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

Sarah J Nevitt; Anthony G Marson; Catrin Tudur Smith

doi:10.1002/14651858.CD001911.pub4

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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 treatment failure ‐ any reason related to the treatment (CBZ: carbamazepine; PHT: phenytoin)

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Figure 5

Time to treatment failure ‐ any reason related to the treatment, by epilepsy type (CBZ: carbamazepine; PHT: phenytoin)

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Figure 6

Time to treatment failure due to adverse events (CBZ: carbamazepine; PHT: phenytoin)

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Figure 7

Time to treatment failure due to adverse events, by epilepsy type (CBZ: carbamazepine; PHT: phenytoin)

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Figure 8

Time to treatment failure due to lack of efficacy (CBZ: carbamazepine; PHT: phenytoin)

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Figure 9

Time to treatment failure due to lack of efficacy, by epilepsy type (CBZ: carbamazepine; PHT: phenytoin)

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Figure 10

Time to first seizure (CBZ: carbamazepine; PHT: phenytoin)

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Figure 11

Time to first seizure, by epilepsy type (CBZ: carbamazepine; PHT: phenytoin)

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Figure 12

Time to 12 month remission (CBZ: carbamazepine; PHT: phenytoin)

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Figure 13

Time to 12 month remission, by epilepsy type (CBZ: carbamazepine; PHT: phenytoin)

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Figure 14

Time to 6 month remission (CBZ: carbamazepine; PHT: phenytoin)

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Figure 15

Time to 6 month remission, by epilepsy type (CBZ: carbamazepine; PHT: phenytoin)

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Figure 16

Cumulative incidence plots, proportional hazards assumption checks

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Analysis 1.1

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 1 Time to treatment failure (any reason related to the treatment).

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Analysis 1.2

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 2 Time to treatment failure due to adverse events.

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Analysis 1.3

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 3 Time to treatment failure due to lack of efficacy.

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Analysis 1.4

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 4 Time to treatment failure (any reason related to the treatment) ‐ by epilepsy type.

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Analysis 1.5

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 5 Time to treatment failure due to adverse events ‐ by epilepsy type.

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Analysis 1.6

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 6 Time to treatment failure due to lack of efficacy ‐ by epilepsy type.

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Analysis 1.7

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 7 Time to first seizure post‐randomisation.

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Analysis 1.8

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 8 Time to first seizure post‐randomisation ‐ by epilepsy type.

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Analysis 1.9

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 9 Time to achieve 12‐month remission.

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Analysis 1.10

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 10 Time to achieve 12‐month remission ‐ by epilepsy type.

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Analysis 1.11

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 11 Time to achieve six‐month remission.

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Analysis 1.12

Comparison 1 Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy, Outcome 12 Time to achieve six‐month remission ‐ by epilepsy type.

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Summary of findings for the main comparison. Carbamazepine compared with phenytoin (time to treatment failure)

Carbamazepine compared with phenytoin for epilepsy
Patient or population: adults and children with new‐onset focal or generalised epilepsy Settings: outpatients Intervention: carbamazepine Comparison: phenytoin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)^a	No. of Participants (studies)	Certainty (quality) of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Phenytoin	Carbamazepine
Time to treatment failure (any reason related to treatment) All participants Range of follow‐up:1 day to 4403 days	The median time to treatment failure was 2135 days in the phenytoin group	The median time to treatment failure was 2422 days (307 days longer) in the carbamazepine group	HR 0.94 (0.70 to 1.26)^a	546 (3 studies)	⊕⊕⊕⊝ moderate^b	HR < 1 indicates a clinical advantage for carbamazepine There was also no statistically significant difference between drugs in treatment failure due to adverse events (HR 1.27, 95% CI 0.87 to 1.86; P = 0.21; I² = 3%), or treatment failure due to lack of efficacy: HR 0.99 (95% CI 0.69 to 1.41; P = 0.94; I² = 0%)
Time to treatment failure (any reason related to treatment) Subgroup: focal onset seizures Range of follow‐up: 1 day to 4064 days	The median time to treatment failure was 1300 days in the phenytoin group	The median time to treatment failure was 2422 days (1122 days longer) in the carbamazepine group	HR 0.83 (0.61 to 1.13)	428 (3 studies)	⊕⊕⊕⊝ moderate^b	HR < 1 indicates a clinical advantage for carbamazepine There was also no statistically significant difference between drugs in treatment failure due to adverse events (HR 1.19, 95% CI 0.80 to 1.78; P = 0.38, I² = 0%), or treatment failure due to lack of efficacy: HR 0.88 (95% CI 0.60 to 1.40, P = 0.52, I² = 0%)
Time to treatment failure (any reason related to treatment) Subgroup: generalised onset tonic clonic seizures Range of follow‐up:1 day to 4403 days	The 10th percentile^c of time to treatment failure was 778 days in the phenytoin group	The 10th percentile^c of time to treatment failure was 108 days (670 days shorter) in the carbamazepine group	HR 2.38 (1.04 to 5.47)	118 (2 studies)	⊕⊕⊝⊝ low^b,d	HR < 1 indicates a clinical advantage for carbamazepine There was no statistically significant difference between drugs in treatment failure due to adverse events (HR 2.31, 95% CI 0.68 to 7.81; P = 0.18; I² = 60% , or treatment failure due to lack of efficacy: HR 1.86 (95% CI 0.74 to 4.67; P = 0.19; I² = 0%) but confidence intervals are wide so we cannot rule out an advantage to either drug or no difference between the drugs
*Illustrative risks in the carbamazepine and phenytoin groups are calculated at the median time to treatment failure (i.e. the time to 50% of participants failing or withdrawing from allocated treatment) within each group across all trials. The relative effect (pooled hazard ratio) shows the comparison of 'Time to treatment failure' between the treatment groups. CI: 95% confidence interval; HR: hazard ratio
GRADE Working Group grades of evidence High certainty (quality): Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty (quality): Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty (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 certainty (quality): We are very uncertain about the estimate.
^aPooled HR for all participants adjusted for seizure type. All pooled HRs presented calculated with fixed‐effect model. ^bDowngraded once for risk of bias: risk of bias unclear for one element of all of the three studies included in the analysis. Additionally, 29 adult participants may have had their seizure type wrongly classified as generalised onset; sensitivity analyses show misclassification may have had an impact on results and conclusions about an association between treatment and seizure type. ^cThe 10th percentile of time to treatment failure (i.e. the time to 50% of participants failing or withdrawing from allocated treatment) is presented for the subgroup with generalised seizures, as fewer than 50% of participants failed/withdrew from treatment, so we could not calculate median time. ^dDowngraded once for imprecision: the subgroup of participants with generalised onset tonic‐clonic seizures is relatively small (22% of total participants) and confidence intervals around pooled results are fairly wide.

Summary of findings for the main comparison. Carbamazepine compared with phenytoin (time to treatment failure)

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Summary of findings 2. Carbamazepine compared with phenytoin (secondary outcomes)

Carbamazepine compared with phenytoin for epilepsy
Patient or population: adults and children with new‐onset focal or generalised epilepsy Settings: outpatients Intervention: carbamazepine Comparison: phenytoin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)^a	No. of Participants (studies)	Certainty (quality) of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Phenytoin	Carbamazepine
Time to first seizure after randomisation All participants Range of follow‐up: 0 days to 4589 days	The median time to first seizure was 124 days in the phenytoin group	The median time to first seizure was 79 days (45 days shorter) in the carbamazepine group	HR 1.15 (0.94 to 1.40)	582 (4 studies)	⊕⊕⊕⊝ moderate^b	HR < 1 indicates a clinical advantage for carbamazepine
Time to first seizure after randomisation Subgroup: focal onset seizures Range of follow‐up: 0 days to 4589 days	The median time to first seizure was 78 days in the phenytoin group	The median time to first seizure was 62 days (16 days shorter) in the carbamazepine group	HR 1.13 (0.89 to 1.43)	432 (4 studies)	⊕⊕⊕⊝ moderate^b	HR < 1 indicates a clinical advantage for carbamazepine
Time to first seizure after randomisation Subgroup: generalised onset tonic clonic seizures Range of follow‐up: 2 days to 4070 days	The median time to first seizure was 323 days in the phenytoin group	The median time to first seizure was 142 days (181 days shorter) in the carbamazepine group	HR 1.19 (0.81 to 1.75)	150 (3 studies)	⊕⊕⊝⊝ low^b,c	HR < 1 indicates a clinical advantage for carbamazepine
Time to achieve 12‐month remission All participants Range of follow‐up: 0 days to 4222 days	The median time to 12‐month remission was 472 days in the phenytoin group	The median time to 12‐month remission was 481 days (9 days longer) in the carbamazepine group	HR 1.00 (0.79 to 1.26)	551 (3 studies)	⊕⊕⊕⊝ moderate^b	HR < 1 indicates a clinical advantage for phenytoin
Time to achieve 12‐month remission Subgroup: focal onset seizures Range of follow‐up: 0 days to 4222 days	The median time to 12‐month remission was 531 days in the phenytoin group	The median time to 12‐month remission was 515 days (16 days shorter) in the carbamazepine group	HR 1.06 (0.80 to 1.42)	430 (3 studies)	⊕⊕⊕⊝ moderate^b	HR < 1 indicates a clinical advantage for phenytoin
Time to achieve 12‐month remission Subgroup: generalised onset tonic clonic seizures Range of follow‐up: 7 days to 4163 days	The median time to 12‐month remission was 366 days in the phenytoin group	The median time to 12‐month remission was 375 days (9 days longer) in the carbamazepine group	HR 0.88 (0.58 to 1.33)	121 (2 studies)	⊕⊕⊝⊝ low^b,d	HR < 1 indicates a clinical advantage for phenytoin
Illustrative risks in the carbamazepine and phenytoin groups are calculated at the median time to first seizure or time to 12‐month remission (i.e. the time to 50% of participants experiencing a first seizure or 12‐months of remission) within each group across all trials. The relative effect (pooled hazard ratio) shows the comparison of 'Time to first seizure' or 'Time to 12‐month remission' between the treatment groups. CI:* 95% confidence interval; HR: hazard ratio
GRADE Working Group grades of evidence High certainty (quality): Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty (quality): Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty (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 certainty (quality): We are very uncertain about the estimate.
^aPooled HR for all participants adjusted for seizure type. All pooled HRs presented calculated with a fixed‐effect model. ^bDowngraded once due to risk of bias: risk of bias unclear for one element of three studies included in the analysis. ^cDowngraded once due to inconsistency: heterogeneity was present between trials (I² = 45%) which could not be explained by sensitivity analyses examining misclassification of seizure type, or age groups recruited within the studies. ^dDowngraded once due to inconsistency: substantial heterogeneity present between trials (I² = 73%). This heterogeneity is likely to be due to misclassification of seizure type of 29 adult participants.

Summary of findings 2. Carbamazepine compared with phenytoin (secondary outcomes)

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Table 1. Outcomes considered and summary of results for trials with no IPD

Trial	Outcomes reported	Summary of results
Callaghan 1985	1. Seizure control: excellent (seizure‐free) good (> 50% reduction) poor (< 50% reduction) 2. Side effects	1. PHT (n = 58); CBZ (n = 59) PHT: 39 (67%); CBZ: 22 (37%) PHT: 7 (12%); CBZ: 22 (37%) PHT: 12 (21%); CBZ: 15 (25%) PHT: 6 (10%); CBZ: 5 (8%)
Czapinski 1997	1. Proportion achieving 24‐month remission at 3 years 2. Proportion excluded after randomisation due to adverse effects or no efficacy	1. PHT: 59%; CBZ: 62% 2. PHT: 23%; CBZ: 30%
Forsythe 1991	1. Cognitive assessments 2. Withdrawals from randomised drug	1. No significant differences between the two treatment groups on any cognitive tests 2. PHT: 6 withdrawals out of 20 participants (30%); CBZ: 9 withdrawals out of 23 participants (39%)
Miura 1993	1. Proportion of all randomised participants with seizure recurrence (by seizure type) 2. Proportion of participants with optimum plasma levels with seizure recurrence (by seizure type)	PHT (n = 51); CBZ (n = 66) 1. PHT (focal): 10/31 (32%); PHT (generalised): 7/20 (35%); CBZ (focal): 21/53 (40%); CBZ (generalised): 2/13 (15%) 2. PHT (focal): 4/17 (24%); PHT (generalised): 1/8 (13%); CBZ (focal): 4/17 (24%); CBZ (generalised): 0/7 (0%)
Pulliainen 1994	1. Cognitive assessments (visual motor speed, co‐ordination, attention and concentration, verbal and visual‐spatial learning, visual and recognition memory, reasoning, mood, handedness) 2. Harmful side effects	1. Compared to CBZ, participants on PHT became slower (motor speed of the hand) and their visual memory decreased. There was an equal decrease in negative mood (helplessness, irritability, depression) on PHT and CBZ 2. 3 participants taking PHT complained of tiredness, and 1 participant taking CBZ complained of facial skin problems, another tiredness and memory problems
Ramsay 1983	1. Side effects (major and minor) 2. Treatment failure/seizure control 3. Laboratory results	1. Incidence of: major side effects (among analysed participants): PHT 8/35 participants (23%); CBZ 8/35 participants (23%) minor side effects: cognitive impairment and sedation twice as likely on CBZ as PHT other minor side effects similar between groups 2. Treatment failures among analysed participants: PHT 4/35 (11%); CBZ: 5/35 (14%) Seizure control (among analysed participants with no major side effects): PHT: 23/27 participants (86%); CBZ: 22/27 participants (82%) 3. Significantly lower mean LDH level at 24 weeks in CBZ participants than PHT participants (P < 0.01). Other laboratory results similar across treatment groups
Ravi Sudhir 1995	1. Cognitive measures (verbal, performance, memory, visual‐motor, perceptomotor organisation, visual organisation, dysfunction)	1. No significant differences between any tests of cognitive function taken before treatment and after 10 ‐ 12 weeks for both treatment groups
CBZ = carbamazepine; LDH = lactate dehydrogenase; PHT= phenytoin

Table 1. Outcomes considered and summary of results for trials with no IPD

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Table 2. Demographic characteristics of trial participants (trials providing individual participant data)

Trial	Focal seizures: n (%)		Male participants: n (%)^a		Age at entry (years): Mean (SD), range^b		Epilepsy duration (years): mean (SD), range^c		Number of seizures in prior 6 months, median (range)^d
Trial	CBZ	PHT	CBZ	PHT	CBZ	PHT	CBZ	PHT	CBZ	PHT
De Silva 1996^e	29 (54%)	30 (56%)	30 (56%)	34 (63%)	9.2 (3.8) 2 to 15	9.5 (3.4) (3 to 16)	1.7 (2.6), 0 to 12	1.0 (2.1) (0 to 14)	3 (1 to 500)	3 (1 to 404)
Heller 1995	24 (39%)	28 (44%)	30 (49%)	34 (54%)	29.3 (14.1) 13 to 69	33.5 (14.3) (14 to 72)	4.4 (7.4), 0.1 to 40	3.8 (5.4) (0 to 24)	2 (1 to 354)	2 (1 to 575)
Mattson 1985	155 (100%)	165 (100%)	133 (87%)	145 (88%)	42.1 (15.9) 18 to 82	40.8 (15.3) (18 to 81)	5.9 (9.1), 0.5 to 55	6.6 (9.1) (0.5 to 59)	1 (1 to 100)	1 (1 to 26)
Ogunrin 2005	5 (26%)	3 (17%)	12 (63%)	11 (61%)	28.2 (5.8) 14 to 38	18.8 (2.6) (15 to 26)	NA	NA	18 (6 to 36)	12 (6 to 18)
n: number of participants; CBZ: carbamazepine; NA: not available; PHT:phenytoin SD: standard deviation ^aSex was missing for two participants on CBZ from Mattson 1985. ^bAge at randomisation was missing for two participants on CBZ from Mattson 1985 and one participant on CBZ from Heller 1995. ^cEpilepsy duration was missing for 41 participants; all 37 participants from Ogunrin 2005, three participants on CBZ from Mattson 1985, one participant on CBZ from Heller 1995. ^dNumber of seizures in the prior six months was missing for eight participants, seven participants from Mattson 1985 (three participants on PHT and four on CBZ), one participant on CBZ from Heller 1995. ^eRandomised drug missing for six participants in De Silva 1996.

Table 2. Demographic characteristics of trial participants (trials providing individual participant data)

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Table 3. Number of participants contributing to each analysis

Trial	Number randomised			Time to treatment failure (any reason, adverse events, lack of efficacy)			Time to 12‐month remission			Time to 6‐month remission			Time to first seizure
Trial	PHT	CBZ	Total	PHT	CBZ	Total	PHT	CBZ	Total	PHT	CBZ	Total	PHT	CBZ	Total
De Silva 1996^a	54	54	108	53	53	106	54	54	108	54	54	108	54	54	108
Heller 1995^b	63	61	124	61	60	121	63	61	124	63	61	124	63	61	124
Mattson 1985^c	165	155	320	165	154	319	165	154	319	165	154	319	162	151	313
Forsythe 1991^d	20	23	43	20	23	43	Information not available			Information not available			Information not available
Ogunrin 2005^e	18	19	37	Information not available			Information not available			Information not available			18	19	37
Total	320	312	632	299	290	589	282	269	551	282	269	551	297	285	582
CBZ = carbamazepine, PHT= phenytoin ^aIndividual participant data (IPD) supplied for 114 participants recruited in De Silva 1996; randomised drug not recorded in six participants. Reasons for treatment failure not available for two participants (one randomised to CBZ and one to PHT); these participants are not included in analysis of time to treatment failure. ^bReasons for treatment failure not available for three participants (one randomised to CBZ and two to PHT) in Heller 1995; these participants are not included in analysis of time to treatment failure. ^cNo follow‐up data after randomisation available for one participant randomised to CBZ in Mattson 1985. Data on seizure recurrence not available for six additional participants (three randomised to CBZ and three to PHT); these participants are not included in the analysis of Time to first seizure. ^dIPD for 'Time to treatment failure' available in the study publication of Forsythe 1991. Data for other outcomes not available. ^eStudy duration of Ogunrin 2005 is 12 weeks, so six‐ and 12‐month remission of seizures could not be achieved and cannot therefore be calculated. All randomised participants completed the study without withdrawing from treatment, so time to treatment failure cannot be analysed.

Table 3. Number of participants contributing to each analysis

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Table 4. Reasons for premature discontinuation

Reason for early termination	De Silva 1996^a		Forsythe 1991		Heller 1995^a,b		Mattson 1985		Total^c
Reason for early termination	CBZ	PHT	CBZ	PHT	CBZ	PHT	CBZ	PHT	CBZ	PHT	Total
Adverse events (Event)	3	2	4	1	8	1	11	8	26	12	38
Seizure recurrence (Event)	12	10	2	1	5	8	3	6	22	25	47
Both seizure recurrence and adverse events (Event)	6	5	0	0	4	2	31	33	31	40	81
Non‐compliance/participant choice (Event)	0	0	3	4	0	0	11	26	14	30	44
Participant went into remission (Censored)	18	24	0	0	6	14	0	0	24	38	62
Lost to follow‐up (Censored)	0	0	0	0	0	0	26	19	26	19	45
Death (Censored)^d	0	0	0	0	0	0	4	5	4	5	9
Other (Censored)^e	0	0	0	0	0	0	16	11	16	11	27
Completed the study (did not withdraw) (Censored)	14	12	14	14	37	38	53	57	118	121	239
Total	53	53	23	20	60	63	155	165	281	301	592
n = number of individuals contributing to the outcome 'Time to treatment failure’ ^aOne participant for Heller 1995 (CBZ) and two for De Silva 1996 (one PHT and one CBZ) have missing reasons for treatment failure. ^bTwo participants from Heller 1995 (both PHT) had missing treatment failure times and did not contribute to analysis, but reasons for treatment failure are given. ^cAll participants in Ogunrin 2005 completed the study without withdrawing, so this study did not contribute to 'Time to treatment failure'. ^dDeath due to reasons not related to the study drug. ^eOther reasons from Mattson 1985: participants developed other medical disorders including neurological and psychiatric disorders.

Table 4. Reasons for premature discontinuation

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Table 5. Sensitivity analysis ‐ Epilepsy type misclassification, fixed‐effect analysis

Outcome

Original analysis

Generalised onset and age at onset > 30 years classified

as focal onset

Generalised onset and age at onset > 30 years classified

as uncertain seizure type

Pooled HR (95% CI)

fixed‐effect model

Test of subgroup

differences

Pooled HR (95% CI)

fixed‐effect model

Test of subgroup

differences

Pooled HR (95% CI)

fixed‐effect model

Test of subgroup

differences

Time to treatment failure

(for any reason related to treatment)^a

F: 0.83 (0.61 to 1.13), I² = 0%

G: 2.38 (1.04 to 5.47), I² = 0%

O: 0.94 (0.70 to 1.26), I² = 35%

Chi² = 5.45, df = 1, P = 0.02, I² = 81.7%

F: 0.88 (0.65 to 1.19), I² = 0%

G: 1.96 (0.81 to 4.78), I² = 0%

O: 0.96 (0.72 to 1.27), I² = 6%

Chi² = 2.83, df = 1,

P = 0.09, I² = 64.6%

F: 0.83 (0.61 to 1.13), I² = 0%

G: 1.96 (0.81 to 4.78), I² = 0%

U: 5.23 (0.47 to 58.71), I² = NA

O: 0.93 (0.70 to 1.24), I² = 7%

Chi² = 5.24, df = 2,

P = 0.07, I² = 61.8%

Time to treatment failure due to adverse events^a

F: 1.19 (0.80 to 1.78), I² = 0%

G: 2.31 (0.68 to 7.81), I² = 60%

O: 1.27 (0.87 to 1.86), I² = 3%

Chi² = 1.02, df = 1,

P = 0.31, I² = 2.2%

F: 1.25 (0.84 to 1.86), I² = 22%

G: 1.72 (0.51 to 5.87), I² = 0%

O: 1.29 (0.88 to 1.88), I² = 0%

Chi² = 0.24, df = 1,

P = 0.62, I² = 0%

F: 1.19 (0.80 to 1.78), I² = 0%

G: 1.72 (0.51 to 5.87), I² = 0%

U: Not estimable^c

O: 1.24 (0.85 to 1.81), I² = 0%

Chi² = 0.31, df = 2,

P = 0.86, I² = 0%

Time to treatment failure due to lack of efficacy^a

F: 0.88 (0.60 to 1.30), I² = 0%

G: 1.86 (0.74 to 4.67), I² = 0%

O: 0.99 (0.69 to 1.41), I² = 0%

Chi² = 2.14, df = 1,

P = 0.14, I² = 53.2%

F: 0.91 (0.62 to 1.34), I² = 0%

G: 1.81 (0.68 to 4.82), I² = 0%

O: 1.00 (0.70 to 1.43), I² = 0%

Chi² = 1.64, df = 1,

P = 0.20, I² = 38.9%

F: 0.88 (0.60 to 1.30), I² = 0%

G: 1.81 (0.68 to 4.82), I² = 0%

U: Not estimable^c

O: 0.97 (0.68 to 1.40), I² = 0%

Chi² = 1.78, df = 2,

P = 0.41, I² = 0%

Time to first seizure^b

F: 1.13 (0.89 to 1.43), I² = 0%

G: 1.19 (0.81 to 1.75), I² = 45%

O: 1.15 (0.94 to 1.40), I² = 0%

Chi² = 0.05, df = 1,

P = 0.83, I² = 0%

F: 1.15 (0.91 to 1.44), I² = 0%

G: 1.19 (0.77 to 1.84), I² = 53%

O: 1.16 (0.94 to 1.42), I² = 0%

Chi² = 0.02, df = 1,

P = 0.88, I² = 0%

F: 1.13 (0.89 to 1.43), I² = 0%

G: 1.19 (0.77 to 1.84), I² = 53%

U: 0.82 (0.29 to 2.34), I² = NA

O: 1.13 (0.92 to 1.39), I² = 0%

Chi² = 0.41, df = 2,

P = 0.82, I² = 0%

Time to 12‐month remission^a

F: 1.06 (0.80 to 1.42), I² = 0%

G: 0.88 (0.58 to 1.33), I² = 73%

O: 1.00 (0.79 to 1.26), I² = 16%

Chi² = 0.54, df = 1,

P = 0.46, I² = 0%

F: 1.10 (0.84 to 1.45), I² = 0%

G: 0.69 (0.43 to 1.11), I² = 0%

O: 0.98 (0.77 to 1.24), I² = 0%

Chi² = 2.79, df = 1,

P = 0.09, I² = 64.2%

F: 1.06 (0.80 to 1.42), I² = 0%

G: 0.69 (0.43 to 1.11), I² = 0%

U: 1.91 (0.74 to 4.90), I² = NA

O: 0.99 (0.78 to 1.25), I² = 15%

Chi² = 4.32, df = 2,

P = 0.12, I² = 53.7%

Time to 6‐month remission^a

F: 0.98 (0.75 to 1.27), I² = 0%

G: 0.77 (0.52 to 1.13), I² = 39%

O: 0.90 (0.73 to 1.12), I² = 0%

Chi² = 1.03, df = 1,

P = 0.31, I² = 3.2%

F: 0.98 (0.76 to 1.26), I² = 0%

G: 0.59 (0.37 to 0.93), I² = 0%

O: 0.87 (0.70 to 1.09), I² = 15%

Chi² = 3.63, df = 1,

P = 0.06, I² = 72.5%

F: 0.98 (0.75 to 1.27), I² = 0%

G: 0.59 (0.37 to 0.93), I² = 0%

U: 1.20 (0.51 to 2.83), I² = NA

O: 0.88 (0.71 to 1.10), I² = 2%

Chi² = 4.01, df = 2,

P = 0.13, I² = 50.1%

Chi²: Chi² statistic; CI: confidence interval; df: degrees of freedom of Chi² distribution; F: focal epilepsy; G: generalised epilepsy; HR: Hazard Ratio; O: overall (all participants); U: uncertain epilepsy; P: P value (< 0.05 are classified as statistically significant)

^a29 participants reclassified to focal epilepsy or uncertain epilepsy type from Heller 1995.
^b35 participants reclassified to focal epilepsy or uncertain epilepsy type from Heller 1995 and Ogunrin 2005.
^cHR and 95% CI not estimable as no participants with uncertainty epilepsy type failed carbamazepine treatment due to lack of efficacy or failed phenytoin treatment due to adverse events in Heller 1995.

Table 5. Sensitivity analysis ‐ Epilepsy type misclassification, fixed‐effect analysis

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Table 6. Adverse event data (narrative report)

Trial	Adverse event data^a	Summary of reported results
Trial	Adverse event data^a	Carbamazepine (CBZ)	Phenytoin (PHT)
Callaghan 1985^b	All adverse events according to drug (note: no participants withdrew due to adverse events)	CBZ (n = 59): drowsiness (n = 2), rash (n = 3)	PHT (n = 58): gum hypertrophy (n = 2), rash (n = 2), ataxia (n = 2)
Czapinski 1997^c	“Exclusions” due to adverse events or no efficacy”	Proportion “excluded”: CBZ: 30% (out of 30 randomised to CBZ)	Proportion “excluded”: PHT: 23.3% (out of 30 randomised to PHT)
De Silva 1996	“Unacceptable” adverse events leading to drug withdrawal^d	CBZ (n = 54): drowsiness (n = 1), blood dyscrasia (n = 1)	PHT (n = 54): drowsiness (n = 2), skin rash (n = 1), blood dyscrasia (n = 1), hirsutism (n = 1)
Forsythe 1991	Withdrawal due to adverse events (no other adverse event data reported)	4 participants out of 23 randomised to CBZ withdrew for the following reasons (some withdrew for more than adverse event): slowing of mental function, headache, anorexia, nausea, abdominal pain, fatigue and drowsiness²	1 participant out of 20 randomised to PHT withdrew from the study due to depression and anorexia
Heller 1995	“Unacceptable” adverse events leading to drug withdrawal^d	CBZ (n = 61): drowsiness (n = 3), rash (n = 2), headache (n = 1), depression (n = 1)	PHT (n = 63): myalgia (n = 1), irritability (n = 1)
Mattson 1985^b	Narrative report of ‘Adverse effects’ and ‘Serious side effects’	CBZ (n = 155): motor disturbance (ataxia, incoordination, nystagmus, tremor: 33%); dysmorphic and idiosyncratic side effects (gum hypertrophy, hirsutism, acne and rash: 14%); gastrointestinal problems (27%); decreased libido or impotence (13%); No serious side effects	PHT (n = 165); motor disturbance (ataxia, inco‐ordination, nystagmus, tremor: 28%); dysmorphic and idiosyncratic side effects (gum hypertrophy, hirsutism, acne and rash: 22 %); gastrointestinal problems (24%); decreased libido or impotence (11%) 1 serious side effect – 1 participant has confirmed lymphoma, rash improved rapidly following discontinuation of PHT
Miura 1993	No adverse events reported	N/A	N/A
Ogunrin 2005^b	Participant reported symptomatic complaints (provided as IPD)	CBZ (n = 19): memory impairment (n = 9) psychomotor retardation (n = 1) inattention (n = 1) transient rash (n = 1) CBZ‐induced cough (n = 1)	PHT (n = 18): memory impairment (n = 7) psychomotor retardation (n = 1) inattention (n = 2) transient rash (n = 1)
Pulliainen 1994	Participant‐reported adverse events	1 participant on CBZ complained of facial skin problems; 1 participant on CBZ complained of tiredness and memory problems	3 participants on PHT complained of tiredness
Ramsay 1983^b	Major and minor side effects	CBZ (n = 35): Major side effects: rash (n = 1), pruritus (n = 1), impotence (n = 2), dizziness (n = 1), headaches (n = 1), impaired cognition (n = 1), elevated liver enzymes (n = 1) Mild side effects: nausea (33%), headaches (24%), cognitive impairment (33%), nystagmus (52%), sedation (33%), fine tremor (20%)	PHT (n = 35): Major side effects: rash (n = 4), exfoliative dermatitis (n = 1), impotence (n = 1), dizziness (n = 1), nausea/vomiting (n = 1) Mild side effects: nausea (38%), gingival hyperplasia (12%), headaches (32%), cognitive impairment (15%), nystagmus (40%), sedation (15%), fine tremor (28%)
Ravi Sudhir 1995	No adverse events reported	N/A	N/A
CBZ = carbamazepine, N/A = not available, PHT= phenytoin ^aAdverse event data are recorded as reported narratively in the publications, so exact definition of a symptom may vary. Adverse event data supplied as IPD for Ogunrin 2005. Adverse event data were not requested in original IPD requests (De Silva 1996; Heller 1995; Mattson 1985) but will be for all future IPD requests. For numbers of treatment withdrawals due to adverse events in studies for which IPD were provided (De Silva 1996; Heller 1995; Mattson 1985) see Table 4. ^bParticipants may report more than one adverse event. ^cCzapinski 1997 is an abstract only, so very little information is reported. ^dParticipants may have withdrawn due to adverse event alone or a combination of adverse events and poor efficacy (seizures).

Table 6. Adverse event data (narrative report)

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Comparison 1. Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to treatment failure (any reason related to the treatment) Show forest plot	4	589	Hazard Ratio (Fixed, 95% CI)	0.99 [0.76, 1.31]

2 Time to treatment failure due to adverse events Show forest plot	4	589	Hazard Ratio (Fixed, 95% CI)	1.35 [0.93, 1.95]

3 Time to treatment failure due to lack of efficacy Show forest plot	4	589	Hazard Ratio (Fixed, 95% CI)	1.02 [0.72, 1.44]

4 Time to treatment failure (any reason related to the treatment) ‐ by epilepsy type Show forest plot	3	546	Hazard Ratio (Fixed, 95% CI)	0.94 [0.70, 1.26]

4.1 Focal onset seizures	3	428	Hazard Ratio (Fixed, 95% CI)	0.83 [0.61, 1.13]
4.2 Generalised onset seizures	2	118	Hazard Ratio (Fixed, 95% CI)	2.38 [1.04, 5.47]
5 Time to treatment failure due to adverse events ‐ by epilepsy type Show forest plot	3	546	Hazard Ratio (Fixed, 95% CI)	1.27 [0.87, 1.86]

5.1 Generalised onset seizures	2	118	Hazard Ratio (Fixed, 95% CI)	2.31 [0.68, 7.81]
5.2 Focal onset seizures	3	428	Hazard Ratio (Fixed, 95% CI)	1.19 [0.80, 1.78]
6 Time to treatment failure due to lack of efficacy ‐ by epilepsy type Show forest plot	3	546	Hazard Ratio (Fixed, 95% CI)	0.99 [0.69, 1.41]

6.1 Focal onset seizures	3	428	Hazard Ratio (Fixed, 95% CI)	0.88 [0.60, 1.30]
6.2 Generalised onset seizures	2	118	Hazard Ratio (Fixed, 95% CI)	1.86 [0.74, 4.67]
7 Time to first seizure post‐randomisation Show forest plot	4	582	Hazard Ratio (Fixed, 95% CI)	1.13 [0.92, 1.39]

8 Time to first seizure post‐randomisation ‐ by epilepsy type Show forest plot	4	582	Hazard Ratio (Fixed, 95% CI)	1.15 [0.94, 1.40]

8.1 Focal onset seizures	4	432	Hazard Ratio (Fixed, 95% CI)	1.13 [0.89, 1.43]
8.2 Generalised onset seizures	3	150	Hazard Ratio (Fixed, 95% CI)	1.19 [0.81, 1.75]
9 Time to achieve 12‐month remission Show forest plot	3	551	Hazard Ratio (Fixed, 95% CI)	1.01 [0.80, 1.27]

10 Time to achieve 12‐month remission ‐ by epilepsy type Show forest plot	3	551	Hazard Ratio (Fixed, 95% CI)	1.00 [0.79, 1.26]

10.1 Focal onset seizures	3	430	Hazard Ratio (Fixed, 95% CI)	1.06 [0.80, 1.42]
10.2 Generalised onset seizures	2	121	Hazard Ratio (Fixed, 95% CI)	0.88 [0.58, 1.33]
11 Time to achieve six‐month remission Show forest plot	3	551	Hazard Ratio (Fixed, 95% CI)	0.92 [0.74, 1.14]

12 Time to achieve six‐month remission ‐ by epilepsy type Show forest plot	3	551	Hazard Ratio (Fixed, 95% CI)	0.90 [0.73, 1.12]

12.1 Focal onset seizures	3	430	Hazard Ratio (Fixed, 95% CI)	0.98 [0.75, 1.27]
12.2 Generalised onset seizures	2	121	Hazard Ratio (Fixed, 95% CI)	0.77 [0.52, 1.13]

Comparison 1. Carbamazepine (CBZ) versus phenytoin (PHT) monotherapy

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