Clinical efficacy and safety of the newer antiepileptic drugs as adjunctive treatment in adults with refractory partial-onset epilepsy: A meta-analysis of randomized placebo-controlled trials.
ABSTRACT OBJECTIVE: To evaluate the clinical efficacy and safety of the newer antiepileptic drugs (AEDs), namely, Eslicarbazepine (ESL), Retigabine/Ezogabine (RTG), Carisbamate (CAR), Lacosamide (LAC), Brivaracetam (BRI) or Perampanel (PER) as adjunctive therapy for adults with partial-onset seizures (POS). METHODS: A systematic review of Randomized placebo-controlled Trials (RCTs) of newer AEDs was conducted. Electronic databases and identified bibliographies were searched to retrieve RCTs. The primary outcomes were responder rates and withdrawal rates, adverse effects. Pooled effects of Odds Ratio (OR), Risk Ratio (RR) and Risk Differences (RD) were derived from meta-analysis implemented in Revmen 5.1. RESULTS: In total, 15 RCTs were included. All the studies contained a baseline and treatment phase. The pooled OR of all newer AEDs vs placebo was 2.16 (95%CI: 1.82, 2.57) for responder rates, 1.54 (1.12, 2.10) for withdrawal rates, 1.67 (1.34, 2.08) for adverse effects. The indirect comparisons between individual newer AED and all other newer AEDs suggested the similar results in responder rates (ORs, BRI 1.79 [-1.50, 5.08], RTG 1.41 [0.49, 2.33]). CONCLUSIONS: The pooled ORs suggested newer AEDs might be more effective than placebo while with higher incidence of adverse effects. The indirect comparisons suggested BRI, followed by RTG, might be more effective than all other newer AEDs, which could be confirmed by future clinical studies.
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ABSTRACT: Aim. The aim of this study was to evaluate the impact of two different therapeutic strategies in patients with partial seizures who were intractable to the first prescribed antiepileptic drug (AED); alternative monotherapy vs early add-on treatment. Methods. We conducted an open, cluster-randomised, prospective, controlled trial in patients with persistent partial seizures, despite treatment with one AED, who were never administered any other AEDs. Neurologists were randomised to two strategies: in group A, an alternative monotherapy with a second AED was employed; in group B, add-on treatment with a second AED was employed. The primary outcome was the percentage of seizure-free patients during a two-month period after six months of treatment. The secondary outcomes were: (i) the percentage of patients achieving a 50% reduction in the number of seizures at six months; (ii) the quality of life based on the Quality Of Life In Epilepsy scale; and (iii) tolerability. Results. A total of 143 neurologists were included and randomised, and 264 patients were evaluated. At six months, the primary outcome was 51% in group A and 45% in group B (p=0.34). The percentage of patients achieving a 50% reduction in the number of seizures at six months was 76% in group A and 84% in group B (p=0.53). The quality of life and the tolerability did not significantly differ between the two groups. Conclusions. Alternative monotherapy or early treatment initiation with another AED drug resulted in similar efficacy, and the side effects associated with monotherapy and combined therapies were similar, which suggests that individual susceptibility is more important than the number and burden of AEDs used.Epileptic disorders: international epilepsy journal with videotape 04/2014; · 0.90 Impact Factor
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ABSTRACT: Network meta-analysis (NMA) is a new technique that allows multiple treatment comparisons and provides estimates of effect sizes for all possible pair-wise comparisons. Several NMAs of antiepileptic drug (AED) efficacy and tolerability in individuals with refractory focal epilepsy, however, came to non-specific and, in some cases, divergent conclusions. We review some clinical factors that may be responsible for these inconsistent findings. A major issue is the small number of individuals included in the meta-analyses with consequent wide confidence intervals and lack of ability to achieve significant results. Further issues are lack of robustness of the measured efficacy outcome-the responder ratio (the percentage of individuals with a >50 % improvement in seizure frequency); the selection of randomized studies (RCTs) included, i.e., the inclusion of studies with heterogeneous populations (children and adults); and inclusion of people treated with different doses of the experimental drug. Some methods of analysing data from RCTs, such as the last observation carried forward (LOCF) analysis, the choice of different phases of the study to compare to baseline, and the year in which the trial was conducted, selectively affect measurement of efficacy outcomes. Titration speed and other methodological aspects selectively affect tolerability. Several factors restrict the analysis of clinically useful estimates of the comparative efficacy of AEDs, while analysis of tolerability may be easier to accomplish.European Journal of Clinical Pharmacology 03/2014; · 2.70 Impact Factor
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ABSTRACT: Perampanel (Fycompa®) is and AMPA receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both cerebral cortex and hippocampus, associated with antiepileptic efficacy, and also in cerebellum, associated with motor side-effects, in rodent and human brain. We also asked if epileptic and non-epileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, perampanel inhibited AMPA receptors from hippocampal tissue that was removed from a patient undergoing surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter demonstrating effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.Journal of Pharmacology and Experimental Therapeutics 07/2014; · 3.86 Impact Factor