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Impact of antiepileptic drugs for seizure prophylaxis on short and long-term functional outcomes in patients with acute intracerebral hemorrhage: A meta-analysis and systematic review
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, The Johns Hopkins Bayview Hospital, Baltimore, MD, United States
Department of Neurology, The Johns Hopkins Bayview Hospital, Baltimore, MD, United StatesAnesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, The Johns Hopkins Bayview Hospital, Baltimore, MD, United StatesAnesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Limited number of studies exist evaluating seizure prophylaxis on outcomes in ICH.
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Significant heterogeneity exists within published studies.
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Seizure prophylaxis is not associated with improved outcomes after acute ICH.
Abstract
Purpose
The purpose of this analysis is to assess the effect of antiepileptics (AEDs) on seizure prevention and short and long term functional outcomes in patients with acute intracerebral hemorrhage.
Method
The meta-analysis was conducted using the PRISMA guidelines. A literature search was performed of the PubMed, the Cochrane Library, and EMBASE databases. Search terms included “Anticonvulsants”, “Intracerebral Hemorrhage”, and related subject headings. Articles were screened and included if they were full-text and in English. Articles that did not perform multivariate regression were not included. Overall effect size was evaluated with forest plots and publication bias was assessed with the Begg’s and Egger’s tests.
Results
A total of 3912 articles were identified during the initial review. After screening, 54 articles remained for full review and 6 articles were included in the final analysis. No significant association between the use of AEDs after ICH and functional outcome (OR 1.53 [95%CI: 0.81–2.88] P = 0.18, I
= 81.7%). Only one study evaluated the effect AEDs had in preventing post-ICH seizures.
Conclusions
The use of prophylactic AEDs was not associated with improved short and long outcomes after acute ICH. This analysis supports the 2015 AHA/ASA recommendation against prophylactic AEDs (class III; level of evidence b).
Heart Disease and Stroke Statistics--2009 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
] One complication is the development of seizures that occurs in 2%–40% of patients post-ICH. The significant variation in incidence is related to the type and duration of monitoring, length of follow-up, and patient characteristics including hemorrhage volume, hemorrhage location, and cortical involvement [
Prophylaxis against seizures in patients with acute ICH remains controversial. It is unclear if the possible acute and long-term benefits of seizure prevention with antiepileptic drugs (AEDs) outweigh the risk of potential adverse drug effects. [
] To date, evaluation of the efficacy and safety of prophylactic AED use in patients with ICH has been mostly limited observational studies. In light of such modest clinical evidence and yet concern for the detrimental effects of seizures in this population, seizure prophylaxis with AEDs is commonly practiced. [
] This treatment algorithm remains popular despite the most recent ICH guidelines from the AHA/ASA (based on their experts’ assessment of this limited data set) recommending that “prophylactic anticonvulsant medication should not be used” [
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association.
]. Thus, considerable controversy exists, and without a large, randomized, placebo-controlled trial, a comprehensive evaluation of current literature is warranted. We therefore conducted a meta-analysis to assess whether the use of AEDs is associated with improved functional outcomes in patients with ICH, or conversely if they confer significant risk and to evaluate their impact on seizure prevention.
2. Methodology
This systematic review and meta-analysis was reported according to the recommendations of the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) assessment [
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
We performed a search of MEDLINE (January 1990 to December 2017), EMBASE (January 1990 to December 2017), and the Cochrane Library (January 1990 to December 2017) to identify literature that evaluated AEDs for seizure prophylaxis in patients with intracerebral hemorrhage. PubMed, EMBASE, and the Cochrane library were searched using MeSH terms, explored EMTREE headings, and keywords respectively. Search terms and Boolean operators included the combination of “anticonvulsants” or “antiepileptics” with “brain hemorrhage” or “intracerebral hemorrhage”. A detailed search strategy is described in Supporting File 1. The results were cross-referenced to identify any additional literature.
2.2 Study selection
Two researchers conducted the database searches independently, as well as screened and evaluated the article titles and abstracts. A third researcher (L.R.L.) was employed in the case of disagreements. Articles were excluded during the screening process if they were not relevant to the use of AEDs in intracerebral hemorrhage or evaluated seizure prophylaxis in other clinical conditions such as subarachnoid hemorrhage. Duplicate records, case-reports, reviews, and non-English articles were also excluded.
Observational or randomized studies were included in the meta-analysis if they compared the use of AEDs for seizure prophylaxis to no pharmacologic prophylaxis in acute ICH. Observational studies that did not perform multivariate analysis were excluded. Seizure prevention and long-term outcomes, as defined by a modified Rankin Score (mRS) at 3 months or greater were evaluated. Data extracted from the articles included year of publication, type of study, sample size, definition of outcomes, effect size of the association between AED use and outcomes, and confounding factors included in the multivariate analysis.
2.3 Quality assessment
The quality of the randomized trials included in this meta-analysis was assessed by the Cochrane review criteria, and for nonrandomized studies, the Modified 11-item Methodological Index for Nonrandomized Studies tool (Supporting File 2), was used. [
] For randomized trials, the score was calculated for each randomized trial based on seven items (random sequence generation, allocation concealment, blinding of personnel who administered AEDs, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias). Each item was scored between 2 and 0 (being 2 “positive”, 1 “unclear”, 0 “negative”). For nonrandomized trials, 11 items were scored: 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate). The global ideal score being 22 using this modified tool for quality assessment. Studies with a score with 18 or higher were considered to be of high methodological quality, while studies between 10 and 17 were considered moderate. Studies with a score less than 10 were not included.
2.4 Statistical analysis
We constructed forest plots to illustrate the estimations and overall effect sizes. Heterogeneity was assessed by (I [
] < 50% and I2 > 50% were considered insignificant and significant heterogeneity, respectively). Publication bias was calculated using Stata version 13.0 (Stata, College Station, TX) with the Begg’s and Egger’s test. [
] Funnel plots were constructed to represent any tendency for publishing in favor to the positive effect. Significant publication bias was considered when there was asymmetry in the funnel plot (meaning that smaller studies tend to show larger risk ratios [RR]) and a statistically significant bias coefficient according to the Egger’s test [
]. P values < 0.05 were considered as statistically significant in all statistical analyses. The meta-analysis was performed using Stata 13.0 (Stata, College Station, TX) with random-effect model (DerSimonian & Laird method). [
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association.
A total of 3912 articles were identified using our search strategies. The initial screening process identified 54 articles for review. Of these, 6 studies met inclusion criteria for analysis. Fig. 1 shows the diagram of the article selection.
In total 6 studies were included in this meta-analysis (two retrospective cohort studies, two prospective cohort studies, and two randomized controlled trials). The studies comprised a total of 3193 patients. Table 1 summarizes the characteristics of the studies included in the analysis. The results of the methodological quality assessment are shown in Supporting File 3. The quality assessment criteria ranged from 13 to 18 points for evidence synthesis.
Table 1Description of studies included in this meta-analysis for poor functional outcomes.
Age, GCS, ICH volume, IVH, ICH score, seizure, AED
OR 1.66 [1.04-2.66] for any AED. OR 1.97 [1.06-3.67] Phenytoin prophylaxis
Abbreviations: AED anti-epileptics; GCS Glasgow Coma Score; ICH intracerebral hemorrhage, mRS modified Rankin scale; NIHSS National Institutes of Health Stroke Scale; OR odds ratio.
3.2.1 Association of the use of AEDs on long term outcomes after ICH
We found no evidence of significant association between the use of AEDs after ICH and functional short and long-term (≥3 months to one year) outcome, defined by modified Rankin scale (mRS) of greater than or equal to 3 or the National Institute of Health Stroke score (NIHSS) of 15 or greater (OR 1.53 [95%CI: 0.81–2.88] P = 0.18, I [
] = 81.7%). In the 5 studies in which the follow-up period was 3 months there was no statistically significant association between using AEDs in ICH and functional outcome (OR 1.70 [95% CI: 0.88–3.28], P = 0.11, I [
]. Fig. 2] shows the forest plot of the main analysis. Sensitivity analysis demonstrated that our results do not vary significantly after excluding each study and therefore it do not depend on individual studies.
Fig. 2Forest plot for effect size evaluating the use of antiepileptic drugs with outcome defined as modified Rankin scale at 3 months or more.
3.2.2 Association of the use of AEDs and seizure prevention after ICH
We found only one study that investigated the association between the use of AEDs and seizure prevention using a multivariate analysis (Table 2). In this prospective study of 761 patients, lobar location of the ICH was the only independent risk factor for development of clinical seizures during the first 30 days after ICH, aOR 2.8 (1.63–4.82). [
] Prophylactic phenobarbital decreased the risk of clinical seizures in the first 30 days after ICH, aOR 0.58 (0.39 – 0.87). However, this finding must be interpreted with caution as it was a non-randomized, observational study.
Table 2Description of other studies that investigated the association between the use of antiepileptic drugs (AED) and other outcomes (i.e. seizures), not included in the meta-analysis due to lack of multivariate models and the small number of studies.
There was no evidence of publication bias in the analysis (Egger’s bias = 2.23, P = 0.23). Funnel plots are shown in Fig. 3, Fig. 4.
Fig. 3Egger’s funnel plot of the included studies that assess the effect of antiepileptic use on poor outcome in patients with intracerebral hemorrhage.
Fig. 4Begg’s funnel plot of the included studies that assess the effect of antiepileptic use on poor outcome in patients with intracerebral hemorrhage.
This meta-analysis evaluated 6 studies that assessed the use of seizure prophylaxis in patients with spontaneous ICH. Our results suggest that the use of prophylactic AED is not associated with improved short and long-term functional outcomes. The only study investigating the effect of AED on seizures post-ICH identified a benefit of AEDs on seizure prevention in the first 30 days after ICH, however this was a non-randomized, observational study and therefore confounding bias may be present.
Our results confirmed a prior meta-analysis results that found no benefit of AED use in ICH. [
] However, our analysis evaluated a greater number of studies (6 vs 4) and included significantly more patients (3193 vs 1285). In the prior meta-analysis the authors extracted data using univariable analysis without adjusting for potential confounding variables, while we extracted data only from studies with a multivariate analysis. The use of adjusted datasets is one of the strengths of this meta-analysis because it increases the validity and consistency of our results. In addition, there was no evidence of publication bias according to Egger’s and Begg’s tests.
The reported rate of seizures in patients with ICH varies greatly and can occur in up to 40% of patients; seizures may be associated with lobar and cortical lesions. [
] Given the unclear risk of seizures after ICH and presumed deleterious effects of seizure on outcomes in critically ill patients, the use of AEDs for seizure prophylaxis is likely extrapolated from data in traumatic brain injury, aneurysmal subarachnoid hemorrhage, craniotomies, and intracerebral tumors. [
] We identified only one study that evaluated the effect of AEDs and the risk of seizures, phenobarbital was shown to reduce the risk of clinical seizures (OR: 0.58 [95% CI: 0.39 – 0.87]) [
]. The study, however, did not find the occurrence of early seizures to be associated with worse outcomes, or late-onset seizures.
Only a few small trials have evaluated the impact of AEDs on functional outcomes in ICH. Two studies published in 2009 found a significant association between AED initiation and poor outcomes defined as an mRS of 5–6 (OR: 9.8 [95% CI: 1.4–68.6]) and 4–6, respectively (OR: 6.8 [2.2–21.2]). [
]. Our results suggest that AED use is not associated with improved outcomes (Fig. 2). There are several considerations when interpreting these data. All studies but one were observational in design, and the lack of randomization leads to an inherent bias. The studies used older AED with more side effects and drug interactions than the ones currently available on the market. Other important outcomes have not been investigated like risk for epilepsy, hospital stay, cognitive and psychiatric outcomes. Lastly, providers may have selectively used prophylaxis in patients that were at a higher risk. For example, the rate of lobar hemorrhages, a significant risk factor for seizures, was frequently higher in the AED-treated groups. [
In addition to diverse patient characteristics, variability of AED selection and use may have contributed to the differences observed within the studies (Table 1). The use of AEDs ranged between 8 and 46% between the observational studies and most frequently consisted of phenytoin, levetiracetam, and valproate. Choice of AED may have a particular large impact on benefit and risk. Four studies reported phenytoin as the predominant AED used, of which three demonstrated poor outcomes. [
] Sub-analyses in two of those studies, found phenytoin was associated with worse and no effect on outcomes (OR: 9.8 [95% CI: 1.4–68.6]; OR: 0.63 [95% CI: 0.31–1.29]). In the same studies, levetiracetam was neutral when adjusted for patients who survived more than 5 days. These data suggest that phenytoin may have a detrimental effect on functional outcomes, consistent with data from prior studies on aneurysmal subarachnoid hemorrhage [
Incidence of delayed seizures, delayed cerebral ischemia and poor outcome with the use of levetiracetam versus phenytoin after aneurysmal subarachnoid hemorrhage.
]. Our results neither demonstrate a risk nor benefit of AED prophylaxis in ICH. This analysis supports the 2015 AHA/ASA recommendation against prophylactic AEDs (class III; level of evidence b) [
] A multi-center, observational study found the rate of prophylactic AED in ICH doubled from 2007 to 2012.39] This increased use of seizure prophylaxis has been associated with a preferential use of levetiracetam and a stark reduction in phenytoin [
]. While levetiracetam has not been shown to have any clinical relevant drug interactions in neurocritical care patients, it should not be considered a benign drug [
]. This uncertainty calls for a large, multicenter, randomized controlled trial evaluating the use of AED for seizure prophylaxis, and of the long- term functional and cognitive outcomes after ICH.
3.4 Limitations
Our analysis has several limitations. First, the majority of the published data included in this meta-analysis was from retrospective observational studies introducing an inherent risk of bias. Our analysis of publication bias analysis is inconclusive because of the limited data points. We limited our results to full-text articles written in English; several studies were only available as abstracts. Abstracts were excluded because multivariate data could not be extracted. Another limitation of our results was the significant heterogeneity, which may be due to differences between patients, study design, factors controlled for, and choice of AED therapy. Finally, the effect of different AEDs or targeted interventions in high risk patients remains unknown. Analysis of patient level data would have provided a more robust evaluation.
4. Conclusion
This meta-analysis indicates that AED use in ICH is not associated with improved functional short and long outcomes. This analysis supports the 2015 AHA/ASA recommendation against prophylactic AEDs. The advantage of one AED over another, or their use in high-risk patients (e.g. with lobar hemorrhage) remains unknown. However, any benefit of AED prophylaxis on long-term outcomes would be marginal as the effect of seizures on outcomes remains small. A large prospective randomized-controlled trial is needed to better demonstrate the effects of newer generation AEDs in patients with ICH on cognitive, psychiatric and functional outcomes.
Author contributions
Brian Spoelhof, PharmD: Design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript for intellectual content
Julian Sanchez-Bautista, MD: analysis or interpretation of the data, drafting or revising the manuscript for intellectual content
Andres Zorrilla-Vaca, BSc: analysis or interpretation of the data
Peter W. Kaplan, MBBS, FRCP: drafting or revising the manuscript for intellectual content
Salia Farrokh, PharmD: analysis or interpretation of the data, drafting or revising the manuscript for intellectual content
Marek Mirski, MD, PhD: drafting or revising the manuscript for intellectual content
Brin Freund, MD: drafting or revising the manuscript for intellectual content
Lucia Rivera-Lara, MD, MPH: Design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript for intellectual content
Author disclosures
Dr. Spoelhof has nothing to disclose.
Dr. Sanchez-Bautista has nothing to disclose.
Mr. Zorrilla-Vaca has nothing to disclose.
Dr. Kaplan has nothing to disclose.
Dr. Farrokh has nothing to disclose.
Dr. Mirski has nothing to disclose.
Dr. Freund has nothing to disclose.
Dr. Rivera-Lara is the PI on an American Academy of Neurology/American Brain Foundation and grant from Medtronic/Covidien, Dublin, IR.
Ethical publication statement
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References
Lloyd-Jones D.
Adams R.
Carnethon M.
et al.
Heart Disease and Stroke Statistics--2009 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
Incidence of delayed seizures, delayed cerebral ischemia and poor outcome with the use of levetiracetam versus phenytoin after aneurysmal subarachnoid hemorrhage.
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