Prophylactic Antiepileptic Drug Use and Outcome in the Ethnic/Racial Variations of Intracerebral Hemorrhage Study
Background and Purpose—The role of antiepileptic drug (AED) prophylaxis after intracerebral hemorrhage (ICH) remains unclear. This analysis describes prevalence of prophylactic AED use, as directed by treating clinicians, in a prospective ICH cohort and tests the hypothesis that it is associated with poor outcome.
Methods—Analysis included 744 patients with ICH enrolled in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study before November 2012. Baseline clinical characteristics and AED use were recorded in standardized fashion. ICH location and volume were recorded from baseline neuroimaging. We analyzed differences in patient characteristics by AED prophylaxis, and we used logistic regression to test whether AED prophylaxis was associated with poor outcome. The primary outcome was 3-month modified Rankin Scale score, with 4 to 6 considered poor outcome.
Results—AEDs were used for prophylaxis in 289 (39%) of the 744 subjects; of these, levetiracetam was used in 89%. Patients with lobar ICH, craniotomy, or larger hematomas were more likely to receive prophlyaxis. Although prophylactic AED use was associated with poor outcome in an unadjusted model (odds ratio, 1.40; 95% confidence interval, 1.04–1.88; P=0.03), this association was no longer significant after adjusting for clinical and demographic characteristics (odds ratio, 1.11; 95% confidence interval, 0.74–1.65; P=0.62).
Conclusions—We found no evidence that AED use (predominantly levetiracetam) is independently associated with poor outcome. A prospective study is required to assess for a more modest effect of AED use on outcome after ICH.
Intracerebral hemorrhage (ICH) is the most devastating stroke subtype.1 There is continued uncertainty about several aspects of acute management, including evaluation and management of seizures and the use of seizure prophylaxis.2 Although seizures are common after ICH, the role of prophylactic antiepileptic drugs (AEDs) is controversial. In patients with ICH, however, AED use has been associated with worse functional and cognitive outcome.3 Previous reports commonly used phenytoin, and data on other anticonvulsants are limited.3,4 As such, National Institute of Neurological Disorders and Stroke has identified the impact and role of AED use after ICH as an important knowledge gap.5 This analysis was designed to test the hypothesis that prophylactic AED use is associated with worse functional outcome after ICH.
Source Sample, Seizure History, and AED Use
Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study methods have been previously described.6 Case report forms and baseline interviews included previous seizure history and AED use before ICH onset; medications, doses, and durations of AED administration during the hospital stay; and whether the agent was given for prophylaxis or seizure treatment. AED administration was at the discretion of treating physicians.
To isolate the impact of prophylactic AED use on outcome, subjects were excluded for seizures in the acute setting, taking an AED appropriate for epilepsy during the 2 weeks before onset, and missing documentation. Subjects without Glasgow Coma Score (GCS) or location, volume, and intraventricular hemorrhage (IVH) presence from computed tomography data were also excluded. Because poor outcome was defined as 3-month modified Rankin Scale score of ≥4,3 patients with preonset modified Rankin Scale scores of 4 or 5, as well as those lost to follow-up, were excluded.
Demographic and clinical characteristics were tested for differences among ethnicities and AED prescription using Wilcoxon rank sum test and χ2 tests for contingency tables. Univariate and multivariate logistic regression models estimated the odds ratio (OR) and 95% confidence interval (CI) for associations of AED use with patient characteristics and tested for association with poor outcome at 3 months. A stepwise logistic regression model (forward selection with backward elimination) was computed with entry and exit criteria of P=0.05. Collinearity and variance inflation diagnostics evaluated model assumptions.
Power analysis estimated the OR for AED use and worse outcome detectable with 0.80 and 0.99 power, given our sample size.7 Power analysis with type 1 error rate α=0.05 gives 0.80 power to detect worse outcome associated with AED prophylaxis at an OR=1.5 (an effect 15.6% of that previously reported3), and 0.99 power to detect an OR=2.0.
Description of the Analytic Cohort
We analyzed data for the first 1143 ERICH study patients who presented to emergency departments at enrolling sites between October 13, 2010 and October 30, 2012. Cases were excluded for the following (not mutually exclusive) reasons: seizure in the acute setting (n=101), AED use during the 2 weeks before onset (n=37), missing documentation about AED in the acute setting (n=8), GCS unavailable (n=29), neuroimaging data unavailable (n=98), preonset modified Rankin Scale score of 4 or 5 (n=29), and loss to follow-up at 3 months (n=194). Overall, the exclusion criteria removed 399 subjects with ICH, leaving 744 for this analysis. Baseline variables are presented in Table 1. Of the 289 subjects (39%) who received AED for prophylaxis, the vast majority (89%) received levetiracetam.
There were important racial/ethnic differences in patient characteristics (Table I in the online-only Data Supplement): white patients were older (P=3.59×10−18), more commonly had lobar ICH (P=8.05×10−6), and were more likely to be on warfarin before ICH (P=1.32×10−5). Black patients had smaller hematoma volumes (P=0.02) and more frequent IVH (P=0.04). Craniotomy was more frequent in Hispanic patients (P=<0.001).
Correlates of AED Use
Baseline characteristics differed between subjects who received AED prophylaxis and those who did not (Table 2). AED use was markedly higher in lobar ICH subjects (P=6.4×10−9) and in those with larger hematomas (P=3.3×10−9). Craniotomy was more common in patients who received AED (P=0.001). AED recipients had lower GCS at admission (P=0.03), but the difference (12.2 versus 12.6) is not clinically significant. In contrast, there were no differences in AED prophylaxis across age, sex, and race/ethnicity. Using stepwise logistic regression, only loge hematoma volume (P=1.4×10−5; OR, 1.38; 95% CI, 1.19–1.59) and lobar/nonlobar dichotomy (P=2.8×10−5; OR, 2.09; 95% CI, 1.48–2.95) were significantly associated with AED prophylaxis (P<0.05).
AED Use as a Predictor of Outcomes
Several baseline variables were associated with poor outcome in unadjusted models (Table II in the online-only Data Supplement). In particular, lower admission GCS strongly predicted poor 3-month outcome (OR, 0.75; P=1.0×10−24). Older age (5-year OR, 1.26; P=5.5×10−6) and female sex (OR, 1.58; P=0.002) were also associated with poor outcome. Larger hematoma volume (loge volume OR, 2.37; P=2.5×10−25), the presence of IVH (OR, 3.81; P=1.0×10−18), craniotomy (OR, 3.08; P<0.001), and prophylactic AED use (OR, 1.40; P=0.03) were each associated with worse outcome at 3 months. We found no differences in 3-month outcome among the 3 ethnicities (P=0.30), or with regard to P. After adjusting for GCS, age, race/ethnicity, sex, loge-transformed hematoma volume, the presence of IVH, and craniotomy, prophylactic AED use was no longer associated with 3-month outcome (Table 3; OR, 1.11; P=0.62). In fact, the univariate association for prophylactic AED use (P=0.03; Table II in the online-only Data Supplement) was no longer significant in simpler models that controlled only for ICH volume (OR, 0.95; P=0.78; 95% CI, 0.68–1.33) or GCS at admission (OR, 1.31; P=0.11; 95% CI, 0.94–1.82). In the full model, age, sex, increasing hematoma volume, lobar ICH, the presence of IVH, and low GCS at admission remained significant predictors of poor outcome at 3 months.
Our analysis of a large prospective observational ICH study does not support the hypothesis that AED prophylaxis, predominantly with the use of levetiracetam, is independently associated with poor outcome at 3 months. Despite recent American Heart Association/American Stroke Association guidelines,8 our observations suggest that AED prophylaxis after ICH is common. Our finding that AED use was no longer associated with poor outcome in univariate analysis after controlling for hematoma volume or admission GCS provides indirect evidence that patients with more severe ICH may preferentially receive AED prophylaxis. In the study by Battey et al9, when the cohort was restricted to patients surviving through day 5, any association between AED exposure and poor outcome disappeared. This also raises the possibility of confounding by indication, and makes adjustment for factors associated with poor outcome in ICH essential.9 Predictors of poor outcome in this analysis—advanced age, increasing hematoma volume, and low admission GCS—mirror other studies.10
In previous reports examining the association of AED prophylaxis with poor outcome, phenytoin was the predominant medication prescribed.3,4,11 Fever and adverse cognitive effects were commonly observed3 and may mediate the relationship between phenytoin and poor outcome.12 Our study—the largest of its kind to date—is powered to detect effect sizes one seventh of those previously reported.3,4 Another report also found no association between levetiracetam use and poor outcome, although the number of subjects was small and short-term seizure recurrence was the end point.11 Levetiracetam has been associated with improved outcome in a small observational analysis of ICH.13 In contrast to earlier reports in which phenytoin was the predominant AED used, the use of levetiracetam does not seem to be associated with poor outcome.
There are potential limitations of this analysis. First, because of the high mortality of ICH, there is the possibility of survival bias. The ERICH methodology reduces this bias by using a hot pursuit method whereby sites screen and enroll patients within 48 hours of admission. Second, we did not use continuous electroencephalogram; future studies examining the role of AED use may focus on identification of subclinical seizures. Evidence from this study indicates that any adverse effect of AED use on outcome is likely small and of little clinical impact, although the role of AED would best be confirmed by a randomized controlled trial. Finally, patients lost to follow-up are a limitation to this analysis, although their ICH severity (volume and initial GCS) and frequency of AED use was less common.
In conclusion, we found that prophylactic AED use, predominantly with the use of levetiracetam, is not associated with poor outcome in ICH after adjusting for hematoma volume or GCS at admission. Our data suggest that AEDs are used by experienced vascular neurologists and neurocritical care specialists in ≈40% of patients with ICH.
Sources of Funding
This study was supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS: U-01-NS069763).
Drs Sheth, Moomaw, Koch, Sung, Kittner, Frankel, Rosand, Langefeld, Waddy, Woo, M.E. Comeau, and J. Osborne received research support from National Institute of Neurological Disorders and Stroke (NINDS) and American Heart Association. Dr Elkind received research support from NINDS and has received honoraria from Boehringer-Ingelheim, Inc and BMS-Pfizer Partnership for participation in advisory boards related to anticoagulants and stroke. The other author report no conflicts.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.010875/-/DC1.
- Received July 17, 2015.
- Revision received September 11, 2015.
- Accepted September 16, 2015.
- © 2015 American Heart Association, Inc.
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