Pharmacological treatments for preventing epilepsy following traumatic head injury

Kara Thompson; Bernhard Pohlmann‐Eden; Leslie A Campbell; Hannah Abel

doi:10.1002/14651858.CD009900.pub2

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Figure 1

Study flow diagram.

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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.

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Figure 3

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

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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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.

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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.

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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.

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Analysis 1.9

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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Analysis 2.1

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

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Analysis 2.2

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

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Analysis 2.3

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

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Analysis 3.1

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

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Analysis 3.2

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

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Analysis 3.3

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

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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

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)	⊕⊕⊝⊝ low^1,2,	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 low^3,4,5	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 low^1,4,5	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)	⊕⊕⊝⊝ low^5,6
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

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

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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)	⊕⊕⊝⊝ low^1,2	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.

Summary of findings 2. Neuroprotective agent versus placebo for people at risk of epilepsy following traumatic head injury

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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)	⊕⊕⊝⊝ low^1,2
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.

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

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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]

Comparison 1. Antiepileptic drug (AED) versus placebo or standard care

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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]

Comparison 2. Neuroprotective agent versus placebo

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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]

Comparison 3. Antiepileptic drug (AED) versus other AED

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