Prophylactic Levetiracetam Fails to Reduce Post-TBI Seizures

NAPLES, FLA. – Early seizure rates after traumatic brain injury were nearly identical whether patients did or did not receive levetiracetam prophylaxis in a retrospective analysis of 5,551 patients.

The seizure rate during the first 7 days post injury was 1.9% among 208 patients given prophylactic levetiracetam (Keppra) vs. 2% among the 5,343 patients who were not (P = .92).

Seizure rates with and without prophylactic phenytoin (Dilantin) were 4.5% vs. 1.8% (P = .053), and 0% vs. 2% with and without prophylactic fosphenytoin (Cerebyx) (P = .75), Dr. Terence O’Keeffe and his colleagues reported in a poster at the Eastern Association for the Surgery of Trauma.

Although a 7-day course of phenytoin is the current standard of care, the authors note that neurosurgeons are substituting levetiracetam, even though data are lacking to show the efficacy of this approach. Levetiracetam is an attractive alternative because, unlike phenytoin, it has predictable pharmacokinetics, does not require serum drug monitoring to ensure that therapeutic levels are achieved and has a low propensity for drug interactions.

The 2010 updated Brain Trauma Foundation guidelines on the management of severe traumatic brain injury recommend anticonvulsants to reduce the incidence of posttraumatic seizures within 7 days of injury, but not thereafter.

The seizure rate in the entire cohort was 0.7%, and the median time to seizure post injury was 3 days. Seven patients had seizures in the emergency department (ED). Seizures were 25 times more likely in patients with severe TBI than in those with mild TBI (2% vs. 0.08%, odds ratio 25.6), according to Dr. O’Keeffe, director of the surgical and trauma ICU at the University of Arizona, Tucson, and his colleagues.

When the 208 levetiracetam patients were propensity matched 1:1 using an 11-variable algorithm with 208 patients who did not receive levetiracetam, seizure rates remained statistically similar at 1.9% with levetiracetam vs. 3.4% without.

"Keppra is ineffective for seizure prophylaxis in a trauma population with a low incidence of post-TBI seizures," the authors wrote.

Based on their data, the authors questioned the need for seizure prophylaxis following TBI, as the seizure rate was so much lower than had been previously reported.

"The incidence is so low in mild TBI as to not merit treatment in my mind," Dr. O’Keeffe said in an interview. "I think we should develop protocols that target high-risk populations, for example penetrating TBI, and that the vast majority of patients need no prophylaxis."

The first study to evaluate levetiracetam for seizure prophylaxis in severe TBI found no difference in seizure rates among 32 patients given levetiracetam and a historical cohort of 41 patients given phenytoin, although levetiracetam was associated with an increased seizure tendency on electroencephalographic (EEG) analysis (Neurosurg. Focus 2008;25:E3). The implication of the EEG finding is unclear, and the study has been criticized for using only 1 hour of EEG monitoring.

The first randomized trial of the two drugs published last year in 52 patients with severe TBI (89%) or subarachnoid hemorrhage reported that patients receiving levetiracetam experienced better long-term outcomes than did those on phenytoin and identified no differences between groups in seizure occurrence during continuous EEG monitoring for the initial 72 hours (Neurocrit. Care 2010;12:165-72).

The current analysis included all patients treated for TBI from January 2007 to December 2009 at a level I, urban trauma center. Patients were stratified by injury severity. Of the 5,551 patients, 3,756 had a mild TBI, defined by a Head Abbreviated Injury Scale (AIS) score of 1 or 2, and 1,795 had severe TBI, defined by a Head AIS score of 3-5.

In multivariate regression analysis, only head AIS and ED heart rate were predictive of seizure. In the severe TBI group, the type of injury (that is, skull fracture, subdural, etc.) was not predictive of seizures. As for why the seizure rate was higher with prophylactic phenytoin than without, Dr. O’Keeffe said it may be the patients receiving the drug as treatment rather than as prophylaxis.

Dr. O’Keeffe and his colleagues acknowledge that propensity scores cannot remove all selection bias, that seizure data were obtained from patient chart/registry review, and that there was no standard prophylaxis over the study period. Possible future areas of study are 2010 data with standardized prophylaxis regimens and a multicenter trial looking at the Extended Glasgow Outcome Scale benefit of levetiracetam vs. placebo.

Balancing the Costs

Phenytoin is more cost-effective in reducing the risk of early posttraumatic seizures than is levetiracetam at all reasonable prices.

"In fact, for levetiracetam to reach cost effectiveness vs. phenytoin, this newer antiepileptic would have to prevent 100% of posttrauma seizures and be less than $400 for a week of therapy," Dr. Bryan Cotton and his colleagues reported in a separate cost-utility analysis at the same meeting.

Based on current data, the cost of a 7-day course of phenytoin (Dilantin) was $37.50 vs. $480 for a 7-day course of levetiracetam (Keppra).

The cost-utility analysis was conducted from the perspective of a university, level 1 urban trauma center, assuming that all patients with traumatic brain injury survived to receive 7 days of either agent to prevent posttraumatic seizures.

Base case assumptions were that all phenytoin patients would receive 1 g fosphenytoin (Cerebyx) intravenous load on day 0 plus 3 days of 100 mg phenytoin every 8 hours and that all levetiracetam patients would receive 500-mg load IV on day 0, followed by 7 days of 500 mg every 12 hours IV. Phenytoin patients would have a free phenytoin level drawn on day 3, with therapeutic patients receiving 100 mg phenytoin every 8 hours from post injury days 4 through 7 and subtherapeutic patients receiving an increased dose of phenytoin 200 mg every 8 hours from days 4 through 7.

The authors pointed out that they chose the smallest, least-expensive intravenous dosing for the levetiracetam arm and the most-expensive intravenous dosing for the phenytoin arm.

Quality-adjusted life years (QALY) were 23.6 for phenytoin and 23.2 for levetiracetam. As a result, the cost/effectiveness ratios were $1.58/QALY for phenytoin and $20.72/QALY for levetiracetam, according to Dr. Cotton, with the University of Texas at Houston, and his colleagues.

Dr. Terence O’Keeffe and his colleagues reported no conflicts of interest.

Dr. Cotton disclosed grant/research support from Haemonetics Corp. for a multicenter trial of rapid thrombelastography.

NAPLES, FLA. – Early seizure rates after traumatic brain injury were nearly identical whether patients did or did not receive levetiracetam prophylaxis in a retrospective analysis of 5,551 patients.

The seizure rate during the first 7 days post injury was 1.9% among 208 patients given prophylactic levetiracetam (Keppra) vs. 2% among the 5,343 patients who were not (P = .92).

Seizure rates with and without prophylactic phenytoin (Dilantin) were 4.5% vs. 1.8% (P = .053), and 0% vs. 2% with and without prophylactic fosphenytoin (Cerebyx) (P = .75), Dr. Terence O’Keeffe and his colleagues reported in a poster at the Eastern Association for the Surgery of Trauma.

Although a 7-day course of phenytoin is the current standard of care, the authors note that neurosurgeons are substituting levetiracetam, even though data are lacking to show the efficacy of this approach. Levetiracetam is an attractive alternative because, unlike phenytoin, it has predictable pharmacokinetics, does not require serum drug monitoring to ensure that therapeutic levels are achieved and has a low propensity for drug interactions.

The 2010 updated Brain Trauma Foundation guidelines on the management of severe traumatic brain injury recommend anticonvulsants to reduce the incidence of posttraumatic seizures within 7 days of injury, but not thereafter.

The seizure rate in the entire cohort was 0.7%, and the median time to seizure post injury was 3 days. Seven patients had seizures in the emergency department (ED). Seizures were 25 times more likely in patients with severe TBI than in those with mild TBI (2% vs. 0.08%, odds ratio 25.6), according to Dr. O’Keeffe, director of the surgical and trauma ICU at the University of Arizona, Tucson, and his colleagues.

When the 208 levetiracetam patients were propensity matched 1:1 using an 11-variable algorithm with 208 patients who did not receive levetiracetam, seizure rates remained statistically similar at 1.9% with levetiracetam vs. 3.4% without.

"Keppra is ineffective for seizure prophylaxis in a trauma population with a low incidence of post-TBI seizures," the authors wrote.

Based on their data, the authors questioned the need for seizure prophylaxis following TBI, as the seizure rate was so much lower than had been previously reported.

"The incidence is so low in mild TBI as to not merit treatment in my mind," Dr. O’Keeffe said in an interview. "I think we should develop protocols that target high-risk populations, for example penetrating TBI, and that the vast majority of patients need no prophylaxis."

The first study to evaluate levetiracetam for seizure prophylaxis in severe TBI found no difference in seizure rates among 32 patients given levetiracetam and a historical cohort of 41 patients given phenytoin, although levetiracetam was associated with an increased seizure tendency on electroencephalographic (EEG) analysis (Neurosurg. Focus 2008;25:E3). The implication of the EEG finding is unclear, and the study has been criticized for using only 1 hour of EEG monitoring.

The first randomized trial of the two drugs published last year in 52 patients with severe TBI (89%) or subarachnoid hemorrhage reported that patients receiving levetiracetam experienced better long-term outcomes than did those on phenytoin and identified no differences between groups in seizure occurrence during continuous EEG monitoring for the initial 72 hours (Neurocrit. Care 2010;12:165-72).

The current analysis included all patients treated for TBI from January 2007 to December 2009 at a level I, urban trauma center. Patients were stratified by injury severity. Of the 5,551 patients, 3,756 had a mild TBI, defined by a Head Abbreviated Injury Scale (AIS) score of 1 or 2, and 1,795 had severe TBI, defined by a Head AIS score of 3-5.

In multivariate regression analysis, only head AIS and ED heart rate were predictive of seizure. In the severe TBI group, the type of injury (that is, skull fracture, subdural, etc.) was not predictive of seizures. As for why the seizure rate was higher with prophylactic phenytoin than without, Dr. O’Keeffe said it may be the patients receiving the drug as treatment rather than as prophylaxis.

Dr. O’Keeffe and his colleagues acknowledge that propensity scores cannot remove all selection bias, that seizure data were obtained from patient chart/registry review, and that there was no standard prophylaxis over the study period. Possible future areas of study are 2010 data with standardized prophylaxis regimens and a multicenter trial looking at the Extended Glasgow Outcome Scale benefit of levetiracetam vs. placebo.

Balancing the Costs

Phenytoin is more cost-effective in reducing the risk of early posttraumatic seizures than is levetiracetam at all reasonable prices.

"In fact, for levetiracetam to reach cost effectiveness vs. phenytoin, this newer antiepileptic would have to prevent 100% of posttrauma seizures and be less than $400 for a week of therapy," Dr. Bryan Cotton and his colleagues reported in a separate cost-utility analysis at the same meeting.

Based on current data, the cost of a 7-day course of phenytoin (Dilantin) was $37.50 vs. $480 for a 7-day course of levetiracetam (Keppra).

The cost-utility analysis was conducted from the perspective of a university, level 1 urban trauma center, assuming that all patients with traumatic brain injury survived to receive 7 days of either agent to prevent posttraumatic seizures.

Base case assumptions were that all phenytoin patients would receive 1 g fosphenytoin (Cerebyx) intravenous load on day 0 plus 3 days of 100 mg phenytoin every 8 hours and that all levetiracetam patients would receive 500-mg load IV on day 0, followed by 7 days of 500 mg every 12 hours IV. Phenytoin patients would have a free phenytoin level drawn on day 3, with therapeutic patients receiving 100 mg phenytoin every 8 hours from post injury days 4 through 7 and subtherapeutic patients receiving an increased dose of phenytoin 200 mg every 8 hours from days 4 through 7.

The authors pointed out that they chose the smallest, least-expensive intravenous dosing for the levetiracetam arm and the most-expensive intravenous dosing for the phenytoin arm.

Quality-adjusted life years (QALY) were 23.6 for phenytoin and 23.2 for levetiracetam. As a result, the cost/effectiveness ratios were $1.58/QALY for phenytoin and $20.72/QALY for levetiracetam, according to Dr. Cotton, with the University of Texas at Houston, and his colleagues.

Dr. Terence O’Keeffe and his colleagues reported no conflicts of interest.

Dr. Cotton disclosed grant/research support from Haemonetics Corp. for a multicenter trial of rapid thrombelastography.

NAPLES, FLA. – Early seizure rates after traumatic brain injury were nearly identical whether patients did or did not receive levetiracetam prophylaxis in a retrospective analysis of 5,551 patients.

The seizure rate during the first 7 days post injury was 1.9% among 208 patients given prophylactic levetiracetam (Keppra) vs. 2% among the 5,343 patients who were not (P = .92).

Seizure rates with and without prophylactic phenytoin (Dilantin) were 4.5% vs. 1.8% (P = .053), and 0% vs. 2% with and without prophylactic fosphenytoin (Cerebyx) (P = .75), Dr. Terence O’Keeffe and his colleagues reported in a poster at the Eastern Association for the Surgery of Trauma.

Although a 7-day course of phenytoin is the current standard of care, the authors note that neurosurgeons are substituting levetiracetam, even though data are lacking to show the efficacy of this approach. Levetiracetam is an attractive alternative because, unlike phenytoin, it has predictable pharmacokinetics, does not require serum drug monitoring to ensure that therapeutic levels are achieved and has a low propensity for drug interactions.

The 2010 updated Brain Trauma Foundation guidelines on the management of severe traumatic brain injury recommend anticonvulsants to reduce the incidence of posttraumatic seizures within 7 days of injury, but not thereafter.

The seizure rate in the entire cohort was 0.7%, and the median time to seizure post injury was 3 days. Seven patients had seizures in the emergency department (ED). Seizures were 25 times more likely in patients with severe TBI than in those with mild TBI (2% vs. 0.08%, odds ratio 25.6), according to Dr. O’Keeffe, director of the surgical and trauma ICU at the University of Arizona, Tucson, and his colleagues.

When the 208 levetiracetam patients were propensity matched 1:1 using an 11-variable algorithm with 208 patients who did not receive levetiracetam, seizure rates remained statistically similar at 1.9% with levetiracetam vs. 3.4% without.

"Keppra is ineffective for seizure prophylaxis in a trauma population with a low incidence of post-TBI seizures," the authors wrote.

Based on their data, the authors questioned the need for seizure prophylaxis following TBI, as the seizure rate was so much lower than had been previously reported.

"The incidence is so low in mild TBI as to not merit treatment in my mind," Dr. O’Keeffe said in an interview. "I think we should develop protocols that target high-risk populations, for example penetrating TBI, and that the vast majority of patients need no prophylaxis."

The first study to evaluate levetiracetam for seizure prophylaxis in severe TBI found no difference in seizure rates among 32 patients given levetiracetam and a historical cohort of 41 patients given phenytoin, although levetiracetam was associated with an increased seizure tendency on electroencephalographic (EEG) analysis (Neurosurg. Focus 2008;25:E3). The implication of the EEG finding is unclear, and the study has been criticized for using only 1 hour of EEG monitoring.

The first randomized trial of the two drugs published last year in 52 patients with severe TBI (89%) or subarachnoid hemorrhage reported that patients receiving levetiracetam experienced better long-term outcomes than did those on phenytoin and identified no differences between groups in seizure occurrence during continuous EEG monitoring for the initial 72 hours (Neurocrit. Care 2010;12:165-72).

The current analysis included all patients treated for TBI from January 2007 to December 2009 at a level I, urban trauma center. Patients were stratified by injury severity. Of the 5,551 patients, 3,756 had a mild TBI, defined by a Head Abbreviated Injury Scale (AIS) score of 1 or 2, and 1,795 had severe TBI, defined by a Head AIS score of 3-5.

In multivariate regression analysis, only head AIS and ED heart rate were predictive of seizure. In the severe TBI group, the type of injury (that is, skull fracture, subdural, etc.) was not predictive of seizures. As for why the seizure rate was higher with prophylactic phenytoin than without, Dr. O’Keeffe said it may be the patients receiving the drug as treatment rather than as prophylaxis.

Dr. O’Keeffe and his colleagues acknowledge that propensity scores cannot remove all selection bias, that seizure data were obtained from patient chart/registry review, and that there was no standard prophylaxis over the study period. Possible future areas of study are 2010 data with standardized prophylaxis regimens and a multicenter trial looking at the Extended Glasgow Outcome Scale benefit of levetiracetam vs. placebo.

Balancing the Costs

Phenytoin is more cost-effective in reducing the risk of early posttraumatic seizures than is levetiracetam at all reasonable prices.

"In fact, for levetiracetam to reach cost effectiveness vs. phenytoin, this newer antiepileptic would have to prevent 100% of posttrauma seizures and be less than $400 for a week of therapy," Dr. Bryan Cotton and his colleagues reported in a separate cost-utility analysis at the same meeting.

Based on current data, the cost of a 7-day course of phenytoin (Dilantin) was $37.50 vs. $480 for a 7-day course of levetiracetam (Keppra).

The cost-utility analysis was conducted from the perspective of a university, level 1 urban trauma center, assuming that all patients with traumatic brain injury survived to receive 7 days of either agent to prevent posttraumatic seizures.

Base case assumptions were that all phenytoin patients would receive 1 g fosphenytoin (Cerebyx) intravenous load on day 0 plus 3 days of 100 mg phenytoin every 8 hours and that all levetiracetam patients would receive 500-mg load IV on day 0, followed by 7 days of 500 mg every 12 hours IV. Phenytoin patients would have a free phenytoin level drawn on day 3, with therapeutic patients receiving 100 mg phenytoin every 8 hours from post injury days 4 through 7 and subtherapeutic patients receiving an increased dose of phenytoin 200 mg every 8 hours from days 4 through 7.

The authors pointed out that they chose the smallest, least-expensive intravenous dosing for the levetiracetam arm and the most-expensive intravenous dosing for the phenytoin arm.

Quality-adjusted life years (QALY) were 23.6 for phenytoin and 23.2 for levetiracetam. As a result, the cost/effectiveness ratios were $1.58/QALY for phenytoin and $20.72/QALY for levetiracetam, according to Dr. Cotton, with the University of Texas at Houston, and his colleagues.

Dr. Terence O’Keeffe and his colleagues reported no conflicts of interest.

Dr. Cotton disclosed grant/research support from Haemonetics Corp. for a multicenter trial of rapid thrombelastography.