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Review
. 2019 Jul 31;7(7):CD002217.
doi: 10.1002/14651858.CD002217.pub3.

Phenobarbitone versus phenytoin monotherapy for epilepsy: an individual participant data review

Affiliations
Review

Phenobarbitone versus phenytoin monotherapy for epilepsy: an individual participant data review

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

Abstract

Background: This is an update of a Cochrane Review first published in 2001, and last updated in 2013. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone.

Objectives: To review the time to treatment failure, remission and first seizure with phenobarbitone compared with phenytoin when used as monotherapy in people with focal onset seizures (simple or complex focal and secondarily generalised), or generalised onset tonic-clonic seizures (with or without other generalised seizure types).

Search methods: For the latest update, we searched the following databases on 21 August 2018: the Cochrane Register of Studies (CRS Web), which includes Cochrane Epilepsy's Specialized Register and CENTRAL; MEDLINE; the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov); and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. SELECTION CRITERIA: Randomised controlled trials comparing monotherapy with either phenobarbitone or phenytoin in children or adults with focal onset seizures or generalised onset tonic-clonic seizures.

Data collection and analysis: This was an individual participant data (IPD), review. Our primary outcome was time to treatment failure. Our secondary outcomes were time to first seizure post-randomisation, time to six-month remission and time to 12-month remission. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs), with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI.

Main results: Individual participant data were obtained for five studies, which recruited a total of 635 participants, representing 80% of 798 individuals from all seven identified eligible trials. For remission outcomes, an HR of less than 1 indicates an advantage for phenytoin and for first seizure and treatment failure outcomes an HR of less than 1 indicates an advantage for phenobarbitone.Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 499 participants: 1.61, 95% CI 1.22 to 2.12, low-certainty evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 499 participants: 1.99, 95% CI 1.37 to 2.87, low-certainty evidence), time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 499 participants: 1.87, 95% CI 1.32 to 2.66, moderate-certainty evidence), showing a statistically significant advantage for phenytoin compared to phenobarbitone.For our secondary outcomes, we did not find any statistically significant differences between phenytoin and phenobarbitone: time to first seizure post-randomisation (pooled HR adjusted for seizure type for 624 participants: 0.85, 95% CI 0.69 to 1.06, moderate-certainty evidence), time to 12-month remission (pooled HR adjusted for seizure type for 588 participants: 0.90, 95% CI 0.69 to 1.19, moderate-certainty evidence), and time to six-month remission pooled HR adjusted for seizure type for 588 participants: 0.91, 95% CI 0.71 to 1.15, moderate-certainty evidence).For individuals with focal onset seizures (73% of individuals contributing to analysis), numerical results were similar and conclusions the same as for analyses of all individuals and for individuals with generalised onset seizures (27% of individuals contributing to analysis), results were imprecise and no clear differences between the drugs were observed.Several confounding factors, most notably the differences in design of the trials with respect to blinding, were likely to have impacted on the results of the primary outcome 'time to treatment failure', and in turn, the treatment failure rates may have impacted on the secondary efficacy outcomes of time to first seizure and time to 12-month and six-month remission.

Authors' conclusions: Low-certainty evidence from this review suggests that phenytoin may be a more effective drug than phenobarbitone in terms of treatment retention (treatment failures due to lack of efficacy or adverse events or both). Moderate-certainty evidence from this review also indicates no differences between the drugs in terms of time to seizure recurrence and seizure remission.However, the trials contributing to the analyses had methodological inadequacies and methodological design differences that may have impacted upon the results of this review. Therefore, we do not suggest that results of this review alone should form the basis of a treatment choice for a patient with newly onset seizures. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

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Conflict of interest statement

Sarah J Nevitt: none known.

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

Catrin Tudur Smith: none known.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Time to treatment failure ‐ any reason related to the treatment (PB: phenobarbitone; PHT: phenytoin)
5
5
Time to treatment failure ‐ any reason related to the treatment, by epilepsy type (PB: phenobarbitone; PHT: phenytoin)
6
6
Time to treatment failure due to adverse events (PB: phenobarbitone; PHT: phenytoin)
7
7
Time to treatment failure due to adverse events, by epilepsy type (PB: phenobarbitone; PHT: phenytoin)
8
8
Time to treatment failure due to lack of efficacy (PB: phenobarbitone; PHT: phenytoin)
9
9
Time to treatment failure due to lack of efficacy, by epilepsy type (PB: phenobarbitone; PHT: phenytoin)
10
10
Time to first seizure (PB: phenobarbitone; PHT: phenytoin)
11
11
Time to first seizure, by epilepsy type (PB: phenobarbitone; PHT: phenytoin)
12
12
Time to 12 month remission (PB: phenobarbitone; PHT: phenytoin)
13
13
Time to 12 month remission, by epilepsy type (PB: phenobarbitone; PHT: phenytoin)
14
14
Time to 6 month remission (PB: phenobarbitone; PHT: phenytoin)
15
15
Time to 6 month remission, by epilepsy type (PB: phenobarbitone; PHT: phenytoin)
16
16
Time to 6 month remission ‐ Mattson 1985 (Proportional Hazards Check)
1.1
1.1. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 1 Time to treatment failure (any reason related to the treatment).
1.2
1.2. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 2 Time to treatment failure due to adverse events.
1.3
1.3. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 3 Time to treatment failure due to lack of efficacy.
1.4
1.4. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 4 Time to treatment failure (any reason related to the treatment) ‐ by epilepsy type.
1.5
1.5. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 5 Time to treatment failure due to adverse events ‐ by epilepsy type.
1.6
1.6. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 6 Time to treatment failure due to lack of efficacy ‐ by epilepsy type.
1.7
1.7. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 7 Time to treatment failure (any reason related to the treatment) ‐ by age of participants.
1.8
1.8. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 8 Time to treatment failure due to adverse events ‐ by age of participants.
1.9
1.9. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 9 Time to treatment failure (any reason related to the treatment) ‐ by blinded study design.
1.10
1.10. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 10 Time to treatment failure due to adverse events ‐ by blinded study design.
1.11
1.11. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 11 Time to first seizure after randomisation.
1.12
1.12. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 12 Time to first seizure after randomisation ‐ by epilepsy type.
1.13
1.13. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 13 Time to achieve 12‐month remission from seizures.
1.14
1.14. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 14 Time to achieve 12 month remission ‐ by seizure type.
1.15
1.15. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 15 Time to achieve 6‐month remission.
1.16
1.16. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 16 Time to achieve 6‐month remission ‐ by seizure type.
1.17
1.17. Analysis
Comparison 1 Phenobarbitone (PB) versus phenytoin (PHT) monotherapy, Outcome 17 Time to achieve 6‐month remission ‐ interval censored.

Update of

  • doi: 10.1002/14651858.CD002217.pub2

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