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Table 10.5 Summary of studies comparing anti-epileptic drugs

 
Author/Year/ Country/Study design/PEDro Score/N Methods Outcome
Javed et al. (2016) Pakistan Cohort N=100 Population: Group 1 (n=50): Mean Age=31.16yr. Group 2 (n=50): Mean Age=34.96. Intervention: Group 1: received IV phenytoin and Levetiracetam (35 mg/kg three times daily). Group 2: EEG monitoring. Outcome Measure: Incidence of post-traumatic seizures.
  1. There were no significant differences between the number patients in each group which had post-traumatic seizures.
Khan et al. (2016) Pakistan Cohort N=154 Population: Mean Age=24.15yr; Gender: Males=115, Females=29; Mean GCS: 59.1% (8-13), 40.9% (3-7). Intervention: Group A received Phenytoin (5 mg/kg/day), group B received Levetiracetam (10-20 mg/kg/day). Outcome Measure: Incidence of post-traumatic seizures, efficacy of drug on moderate vs severe TBIs.
  1. There were no significant differences between groups in terms of the drug efficacy of Phenytoin vs Levetiracetam.
  1. There was no significant difference in how each drug impacted moderate vs severe TBI and seizure rates.
Radic et al. (2014) USA Case Control N=288 Population: Subdural Hematoma; Levetiracetam group (LEV; n=164): Mean Age=65.96yr; Gender: Male=98, Female=66; Mean GCS=13.5.  Phenytoin group (PHT; n=124): Mean Age=62yr; Gender: Male=85, Female=39; Mean GCS=12.7. Treatment: Patients were retrospectively analyzed. Those who received LEV were compared to those who received PHT for seizure prophylaxis. Outcome Measure: Seizure rate and adverse drug events.
  1. There was no significant difference between LEV and PHT in clinical or electrographic seizure risk for patients without a midline shift.
  2. In subjects with midline shift >0 mm, LEV was associated with an increased risk of electrographic seizures during hospitalization (p=0.028) and a decreased risk of adverse drug effects (p=0.001), compared with PHT use.
Gabriel & Rowe (2014) USA Cohort N=19 Population: TBI; Phenytoin Group (PHT, n=14): Mean Age=46.8yr; Gender: Male=10, Female=4; Mean GCS=3. Levetiracetam Group (LEV, n=5): Mean Age=48.8yr; Gender: Male=3, Female=2; Mean GCS=14. Treatment: Participants were divided based on prophylactic treatment: PHT or LEV. Follow-up interview conducted. Outcome Measure: Glasgow Outcome Scale- Extended (GOS-E), occurrence of seizures, medication-related complications.
  1. Groups were not similar at baseline in terms of median GCS at presentation (p=0.016) and ICU discharge (p=0.044). The PHT group, compared to the LEV group, also had a longer period of time between injury and GOS-E assessment (808.8 versus 484.4d, p=0.001).
  2. There was no significant difference in the mean GOS-E scores at follow-up (PHT 5.07 versus LEV 5.60, p=0.58).
  3. There was no significant difference between groups for occurrence of early or late seizures (both p=0.53).
  4. Compared to the PHT group, the LEV group was significantly less likely to experience mediation-related complications (p=0.038); the PHT group had a significantly higher rate of days with fever (p=0.014).
Inaba et al. (2013) USA Prospective Controlled Trial N=813 Population: TBI; Levetiracetam Group (LEV, n=406): Mean Age=51.7yr; Gender: Male=300, Female=106; Mean GCS=12.1. Phenytoin Group (PHT, n=407): Mean Age=53.6yr; Gender: Male=280, Female=127; Mean GCS=12.6. Treatment: Participants were administered either LEV at 1000mg every 12h or PHT. In the PHT group the loading dose was 20mg/kg then 5mg/kg/d every 8h. Treatment lasted 7d. Outcome Measure: Seizure occurrence.
  1. There was no significant difference in seizure rates between groups (1.5% versus 1.5%, p=0.997).
  2. There was no significant differences between groups (LEV versus. PHT) in terms of adverse drug reactions (7.9% versus 10.3%, p=0.227), complications (28.3% versus 27.0%, p=0.679) or mortality rates (5.4% versus 3.7%, p=0.236).
Kruer et al. (2013) USA Retrospective Cohort N=109 Population: TBI; Median GCS=5. Phenytoin Group (PHT, n=89): Median Age=43.1yr; Gender: Male=76, Female=13. Levetiracetam Group (LEV, n=20): Median Age=34.1yr; Gender: Male=19, Female=1. Treatment: Retrospective review of patients administered PHT or LEV. Outcome Measure: Occurrence of early seizures.
  1. One patient from each group seized in the first 7d (p=0.335).
  2. Hospital length of stay did not differ significantly between groups (median days, LEV 26.5 versus PHT 11, p=0.134).
Szaflarski et al. (2010) USA RCT PEDro=8 N=52 Steinbaugh et al. (2012) USA Addition to Szaflarski et al. 2010 RCT Population: TBI=46; SAH=6; Phenytoin group (PHT; n=18): Mean Age=35yr; Gender: Male=13, Female=5; Mean GCS=4. Levetiracetam group (LEV; n=34): Mean Age=44yr; Gender: Male=26, Female=8; Mean GCS=5. Treatment: Patients were randomized within 24h of injury. Patients received either a loading dose of intravenous PHT 20mg/kg, then 5mg/kg/d or intravenous LEV at 20mg/kg, and then 1000mg every 12hr/7d. Outcome Measure: Occurrence of early seizures, Glasgow Outcome Scale (GOS), GOS-Extended (GOSE), Disability Rating Scale (DRS), Resource Utilization Questionnaire. Addition: Patients received continuous video EEG (cEEG) for up to 72h which was compared to the outcomes collected.
  1. There were no significant differences in the occurrence of early seizures between the PHT and LEV groups (3 versus 5, p=1.0)
  2. There were no significant between-group differences in GOS at discharge (p=0.33) and 6mo post discharge (p=0.89).
  3. There were no significant differences in the occurrence of fever, increased intracranial pressure, stroke, hypotension, arrhythmia, renal/ liver abnormalities or death between the two groups (p>0.15 for all).
  4. Compared to the LEV group, those in the PHT group experienced a significant worsening of their neurological status more often (p=0.024), and experienced anemia less often (p=0.076).
  5. Compared to PHT group, the LEV group showed significantly lower DRS at 3 and 6mo (p=0.006 and p=0.037), and higher GOSE at 6mo (p=0.016) in patients who survived.
  6. The presence of focal slowing, epileptiform discharges, and seizures were not predictive of outcome (GOS-E, DRS). More severe slowing was positively associated with DRS at discharge, 3 and 6mo (p=0.084) and negatively associated with GCS at discharge.
Jones et al. (2008) USA Cohort N=27 Population: Severe TBI; Gender: Male=20, Female=7. Treatment: Patients received Levetiracetam (n=15; 500mg IV every 12h for 7d) administered within 24hr of injury and were compared to a retrospective cohort of patients who received phenytoin (n=12). Outcome Measure: Occurrence of early seizures.
  1. There was a significant difference in the occurrence of abnormal EEG findings (seizure or seizure tendency with epileptiform activity) between groups (p= 0.003), with the Levetiracetam group having more abnormal findings.
  2. There was no significant difference between groups for actual seizures (p=0.556).
Dikmen et al. (2000) USA RCT PEDro=8 NInitial=279, NFinal=107 Population: TBI; Gender: Male=228, Female=51. Group 1 (n=94): Mean Age=37.14yr; Mean GCS=11.3. Group 2 (n=91): Mean Age=36.58yr; Mean GCS=11.23. Group 3 (n=94): Mean Age=35.85yr; Mean GCS=12.11. Treatment: Patients were randomized into three groups within 24h of injury: 1) valproic acid (VPA) for 1mo then 5mo of placebo; 2) VPA for 6mo; and 3) phenytoin (PHT) for 1wk then placebo until 6mo post injury. Outcome Measure: A battery of neuropsychological measures.
  1. There was a trend towards a higher mortality rate in the VPA groups compared to the PHT group (p=0.07).
  2. There were no significant differences at 1, 6 or 12mo on the composite measures based on all the neuropsychological measures, or on only the cognitive measures (0.551<p<0.812).
  1. No individual measure showed a significant difference among the treatment groups at 1, 6 or 12 months post injury.
Temkin et al. (1999) USA RCT PEDro=7 NInitial=379, NFinal=283 Population: TBI; Gender: Male=310, Female=69. Phenytoin Group (n=132): Mean Age=36yr; Mean GCS=11.7. Valproate (1mo, n=120): Mean Age=40yr; Mean GCS=11.6. Valproate (6mo, n=127): Mean Age=36yr; Mean GCS=11.1. Treatment: Patients were divided into three groups within 24h of injury: (1) phenytoin for 1wk (20mg/kg then 5mg/kg/d), placebo until 6mo post injury; (2) Valproate (20mg/kg, then 15mg/kg/d) for 1mo, placebo for 5mo; or (3) valproate for 6mo. Follow-up continued for 2yr. Outcome Measure: Incidence of early and late (>7d post injury) seizures, mortality rates.
  1. There was no significant difference in the number of early seizures between the combined valproate (4.5%) and phenytoin (1.5%, p=0.14) groups.
  2. There was no significant difference between groups (p=0.19) in the occurrence of late seizures.
  3. Late seizures occurred in 11, 17, and 15 participants in the 1mo and 6mo valproate groups and the phenytoin group, respectively.
  4. There were no significant differences in mortality rates between groups (7.2% phenytoin versus 13.4% in the combined valproate group, p=0.07).
  5. In the phenytoin group, a participant had a rash requiring medication at 1wk and in the valproate (6mo) group a participant had low neutrophil count at 2-4wk, both thought to be treatment related.