Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes
TL;DR: 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.
Abstract: 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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TL;DR: Overall outcomes in newly diagnosed epilepsy have not improved and most patients who attain control do so with the first or second AED, although the probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried.
Abstract: Importance A study published in 2000 showed that more than one-third of adults with epilepsy have inadequate control of seizures with antiepileptic drugs (AEDs). This study evaluates overall treatment outcomes in light of the introduction of more than 1 dozen new AEDs in the past 2 decades. Objective To assess long-term treatment outcome in patients with newly diagnosed and treated epilepsy. Design, Setting, and Participants This longitudinal observational cohort study was conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. A total of 1795 individuals who were newly treated for epilepsy with AEDs between July 1, 1982, and October 31, 2012, were included in this analysis. All patients were followed up for a minimum of 2 years (until October 31, 2014) or until death, whichever came sooner. Data analysis was completed between March 2015 and May 2016. Exposures Treatment with antiepileptic drugs for patients newly diagnosed with epilepsy. Main Outcomes and Measures Seizure control was assessed at the end of the study period. Probability of achieving 1-year seizure freedom was estimated for each AED regimen prescribed. Multivariable models assessed the associations between risk factors and AED treatment outcome after adjustments were made for demographic and clinical characteristics. Results Of the 1795 included patients, 964 (53.7%) were male; the median age was 33 years (range, 9-93 years). At the end of the study period, 1144 patients (63.7%) had been seizure free for the previous year or longer. Among those achieving 1-year seizure freedom, 993 (86.8%) were taking monotherapy and 1028 (89.9%) had achieved seizure control with the first or second AED regimens. Of the total patient pool, 906 (50.5%) remained seizure free for 1 year or longer with the initial AED. If this AED failed, the second and third regimens provided an additional 11.6% and 4.4% likelihoods of seizure freedom, respectively. Only 2.12% of patients attained optimal seizure control with subsequent AEDs. Epilepsy that was not successfully controlled with the first AED had 1.73 times greater odds of not responding to treatment for each subsequent medication regimen (odds ratio, 1.73; 95% CI, 1.56-1.91;P Conclusions and Relevance Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved. Most patients who attain control do so with the first or second AED. The probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried. More than one-third of patients experience epilepsy that remains uncontrolled.
768 citations
TL;DR: The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research and Concerted actions to address these challenges are urgently needed.
674 citations
TL;DR: It is proposed that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs.
Abstract: Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs.
511 citations
TL;DR: The clinical aspects of seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.
Abstract: Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.
499 citations
TL;DR: The development of antiepileptic drugs urgently needs to be revitalized so that the authors can discover more effective antiseizure drugs for the treatment of drug resistant epilepsy, including catastrophic forms.
Abstract: Epilepsy is a serious, potentially life shortening brain disorder, the symptoms of which can be successfully treated in most patients with one or more antiepileptic drug. About two in three adults with new onset epilepsy will achieve lasting seizure remission on or off these drugs, although around half will experience mild to moderately severe adverse effects. Patients with epilepsy, especially the 20-30% whose seizures are not fully controlled with available drugs (drug resistant epilepsy), have a significantly increased risk of death, as well as psychiatric and somatic comorbidities, and adverse effects from antiepileptic drugs. Newer drugs have brought more treatment options, and some such as levetiracetam cause fewer drug interactions and less hypersensitivity than older ones. However, they do not reduce the prevalence of drug resistant epilepsy or prevent the development of epilepsy in patients at high risk, such as those with a traumatic brain injury. The development of antiepileptic drugs urgently needs to be revitalized so that we can discover more effective antiseizure drugs for the treatment of drug resistant epilepsy, including catastrophic forms. Antiepileptogenic agents to prevent epilepsy before the first seizure in at risk patients and disease modifying agents to control ongoing severe epilepsy associated with progressive underlying disease are also needed.
261 citations
References
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01 Jul 2009-Epidemiologia E Psichiatria Sociale-an International Journal for Epidemiology and Psychiatric Sciences
TL;DR: The Consolidated Statement of Reporting Trials (CONSORT) provides readers of RCTs with a list of criteria useful to assess trial validity (for full details visit www.consortstatement.org).
Abstract: Method Fifty-seven parents randomised to I0 weeks ofex~erimental Habilitation programmes for intellectual disability are primitive in developing countries (Heron & Myers, 1983). Resources to develop specialist care are scarce in these nations. One compensatory option for this deficit is to facilitate the primary care-giver to take on the role of therapist (McLoughlin, 1992), because parents are the focus of intervention (Myreddi, 1992). Parental attitude influences the development and training of the developmentally disabled child (Beckett-Edwards, 1994) and is a dynamic adaptational process subject to change (Gallimore et al, 1993). Changes in and control therapy were assessed using parental attitude occur with intervention the Parental Attitude Scale towards the (Bruiner & Beck, 1984; Sameroff & Managementof Intellectual DisabilityThe 1990). Interventions with parents are varpreand post-intervention measurements ied (Girimaii, 19931, including a model were done by a single-blinded rater and with an O ~ ~ O r m n i t y raise questions and discuss problems over a period of time (Stecompared. phens & Wyatt, 1969; Cunningham et al, Results The intervention group had a 1993). This randomised-controlled ma1 evalustatistically significant increase in the ates the efficacy of Interactive Group outcome scores and clinical improvement psychoeducation (IGP) in changing attiin the total parental attitude score, tudes towards children with intellectual orientation towards child-rearing, disability.
4,388 citations
TL;DR: Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.
Abstract: We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic—clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P<0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic—clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete c...
1,079 citations
"Updated ILAE evidence review of ant..." refers background in this paper
...…difference standard has been detected in previously Epilepsia, 54(3):551–563, 2013 doi: 10.1111/epi.12074 successful class 1 superiority studies (Mattson et al., 1985; Chadwick, 1999; Glauser et al., 2010) and sets a practical and clinically relevant efficacy/effectiveness threshold for…...
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...…1981; Shakir et al., 1981; Gibberd et al., 1982; Turnbull et al., 1982; Ramsay et al., 1983, 2010; Loiseau et al., 1984; Callaghan et al., 1985; Mattson et al., 1985; Turnbull et al.,1985; Dam et al., 1989; Feksi et al., 1991; Rastogi et al., 1991; Mattson et al., 1992; Placencia et al., 1993;…...
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University of Liverpool1, Royal Shrewsbury Hospital2, Royal London Hospital3, University of Newcastle4, Leeds General Infirmary5, Royal Hallamshire Hospital6, Arrowe Park Hospital7, Royal Victoria Infirmary8, Southern General Hospital9, Great Ormond Street Hospital10, Ninewells Hospital11, Walton Centre12, University Hospital of Wales13
TL;DR: Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.
785 citations
"Updated ILAE evidence review of ant..." refers background or methods in this paper
...The number of studies for each AED and their distribution by RCT class of evidence is shown in Table S1....
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...The search strategies for this evidence review were identical to the 2006 report, except for publication dates searched (now up to March 31, 2012) and the addition of four AEDs (lacosamide, rufinamide, potassium bromide, or trimethadione)....
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University of Liverpool1, Royal Shrewsbury Hospital2, Royal London Hospital3, University of Newcastle4, Leeds General Infirmary5, Royal Hallamshire Hospital6, Arrowe Park Hospital7, Royal Victoria Infirmary8, Southern General Hospital9, Great Ormond Street Hospital10, Ninewells Hospital11, Walton Centre12, University Hospital of Wales13
TL;DR: Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies, and because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.
774 citations
"Updated ILAE evidence review of ant..." refers background in this paper
...Since the last review, four RCTs (Steinhoff et al., 2005; Brodie et al., 2007; Marson et al., 2007b; Ramsay et al., 2010) and four new meta-analyses (Gamble et al., 2006a,b; Muller et al., 2006; Koch & Polman, 2009) examined initial monotherapy of adults with generalized-onset…...
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...…relevant RCTs were identified (Sobaniec et al., 2005; Steinhoff et al., 2005; Brodie et al., 2007; Coppola et al., 2007; Levisohn & Holland, 2007; Marson et al., 2007a,b,c; Saetre et al., 2007; Glauser et al., 2010; Ramsay et al., 2010; Eun et al., 2011; Fattore et al., 2011; Kwan et al., 2011;…...
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...The four recent RCTs were considered class III studies because of either an open-label design (Steinhoff et al., 2005; Marson et al., 2007b), too brief treatment duration (Steinhoff et al., 2005; Ramsay et al., 2010), or lack of an adequate comparator (Brodie et al., 2007)....
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...Since the last report, a total of six RCTs (Steinhoff et al., 2005; Brodie et al., 2007; Marson et al., 2007a; Ramsay et al., 2010; Kwan et al., 2011; Baulac et al., 2012) and four new meta-analyses (Gamble et al., 2006a,b; Muller et al., 2006; Koch & Polman, 2009) examined the Epilepsia,…...
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...A 2007 large-scale, open-label RCT compared CBZ, GBP, LTG, OXC, and TPM in 1,721 patients with partial-onset seizures (Marson et al., 2007a)....
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TL;DR: In this article, a 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE) evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005.
Abstract: Summary: Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy.
Methods: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, ≥48-week treatment duration without forced exit criteria, information on ≥24-week seizure freedom data (efficacy) or ≥48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a ≤20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21–30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation.
Results: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic–clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy.
Conclusions: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.
704 citations