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. 2022 Apr 1;4(4):CD011412.
doi: 10.1002/14651858.CD011412.pub4.

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

Sarah J Nevitt  1 , Maria Sudell  1 , Sofia Cividini  1 , Anthony G Marson  2 , Catrin Tudur Smith  1
Affiliations

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

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

Abstract

Background: This is an updated version of the original Cochrane Review published in 2017. 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 focal 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 treatment failure, remission and first seizure of 12 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide, eslicarbazepine acetate, lacosamide) currently used as monotherapy in children and adults with focal onset seizures (simple focal, complex focal or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).

Search methods: For the latest update, we searched the following databases on 12 April 2021: the Cochrane Register of Studies (CRS Web), which includes PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Epilepsy Group Specialised Register and MEDLINE (Ovid, 1946 to April 09, 2021). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field.

Selection criteria: We included randomised controlled trials of a monotherapy design in adults or children with focal 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) and network meta-analysis (NMA) review. Our primary outcome was 'time to treatment failure', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', and 'time to first seizure post-randomisation'. We performed frequentist NMA to combine direct evidence with indirect evidence across the treatment network of 12 drugs. We investigated inconsistency between direct 'pairwise' estimates and NMA results via node splitting. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs) and we assessed the certainty of the evidence using the CiNeMA approach, based on the GRADE framework. We have also provided a narrative summary of the most commonly reported adverse events.

Main results: IPD were provided for at least one outcome of this review for 14,789 out of a total of 22,049 eligible participants (67% of total data) from 39 out of the 89 eligible trials (43% of total trials). We could not include IPD from the remaining 50 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. No IPD were available from a single trial of eslicarbazepine acetate, so this AED could not be included in the NMA. Network meta-analysis showed high-certainty evidence that for our primary outcome, 'time to treatment failure', for individuals with focal seizures; lamotrigine performs better than most other treatments in terms of treatment failure for any reason and due to adverse events, including the other first-line treatment carbamazepine; HRs (95% CIs) for treatment failure for any reason for lamotrigine versus: levetiracetam 1.01 (0.88 to 1.20), zonisamide 1.18 (0.96 to 1.44), lacosamide 1.19 (0.90 to 1.58), carbamazepine 1.26 (1.10 to 1.44), oxcarbazepine 1.30 (1.02 to 1.66), sodium valproate 1.35 (1.09 to 1.69), phenytoin 1.44 (1.11 to 1.85), topiramate 1.50 (1.23 to 1.81), gabapentin 1.53 (1.26 to 1.85), phenobarbitone 1.97 (1.45 to 2.67). No significant difference between lamotrigine and levetiracetam was shown for any treatment failure outcome, and both AEDs seemed to perform better than all other AEDs. For people with generalised onset seizures, evidence was more limited and of moderate certainty; no other treatment performed better than first-line treatment sodium valproate, but there were no differences between sodium valproate, lamotrigine or levetiracetam in terms of treatment failure; HRs (95% CIs) for treatment failure for any reason for sodium valproate versus: lamotrigine 1.06 (0.81 to 1.37), levetiracetam 1.13 (0.89 to 1.42), gabapentin 1.13 (0.61 to 2.11), phenytoin 1.17 (0.80 to 1.73), oxcarbazepine 1.24 (0.72 to 2.14), topiramate 1.37 (1.06 to 1.77), carbamazepine 1.52 (1.18 to 1.96), phenobarbitone 2.13 (1.20 to 3.79), lacosamide 2.64 (1.14 to 6.09). Network meta-analysis also showed high-certainty evidence that for secondary remission outcomes, few notable differences were shown for either seizure type; for individuals with focal seizures, carbamazepine performed better than gabapentin (12-month remission) and sodium valproate (six-month remission). No differences between lamotrigine and any AED were shown for individuals with focal seizures, or between sodium valproate and other AEDs for individuals with generalised onset seizures. Network meta-analysis also showed high- to moderate-certainty evidence that, for 'time to first seizure,' in general, the earliest licensed treatments (phenytoin and phenobarbitone) performed better than the other treatments for individuals with focal seizures; phenobarbitone performed better than both first-line treatments carbamazepine and lamotrigine. There were no notable differences between the newer drugs (oxcarbazepine, topiramate, gabapentin, levetiracetam, zonisamide and lacosamide) for either seizure type. Generally, direct evidence (where available) and network meta-analysis estimates were numerically similar and consistent with confidence intervals of effect sizes overlapping. There was no important indication of inconsistency between direct and network meta-analysis results. The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders; however, reporting of adverse events was highly variable across AEDs and across studies.

Authors' conclusions: High-certainty evidence demonstrates that for people with focal onset seizures, current first-line treatment options carbamazepine and lamotrigine, as well as newer drug levetiracetam, show the best profile in terms of treatment failure and seizure control as first-line treatments. For people with generalised tonic-clonic seizures (with or without other seizure types), current first-line treatment sodium valproate has the best profile compared to all other treatments, but lamotrigine and levetiracetam would be the most suitable alternative first-line treatments, particularly for those for whom sodium valproate may not be an appropriate treatment option. Further evidence from randomised controlled trials recruiting individuals with generalised tonic-clonic seizures (with or without other seizure types) is needed.

PubMed Disclaimer

Conflict of interest statement

SJN: none known CTS: none known SC: none known 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 Marson is funded in part by The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care North West Coast (NIHR CLAHRC NWC). Professor Marson is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care. Professor Marson is the Co‐ordinating Editor of the Cochrane Epilepsy Group; however, he was not involved in the editorial process of this review update.

Figures

1
1
Network plot of pairwise comparisons regardless of whether any outcome data (IPD or aggregate data) were available; all individuals included within the review, (total 22,040 participants), participants with focal seizures and participants with generalised tonic‐clonic seizures with or without other seizure types (shortened to 'generalised seizures' for brevity). Out of a total of 22,040 participants, 15,148 participants were classified as experiencing focal onset seizures (69% of total), 5268 participants were classified as experiencing generalised onset seizures (24% of total) and 1624 had an unclassified or missing seizure type (7% 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; ESL: eslicarbazepine acetate; GBP: gabapentin; LCM: lacosamide; 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.
2
2
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; ESL: eslicarbazepine acetate; GBP: gabapentin; LCM: lacosamide; 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.
3
3
Study flow diagram
4
4
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
5
5
Network meta‐analysis results (direct and indirect evidence combined) for individuals with focal 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
6
6
Network meta‐analysis results (direct and indirect evidence combined) for individuals with focal 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
7
7
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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
8
8
Network meta‐analysis results (direct and indirect evidence combined) for individuals with focal seizures, all pairwise comparisons for time to treatment failure outcomes 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
9
9
Network meta‐analysis results (direct and indirect evidence combined) for individuals with generalised seizures, all pairwise comparisons for time to treatment failure outcomes 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
10
10
Consistency: direct, indirect and network estimates for individuals with focal seizures compared to carbamazepine (CBZ) for time to treatment failure outcomes. Numerical results from investigations of inconsistency for all pairwise comparisons are available from the corresponding author on request. 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). AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
11
11
Consistency: direct, indirect and network estimates for individuals with focal seizures compared to lamotrigine (LTG) for time to treatment failure outcomes. Numerical results from investigations of inconsistency for all pairwise comparisons are available from the corresponding author on request. 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). AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
12
12
Consistency: Direct, indirect and network estimates for individuals with generalised seizures compared to sodium valproate (VPS) for time to treatment failure outcomes. Numerical results from investigations of inconsistency for all pairwise comparisons are available from the corresponding author on request. 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
13
13
Network meta‐analysis results (direct and indirect evidence combined) for individuals with focal seizures, all pairwise comparisons for time to 12‐month remission, 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
14
14
Network meta‐analysis results (direct and indirect evidence combined) for individuals with generalised seizures, all pairwise comparisons for time to 12‐month remission, 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
15
15
Consistency: direct, indirect and network estimates for individuals with focal seizures compared to carbamazepine (CBZ) for time to 12‐month remission, time to six‐month remission and time to first seizure. Numerical results from investigations of inconsistency for all pairwise comparisons are available from the corresponding author on request. 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). AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
16
16
Consistency: direct, indirect and network estimates for individuals with focal seizures compared to lamotrigine (LTG) for time to 12‐month remission, time to six‐month remission and time to first seizure. Numerical results from investigations of inconsistency for all pairwise comparisons are available from the corresponding author on request. 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). AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
17
17
Consistency: direct, indirect and network estimates for individuals with generalised seizures compared to sodium valproate (VPS) for time to 12‐month remission, time to six‐month remission and time to first seizure. Numerical results from investigations of inconsistency for all pairwise comparisons are available from the corresponding author on request. 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. AED: antiepileptic drug
CBZ: carbamazepine
CI: confidence interval
GBP: gabapentin
LCM: lacosamide
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
See this image and copyright information in PMC

Update of

References

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    1. Cho YW, Kim DH, Motamedi GK.The effect of levetiracetam monotherapy on subjective sleep quality and objective sleep parameters in patients with epilepsy: compared with the effect of carbamazepine-CR monotherapy. Seizure 2011;20(4):336-9. - PubMed
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Dizdarer 2000 {published data only}
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Donati 2007 {published data only}
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    1. Eun S-H, Eun B-L, Lee JS, Hwang YS, Kim KJ, Lee Y-M, et al.Effects of lamotrigine on cognition and behavior compared to carbamazepine as monotherapy for children with partial epilepsy. Brain & Development 2012;34(10):818-23. - PubMed
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Forsythe 1991 {published data only}
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Gilad 2007 {published data only}
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    1. Jung DE, Yu R, Yoon JR, Eun BL, Kwon SH, Lee YJ, et al.Neuropsychological effects of levetiracetam and carbamazepine in children with focal epilepsy. Neurology 2015;84(23):2312-9. - PubMed
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Kim 2017 {published data only}
    1. Kim JH, Lee SK, Loesch C, Namgoong K, Lee HW, Hong SB, et al.Comparison of levetiracetam and oxcarbazepine monotherapy among Korean patients with newly diagnosed focal epilepsy: a long-term, randomized, open-label trial. Epilepsia 2017;58(4):e70-4. - PubMed
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Kopp 2007 {published data only}
    1. Kopp UA, Gaus V, Wandschneider B, Schmitz B.Cognitive side effects of levetiracetam in monotherapy: comparison with carbamazepine and valproate. Epilepsia 2007;48(Suppl 3):39-40, Abstract No: P178.
Korean Lamotrigine Study Group 2008 {published data only}
    1. Korean Lamotrigine Study Group.An open, randomized, multicenter comparative clinical trial of lamotrigine and carbamazepine as initial monotherapy in previously untreated epilepsies. Journal of Korean Epilepsy Society 2008;12(1):27-34.
Korean Zonisamide Study 1999 {published data only}
    1. Korean Zonisamide Study Group.Double-blind, randomized, comparative clinical trial of zonisamide and carbamazepine as initial monotherapy in newly diagnosed epilepsy. Journal of Korean Epilepsy Society 1999;3(1):50-7.
Kwan 2009 {published data only}
    1. Kwan P, Yip FP, Hui ACF, Leung H, Ng PW, Hui KF, et al.Effects of valproate or lamotrigine monotherapy on the reproductive endocrine and insulin-related metabolic profile in Chinese adults with epilepsy: a prospective randomized study. Epilepsy & Behavior 2009;14(4):610-6. - PubMed
Lee 2011 {published data only}
    1. Ju KM, Lee SA, Lee HW, Heo K, Shin DJ, Song HK, et al.Effect of seizures on cognition, behavior, and quality of life during carbamazepine or lamotrigine monotherapy in patients with newly diagnosed partial epilepsy. Epilepsy Currents/American Epilepsy Society 2011;11 (Suppl 1):399, Abstract no: 3.090.
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Lukic 2005 {published data only}
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Maiti 2018 {published data only}
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Mattson 1992 {published data only}
    1. Mattson RH, Cramer JA, Collins JF, Department of Veterans Affairs Epilepsy Cooperative Study No 264 Group.A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. New England Journal of Medicine 1992;327(11):765-71. - PubMed
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Motamedi 2013 {published data only}
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NCT01954121 {published data only}
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Nieto‐Barrera 2001 {published data only}
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Ramsay 1983 {published data only}
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Ramsay 2010 {published data only}
    1. EUCTR2015-001222-42-Outside-EU/EEA.A comparison of the effectiveness and safety of topiramate and phenytoin in patients with new onset epilepsy requiring rapid initiation of antiepileptic drug treatment. who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2015-001222-42-Outside-EU/EEA (accessed 08 April 2021).
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Reunanen 1996 {published data only}
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SANAD A 2007 {published data only}
    1. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al, SANAD Study Group.The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369(9566):1000-15. - PMC - PubMed
SANAD B 2007 {published data only}
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SANAD II A 2021 {published data only}
    1. Balabanova S, Taylor C, Sills G, Burnside G, Plumpton C, Smith PEM, et al.Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs (SANAD-II). BMJ Open 2020;10:e040635. [DOI: 10.1136/bmjopen-2020-040635] - DOI - PMC - PubMed
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    1. Balabanova S, Taylor C, Sills G, Burnside G, Plumpton C, Smith PEM, et al.Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs (SANAD-II). BMJ Open 2020;10:e040635. [DOI: 10.1136/bmjopen-2020-040635] - DOI - PMC - PubMed
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Sidhu 2018 {published data only}
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Werhahn 2015 {published data only}
    1. EUCTR2005-003324-19-AT.STEP ONE (Study on the Treatment of Elderly Patients with Older and Newer antiEpileptic drugs) trial: a multicentre, double-blind, randomized, phase IV clinical trial comparing the safety, tolerability and efficacy of levetiracetam versus lamotrigine and carbamazepine in the oral antiepileptic therapy of newly diagnosed elderly patients with focal epilepsy - STEP ONE. who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2005-003324-19-AT (accessed 08 April 2021).
    1. Werhahn KJ, Trinka E, Dobesberger J, Ruckes C, Krämer G.Levetiracetam is superior to carbamazepine-SR in newly diagnosed epilepsy in the elderly: results of the STEP-ONE trial. Epilepsia 2012;53 Suppl 5:49, Abstract no: p164.
    1. Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, et al.A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56(3):450-9. - PubMed
    1. Wild I, Noack-Rink M, Ramirez F, Tofighy A, Werhahn K.Comparative effectiveness of the antiepileptic drugs (AEDs) levetiracetam, valproate and carbamazepine among patients aged 60 years and over with newly diagnosed epilepsy. Journal of Neurology 2014;261 (Suppl 1):S159-S60, Abstract no: EP2238. - PMC - PubMed
Wu 2018 {published data only}
    1. Wu D, Chen L, Ji F, Si Y, Sun H.The effects of oxcarbazepine, levetiracetam, and lamotrigine on semen quality, sexual function, and sex hormones in male adults with epilepsy. Epilepsia 2018;59(7):1344-50. - PubMed
Xu 2012 {published data only}
    1. Xu F, Sun HB.Comparative study for retention rate of new antiepileptic drugs as an initial monotherapy in complex partial epilepsy. Chinese Journal of New Drugs 2012;21(11):1265-8.

References to studies excluded from this review

Albani 2006 {published data only}
    1. Albani F, Baruzzi A, Primo Study Group.Oxcarbazepine long-term treatment retention in patients switched over from carbamazepine. Neurological Sciences 2006;27(3):173-5. - PubMed
Alsaadi 2002 {published data only}
    1. Alsaadi TM, Thieman C, Zusman EE.Levetiracetam monotherapy for adults with localization-related epilepsy. Epilepsy and Behavior 2002;3(5):471-4. - PubMed
Alsaadi 2005 {published data only}
    1. Alsaadi TM, Shatzel A, Marquez AV, Jorgensen J, Farias S.Clinical experience of levetiracetam monotherapy for adults with epilepsy: 1-year follow-up study. Seizure 2005;14(2):139-42. - PubMed
Baxter 1998 {published data only}
    1. Baxter L, Cheesbrough A.An open randomised comparison of Lamictal (lamotrigine) with physicians preferred choice of either valproate or carbamazepine as monotherapy in patients over 12 years of age with newly diagnosed epilepsy. Clinical summary report (unpublished) 1998.
Ben‐Menachem 2003 {published data only}
    1. Ben-Menachem E.Preliminary efficacy of levetiracetam in monotherapy. Epileptic Disorders 2003;5(Suppl 1):S51-5. - PubMed
Beydoun 1997 {published data only}
    1. Beydoun A, Fischer J, Labar DR, Harden C, Cantrell D, Uthman BM, et al, The US Gabapentin Study Group 82/83.Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49(3):746-52. - PubMed
Beydoun 1998 {published data only}
    1. Beydoun A, Fakhoury T, Nasreddine W, Abou-Khalil B.Conversion to high dose gabapentin monotherapy in patients with medically refractory partial epilepsy. Epilepsia 1998;39(2):188-93. - PubMed
Beydoun 2000 {published data only}
    1. Beydoun A, Sachdeo RC, Rosenfeld WE, Krauss GL, Sessler N, Mesenbrink P, et al.Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial. Neurology 2000;54(12):2245-51. - PubMed
Bittencourt 1993 {published data only}
    1. Bittencourt PR, Antoniuk SA, Bigarella MM, Da Costa JC, Doro MP, Ferreira AS, et al.Carbamazepine and phenytoin in epilepsies refractory to barbiturates: efficacy, toxicity and mental function. Epilepsy Research 1993;16(2):147-55. - PubMed
Canadian Group 1999 {published data only}
    1. Bawden HN, Camfield CS, Camfield PR, Cunningham C, Darwish H, Dooley JM, et al, Canadian Study Group for Childhood Epilepsy.The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Epilepsy Research 1999;33(2-3):133-43. - PubMed
Cereghino 1974 {published data only}
    1. Cereghino JJ, Brock JT, Van Meter JC, Penry JK, Smith LD, White BG.Carbamazepine for epilepsy. A controlled prospective evaluation. Neurology 1974;24(5):401-10. - PubMed
Chung 2012 {published data only}
    1. Chung S, Ceja H, Gawlowicz J, Avakyan G, McShea C, Schiemann J, et al.Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study. Epilepsy Research 2012;101(1-2):92-102. - PubMed
DeToledo 2000 {published data only}
    1. DeToledo JC, Ramsay RE, Lowe MR, Greiner M, Garofalo EA.Increased seizures after discontinuing carbamazepine: results from the gabapentin monotherapy trial. Therapeutic Drug Monitoring 2000;22(6):753-6. - PubMed
EUCTR2004‐004053‐26‐SE {published data only}
    1. EUCTR2004-004053-26-SE.An explorative use open-label, multi-center, randomized trial studying the safety and efficacy of levetiracetam (500 mg/day to 3000 mg/day) and valproate (600 mg/day to 3000 mg/day) as monotherapy in newly diagnosed patients over the age of 65 years - Scandinavian elderly study. www.clinicaltrialsregister.eu (accessed 08 April 2021).
EUCTR2010‐018284‐42‐NL {published data only}
    1. EUCTR2010-018284-42-NL.A trial comparing efficacy, safety and tolerance between levetiracetam and valproic acid in children with epilepsy. www.clinicaltrialsregister.eu (accessed 08 April 2021).
Fakhoury 2004 {published data only}
    1. Fakhoury TA, Hammer AE, Vuong A, Messenheimer JA.Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy. Epilepsy & Behavior 2004;5(4):532-8. - PubMed
Foldvary‐Schaefer 2017 {published data only}
    1. Foldvary-Schaefer N, Neme-Mercante S, Andrews N, Bruton M, Wang L, Morrison S, et al.Wake up to sleep: the effects of lacosamide on daytime sleepiness in adults with epilepsy. Epilepsy & Behavior 2017;75:176-82. - PubMed
French 2012 {published data only}
    1. French JA, Temkin NR, Shneker BF, Hammer AE, Caldwell PT, Messenheimer JA.Lamotrigine XR conversion to monotherapy: first study using a historical control group. Neurotherapy 2012;9(1):176-84. - PMC - PubMed
Gilliam 1998 {published data only}
    1. Gilliam F, Vazquez B, Sackellares JC, Chang GY, Messenheimer J, Nyberg J, et al.An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51(4):1018-25. - PubMed
Gruber 1962 {published data only}
    1. Gruber CM, Brock JT, Dyken MD.Comparison of the effectiveness of phenobarbital, mephobarbital, primidone, dipheylhydantoin, ethotoin, metharbital, and methylphenylhydantion in motor seizures. Clinical Pharmacology & Therapeutics 1962;3:23-8. - PubMed
Hakami 2012 {published data only}
    1. Hakami T, O'Brien TJ, Petty SJ, Sakellarides M, Christie J, Kantor S, et al.Monotherapy with levetiracetam versus older AEDs: a randomized comparative trial of effects on bone health. Calcified Tissue International 2016;98(6):556-65. - PubMed
    1. Hakami T, Todaro M, Petrovski S, MacGregor L, Velakoulis D, Tan M, et al.Substitution monotherapy with levetiracetam vs older antiepileptic drugs: a randomized comparative trial. Archives of Neurology 2012;69(12):1563-71. - PubMed
Hu 2012 {published data only}
    1. ChiCTR-TRC-10001131.The efficacy and safety of topiramate and valproate in treatment of Chinese patients with partial and generalised epilepsy: a multi-center, long-term follow up randomised controlled trial. http://www.chictr.org.cn/historyversionpub.aspx?regno=ChiCTR-TRC-10001131 (first posted 04 July 2015).
    1. Hu Y, Huang X, Shen D, Ding M, Sun H, Peng B, et al.Outcomes of sustained-release formulation of valproate and topiramate monotherapy in patients with epilepsy: a multi-centre, cohort study. PLOS One 2012;7(12):e47982. - PMC - PubMed
ISRCTN73223855 {published data only}
    1. ISRCTN73223855.A randomised controlled trial of phenobarbitone and phenytoin for newly diagnosed epilepsy in adults. https://doi.org/10.1186/ISRCTN73223855 (first posted 17 July 2007).
Kaminow 2003 {published data only}
    1. Kaminow L, Schimschock JR, Hammer AE, Vuong A.Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy. Epilepsy & Behavior 2003;4(6):659-66. - PubMed
Kerr 1999 {published data only}
    1. Kerr M, Kane K, Moorat A.Switching patients to monotherapy: efficacy and tolerability for Lamictal(r) compared to valproate. European Journal of Neurology 1999;6(Suppl 3):17.
Kerr 2001 {published data only}
    1. Kerr M, Moorat A, Curtis P.Lamotrigine compared to valproate: a randomised open label switch to monotherapy study in patients with uncontrolled epilepsy. Journal of the Neurological Sciences 2001;187(Suppl 1):S291-2.
Loiseau 1984 {published data only}
    1. Loiseau P, Cohadon S, Jogeix M, Legroux M, Dartigues JF.Efficacy of sodium valproate in partial epilepsy. Crossed study of valproate and carbamazepine. Revue Neurologique 1984;140(6-7):434-7. - PubMed
Loring 2020 {published data only}
    1. Loring DW, Meador KJ, Shinnar S, Gaillard WD, Wheless JW, Kessler SK, et al.Differential antiseizure medication sensitivity of the Affective Reactivity Index: a randomized controlled trial in new-onset pediatric focal epilepsy. Epilepsy & Behavior 2020;102:106687. - PMC - PubMed
NCT01891890 {published data only}
    1. NCT01891890.Cognitive AED outcomes in pediatric localization related epilepsy (COPE). https://clinicaltrials.gov/ct2/show/NCT01891890 (first posted 19 September 2017).
Park 2001 {published data only}
    1. Park WS, Kim CW, Park SP, Kwon SH.Safety and efficacy of topiramate monotherapy in children with recent-onset seizures. Journal of Korean Epilepsy Society 2001;5(1):65-9.
Reinikainen 1984 {published data only}
    1. Reinikainen K, Keranen T, Hallikainen E, Riekkinen PJ.Substitution of diphenylhydantoin by oxcarbazepine or carbamazepine: double-blind study. Acta Neurologica Scandinavica 1984;69(Suppl 98):89-90.
Reinikainen 1987 {published data only}
    1. Reinikainen KJ, Keranen T, Halonen T, Komulainen H, Riekkinen PJ.Comparison of oxcarbazepine and carbamazepine: a double-blind study. Epilepsy Research 1987;1(5):284-9. - PubMed
Rosenow 2012 {published data only}
    1. Rosenow F, Schade-Brittinger C, Burchardi N, Bauer S, Klein KM, Weber Y, et al, LaLiMo Study Group.The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy - an open-label, prospective, randomised controlled multicenter study. Journal of Neurology, Neurosurgery & Psychiatry 2012;83(11):1093-8. - PubMed
Rysz 1994 {published data only}
    1. Rysz A.Effect of monotherapy with phenytoin or carbamazepine on somatosensory evoked potentials in patients with newly diagnosed epilepsy. Polski Tygodnik Lekarski 1994;49(4-5):79-81. - PubMed
Simonsen 1975a {published data only}
    1. Simonsen N, Olsen PZ, Kuhl V.Carbamazepine versus diphenylhydantoin in psychomotor epilepsy. A double blind study of antiepileptic effect and side effects. Ugeskrift for Laeger 1975;137(41):2392-6. - PubMed
Simonsen 1975b {published data only}
    1. Simonsen N, Zander Olsen P, Kuhl V.A double blind study of carbamazepine and diphenylhydantoin in temporal lobe epilepsy. Acta Neurologica Scandinavica 1975;52(Suppl 60):39-42. - PubMed
Tabrizi 2019 {published data only}
    1. Tabrizi N, Zarvani A, Rezaei P, Cheraghmakani H, Alizadeh-Navaei R.Levetiracetam in genetic generalized epilepsy:a prospective unblinded active-controlled trial. Epilepsy Research 2019;157:106214. - PubMed
Taragano 2003 {published data only}
    1. Taragano FE, Loñ L, Sarasola D, Serrano C.Is oxcarbazepine better than phenytoin for the treatment of dementia patients complicated with secondary epilepsy? A comparative study. Revista Neurologica Argentina 2003;28(4):209-16.

References to studies awaiting assessment

Ahadi 2020 {published data only}
    1. Ahadi P, Nasiri J, Ghazavi MR, Mosavian T, Mansouri V.A comparative study on the efficacy of levetiracetam and carbamazepine in the treatment of rolandic seizures in children: an open-label randomized controlled trial. Journal of Research in Pharmacy Practice 2020;9(2):68-72. - PMC - PubMed
    1. IRCT20190208042654N3.The comparison of efficacy of levetiracetam and carbamazepine in the treatment of rolandic seizures in children. https://en.irct.ir/trial/44791 (registered on 07 January 2020).
Akhondian 2020 {published data only}
    1. Akhondian J, Ashrafzadeh F, Eslamiyeh H.Levetiracetam (levebel) versus carbamazepine monotherapy for focal epilepsy in children: a randomized clinical trial [Iranian Journal of Child Neurology]. 2020 14;2:69-77. - PMC - PubMed
    1. IRCT2015030821355N1.Levetiracetam versus carbamazepine monotherapy in the treatment of focal epilepsy of children. en.irct.ir/trial/18738 (registered on 12 January 2017).
CTRI/2011/08/001959 {published data only}
    1. CTRI/2011/08/001959.A phase III clinical trial to evaluate the efficacy and safety profile of eslicarbezepine acetate as monotherapy in patients with partial onset seizures. http://www.ctri.nic.in/Clinicaltrials/showallp.php?mid1=3329&EncHid=... (registered on 23 August 2011).
Du 2016 {published data only}
    1. Du Z, Jiao Y, Shi L.Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Medical Science Monitor 2016;22:4107. - PMC - PubMed
Goyal 2016 {published data only}
    1. Goyal M, Lal V, Sandal R, Modi M, Sachdeva J, Kharbanda P.A comparative blinded study of cognitive effects of carbamazepine, valproate, lamotrigine and levetiracetam in adult epileptic patients. Annals of Indian Academy of Neurology 2016;19(Suppl 2):S93, Abstract no: EP23/305.
IRCT201202068943N1 {published data only}
    1. IRCT201202068943N1.Efficacy of oxcarbazepine and phenytoin in control of epilepsy in the elderly. https://en.irct.ir/trial/9406?revision=9406 (registered on 17 March 2012).
NCT00154076 {published data only}
    1. NCT00154076.A multicenter comparative trial of zonisamide and topiramate as initial monotherapy in untreated epilepsies. https://clinicaltrials.gov/ct2/show/NCT00154076 (first posted 12 September 2005).
Shi 2020 {published data only}
    1. Shi KL, Guo JX, Zhao HM, Hong H, Yang CZ, Wu YH, et al.The effect of levetiracetam and oxcarbazepine monotherapy on thyroid hormones and bone metabolism in children with epilepsy: a prospective study. Epilepsy & Behavior 2020;113:107555. - PubMed
Suo 2021 {published data only}
    1. Suo GH, Zheng YQ, Wu YJ, Tang JH.Effects of levetiracetam and oxcarbazepine monotherapy on intellectual and cognitive development in children with benign epilepsy with centrotemporal spikes. Acta Neurologica Belgica 2021;15:15. - PMC - PubMed
Wang 2016 {published data only}
    1. Wang YY, Wang MG, Yao D, Huang XX, Zhang T, Deng XQ.Comparison of impact on seizure frequency and epileptiform discharges of children with epilepsy from topiramate and phenobarbital. European Review for Medical and Pharmacological Sciences 2016;20(5):993-7. - PubMed
Zhou 2019 {published data only}
    1. Zhou S, Zhan Q, Wu X.Effect of levetiracetam on cognitive function and clonic seizure frequency in children with epilepsy. Current Molecular Medicine 2019;19(9):699-703. - PubMed

References to ongoing studies

CTRI/2017/11/010605 {published data only}
    1. CTRI/2017/11/010605.Comparsion of levetiracetam and sodium valproate mono therapy in childhood epilepsy. http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=18800&EncHid=&am... (registered 23 November 2017).
CTRI/2019/04/018520 {published data only}
    1. CTRI/2019/04/018520.Comparison of the efficacy of sodium valproate with levetiracetam in controlling seizure in the age group of 2 to 18 years, a randomised control trial. http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=32252&EncHid=&am... (registered 09 April 2019).
CTRI/2019/05/018990 {published data only}
    1. CTRI/2019/05/018990.Comparison of the seizure drug levetiracetam with controlled release carbamazepine in new focal seizure patients. http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=30242&EncHid=&am... (registered on 08 May 2019).
CTRI/2020/09/027792 {published data only}
    1. CTRI/2020/09/027792.Open labeled randomized controlled trial comparing efficacy of oral levetiracetam vs sodium valproate as first line monotherapy in newly diagnosed generalized epilepsy in children. http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=39204&EncHid=&am... (registered 14 September 2020).
EpiNet‐First Trial 1 {published data only}
    1. ACTRN12615000643572.EpiNet-First Trial 1: comparison of efficacy of levetiracetam, lamotrigine and carbamazepine in people with previously untreated epilepsy who have focal seizures. anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368678&showOrig... (registered on 02 June 2015).
EpiNet‐First Trial 2 {published data only}
    1. ACTRN12615000556549.EpiNet-First Trial 2: comparison of efficacy of levetiracetam and sodium valproate in people with previously untreated epilepsy who have generalised seizures. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368462 (registered 29 May 2015).
EpiNet‐First Trial 3 {published data only}
    1. ACTRN12615000639527.EpiNet-First Trial 3: comparison of efficacy of levetiracetam and lamotrigine in people with previously untreated epilepsy who have generalised seizures, and for whom sodium valproate is not deemed an acceptable anti-epileptic drug. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368675 (registered 22 June 2015).
EpiNet‐First Trial 4 {published data only}
    1. ACTRN12615000640505.EpiNet-First Trial 4: comparison of efficacy of levetiracetam, lamotrigine and sodium valproate in people with previously untreated epilepsy who have unclassified seizures. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368663;... 22 June 2015).
EpiNet‐First Trial 5 {published data only}
    1. ACTRN12615000641594.EpiNet-First Trial 5: comparison of efficacy of levetiracetam and lamotrigine in people with previously untreated epilepsy who have unclassified seizures, and for whom sodium valproate is not deemed an acceptable anti-epileptic drug. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261... (registered on 22 June 2015).
IRCT20120215009014N351 {published data only}
    1. IRCT20120215009014N351.Effect of levetiracetam monotherapy versus sodium valproate on treatment of children with generalized or focal epilepsy. https://en.irct.ir/trial/46862 (registered 04 April 2020).
IRCT20170216032603N2 {published data only}
    1. IRCT20170216032603N2.Analysis of the efficacy and side effects of levetiracetam and carbamazepine on treatment of children's epilepsy. https://en.irct.ir/trial/44705 (registered 19 June 2020).
NCT02201251 {published data only}
    1. EUCTR2012-001552-19-HU.A study to investigate the safety of the drugs topiramate and levetiracetam in treating children recently diagnosed with epilepsy. https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-001552-19/HU (first posted 30 October 2014).
    1. NCT02201251.A study to investigate the safety of the drugs topiramate and levetiracetam in treating children recently diagnosed with epilepsy. https://clinicaltrials.gov/ct2/show/NCT02201251 (first posted 28 July 2021).

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References to other published versions of this review

Nevitt 2017a
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