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. 2017 Jun 29;6(6):CD011412.
doi: 10.1002/14651858.CD011412.pub2.

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

Sarah J Nevitt  1 , Maria Sudell, Jennifer Weston, Catrin Tudur Smith, Anthony G Marson
Affiliations

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

Sarah J Nevitt et al. Cochrane Database Syst Rev. .

Update in

Abstract

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.

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Conflict of interest statement

SJN was funded between 2011 and 2014 as part of a three‐year research programme, ‘Clinical and cost effectiveness of interventions for epilepsy in the National Health Service (NHS)’, which receives financial support from the National Institute of Health Research (NIHR).

JW was funded between 2011 and 2014 as part of a three‐year research programme, ‘Clinical and cost effectiveness of interventions for epilepsy in the National Health Service (NHS)’, which receives financial support from the National Institute of Health Research (NIHR).

AGM: a consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) funded the National Audit of Seizure Management in Hospitals (NASH) through grants paid to the University of Liverpool. Professor Tony Marson is Theme Leader for Managing Complex Needs at NIHR CLAHRC NWC.

Figures

Figure 1
Figure 1
Network plot of pairwise comparisons in all included studies, studies providing individual participant data (IPD) and studies without IPD Note that the size of the node indicates the number of studies the drug is included in and the thickness of the edges corresponds to the number of participants contributing to the comparison (i.e. larger node = more studies, thicker edge = more participants). CBZ: carbamazepine; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 2
Figure 2
Network plot of pairwise comparisons for all included participants (total 17,961 participants), participants with partial seizures and participants with generalised tonic‐clonic seizures with or without other seizure types (shortened to 'generalised seizures' for brevity). 11978 participants were classified as experiencing partial seizures (66.7% of total), 4407 participants were classified as experiencing generalised seizures (24.5% of total) and 1576 had an unclassified or missing seizure type (8.8% of total). Note that the size of the node indicates the number of studies the drug is included in and the thickness of the edges corresponds to the number of participants contributing to the comparison (i.e. larger node = more studies, thicker edge = more participants). CBZ: carbamazepine; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 3
Figure 3
Study flow diagram
Figure 4
Figure 4
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial
Figure 5
Figure 5
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with partial seizures, all drugs compared to carbamazepine (CBZ) Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 6
Figure 6
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with partial seizures, all drugs compared to lamotrigine (LTG) Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 7
Figure 7
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with generalised seizures, all drugs compared to sodium valproate (VPS) Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. Generalised tonic‐clonic seizures with or without other seizure types is shortened to 'Generalised seizures' for brevity. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 8
Figure 8
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with partial seizures, all pairwise comparisons for time to withdrawal of allocated treatment and time to 12‐month remission. Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 9
Figure 9
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with generalised seizures, all pairwise comparisons for time to withdrawal of allocated treatment and time to 12‐month remission. Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. Generalised tonic‐clonic seizures with or without other seizure types is shortened to 'Generalised seizures' for brevity. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 10
Figure 10
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with partial seizures, all pairwise comparisons for time to six‐month remission and time to first seizure. Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 11
Figure 11
AED: antiepileptic drug; CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Network meta‐analysis results (direct and indirect evidence combined) for individuals with generalised seizures, all pairwise comparisons for time to six‐month remission and time to first seizure. Note: direct evidence (%) is the proportion of the estimate contributed by direct evidence and the box size is proportional to the number of participants contributing direct evidence. Generalised tonic‐clonic seizures with or without other seizure types is shortened to 'Generalised seizures' for brevity. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 12
Figure 12
CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Consistency: direct, indirect and network estimates for individuals with partial seizures compared to carbamazepine (CBZ) for time to withdrawal of allocated treatment and time to 12‐month remission. Note: direct evidence comes from studies that compared the drugs (head‐to‐head comparisons), indirect evidence comes from studies that did not compare the drugs (indirect comparisons) and network evidence comes from the whole network (head‐to‐head and indirect comparisons for all drugs). To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 13
Figure 13
CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Consistency: direct, indirect and network estimates for individuals with partial seizures compared to lamotrigine (LTG) for time to withdrawal of allocated treatment and time to 12‐month remission. Note: direct evidence comes from studies that compared the drugs (head‐to‐head comparisons), indirect evidence comes from studies that did not compare the drugs (indirect comparisons) and network evidence comes from the whole network (head‐to‐head and indirect comparisons for all drugs). To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 14
Figure 14
CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Consistency: Direct, Indirect and Network estimates for individuals with generalised seizures compared to sodium valproate (VPS) for time to withdrawal of allocated treatment and time to 12‐month remission. Note: direct evidence comes from studies that compared the drugs (head‐to‐head comparisons), indirect evidence comes from studies that did not compare the drugs (indirect comparisons) and network evidence comes from the whole network (head‐to‐head and indirect comparisons for all drugs). Generalised tonic‐clonic seizures with or without other seizure types is shortened to 'Generalised seizures' for brevity. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 15
Figure 15
CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Consistency: direct, indirect and network estimates for individuals with partial seizures compared to carbamazepine (CBZ) for time to six‐month remission and time to first seizure. Note: direct evidence comes from studies that compared the drugs (head‐to‐head comparisons), indirect evidence comes from studies that did not compare the drugs (indirect comparisons) and network evidence comes from the whole network (head‐to‐head and indirect comparisons for all drugs). To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 16
Figure 16
CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Consistency: direct, indirect and network estimates for individuals with partial seizures compared to lamotrigine (LTG) for time to six‐month remission and time to first seizure. Note: direct evidence comes from studies that compared the drugs (head‐to‐head comparisons), indirect evidence comes from studies that did not compare the drugs (indirect comparisons) and network evidence comes from the whole network (head‐to‐head and indirect comparisons for all drugs). To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
Figure 17
Figure 17
CBZ: carbamazepine; CI: confidence interval; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PHB: phenobarbitone; PHT: phenytoin; TPM: topiramate; VPS: sodium valproate; ZNS: zonisamide Consistency: direct, indirect and network estimates for individuals with generalised seizures compared to sodium valproate (VPS) for time to six‐month remission and time to first seizure. Note: direct evidence comes from studies that compared the drugs (head‐to‐head comparisons), indirect evidence comes from studies that did not compare the drugs (indirect comparisons) and network evidence comes from the whole network (head‐to‐head and indirect comparisons for all drugs). Generalised tonic‐clonic seizures with or without other seizure types is shortened to 'Generalised seizures' for brevity. To see a magnified version of this figure, please see https://epilepsy.cochrane.org/network‐meta‐analysis‐figures.
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References

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