Scolaris Content Display Scolaris Content Display

Study flow diagram.
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Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
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Figure 2

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

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
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Figure 3

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

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 1 Early seizure.
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Analysis 1.1

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 1 Early seizure.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 2 Late seizure.
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Analysis 1.2

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 2 Late seizure.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 3 All‐cause mortality.
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Analysis 1.3

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 3 All‐cause mortality.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 4 Any serious event.
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Analysis 1.4

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 4 Any serious event.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 5 Skin rash.
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Analysis 1.5

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 5 Skin rash.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 6 Sensitivity analysis ‐ early seizure: age of population.
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Analysis 1.6

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 6 Sensitivity analysis ‐ early seizure: age of population.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 7 Sensitivity analysis ‐ early seizure: study quality.
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Analysis 1.7

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 7 Sensitivity analysis ‐ early seizure: study quality.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 8 Subgroup: late seizure: type of AED.
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Analysis 1.8

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 8 Subgroup: late seizure: type of AED.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 9 Subgroup ‐ late seizure: treatment duration.
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Analysis 1.9

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 9 Subgroup ‐ late seizure: treatment duration.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 10 Sensitivity analysis ‐ late seizure: age of population.
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Analysis 1.10

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 10 Sensitivity analysis ‐ late seizure: age of population.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 11 Sensitivity analysis ‐ late seizure: comparison group.
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Analysis 1.11

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 11 Sensitivity analysis ‐ late seizure: comparison group.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 12 Sensitivity analysis ‐ late seizure: study quality.
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Analysis 1.12

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 12 Sensitivity analysis ‐ late seizure: study quality.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 13 Subgroup Analysis ‐ all‐cause mortality: age of population.
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Analysis 1.13

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 13 Subgroup Analysis ‐ all‐cause mortality: age of population.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 14 Subgroup analysis ‐ all‐cause mortality: treatment duration.
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Analysis 1.14

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 14 Subgroup analysis ‐ all‐cause mortality: treatment duration.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 15 Sensitivity analysis ‐ all‐cause mortality: type of AED.
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Analysis 1.15

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 15 Sensitivity analysis ‐ all‐cause mortality: type of AED.

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 16 Sensitivity analysis ‐ all‐cause mortality: study quality.
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Analysis 1.16

Comparison 1 Antiepileptic drug (AED) versus placebo or standard care, Outcome 16 Sensitivity analysis ‐ all‐cause mortality: study quality.

Comparison 2 Neuroprotective agent versus placebo, Outcome 1 Early seizure.
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Analysis 2.1

Comparison 2 Neuroprotective agent versus placebo, Outcome 1 Early seizure.

Comparison 2 Neuroprotective agent versus placebo, Outcome 2 Late seizure.
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Analysis 2.2

Comparison 2 Neuroprotective agent versus placebo, Outcome 2 Late seizure.

Comparison 2 Neuroprotective agent versus placebo, Outcome 3 All‐cause mortality.
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Analysis 2.3

Comparison 2 Neuroprotective agent versus placebo, Outcome 3 All‐cause mortality.

Comparison 3 Antiepileptic drug (AED) versus other AED, Outcome 1 Early seizure.
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Analysis 3.1

Comparison 3 Antiepileptic drug (AED) versus other AED, Outcome 1 Early seizure.

Comparison 3 Antiepileptic drug (AED) versus other AED, Outcome 2 Late seizure.
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Analysis 3.2

Comparison 3 Antiepileptic drug (AED) versus other AED, Outcome 2 Late seizure.

Comparison 3 Antiepileptic drug (AED) versus other AED, Outcome 3 All‐cause mortality.
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Analysis 3.3

Comparison 3 Antiepileptic drug (AED) versus other AED, Outcome 3 All‐cause mortality.

Summary of findings for the main comparison. Antiepileptic drugs compared with placebo or standard care for people at risk of epilepsy following traumatic head injury

Antiepileptic drugs compared with placebo or standard care for people at risk of epilepsy following traumatic head injury

Patient or population: people with traumatic head injuries
Settings: Neurosurgery departments, ICU and trauma centers in North America, UK and Europe
Intervention: antiepileptic drugs
Comparison: placebo or standard care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo or standard care

Antiepilepticdrugs

Early seizures
Count of events
Follow‐up: 5‐7 days

139 per 1000

59 per 1000
(32 to 102)

RR 0.42
(0.23 to 0.74)

987
(5 studies)

⊕⊕⊝⊝
low1,2,

Sensitivity analysis by quality of the study shows that RR for early seizures in low/unclear risk studies was no longer significant (RR 0.59, 95% CI 0.20 and 1.73)

Late seizures
Count of events
Follow‐up: 3‐24 months

178 per 1000

162 per 1000
(100 to 260)

RR 0.91
(0.57 to 1.46)

1029
(6 studies)

⊕⊝⊝⊝
very low3,4,5

RR of late seizures remained insignificant regardless of type of antiepileptic drug, treatment duration, age of population or quality of the study

All‐cause mortality
Follow‐up: 5 days to 24 months

174 per 1000

188 per 1000
(138 to 255)

RR 1.08
(0.79 to 1.46)

1065
(5 studies)

⊕⊝⊝⊝
very low1,4,5

RR for all‐cause mortality remained insignificant regardless of treatment duration, age of population or quality of the study

Any serious adverse event of treatment

count of events

Follow up: 12 months

94 per 1000

154 per 1000

(69 to 345)

RR 1.63

(0.73 to 3.66)

568

(2 studies)

⊕⊕⊝⊝
low5,6

Time to first seizure from randomization

See comment

See comment

Not estimable

0
(0 studies)

See comment

No study reported time to first seizure in an interpretable way

*The basis for the assumed risk is the event rate in the control (placebo or standard care) 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).
CI: confidence interval; RR: risk 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.

1 Downgraded one level due to serious risk of bias: Two studies included in this outcome had instances of high risk of bias assessment. The remaining studies had a mix of low and unclear risk of bias.
2 Downgraded one level due to imprecision: RR for early seizures by study was inconsistent and ranged from 0.24 to 1.22. The difference in risk tends to be associated with differences in risk of bias between studies.
3 Downgraded one level due to serious risk of bias: Four studies included in this outcome had one to four instances of high risk in risk of bias assessment. The remaining two studies had a mix of low and unclear risk of bias.
4Downgraded one level due to inconsistency of results (I2=54%): Some heterogeneity may be explained by study design, population, intervention (dose) or follow‐up. However, there is wide variation in the results showing both considerable harm and considerable benefit.

5 Downgraded one level due to imprecision of results: wide 95% CI that includes both considerable harm and benefit.

6 Downgraded one level due to serious risk of bias: selection bias was likely in both trials

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Summary of findings for the main comparison. Antiepileptic drugs compared with placebo or standard care for people at risk of epilepsy following traumatic head injury
Summary of findings 2. Neuroprotective agent versus placebo for people at risk of epilepsy following traumatic head injury

Neuroprotective agents compared with placebo for people at risk of epilepsy following traumatic head injury

Patient or population: people with traumatic head injuries
Settings: Neurosurgery departments, ICU and trauma centers in North America, UK and Europe
Intervention: Neuroprotective agents
Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Neuroprotective agents

Early seizure

Count of events

Follow‐up: 7 days

0 per 1000

0 per 1000
(0 to 0)

RR 2.99

(0.12 to 73.00)

499
(1 study)

⊕⊕⊝⊝
low1,2

No events occurred in the control group therefore corresponding risk is also zero

Late seizure

Count of events

Follow‐up: 6 months

56 per 1000

60 per 1000
(30 to 122)

RR 1.07

(0.53 to 2.17)

498
(1 study)

⊕⊕⊕⊕
high

All‐cause mortality

Follow‐up: 6 months

150 per 1000

180 per 1000
(120 to 272)

RR 1.20

(0.80 to 1.81)

466
(1 study)

⊕⊕⊕⊕
high

Any serious adverse event of treatment

See comment

See comment

Not estimable

0
(0 studies)

See comment

No study reported adverse event data

Time to first seizure from randomization

See comment

See comment

Not estimable

0
(0 studies)

See comment

No study reported time to first seizure in an interpretable way

*The basis for the assumed risk is the event rate in the control (placebo or standard care) 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).
CI: confidence interval; RR: risk 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.

1 Downgraded one level due to risk of bias: As reported in the study paper, 96% of participants received phenytoin for the first week in both treatment groups. This may have resulted in a very low early seizure rate

2 Downgraded one level due to imprecision of results: wide 95% CI that includes both considerable harm and benefit.

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Summary of findings 2. Neuroprotective agent versus placebo for people at risk of epilepsy following traumatic head injury
Summary of findings 3. Anti‐epileptic drugs compared to other anti‐epileptic drugs for people at risk of epilepsy following traumatic head injury

Anti‐epileptic drugs compared to other anti‐epileptic drugs for people at risk of epilepsy following traumatic head injury

Patient or population: people with traumatic head injuries
Settings: Neurosurgery departments, ICU and trauma centers in North America, UK and Europe
Intervention: Phenytoin
Comparison: Other anti‐epileptic drugs (AEDs)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Other AEDs

Phenytoin

Early seizure

Counts of events

Follow up: 7 days

57 per 1000

38 per 1000
(11 to 121)

RR 0.66

(0.20 to 2.12)

431
(2 studies)

⊕⊕⊝⊝
low1,2

Late seizure

Counts of events

Follow up: 6 months to 2 years

166 per 1000

128 per 1000
(76 to 216)

RR 0.77

(0.46 to 1.30)

378
(2 studies)

⊕⊕⊕⊝
moderate1

All‐cause mortality

Follow up: 6 months to 2 years

164 per 1000

87 per 1000
(49 to 154)

RR 0.53

(0.30 to 94)

431
(2 studies)

⊕⊕⊕⊝
moderate1

Any serious adverse event of treatment

See comment

See comment

Not estimable

0
(0 studies)

See comment

No study reported adverse event data

Time to first seizure from randomization

See comment

See comment

Not estimable

0
(0 studies)

See comment

No study reported time to first seizure in an interpretable way

*The basis for the assumed risk is the event rate in the control (placebo or standard care) 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).
CI: confidence interval; RR: risk 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.

1 Downgraded one level due to risk of bias; unclear information reported in one study regarding study design (randomisation and blinding) and loss to follow up from the study

2 Downgraded one level due to imprecision of results: wide 95% CI that includes both considerable harm and benefit.

Figures and Tables -
Summary of findings 3. Anti‐epileptic drugs compared to other anti‐epileptic drugs for people at risk of epilepsy following traumatic head injury
Comparison 1. Antiepileptic drug (AED) versus placebo or standard care

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Early seizure Show forest plot

5

987

Risk Ratio (IV, Random, 95% CI)

0.42 [0.23, 0.73]

2 Late seizure Show forest plot

6

1029

Risk Ratio (IV, Random, 95% CI)

0.91 [0.57, 1.46]

3 All‐cause mortality Show forest plot

5

1065

Risk Ratio (IV, Random, 95% CI)

1.08 [0.79, 1.46]

4 Any serious event Show forest plot

2

568

Risk Ratio (IV, Random, 95% CI)

1.63 [0.73, 3.66]

5 Skin rash Show forest plot

2

568

Risk Ratio (IV, Random, 99% CI)

1.65 [0.54, 5.04]

6 Sensitivity analysis ‐ early seizure: age of population Show forest plot

4

885

Risk Ratio (IV, Random, 95% CI)

0.36 [0.21, 0.60]

7 Sensitivity analysis ‐ early seizure: study quality Show forest plot

2

506

Risk Ratio (IV, Random, 95% CI)

0.48 [0.11, 2.18]

8 Subgroup: late seizure: type of AED Show forest plot

6

1029

Risk Ratio (IV, Random, 95% CI)

0.91 [0.57, 1.46]

8.1 Late seizure ‐ phenytoin

4

752

Risk Ratio (IV, Random, 95% CI)

0.83 [0.40, 1.70]

8.2 Late seizure ‐ other AED

2

277

Risk Ratio (IV, Random, 95% CI)

0.96 [0.46, 1.99]

9 Subgroup ‐ late seizure: treatment duration Show forest plot

6

1029

Risk Ratio (IV, Random, 95% CI)

0.91 [0.57, 1.46]

9.1 Long treatment duration

5

943

Risk Ratio (IV, Random, 95% CI)

1.08 [0.81, 1.46]

9.2 Short treatment duration

1

86

Risk Ratio (IV, Random, 95% CI)

0.14 [0.03, 0.55]

10 Sensitivity analysis ‐ late seizure: age of population Show forest plot

5

706

Risk Ratio (IV, Random, 95% CI)

0.81 [0.44, 1.48]

11 Sensitivity analysis ‐ late seizure: comparison group Show forest plot

5

903

Risk Ratio (IV, Random, 95% CI)

0.83 [0.48, 1.41]

12 Sensitivity analysis ‐ late seizure: study quality Show forest plot

1

323

Risk Ratio (IV, Fixed, 95% CI)

1.25 [0.79, 1.96]

13 Subgroup Analysis ‐ all‐cause mortality: age of population Show forest plot

5

Risk Ratio (IV, Random, 95% CI)

Subtotals only

13.1 All‐cause mortality ‐ children only

2

143

Risk Ratio (IV, Random, 95% CI)

0.54 [0.25, 1.19]

13.2 All‐cause mortality ‐ adults and children

2

315

Risk Ratio (IV, Random, 95% CI)

1.43 [0.90, 2.27]

13.3 All‐cause mortality ‐ adults only

1

404

Risk Ratio (IV, Random, 95% CI)

1.13 [0.78, 1.62]

14 Subgroup analysis ‐ all‐cause mortality: treatment duration Show forest plot

5

Risk Ratio (IV, Random, 95% CI)

Subtotals only

14.1 All‐cause mortality ‐ short‐term treatment duration

2

346

Risk Ratio (IV, Random, 95% CI)

0.69 [0.39, 1.24]

14.2 All‐cause mortality ‐ long‐term treatment duration

3

719

Risk Ratio (IV, Random, 95% CI)

1.24 [0.93, 1.65]

15 Sensitivity analysis ‐ all‐cause mortality: type of AED Show forest plot

4

914

Risk Ratio (IV, Random, 95% CI)

0.97 [0.65, 1.43]

16 Sensitivity analysis ‐ all‐cause mortality: study quality Show forest plot

2

506

Risk Ratio (IV, Fixed, 95% CI)

1.00 [0.72, 1.41]

Figures and Tables -
Comparison 1. Antiepileptic drug (AED) versus placebo or standard care
Comparison 2. Neuroprotective agent versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Early seizure Show forest plot

1

Risk Ratio (IV, Random, 95% CI)

Totals not selected

2 Late seizure Show forest plot

1

498

Risk Ratio (IV, Random, 95% CI)

1.07 [0.53, 2.17]

3 All‐cause mortality Show forest plot

1

466

Risk Ratio (IV, Random, 95% CI)

1.2 [0.80, 1.81]

Figures and Tables -
Comparison 2. Neuroprotective agent versus placebo
Comparison 3. Antiepileptic drug (AED) versus other AED

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Early seizure Show forest plot

2

431

Risk Ratio (IV, Random, 95% CI)

0.66 [0.20, 2.12]

2 Late seizure Show forest plot

2

378

Risk Ratio (IV, Random, 95% CI)

0.77 [0.46, 1.30]

3 All‐cause mortality Show forest plot

2

431

Risk Ratio (IV, Random, 95% CI)

0.53 [0.30, 0.94]

Figures and Tables -
Comparison 3. Antiepileptic drug (AED) versus other AED