Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic‐clonic seizures: an individual participant data review

Sarah J Nevitt; Anthony G Marson; Jennifer Weston; Catrin Tudur Smith

doi:10.1002/14651858.CD001769.pub3

Cochrane Database of Systematic Reviews

Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic‐clonic seizures: an individual participant data review

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DOI:

https://doi.org/10.1002/14651858.CD001769.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

28 abril 2016see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Epilepsia

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Sarah J Nevitt

Correspondencia a: Department of Biostatistics, University of Liverpool, Liverpool, UK

[email protected]
Anthony G Marson

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Jennifer Weston

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Catrin Tudur Smith

Department of Biostatistics, University of Liverpool, Liverpool, UK

Contributions of authors

SJ Nolan assessed studies for inclusion in the review update, assessed risk of bias in all included studies, performed analyses in SAS version 9.2, Stata version 11.2 and Metaview, added survival plots and a 'Summary of findings' table and updated the text of the review under the supervision of C Tudur Smith and AG Marson.

C Tudur Smith was the lead investigator on the original review, assessed eligibility and methodological quality of original individual studies, organised and cleaned the individual participant data sets, performed data validation checks and statistical analyses and co‐wrote the original review.

AG Marson obtained individual participant data from trial investigators, provided guidance with the clinical interpretation of results, assessed eligibility and methodological quality of individual studies and co‐wrote the original review.

J Weston independently assessed risk of bias in all included studies.

Sources of support

Internal sources

University of Liverpool, UK.
Walton Centre for Neurology and Neurosurgery, UK.

External sources

Medical Research Council, UK.
National Institute for Health Research (NIHR), UK.

This review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Epilepsy Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service (NHS) or the Department of Health.

Declarations of interest

SJ Nolan has no declarations of interest.

C Tudur Smith has no declarations of interest.

J Weston has no declarations of interest.

AG 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.

Acknowledgements

We are greatly indebted to all of the trialists who have provided individual participant data (IPD) and input and review. They have shown great patience in the way our data queries were handled.
Kenneth Sommerville and Roger Deaton at Abbott Laboratories.
We acknowledge Paula Williamson for contributions to the original review.

Version history

Published

Title

Stage

Authors

Version

2018 Aug 09

Sodium valproate versus phenytoin monotherapy for epilepsy: an individual participant data review

Review

Sarah J Nevitt, Anthony G Marson, Jennifer Weston, Catrin Tudur Smith

https://doi.org/10.1002/14651858.CD001769.pub4

2016 Apr 28

Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic‐clonic seizures: an individual participant data review

Review

Sarah J Nevitt, Anthony G Marson, Jennifer Weston, Catrin Tudur Smith

https://doi.org/10.1002/14651858.CD001769.pub3

2013 Aug 23

Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic‐clonic seizures

Review

Sarah J Nolan, Anthony G Marson, Jennifer Pulman, Catrin Tudur Smith

https://doi.org/10.1002/14651858.CD001769.pub2

2001 Oct 23

Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic‐clonic seizures

Review

Catrin Tudur Smith, Anthony G Marson, Paula R Williamson

https://doi.org/10.1002/14651858.CD001769

Differences between protocol and review

December 2014: title was changed to specify that the review uses individual participant data.

Sensitivity analyses added following identification of potential misclassification of seizure type. The existence of misclassification in the individual studies could not have been known at the time of writing the original protocol.

Addition of the outcome 'time to six‐month remission' for consistency with the other reviews in the series of Cochrane IPD reviews investigating pair‐wise monotherapy comparisons and removal of the outcome 'Quality of Life' which was found to not be readily available in an analysable format from early IPD requests

Notes

The protocol for this review was published with Catrin Tudur as the contact review author. Catrin is now known as Catrin Tudur Smith.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Time to withdrawal of allocated treatment.

One participant randomised to phenytoin (PHT) and nine participants randomised to valproate (SV) had time to withdrawal of zero days, and are therefore not included in "Number at Risk".

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Figure 5

Time to withdrawal of allocated treatment ‐ stratified by epilepsy type.

One participant with generalised epilepsy randomised to phenytoin (PHT) and nine participants with generalised epilepsy randomised to valproate (SV) had time to withdrawal of zero days, and are therefore not included in "Number at Risk".

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Figure 6

Time to achieve 12‐month remission.

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Figure 7

Time to achieve 12‐month remission ‐ stratified by epilepsy type.

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Figure 8

Time to achieve six‐month remission.

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Figure 9

Time to achieve six‐month remission ‐ stratified by epilepsy type.

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Figure 10

Time to first seizure.

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Figure 11

Time to first seizure ‐ stratified by epilepsy type.

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Figure 12

Time to withdrawal of allocated treatment ‐ Ramsay 1992.

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Analysis 1.1

Comparison 1 Phenytoin versus sodium valproate, Outcome 1 Time to withdrawal of allocated treatment.

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Analysis 1.2

Comparison 1 Phenytoin versus sodium valproate, Outcome 2 Time to withdrawal of allocated treatment ‐ stratified by epilepsy type.

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Analysis 1.3

Comparison 1 Phenytoin versus sodium valproate, Outcome 3 Time to achieve 12‐month remission.

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Analysis 1.4

Comparison 1 Phenytoin versus sodium valproate, Outcome 4 Time to achieve 12‐month remission ‐ stratified by epilepsy type.

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Analysis 1.5

Comparison 1 Phenytoin versus sodium valproate, Outcome 5 Time to achieve six‐month remission.

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Analysis 1.6

Comparison 1 Phenytoin versus sodium valproate, Outcome 6 Time to achieve six‐month remission ‐ stratified by epilepsy type.

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Analysis 1.7

Comparison 1 Phenytoin versus sodium valproate, Outcome 7 Time to first seizure.

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Analysis 1.8

Comparison 1 Phenytoin versus sodium valproate, Outcome 8 Time to first seizure ‐ stratified by epilepsy type.

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Analysis 1.9

Comparison 1 Phenytoin versus sodium valproate, Outcome 9 Time to first seizure ‐ epilepsy type reclassified to uncertain for generalised and age of onset > 30 years.

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Analysis 1.10

Comparison 1 Phenytoin versus sodium valproate, Outcome 10 Time to first seizure ‐ epilepsy type reclassified to partial for generalised and age of onset > 30 years.

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Phenytoin compared with valproate for partial onset seizures and generalised onset tonic‐clonic seizures
Patient or population: Adults and children with newly‐onset partial or generalised tonic‐clonic seizures Settings: Outpatients Intervention: Valproate Comparison: Phenytoin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Phenytoin	Valproate
Time to withdrawal of allocated treatment (retention time) ‐ stratified by epilepsy type Range of follow‐up (all participants): 1‐91 months	27 per 100	25 per 100 (18 to 33)	HR 1.09 (0.76 to 1.55)¹	528 (5 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for valproate
Time to withdrawal of allocated treatment (retention time) ‐ stratified by epilepsy type: generalised onset seizures (tonic‐clonic only) Range of follow‐up (all participants): 1‐91 months	18 per 100	19 per 100 (12 to 29)	HR 0.98 (0.59 to 1.64)	341 (5 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for valproate
Time to withdrawal of allocated treatment (retention time) ‐ stratified by epilepsy type: partial onset seizures Range of follow‐up (all participants): 1‐91 months	39 per 100	34 per 100 (23 to 49)	HR 1.20 (0.74 to 1.95)	187 (4 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for valproate
Time to achieve 12‐month remission (seizure‐free period) ‐ stratified by epilepsy type Range of follow‐up (all participants): 1‐91 months	67 per 100	67 per 100 (58 to 75)	HR 0.98 (0.78 to 1.23)¹	514 (4 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for phenytoin
Time to achieve 12‐month remission (seizure‐free period) ‐ stratified by epilepsy type: generalised onset seizures (tonic‐clonic only) Range of follow‐up (all participants): 1 ‐ 91 months	67 per 100	69 per 100 (58 to 79)	HR 1.04 (0.77 to 1.40)	270 (4 studies)	⊕⊕⊝⊝ low^2,4,5	HR > 1 indicates a clinical advantage for phenytoin
Time to achieve 12‐month remission (seizure‐free period) ‐ stratified by epilepsy type: partial onset seizures Range of follow up (all participants): 1‐91 months	67 per 100	63 per 100 (50 to 76)	HR 0.90 (0.63 to 1.29)	244 (4 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for phenytoin
Time to achieve 6‐month remission (seizure‐free period) ‐ stratified by epilepsy type Range of follow‐up (all participants): 1 ‐ 91 months	60 per 100	58 per 100 (51 to 65)	HR 0.95 (0.78 to 1.15)¹	639 (5 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for phenytoin
Time to achieve 6‐month remission (seizure‐free period) ‐ stratified by epilepsy type: generalised onset seizures (tonic‐clonic only) Range of follow‐up (all participants): 1 ‐ 91 months	69 per 100	66 per 100 (57 to 75)	HR 0.92 (0.72 to 1.18)	395 (5 studies)	⊕⊕⊝⊝ low^2,4,5	HR > 1 indicates a clinical advantage for phenytoin
Time to achieve 6‐month remission (seizure‐free period) ‐ stratified by epilepsy type: partial onset seizures Range of follow‐up (all participants): 1‐91 months	51 per 100	50 per 100 (40 to 62)	HR 0.99 (0.73 to 1.35)	244 (4 studies)	⊕⊕⊕⊝ moderate^2,4	HR > 1 indicates a clinical advantage for phenytoin
Time to first seizure (post‐randomisation) ‐ stratified by epilepsy type Range of follow‐up (all participants): 1‐91 months	59 per 100	62 per 100 (55 to 70)	HR 0.93 (0.75 to 1.14)¹	639 (5 studies)	⊕⊕⊝⊝ low^2,3	HR > 1 indicates a clinical advantage for valproate
Time to first seizure (post‐randomisation) ‐ stratified by epilepsy type: generalised onset seizures (tonic‐clonic only) Range of follow‐up (all participants): 1‐91 months	48 per 100	47 per 100 (38 to 58)	HR 1.03 (0.77 to 1.39)	395 (5 studies)	⊕⊝⊝⊝ very low^2,3,5	HR > 1 indicates a clinical advantage for valproate
Time to first seizure (post‐randomisation) ‐ stratified by epilepsy type: partial onset seizures Range of follow‐up (all participants): 1‐91 months	75 per 100	81 per 100 (71 to 89)	HR 0.83 (0.62 to 1.11)	244 (4 studies)	⊕⊕⊝⊝ low^2,3	HR > 1 indicates a clinical advantage for valproate
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The assumed risk is calculated as the event rate in the phenytoin treatment group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk is calculated as the assumed risk x the relative risk (RR) of the intervention where RR = (1 ‐ exponential(HR x ln(1 ‐ assumed risk)) ) / assumed risk CI: confidence interval; HR: Hazard Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Pooled HR for all participants adjusted for seizure type. ² Downgraded once as risk of bias judged high for four unblinded studies (Craig 1994; De Silva 1996; Heller 1995; Ramsay 1992) ³ Downgraded once as up to 190 out of 384 (49%) adult participants (in Craig 1994; De Silva 1996; Heller 1995; Ramsay 1992; Shakir 1981; Turnbull 1985) may have had their seizure type wrongly classified as generalised onset; sensitivity analyses show misclassification has an impact on results and conclusions. ⁴Sensitivity analysis for misclassification of epilepsy type shows similar results and unchanged conclusions, so misclassification is unlikely to impact on results ‐ no downgrade for this reason. ⁵Downgraded once as only one trial collected data on generalised seizure types other than generalised tonic‐clonic seizures (Ramsay 1992). Hence, the results apply only to generalised tonic‐clonic seizures, despite the fact that individuals may have been experiencing other generalised seizure types.

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Table 1. Outcomes considered and summary of results for trials with no individual participant data (IPD)

Trial

Outcomes reported

Summary of results

Callaghan 1985

1. Seizure control:

(a) excellent (seizure‐free)

(b) good (> 50% reduction)

(c) poor (< 50% reduction)

2. Adverse events

1. PHT (n = 58); SV (n = 64)

(a) 39 (67%) 34 (53%)

(b) 7 (12%) 16 (25%)

(c) 12 (21%) 14 (22%)

2. 6 (10%) 7 (11%)

Czapinski 1997a

1. Proportion achieving 24‐month remission at 3 years

2. Proportion excluded after randomisation due to adverse events or no efficacy

1. PHT: 59%; SV: 64%

2. PHT: 23%; SV: 23%

Forsythe 1991

1. Cognitive assessments

2. Withdrawals from randomised drug

1. Significant difference favouring SV test of speed of information processing (P < 0.01)

No significant differences between treatment groups for any other cognitive tests

2. PHT: 6/20 (30%); SV: 7/21 (33%)

Rastogi 1991

1. Reduction in frequency of seizures at 24 weeks:

(a) excellent (100% reduction)

(b) good (75%‐99% reduction)

(c) fair (50%‐74% reduction)

(d) poor (< 50% reduction)

2. Adverse events

1. PHT (n = 45); SV (n = 49)

(a) 23 (51%) 24 (49%)

(b) 13 (24%) 17 (35%)

(c) 8 (18%) 5(10%)

(d) 1 (2%) 3 (6%)

2. All reported adverse events were minor

PHT: gum hyperplasia (18%), nystagmus (13%), gastrointestinal symptoms (4%), drowsiness (4%), ataxia (2%)

SV: gastrointestinal symptoms (12%), drowsiness (6%), weight gain (2%)

Shakir 1981

1.Seizures during treatment

2. Adverse events

1. PHT: 5 (33%); SV: 7 (39%)

2. PHT: 1 case of ataxia, 5 cases of acne. SV: 2 cases of gastrointestinal symptoms, 2 cases of hair loss, 4 cases of weight gain

Thilothammal 1996

1. Recurrence of seizures

2. Adverse events

1. PHT: 14/52 (27%) SV: 10/48 (21%)

2. PHT: 33/52 (63%) SV: 15/48 (31%)

PHT: phenytoin; SV: sodium valproate

Table 1. Outcomes considered and summary of results for trials with no individual participant data (IPD)

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Table 2. Number of individuals contributing to each analysis

Trial	Number randomised			Time to withdrawal of allocated treatment			Time to achieve 12‐month remission			Time to achieve 6‐month remission			Time to first seizure
Trial	PHT	SV	Total	PHT	SV	Total	PHT	SV	Total	PHT	SV	Total	PHT	SV	Total
Craig 1994¹	81	85	166	0	0	0	71	76	147	71	76	147	71	76	147
De Silva 1996	54	49	103	53	47	100	54	49	103	54	49	103	54	49	103
Forsythe 1991³	20	21	41	20	21	41	0	0	0	0	0	0	0	0	0
Heller 1995	63	61	124	61	58	119	63	61	124	63	61	124	63	61	124
Ramsay 1992²	50	86	136	50	86	136	0	0	0	48	77	125	48	77	125
Turnbull 1985	70	70	140	70	70	140	70	70	140	70	70	140	70	70	140
Shakir 1981³	15	18	33	15	18	33	0	0	0	0	0	0	0	0	0
Total	353	390	743	269	300	569	258	256	514	306	333	639	306	333	639
¹Withdrawal information not provided for Craig 1994, so cannot contribute to 'Time to withdrawal of allocated treatment'. ²Follow‐up for Ramsay 1992 is less than 12 months so cannot contribute to 'Time to achieve 12‐month remission'. ³Data extracted from Forsythe 1991 and Shakir 1981 publications to calculate time to withdrawal of allocated treatment. Insufficient published data to calculate other outcomes. PHT: phenytoin; SV: sodium valproate

Table 2. Number of individuals contributing to each analysis

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Table 3. Results of analysis (heterogeneity, overall effect and interaction)

	Statistic	Time to withdrawal of allocated treatment	Time to achieve 12‐month remission	Time to achieve six‐month remission	Time to first seizure
Test for heterogeneity	Chi²	(df = 5) 5.95	(df = 3) 0.19	(df = 4) 1.66	(df = 4) 4.23
	P value	0.31	0.98	0.80	0.38
	I²	16%	0%	0%	5%
Overall effect	HR (95% CI)	1.02 (0.73 to 1.49)	0.97 (0.77 to 1.22)	0.92 (0.76 to 1.12)	0.96 (0.78 to 1.18)
Overall effect	P value	0.92	0.81	0.42	0.70
Test for interaction between treatment and epilepsy type	Chi²	(df = 1) 0.31	(df = 1) 0.39	(df = 1) 0.13	(df = 1) 1.06
	P value	0.58	0.53	0.72	0.3
	I²	0%	0%	0%	5.6%
Overall effect adjusted for epilepsy type	HR (95% CI)	1.09 (0.76 to 1.55)	0.98 (0.78 to 1.23)	0.95 (0.78 to 1.15)	0.93 (0.75 to 1.14)
Overall effect adjusted for epilepsy type	P value	0.19	0.87	0.60	0.47
CI: confidence interval; df: degrees of freedom of Chi² distribution; HR: Hazard ratio; P < 0.05 is classified as statistically significant

Table 3. Results of analysis (heterogeneity, overall effect and interaction)

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Table 4. Reasons for premature discontinuation (withdrawal of allocated treatment)

Reason for early termination	Classification	De Silva 1996²		Heller 1995^2,3		Ramsey 1992		Turnbull 1985		Total¹
Reason for early termination	Classification	PHT n = 53	SV n = 47	PHT n = 63	SV n = 58	PHT n = 50	SV n = 86	PHT n = 70	SV n = 70	PHT n = 236	SV n = 261
Adverse events/intoxication	Event	2	2	1	4	5	7	14	7	22	20
Poor seizure control/lack of efficacy	Event	10	11	8	9	2	1	0	2	20	23
Both adverse events and lack of efficacy	Event	5	4	2	6	0	0	2	1	9	11
Non‐compliance	Event	0	0	0	0	1	7	2	2	3	9
Participant went into remission	Censored	24	16	14	13	0	0	0	0	38	29
Lost to follow‐up	Censored	0	0	0	0	4	10	7	7	11	17
Death⁴	Censored	0	0	0	0	0	0	3	3	3	3
Other⁵	Censored	0	0	0	0	2	1	0	0	2	1
Completed the study/did not withdraw	Censored	12	14	38	26	36	60	42	48	128	148
n = number of individuals contributing to the outcome 'Time to withdrawal of allocated treatment'; PHT: phenytoin; SV: sodium valproate ¹IPD for 'Time to withdrawal of allocated treatment' was not provided for Craig 1994. ²Three participants for Heller 1995 (all SV) and three for De Silva 1996 (one PHT and two SV) have missing reasons for treatment withdrawal. ³Four participants from Heller 1995 had missing withdrawal times and did not contribute to analysis but reasons for withdrawal are given. ⁴Death due to reasons not related to the study drug. ⁵Other reasons from Ramsay 1992 – two participants withdrew due to pregnancy and one for personal reasons.

Table 4. Reasons for premature discontinuation (withdrawal of allocated treatment)

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Table 5. Adverse event data (narrative report)

Trial	Adverse event data¹	Summary of reported results
Trial	Adverse event data¹	Phenytoin (PHT)	SV (Sodium Valproate)
Callaghan 1985	All adverse events developed (by drug) and adverse events leading to discontinuation of treatment	PHT (n = 58): gum hypertrophy (n = 2), rash (n = 2), ataxia (n = 2)	SV (n = 64): weight gain (n = 4 – all discontinued treatment), drowsiness (n = 2), aggressive behaviour (n = 1 – discontinued treatment)
Craig 1994	Adverse event frequency (spontaneous reports)² Discontinuations due to adverse events³	PHT (n = 25): unsteadiness (n = 9), sleepiness (n = 7), drowsiness (n = 2), impaired concentration (n = 2), confusion (n = 1), constipation (n = 1), diarrhoea (n = 1), dysarthria (n = 1), lethargy (n = 1), nystagmus (n = 1), rash (n = 1), tired legs (n = 1) PHT discontinuations (n = 6): rash (n =1), diarrhoea (n = 1), confusion (n = 1), unsteadiness (n = 1), constipation (n = 1), sleepiness (n = 1)	SV (n = 17): unsteadiness (n = 2), sleepiness (n = 3), tremor (n = 5), oedema (n = 3), alopecia (n = 2), depression (n = 2), weight gain (n = 2) SV discontinuations (n = 2): weight gain and depression (n = 1), unsteadiness (n =1)
Czapinski 1997a	“Exclusions” due to adverse events or no efficacy⁴	Proportion “excluded”: PHT: 33.3%	Proportion “excluded”: SV: 23.3%
De Silva 1996	“Unacceptable” adverse events leading to drug withdrawal⁵	PHT (n = 54): drowsiness (n = 2), skin rash (n = 1) blood dyscrasia (n = 1), hirsutism (n = 1)	SV (n = 49): behavioural (n = 1), tremor (n = 1)
Forsythe 1991	No adverse event data reported (Withdrawal data only reported)	1 participant (PHT) withdrew from the study due to depression and anorexia	No adverse event data (or withdrawals due to adverse events) reported
Heller 1995	“Unacceptable” adverse events leading to drug withdrawal⁵	PHT (n = 63): myalgia (n = 1), irritability (n = 1)	SV (n = 61): dizziness (n = 2) abnormal liver function test (n = 1)
Ramsay 1992	Most common adverse events (by treatment group)⁶	PHT (n = 50): dyspepsia (n = 1), nausea (n = 2), dizziness (n = 2), somnolence (n = 5), tremor (n = 2), rash (n = 4)	SV (n = 86): dyspepsia (n = 7), nausea (n = 10), dizziness (n = 5), somnolence (n = 8), tremor (n = 5), rash (n = 3)
Rastogi 1991	Commonest adverse events (reported as percentages by treatment group)⁶	PHT (n = 45): gum hyperplasia (17.7%), nystagmus (13.33%), ataxia (2.2%), gastrointestinal disturbances (4.44%), drowsiness (4.44%)	SV (n = 49): gastrointestinal disturbances (12%), drowsiness (6.12%), weight gain (2.04%)
Shakir 1981	Adverse events (narrative description)²	PHT (n = 15): 1 case of ataxia, 5 cases of acne	SV (n = 18): 2 cases of gastrointestinal symptoms, 2 cases of hair loss, 4 cases of weight gain
Thilothammal 1996	Assessment of adverse events²	PHT (n = 52): 33 participants reported at least one side effect Reported frequencies: gingival hypertrophy (n = 30), ataxia (n = 13), sedation (n = 12), nausea and vomiting (n = 1) Other reported adverse events (no frequencies): nystagmus, confusion	SV (n = 48): 15 participants reported at least one side effect Reported frequencies: hyperactivity (n = 6), impaired school performance (n = 4), severe skin allergy (n = 1)
Turnbull 1985	Withdrawals due to dose‐related and idiosyncratic adverse events	PHT (n = 70): 11 withdrawals due to dose‐related adverse events (nystagmus, ataxia, tremor, diplopia and mental change) 5 withdrawals due to idiosyncratic adverse events (skin eruption, erythroderma and jaundice)	SV (n = 70): 9 withdrawals due to dose‐related adverse events (tremor, irritability, restlessness and alopecia) No withdrawals due to idiosyncratic adverse events
¹Adverse event data, as reported narratively in the publications. Adverse event data were not requested in original IPD requests but will be for all future IPD requests. For numbers of withdrawals due to adverse events in studies for which IPD were provided (De Silva 1996; Heller 1995; Ramsay 1992; Turnbull 1985) see Table 4. ²Participants may report more than one adverse event. ³The published paper, Craig 1994, reports on a subset of 38 participants, so the adverse event data summary applies only to this subset. IPD were provided for 166 participants (no additional adverse event data provided). ⁴Czapinski 1997a is an abstract only so very little information is reported. ⁵Participants may have withdrawn due to adverse event alone or a combination of adverse events and poor efficacy (seizures). ⁶Most commonly reported adverse events only, no indication of overall frequency of all adverse events.

Table 5. Adverse event data (narrative report)

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Table 6. Sensitivity analysis ‐ epilepsy type misclassification, fixed‐effect analysis

Time to withdrawal of

allocated treatment

Time to achieve 12‐month remission

Time to achieve 6‐month remission

Time to first seizure

(i) Original analysis

P: 1.20 (0.76 to 1.95)

G: 0.98 (0.59 to 1.64)

O: 1.09 (0.76 to 1.55)

P: 0.90 (0.63 to 1.29)

G: 1.04 (0.77 to 1.40)

O: 0.98 (0.78 to 1.23)

P: 0.99 (0.73 to 1.35)

G: 0.92 (0.72 to 1.18)

O: 0.95 (0.78 to 1.15)

P: 0.83 (0.62 to 1.11)

G: 1.03 (0.77 to 1.39)

O: 0.93 (0.75 to 1.14)

(i) Test for interaction

Chi² = 0.31, df = 1,

P = 0.58, I² = 0%

Chi² = 0.39, df = 1,

P = 0.53, I² = 0%

Chi² = 0.13, df = 1,

P = 0.72, I² = 0%

Chi² = 1.06, df = 1,

P = 0.30, I² = 5.6%

(ii) Generalised onset and age at onset > 30 classified as uncertain seizure type

P: 1.20 (0.76 to 1.95)

G: 1.33 (0.74 to 2.38)

U: 0.47 (0.12 to 1.85)

O: 1.17 (0.82 to 1.67)

P: 0.90 (0.63 to 1.29)

G: 0.93 (0.63 to 1.39)

U: 1.36 (0.85 to 2.17)

O: 1.01 (0.80 to 1.27)

P: 0.99 (0.73 to 1.35)

G: 0.88 (0.62 to 1.25)

U: 1.11 (0.76 to 1.61)

O: 0.99 (0.81 to 1.20)

P: 0.83 (0.62 to 1.11)

G: 1.34 (0.91 to 1.97)

U: 0.74 (0.47 to 1.17)

O: 0.93 (0.76 to 1.15)

(ii) Test for interaction

Chi² = 1.88, df = 2,

P = 0.39, I² = 0%

Chi² = 2.07, df = 2,

P = 0.36, I² = 3.3%

Chi² = 0.78, df = 2,

P = 0.68, I² = 0%

Chi² = 4.87, df = 2,

P = 0.09, I²= 58.9%

(iii) Generalised onset and age at onset > 30 reclassified as partial onset

P: 0.98 (0.63 to 1.53)

G: 1.33 (0.74 to 2.38)

O: 1.10 (0.77 to 1.56)

P: 1.01 (0.76 to 1.34)

G: 0.93 (0.63 to 1.39)

O: 0.98 (0.78 to 1.24)

P: 1.00 (0.79 to 1.27)

G: 0.88 (0.62 to 1.25)

O: 0.97 (0.80 to 1.18)

P: 0.81 (0.64 to 1.04)

G: 1.34 (0.91 to 1.97)

O 0.94 (0.76 to 1.15)

(iii) Test for interaction

Chi² = 0.67, df = 1,

P = 0.41, I² = 0%

Chi² = 0.10, df = 1,

P = 0.75, I² = 0%

Chi² = 0.36, df = 1

P = 0.55, I² = 0%

Chi² = 4.55, df = 1

P = 0.03, I² = 78%

P: partial epilepsy; G: generalised epilepsy; O: overall (all participants); U: uncertain epilepsy. Results are presented as pooled HR (95% CI) with fixed‐effect
Chi²: Chi² statistic; df: degrees of freedom of Chi² distribution.
P: P value (< 0.05 are classified as statistically significant).
100 participants reclassified to partial epilepsy or uncertain epilepsy type for outcome 'Time to withdrawal of allocated treatment'.
145 participants reclassified to partial epilepsy or uncertain epilepsy type for outcome 'Time to achieve 12‐month remission'.
171 participants reclassified to partial epilepsy or uncertain epilepsy type for outcome 'Time to achieve 6‐month remission' or 'Time to first seizure'.

See Analysis 1.2, Analysis 1.4, Analysis 1.6, and Analysis 1.8 for original analyses of 'Time to withdrawal of allocated treatment', 'Time to achieve 12‐month remission', 'Time to achieve 6‐month remission', and 'Time to first seizure' respectively.

See Analysis 1.9 and Analysis 1.10 for forest plots of 'Time to first seizure' sensitivity analyses for generalised and age at onset > 30 reclassified as uncertain epilepsy type and partial epilepsy, respectively. Forest plots are not presented for 'Time to withdrawal of allocated treatment', 'Time to achieve 6‐month remission', 'Time to achieve 12‐month remission' sensitivity analyses, as results were similar for partial onset and generalised onset subgroups, and conclusions are unchanged.

Table 6. Sensitivity analysis ‐ epilepsy type misclassification, fixed‐effect analysis

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Comparison 1. Phenytoin versus sodium valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to withdrawal of allocated treatment Show forest plot	6	569	Hazard Ratio (Fixed, 95% CI)	1.02 [0.73, 1.42]

2 Time to withdrawal of allocated treatment ‐ stratified by epilepsy type Show forest plot	5	528	Hazard Ratio (Fixed, 95% CI)	1.09 [0.76, 1.55]

2.1 Generalised onset seizures (tonic‐clonic only)	5	341	Hazard Ratio (Fixed, 95% CI)	0.98 [0.59, 1.64]
2.2 Partial onset seizures	4	187	Hazard Ratio (Fixed, 95% CI)	1.20 [0.74, 1.95]
3 Time to achieve 12‐month remission Show forest plot	4	514	Hazard Ratio (Fixed, 95% CI)	0.97 [0.77, 1.22]

4 Time to achieve 12‐month remission ‐ stratified by epilepsy type Show forest plot	4	514	Hazard Ratio (Fixed, 95% CI)	0.98 [0.78, 1.23]

4.1 Generalised onset seizures (tonic‐clonic only)	4	270	Hazard Ratio (Fixed, 95% CI)	1.04 [0.77, 1.40]
4.2 Partial onset seizures	4	244	Hazard Ratio (Fixed, 95% CI)	0.90 [0.63, 1.29]
5 Time to achieve six‐month remission Show forest plot	5	639	Hazard Ratio (Fixed, 95% CI)	0.92 [0.76, 1.12]

6 Time to achieve six‐month remission ‐ stratified by epilepsy type Show forest plot	5	639	Hazard Ratio (Fixed, 95% CI)	0.95 [0.78, 1.15]

6.1 Generalised onset seizures (tonic‐clonic only)	5	395	Hazard Ratio (Fixed, 95% CI)	0.92 [0.72, 1.18]
6.2 Partial onset seizures	4	244	Hazard Ratio (Fixed, 95% CI)	0.99 [0.73, 1.35]
7 Time to first seizure Show forest plot	5	639	Hazard Ratio (Fixed, 95% CI)	0.96 [0.78, 1.18]

8 Time to first seizure ‐ stratified by epilepsy type Show forest plot	5	639	Hazard Ratio (Fixed, 95% CI)	0.93 [0.75, 1.14]

8.1 Generalised onset seizures (tonic‐clonic only)	5	395	Hazard Ratio (Fixed, 95% CI)	1.03 [0.77, 1.39]
8.2 Partial onset seizures	4	244	Hazard Ratio (Fixed, 95% CI)	0.83 [0.62, 1.11]
9 Time to first seizure ‐ epilepsy type reclassified to uncertain for generalised and age of onset > 30 years Show forest plot	5	649	Hazard Ratio (Fixed, 95% CI)	0.93 [0.76, 1.15]

9.1 Generalised onset seizures (tonic‐clonic only)	4	223	Hazard Ratio (Fixed, 95% CI)	1.34 [0.91, 1.97]
9.2 Partial onset seizures	4	255	Hazard Ratio (Fixed, 95% CI)	0.83 [0.62, 1.11]
9.3 Uncertain seizure type	4	171	Hazard Ratio (Fixed, 95% CI)	0.74 [0.47, 1.17]
10 Time to first seizure ‐ epilepsy type reclassified to partial for generalised and age of onset > 30 years Show forest plot	5	639	Hazard Ratio (Fixed, 95% CI)	0.94 [0.76, 1.15]

10.1 Generalised onset seizures (tonic‐clonic only)	4	223	Hazard Ratio (Fixed, 95% CI)	1.34 [0.91, 1.97]
10.2 Partial onset seizures	5	416	Hazard Ratio (Fixed, 95% CI)	0.81 [0.64, 1.04]

Comparison 1. Phenytoin versus sodium valproate

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Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic‐clonic seizures: an individual participant data review

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