Web Publication18-Oct-2017

Correspondence Address:
Easwaran Vigneshwaran
Department of Clinical Pharmacy, King Khalid University, Abha
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ddt.DDT_16_16

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  Abstract 

Introduction: Developing countries contribute to major number of patients living with epilepsy, around five million people are living with epilepsy in India alone. Most of the epileptic children may require multiple antiepileptic therapy due to the failure of monotherapy. Basic research evidence suggest that sodium valproate and carbamazepine (CBZ) may have synergistic anticonvulsant effects when they are used together. In addition to that, chronic disorders make the patients economically weak and produce more burden. Aim and Objective: Therefore, this study was designed to compare the efficacy of valproate monotherapy with valproate and CBZ dual therapy. Methodology: It is a prospective, comparative study conducted at a secondary care referral hospital and private clinic. A nonprobabilistic convenient sampling was done to recruit the study subjects. A total of fifty subjects were recruited into the present study, and they were divided into two groups, i.e., monotherapy group (CBZ) and dual therapy group (CBZ and valproate). After providing appropriate counseling, subjects were interviewed to estimate the quality of life (QOL) using child version of TNO-AZL Children's Quality of Life questionnaire. Hospital patient records, prescription data from the pharmacy were also used to obtain the direct and indirect cost of treatment. Results: Our study results showed that monotherapy has a potential to produce a higher level of QOL than dual therapy. It also involved with decreased seizure frequency. Although there was no statistically significant difference in terms of cost for both the treatment groups, still dual therapy is associated with higher cost burden. The average costs per QOL and changes in the frequency of seizure are also identified to produce higher economic burden to the patients.Conclusion: Thus, the present study has concluded that monotherapy may be considered as better cost-effective treatment in partial seizures than dual therapy, unless if there is no treatment failure with monotherapy.

Keywords: Cost, epilepsy, quality of life


How to cite this article:
Vigneshwaran E, Madineni M, Sake K, Alakhali KM, Sirajudeen SA, Khan NA. Comparative analysis of cost and efficacy for mono and dual therapy of antiepileptics among children. Drug Dev Ther 2017;8:25-9

How to cite this URL:
Vigneshwaran E, Madineni M, Sake K, Alakhali KM, Sirajudeen SA, Khan NA. Comparative analysis of cost and efficacy for mono and dual therapy of antiepileptics among children. Drug Dev Ther [serial online] 2017 [cited 2017 Nov 17];8:25-9. Available from: http://www.ddtjournal.org/text.asp?2017/8/1/25/216930




  Introduction Top


Epilepsy is a common neurological disease affecting almost 50 million people worldwide. It is an alarming problem in children, where they are most frequently affected with afebrile seizures.[1],[2] Epilepsy syndromes start in infancy or childhood in majority of the population.[3] The etiology for acute seizure in infants and children could be diverse ranging from infective, traumatic, vascular, structural cause, toxics, etc.[3],[4]

Developing countries contribute to the major amount of patients living with epilepsy, around 5 million people are living with epilepsy in India alone.[5] Pharmacological treatment is the major and first line of treatment to control epilepsy.[6] The goal of treatment is restoration of near normal life with complete seizure control using a single antiepileptic drug (AED) and increased quality of life (QOL). Valproate is one of the AEDs widely used as first-line treatment for epilepsy in children,[7] and it is approved primarily for patients with absence seizures. Moreover, it has broad spectrum of antiepileptic activity to all types of seizures.[8]

Carbamazepine (CBZ) is an approved drug of choice for the patients with simple or complex partial seizures and secondary generalized seizures in adults and children. Usually, patients with partial seizures are not well controlled by monotherapy with available AEDs.[9],[10],[11],[12] Patient's clinical characteristics such as frequent, focal and long duration of seizures, symptomatic epilepsy, and status epilepticus may lead to treatment failure for monotherapy. The data from developing countries show that around 17%–40% of children with epilepsy require multiple antiepileptic therapy due to failure of monotherapy.[13],[14],[15]

Basic research evidence suggests that sodium valproate and CBZ may have synergistic anticonvulsant effects when they are used together. This response to the combination appeared to be due to pharmacodynamic rather than pharmacokinetic effects.[12]

In addition to that, chronic disorders make the patients economically weak and produce more burden.[9] Economy plays a major role in the management of epilepsy in developing countries. In 2001, Thomas et al. reported that the annual economic burden of epilepsy in India is 88.2% of gross national product (GNP) per capita and 0.5% of the GNP. Recently, it is estimated that the direct treatment cost per month due to drugs, travel, and investigations is Rs. 219. Further, the rural residents who are financially weaker spend more money out of their pocket for the treatment expenditure of epilepsy.[10],[16] The results from the studies conducted in India had discussed the QOL and economic aspects of antiepileptic treatment for monotherapy or polytherapy. The available studies are very scarce to discuss the cost of antiepileptic treatment and its impact on QOL with dual therapy or in comparison with monotherapy. Therefore, the primary objective was designed for this study as to compare the efficacy of valproate monotherapy with valproate and CBZ dual therapy with QOL. The secondary objective of this study is to do a cost-effective analysis between monotherapy and dual therapy for their seizure control activity.


  Methodology Top


Study design and sampling

It is a prospective, comparative study conducted at a secondary care referral hospital and private clinic, situated in one of the resource-limited settings in South India known as Anantapur, Andhra Pradesh, during November 2014–April 2015.

A nonprobabilistic convenient sampling was done to recruit the study subjects based on their availability and willingness to participate in the study. Both male and female pediatric subjects with previous history of AED use for at least 2 months before the initiation of the study was included in the present study. Children aged 6–15 years, who had been having seizures for 6 months or more were also included in this study. The patients with other neurological disorders and other intellectual impairment in whom epilepsy is not the etiology were excluded from the study. Further, children who had no interest to participate were also excluded from the study.

Ethical considerations

The present study was approved by the Institutional Review Board of Raghavendra Institute of Pharmaceutical Education and Research (Approval Number RIPERIRB/2015/04). Sixty days of the initial period was taken to recruit the study subjects from both inpatient and outpatients' pediatric department. Informed written consent was obtained from the parents or caregivers of study subjects that clarified study purpose and protocol before the study. Further, study subjects were also informed about the study through oral communication to make the interview more efficient. The choice of the treatment options for the present study was based on the common clinical practice in our study centers.

Grouping of study subjects

All the recruited study subjects were divided into two groups based on their treatment, i.e. monotherapy group (CBZ) and dual therapy group (CBZ and valproate). Their prescriptions were filled and dispensed with an appropriate counseling on proper usage of drugs by the pharmacist.

Quality of life measurement tool

After providing appropriate counseling, subjects were interviewed to estimate the QOL using child version of TNO-AZL Children's Quality of Life (TACQOL) questionnaire. It is known as Netherland organization for applied scientific research academic medical Center (TNO-AZL) QOL questionnaire. It is meant for children those who are aged 6–15 years. It includes seven domains such as physical, motor, autonomy functioning, social, cognitive functioning, positive, and negative emotions. It comprises a total of 56 questions or items and eight questions in each individual domain with three options, i.e. never, occasionally, and often. The options “occasionally” and “often” were provided with suboptions such as fine, not so good, quite bad, and bad. The score ranges from zero to four. The scores given to the combination of answers from options and sub options, where, four indicates a higher QOL and zero indicates least QOL.[11],[17]

In case of domains related to positive emotions and negative emotions, each item consists of single question with three options. The answers coded in such a way that zero indicates lower QOL and two indicate higher QOL.[11],[17]

The questionnaire used in this study was translated into Telugu (regional language) by both medical and nonmedical experts. Further, the translated version of the questionnaire was retranslated into English to ensure the exact meaning of the original version. Cronbach alpha was calculated to ensure the internal consistency and reliability for the translated version of the questionnaire, and the value was found to be 0.59.

Other data collection

Hospital patient records, prescription data from the pharmacy were used to obtain the cost of treatment such as cost of laboratory investigations, consultation fees, medical cost, and hospital readmission cost. The cost of the treatment was measured in Indian Rupees (INR). Follow-up was done for all the patients based on their physician visit approximately with an interval of 2 months.

Patients were also reminded through phone for their follow-up physician visit. During follow-up once again, variables such as QOL and seizure frequency were estimated through questionnaire and seizure diary, respectively. After collection of both effectiveness parameters and costs, average cost-effectiveness ratio also calculated. Cost-effectiveness was calculated as ratio of cost of treatment and improvement in QOL with each treatment. The direct medication cost was calculated in INR.

Retail price of each drug was recorded based on ceiling price suggested by National Pharmaceutical Pricing Authority, compendium of notified ceiling prices of scheduled drugs – 2015.[18] Statistical analyses were performed using Instat 3.4 version. It is a commercial scientific statistics software developed and published by Graphpad software Inc.


  Results Top


The baseline characteristics of the present study were represented in [Table 1]. A total of fifty subjects were recruited in the study, and they were divided into two groups based on their treatment. Twenty-five subjects were included in each group. The dual therapy group has a high proportion of male subjects than the other group. There was no statistical significant difference found between two groups in terms of gender distribution at the confidence level of 95% (Fisher's exact test, P = 0.7761). The mean age of the present study population was found to be 9.96 ± 3.0 and 9.28 ± 3.0 for monotherapy and dual therapy groups, respectively. There was no significant difference between two treatment groups based on age distribution.
Table 1: Baseline characteristics

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The frequency of seizures was measured in baseline evaluation for measuring the severity of disease. We found that there is no significant difference between two groups in terms of seizures frequency based on Student's t-test (P = 0.5745). Comparison of baseline scores of various domains in TAC-QOL Child Form questionnaire between two different treatment groups was found to have no statistical difference except positive and negative emotions. The “P” value of different domains such as body, motor, autonomy, cognition, social, positive emotions, and negative emotions was found to be 0.9153, 0.7247, 0.6074, 0.1827, 0.9462, 0.0076, and 0.007, respectively. The results also clearly revealed that there is no significant difference in overall QOL of study subjects from both groups.

[Table 2] represents the comparison of efficacy outcome of two different treatment groups based on unpaired Student's t-test. Scores of various domains of TACQOL questionnaire between two different treatments were compared after treatment. They were found to have a significant difference in most of the QOL domains except bodily function and autonomy. The overall QOL score between two different treatment groups was found to have statistically significant difference (P = 0.0091). We found a significant difference in terms of changes in seizure frequency between two different groups (P = 0.0343).
Table 2: Efficacy outcome of monotherapy and dual therapy groups

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The comparison of cost of treatment between two groups has been described in [Table 3]. It reveals that there is no significant difference in the costs of treatment between two groups. Direct medical costs such as cost for medication, laboratory costs, and hospital readmission costs were measured at 95% confidence interval (P = 0.7225, 0.0996 and 0.5606, respectively). Even the total cost found to have no difference between treatment groups.
Table 3: Direct cost of two different treatment groups

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Total direct costs for both the treatment groups were compared using Student's t-test. We found that there is no significant difference between two different groups, and the “P” value was found to be 0.4187.

[Table 4] represents the average cost-effectiveness ratio of two treatment groups. The cost per patient in monotherapy and dual therapy was found to be Rs. 2110.25 and 2321.89, respectively. The QOL per patient in monotherapy and dual therapy was 25.03 and 21.42, respectively. The change in frequency of seizures in monotherapy and dual therapy was found to be 1.96 and 2.16, respectively. The average cost required per QOL score for monotherapy is Rs. 84.30 and Rs. 108.3 for dual therapy. The incremental cost-effectiveness ratio with regard to QOL was found to be 58.62.
Table 4: Cost-effectiveness ratio

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  Discussion Top


Epilepsy is a chronic disease requires continuous and long-term treatment with AEDs. The main aim of pharmacological therapy in epilepsy is to attain a state of absence of seizures and increased QOL. The research data describing the fact that most of the epileptic patients may have remission on seizure episodes while on their single AEDs and may require second AED to control seizures.[19],[20],[21]

A total of fifty children were recruited in the present study. The mean age of the present study population is 9.96, 9.28 for monotherapy, and dual therapy group, respectively. These results were similar to an another study conducted by Sobaniec et al.[22] In our study, the percentage of male gender is 40 and 48 in mono and dual therapy, respectively. These results were contrast with the study published by Frew et al.[3] It might be due to our nonprobabilistic convenience sampling technique and most of our study subjects are from resource-limited settings. The present study results showed that generalized tonic-clonic seizure was found to be more prevalent. The study conducted among adult subjects revealed that complex partial seizure and partial evolving to secondarily generalized was found to be more prevalent.[23] Some other Indian studies have also reported that the generalized seizure is most predominant.[19] Testing for baseline differences is often necessary because it identifies the real or important differences between various treatment groups.[24] Similar to the comparative study published by Vigneshwaran et al., we found no significant difference in terms of baseline demographic and clinical characteristics.[25] It implicated that treatment groups are similar while the study was initiated.

QOL is a primary efficacy outcome measure used in this study; hence, it is known as subjective evaluation provides a clue to determine how and how much the disease and the therapy is influencing the normal life of patients.[26] In this study, we noted that there is a significant difference in terms of QOL and seizure frequency between two treatment groups. It might be due to reduce seizure frequency with the monotherapy than dual therapy. These results are similar to other studies published in this area earlier, and it showed that seizure frequency is an important factor in reducing the stigma and other negative feelings.[1],[22],[27] A 1-year observational study reported that the polytherapy can impair the QOL of patients with generalized tonic-clonic seizures,[1] whereas, another study reported that the QOL can be improved by dual or polytherapy.[26] Hence, it is an interesting and important area to know about the efficacy of mono-, dual- and polytherapy. The present study results showed that the monotherapy was found to have higher QOL than dual therapy. In addition to that, the seizure frequency was reduced with monotherapy. The similar kind of results was already reported in the previously published literature.[23],[28],[29] The direct treatment cost of valproic acid and CBZ was Rs. 1629.31 as per the report of Goyal et al. 2011, and in our study, it was found to be Rs. 2321.89.[1] This difference might be because of the difference in the study settings and study sample.

Although it is recommended that, the adverse effects and efficacy of AEDs must be considered while evaluating cost-effectiveness,[30],[31] the present study has a limitation of availability and analysis of safety data alone. Still, we observed that monotherapy was found to be cost-effective than dual therapy. Not only on direct cost but also included cost per patient, QOL per patient, seizure frequency reduction, average cost per QoL, and average cost per frequency change of seizures. The previous studies have not given the certainty of cost-effective drug among antiepileptics, but fewer reports established a role of monotherapy in reducing the cost of treatment.[3],[32]


  Conclusion Top


Our study results showed that monotherapy has a potential to produce a higher level of QOL than dual therapy. It also involved with decreased seizure frequency.

Although there was no statistically significant difference in terms of cost for both the treatment groups, still dual therapy is associated with higher cost burden. The high rate of hospital admissions and rehospitalizations is associated with dual therapy. The average costs per QOL and changes in the frequency of seizure are also identified to produce higher economic burden to the patients. Thus, the present study has concluded that monotherapy may be considered as better cost-effective treatment in partial seizures than dual therapy, unless if there is no treatment failure with monotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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