Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
Epilepsia (Impact Factor: 4.57). 01/2013; 54(3). DOI: 10.1111/epi.12074
Source: PubMed


The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered.

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    • "These trials raise important ethical concerns due to the fact that patients with severe epilepsy may be exposed to placebo and undue morbidity, especially because they may also be good candidates for epilepsy surgery [1]. Clinical trials involving newly diagnosed patients, on the other hand, usually include an established AED as an active comparator, but these studies may still fail to yield answers to important questions [2]. "
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    ABSTRACT: To ensure the development of new effective treatments in medicine, clinical trials (CTs) need to be conducted. The study was aimed at assessing knowledge of and attitudes toward clinical drug trials among patients with epilepsy, along with factors that motivate them to participate in CTs. Use of this information could improve recruitment for future trials and enhance their quality. A 45-item questionnaire on the views of patients with epilepsy about CTs was developed. It included statements that the respondents assessed on a Likert scale from 1 ('strongly disagree') to 5 ('strongly agree'). The questionnaire was mailed to a random sample (n=1875) of members of the Finnish Epilepsy Association aged at least 18years. In all, 342 questionnaires were returned, and 325 were accepted after exclusion. The analysis indicates that the general attitudes of patients with epilepsy toward CTs are positive. Most of the patients with epilepsy saw participation in clinical trials as indispensable to new treatments becoming available. Retired respondents and persons who had developed epilepsy when young had inadequate knowledge of general issues related to CTs. Level of education and number of antiepileptic medications (AEDs) were significant predictors for failure to understand the nature and purpose of clinical research - i.e., for therapeutic misconception (TM). Additionally, strong correlation was found between TM and respondents' willingness to participate in clinical trials. The new treatments are often studied in patients with a high risk of TM and impaired comprehension of general procedures associated with CTs. Clinically, it may be worthwhile for the investigators to be able to recognize vulnerable individuals and pay special attention to the information provided on the purposes and methods of the trial, to contribute to high-quality AED studies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Epilepsy & Behavior
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    • "To a large degree, the newer drugs such as gabapentin, lamotrigine, and levetiracetam are better tolerated than older agents such as phenytoin and phenobarbital.1 However, efficacy of the newer drugs, as defined by seizure control, was not demonstrably different from drugs available before 1980.2 The proportion of patients diagnosed with epilepsy that subsequently become medically refractory remains at around 30%, despite the introduction of over 15 new antiepileptic drugs in the last 20 years.3 "
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    ABSTRACT: Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile hydrate) is the latest in the line of new antiepileptic drugs with a novel mechanism of action. Perampanel inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-induced increases in intracellular Ca(2+) and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation. Three Phase III multicenter, randomized, double-blind, placebo-controlled trials demonstrated the efficacy and good tolerability of perampanel as adjunctive treatment in patients with refractory partial-onset seizures. The drug is approved for use in the European Union and United States, with expected release onto the American market in June-September 2013, pending US Drug Enforcement Agency classification. The pharmacology of perampanel offers potential as more than just another new antiepileptic drug. This first-in-class drug will provide another option for practitioners of rational polytherapy. As an AMPA-receptor antagonist, perampanel may possess antiepileptogenic properties in addition to its demonstrated antiseizure properties.
    Full-text · Article · Jul 2013 · Therapeutics and Clinical Risk Management
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    ABSTRACT: To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs) for monotherapy of adult patients with focal epilepsy in routine clinical practice. Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), topiramate (TPM), or oxcarbazepine (OXC) as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD), were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure. This study included 654 patients: CBZ (n=125), VPA (n=151), LTG (n=135), TPM (n=76), and OXC (n=167). The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]); TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74]), and OXC was better than VPA (0.86 [0.78-0.96]). After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82]) and OXC (LTG vs. OXC, 0.76 [0.63-0.93]); OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40]). LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not.
    Full-text · Article · Jul 2015 · PLoS ONE
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