Experience with new antiepileptic drugs among Indians with refractory epilepsy

Objectives: We assessed the comparative efficacy and tolerability of topiramate (TPM), lamotrigine (LTG), gabapentin (GBP) and clobazam (CLB) with an aim to formulate clinical guidelines while initiating treatment with new anti-epileptic drugs (AEDs). Methods: A prospective open label, nonrandomized, add-on study was conducted on 203 Indian patients with seizures refractory to conventional AEDs (age 1-63yrs, mean age 19.4±13.4 yrs) who were started on any of the four new AEDs, as and when the AEDs were available, either singly or in combination. Patients were prospectively followed up for a minimum period of four months and the 50% seizure reduction, seizure freedom, adverse events and cost of daily therapy were assessed. Results: At the end of four months, 166 patients had completed follow up. Baseline seizure frequencies were significantly different across the groups (p<0.01). The proportion of patients with >50% seizure reduction, seizure freedom, adverse events and the increase in cost over the baseline respectively were: TPM (63 patients) (51%, 13%, 52%, 4 times), LTG (62 patients) (73%, 27%, 34%, 3 times), CLB (16 patients) (69%, 56%, 56%, 2 times) and patients on two of these new AEDs (25 patients) (52%, 16%, 40%, 4 times). The seizure change across all the groups was similar. In conclusions: The three new AEDs studied (TPM, LTG, CLB) resulted in similar seizure control when used as add on therapy. Based on cost, we recommend addition of the new AEDs sequentially: CLB, LTG and TPM in that order and then try a combination of two new AEDs. Neurol J Southeast Asia 2003; 8 : 87 – 95 Address corresponding to: Prof. Satish Jain, MD; DM, Director – Indian Epilepsy Centre, A-258, Defense Colony, New Delhi 110 024 (India). Phone: 91-11-2433 3331, 91-11-2433 5214, Fax: 91-112433 3330, Email: [email protected] INTRODUCTION Epilepsy affects 2-3% of the population.1 The prevalence of epilepsy in India ranges from 1.71 to 11.9 (mean 5.35) per 1000 population.2 Approximately 20% of patients have refractory epilepsy despite optimal anti-epileptic drugs (AEDs).3 In randomized controlled trials (RCTs) many new AEDs are reported to be more effective than placebo in the treatment of refractory seizures in adults and children.4 A meta-analysis of RCTs involving the new AEDs reported similar efficacy or tolerability of topiramate (TPM), gabapentin (GBP), lamotrigine (LTG), tiagabine, vigabatrin and zonisamide.5 These studies have been mainly conducted in the developed countries. There is limited data on the usefulness of new AEDs among Asians. The new AEDs being more expensive than the conventional AEDs, their affordability is a major problem in developing countries. We report our experience on the comparative efficacy, tolerability and cost of TPM, LTG, GBP and clobazam (CLB) among patients with refractory epilepsy treated at a tertiary care hospital in northern India. METHODS All cases of refractory epilepsy (age > 1 year) attending the Neurology outpatient department of All India Institute of Medical Sciences, New Delhi, India who were started on TPM, LTG, CLB or GBP were included in the study and prospectively followed up on a bimonthly basis for 6 months. Refractory epilepsy was defined as seizures frequent or severe enough to interfere with the quality of life or if the patient developed intolerable side effects when on maximally tolerated doses of one or more AEDs without seizure control.6 Patients with progressive neurological disorders and pseudoseizures were excluded from the study. Video EEG recording was obtained for the diagnosis in cases suspected to have pseudoseizures. Patient selection and seizure classification This was an open label, non-randomized study. All patients studied were interviewed in detail and examined by one author (SJ). Patient demographic data, age of onset of seizures, type of seizure, epileptic syndrome, history of status Neurol J Southeast Asia Dec 2003 88 epilepticus, febrile convulsions, family history of epilepsy and other risk factors for epilepsy were recorded in a pre-designed proforma by one author (PRK). EEGs were done in all patients. CT/MRI brain scans were done if indicated. Seizures were classified according to the ILAE classification of epileptic seizures7 and epilepsies were classified according to the ILAE classification of epilepsy and epileptic syndromes8 by one author (SJ). Initiation of new AED therapy All patients received oral therapy. Baseline monthly seizure frequency during previous 6 months and body weight was recorded. TPM was started at a dose of 25mg daily, and increased at fortnightly intervals by 25-50mg up to a maximum of 10mg/kg/day. Children were started on TPM at a dose of 0.5mg/kg/day and titrated similarly. LTG was started as 25mg on alternate days for 2 weeks then increased to 25mg daily in patients on Valproate increasing up to 5mg/kg/day. In patients not on valproate, 25-50mg/day of LTG was started and increased every two weeks. GBP was started in the dose of 900-2400 mg/day.9 CLB was introduced as 5-10mg/day increasing over 2-3 weeks up to 0.5mg/kg/day. All new AEDs were tried to the minimum effective or maximally tolerated dose. Although the groups were not strictly comparable in terms of the number of AEDs used, the patients could be treated with any combinations of conventional (valproate, carbamazepine, phenytoin, phenobarbitone, clonazepam and new AEDs (TPM, LTG, CLB or GBP) before inclusion in the study. In case of early intolerance to any of the new AEDs, the titration phase was extended suitably to the patients’ benefit or the new AED was withdrawn if considered necessary. Follow-up and assessment of efficacy of new AEDs Patients were prospectively followed up at bimonthly intervals. The monthly seizure frequency and adverse events for a period of 6 months were recorded. Patients were compared at a minimum follow up of 4 months and were divided into four groups based on the new AED they received at entry (TPM, LTG, CLB alone and patients receiving two new AED). Only one patient receiving GBP alone and was excluded from analysis. The baseline seizure frequency among all the groups was taken as the seizure frequency before addition of the first new AED. Seizure control was calculated as >50% reduction and <50% reduction in seizure frequency from the baseline. The seizure change over 4 months (absolute seizure reduction) was calculated as the difference in seizure frequency between baseline and follow up at 4 months. Cost of therapy was calculated in Indian Rupees (1US$=47 INR) based on the price of the lowest available dose unit of one leading brand. The dose units taken for calculation were: 100mg for Phenytoin, 200mg for Cabamazepine and Valproate, 30 mg for Phenobarbitone, 0.5mg for Clonazepam, 25mg for TPM and LTG, 5mg for CLB and 300mg for GBP. These units were used to calculate the cost of the daily total dose of one or more conventional or new AEDs. The mean daily cost of conventional and new AEDs was also calculated for each group for comparison. Statistical analysis Data was entered into a Microsoft Excel spreadsheet and analyzed using SPSS version 10 statistical software for Windows and Systat 7 for Windows. Subgroup analysis was done in each of the four groups between those with >50% seizure reduction and <50% seizure reduction. The four groups were then compared against each other on all variables. The categorical variables were compared using Pearson’s chi square or Fisher’s exact test and continuous variables were compared using the t test or Wilcoxon rank sum test. Kruskall Wallis test was used to compare the seizure frequency across all the 4 groups. Logistic regression was done to further analyze the four groups with the dichotomous variables of 50% seizure reduction and side effects. Statistical significance was considered when p ≤ 0.05.