NIHR Signal A range of anti-epilepsy drugs are effective as first-line treatment

Published on 12 September 2017

Lamotrigine and levetiracetam are emerging as first-line treatments for epilepsy, which people may be more likely to keep taking than carbamazepine. Reducing the risk of adverse events and treatment withdrawal is important when selecting an anti-epilepsy drug as it usually will need to be taken long-term.

This study reviewed evidence on anti-epilepsy drugs in adults and children. The drugs were compared directly or indirectly with each other. The main outcome of interest was time to withdrawal from treatment, which indicates effectiveness and tolerability.

The findings support NICE recommendations to use carbamazepine or lamotrigine as first-line therapies for epilepsy with partial seizures, with levetiracetam as an alternative. Sodium valproate or lamotrigine are recommended for people with generalised tonic-clonic seizures, and levetiracetam is an alternative option.

A range of anti-epilepsy drugs are effective as first-line treatment

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Why was this study needed?

Epilepsy is common, affecting around one in every hundred people in the UK. People with epilepsy experience seizures due to abnormal electrical activity in the brain. Some types of epilepsy occur in one part of the brain (partial seizures) while others are more widespread (generalised seizures).

Drug treatments can reduce the number or the severity of seizures, or stop them completely. They usually need to be taken long-term, but some people stop taking them because of side effects. In the UK, an estimated 400 deaths due to epilepsy could be avoided each year through optimum treatment.

Up to 70% of people have good long term control of seizures after being prescribed their first anti-epilepsy drug, but others may need to try several different drugs.

This research from the Cochrane Epilepsy Group combines direct and indirect comparisons of drugs to inform which are best for first-line use in different types of epilepsy.

What did this study do?

This was a systematic review and network meta-analysis using individual participant data from many trials. It included randomised and quasi-randomised controlled trials which had compared 10 different anti-epilepsy drugs with each other: carbamazepine, phenobarbitone, phenytoin, sodium valproate, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam and zonisamide.

The study identified 77 eligible trials from which the authors obtained data on at least one outcome from 12,391 adults and children in 36 trials. The main outcome was time to withdrawal from treatment - a mixture of how effective and tolerable the drug was.

Evidence was of moderate to high quality, but the absence of individual data from over half of the eligible trials may introduce selection bias.

What did it find?

For partial seizures:

  • Compared to carbamazepine, people were less likely to stop treatment if taking lamotrigine (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65 to 0.86) or levetiracetam (HR 0.82, 95% CI 0.69 to 0.97). Those on phenobarbitone were more likely to stop (HR 1.55, 95% CI 1.18 to 2.04) and there was no difference for the other drugs.
  • Compared to lamotrigine, only people on levetiracetam were as likely to stop treatment (HR 1.10, 95% CI 0.89 to 1.35). People taking any of the other drugs were more likely to stop treatment, such as those on carbamazepine (HR 1.34, 95% CI 1.17 to 1.54) and phenobarbitone (HR 2.08, 95% CI 1.53 to 2.83).

For generalised seizures:

  • Compared to sodium valproate, people were as likely to stop taking lamotrigine (HR 0.90, 95% CI 0.60 to 1.35) or levetiracetam (HR 1.05, 95% CI 0.58 to 1.90). Results were less clear for gabapentin, phenytoin or oxcarbazepine due to wide confidence intervals.
  • Compared to sodium valproate, people were more likely to stop taking carbamazepine (HR 1.42, 95% CI 1.09 to 1.85), topiramate (HR 1.76, 95% CI 1.22 to 2.53) and phenobarbitone (HR 2.09, 95% CI 1.17 to 3.75).

Adverse events:

  • Side effects the drugs included stomach upsets, dizziness, faintness, skin disorders (including rashes), headaches, migraines, drowsiness and fatigue.

What does current guidance say on this issue?

NICE 2016 guidelines recommend carbamazepine or lamotrigine as first-line treatment for children, young people and adults with newly diagnosed partial seizures. If not tolerated then levetiracetam, oxcarbazepine or sodium valproate can be used.

For generalised tonic-clonic seizures, sodium valproate is recommended as first-line treatment. If this is unsuitable, lamotrigine is recommended. Carbamazepine and oxcarbazepine can be considered as alternatives.

Because of risks to the unborn baby sodium valproate should not be given to women or girls of childbearing age unless all other treatment options have failed.

What are the implications?

Using time to withdrawal from treatment, this analysis indicates that lamotrigine may be preferable to carbamazepine for initial treatment of partial seizures. Levetiracetam at its current price may now be the next best choice before carbamazepine in the UK. The results for generalised seizures are in line with NICE guidelines, to use sodium valproate or lamotrigine. Levetiracetam could now be an alternative option.

Though time to withdrawal of treatment is a good indicator of effectiveness and tolerability, factors such as side effects, compatibility with other medication, child-bearing potential and personal preference will be important when deciding on which anti epilepsy drug to try first.

Citation and Funding

Nevitt SJ, Sudwell M, Weston J, et al. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2017;(6):CD011412.

Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Epilepsy. London: Department of Health; 2014.

NICE. Epilepsies: diagnosis and management. GC137. London: National Institute for Health and Care Excellence; 2016.

Why was this study needed?

Epilepsy is common, affecting around one in every hundred people in the UK. People with epilepsy experience seizures due to abnormal electrical activity in the brain. Some types of epilepsy occur in one part of the brain (partial seizures) while others are more widespread (generalised seizures).

Drug treatments can reduce the number or the severity of seizures, or stop them completely. They usually need to be taken long-term, but some people stop taking them because of side effects. In the UK, an estimated 400 deaths due to epilepsy could be avoided each year through optimum treatment.

Up to 70% of people have good long term control of seizures after being prescribed their first anti-epilepsy drug, but others may need to try several different drugs.

This research from the Cochrane Epilepsy Group combines direct and indirect comparisons of drugs to inform which are best for first-line use in different types of epilepsy.

What did this study do?

This was a systematic review and network meta-analysis using individual participant data from many trials. It included randomised and quasi-randomised controlled trials which had compared 10 different anti-epilepsy drugs with each other: carbamazepine, phenobarbitone, phenytoin, sodium valproate, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam and zonisamide.

The study identified 77 eligible trials from which the authors obtained data on at least one outcome from 12,391 adults and children in 36 trials. The main outcome was time to withdrawal from treatment - a mixture of how effective and tolerable the drug was.

Evidence was of moderate to high quality, but the absence of individual data from over half of the eligible trials may introduce selection bias.

What did it find?

For partial seizures:

  • Compared to carbamazepine, people were less likely to stop treatment if taking lamotrigine (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65 to 0.86) or levetiracetam (HR 0.82, 95% CI 0.69 to 0.97). Those on phenobarbitone were more likely to stop (HR 1.55, 95% CI 1.18 to 2.04) and there was no difference for the other drugs.
  • Compared to lamotrigine, only people on levetiracetam were as likely to stop treatment (HR 1.10, 95% CI 0.89 to 1.35). People taking any of the other drugs were more likely to stop treatment, such as those on carbamazepine (HR 1.34, 95% CI 1.17 to 1.54) and phenobarbitone (HR 2.08, 95% CI 1.53 to 2.83).

For generalised seizures:

  • Compared to sodium valproate, people were as likely to stop taking lamotrigine (HR 0.90, 95% CI 0.60 to 1.35) or levetiracetam (HR 1.05, 95% CI 0.58 to 1.90). Results were less clear for gabapentin, phenytoin or oxcarbazepine due to wide confidence intervals.
  • Compared to sodium valproate, people were more likely to stop taking carbamazepine (HR 1.42, 95% CI 1.09 to 1.85), topiramate (HR 1.76, 95% CI 1.22 to 2.53) and phenobarbitone (HR 2.09, 95% CI 1.17 to 3.75).

Adverse events:

  • Side effects the drugs included stomach upsets, dizziness, faintness, skin disorders (including rashes), headaches, migraines, drowsiness and fatigue.

What does current guidance say on this issue?

NICE 2016 guidelines recommend carbamazepine or lamotrigine as first-line treatment for children, young people and adults with newly diagnosed partial seizures. If not tolerated then levetiracetam, oxcarbazepine or sodium valproate can be used.

For generalised tonic-clonic seizures, sodium valproate is recommended as first-line treatment. If this is unsuitable, lamotrigine is recommended. Carbamazepine and oxcarbazepine can be considered as alternatives.

Because of risks to the unborn baby sodium valproate should not be given to women or girls of childbearing age unless all other treatment options have failed.

What are the implications?

Using time to withdrawal from treatment, this analysis indicates that lamotrigine may be preferable to carbamazepine for initial treatment of partial seizures. Levetiracetam at its current price may now be the next best choice before carbamazepine in the UK. The results for generalised seizures are in line with NICE guidelines, to use sodium valproate or lamotrigine. Levetiracetam could now be an alternative option.

Though time to withdrawal of treatment is a good indicator of effectiveness and tolerability, factors such as side effects, compatibility with other medication, child-bearing potential and personal preference will be important when deciding on which anti epilepsy drug to try first.

Citation and Funding

Nevitt SJ, Sudwell M, Weston J, et al. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2017;(6):CD011412.

Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Epilepsy. London: Department of Health; 2014.

NICE. Epilepsies: diagnosis and management. GC137. London: National Institute for Health and Care Excellence; 2016.

Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data

Published on 1 July 2017

Nevitt, S. J.,Sudell, M.,Weston, J.,Tudur Smith, C.,Marson, A. G.

Cochrane Database Syst Rev Volume 6 , 2017

BACKGROUND: Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. OBJECTIVES: To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). SEARCH METHODS: We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. SELECTION CRITERIA: We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events. MAIN RESULTS: IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders. AUTHORS' CONCLUSIONS: Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.

Network meta-analysis allows interventions to be compared which have never been directly compared in previous studies, as long as they have both been compared to something else in common.

Expert commentary

In general, epilepsy treatment is long-term, so minimisation of adverse effects is key. The composite outcome measure of time remaining on treatment takes efficacy and adverse effects into account. This meta-analysis supports NICE evaluations (2004, 2012) that carbamazepine and lamotrigine are suitable for focal seizures and levetiracetam is an alternative. Also, valproate is effective for generalised tonic-clonic seizures, with lamotrigine and levetiracetam alternatives, particularly if pregnancy is contemplated.

The availability of many medications that suppress seizures brings choice and the ability to minimise adverse-effects, but these have not affected remission rates. We await therapies that prevent the development of epilepsy and alter its natural history.

John Duncan, Professor of Neurology, UCL; Divisional Clinical Director, National Hospital for Neurology and Neurosurgery

Categories

  •   Medicines, Nervous system disorders, Acute and general medicine