Title: Effects of long-term Antiepileptic Drug Monotherapy on All-cause Death in Patients with Post-Stroke Epilepsy: A Nationwide Population-based Study Cover title: Antiepileptic drugs for post-stroke epilepsy


 Objective We aim to compare the effect of long-term antiepileptic drug (AED) monotherapy on the risk of death and recurrent ischemic stroke in patients with post-stroke epilepsy (PSE). Patients and Methods We identified all hospitalized patients (≥20 years) with a primary diagnosis of ischemic or hemorrhagic stroke from 2001 to 2012 using the National Health Insurance Research Database in Taiwan. The PSE cohorts were defined as the stroke patients (1) who had no epilepsy and no AEDs use before the index stroke, and (2) who had epilepsy and AEDs use after 14 days from the stroke onset. The PSE patients receiving AED monotherapy were enrolled and were categorized into phenytoin, valproic acid, carbamazepine, and new AED groups. We employed the Cox regression model to estimate the unadjusted and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of death and recurrent ischemic stroke within 5 years across all groups, using the new AED group as the reference. Results Of 6962 PSE patients using AED monotherapy, 3917 (56%) were on phenytoin, 1623 (23%) on valproic acid, 457 (7%) on carbamazepine, and 965 (14%) on new AEDs. After adjusting for confounders, compared with new AED users, phenytoin users had a higher risk of death in 5 years (HR: 1.64; 95% CI: 1.06-2.55). On the other hand, all AED groups showed a similar risk of recurrent ischemic stroke. Conclusion Among PSE patients on first-line monotherapy, compared to new AEDs, use of phenytoin was associated with a higher risk of death in 5 years.


INTRODUCTION
Cerebrovascular disease is a common underlying mechanism for late-onset epilepsy. 1 Long term cumulative risk of post-stroke epilepsy (PSE) after a cerebrovascular event varies from 2% to 15% according to different definitions of PSE, stroke types, and follow-up durations. 2 Antiepileptic drugs (AEDs) are often administered to prevent recurrent seizures in PSE patients. 3 The choice of first-line AEDs in PSE patients are diverse. International League Against Epilepsy had reported that carbamazepine, phenytoin, levetiracetam and zonisamide had level A evidence of efficacy for adults with focal seizures; gabapentin and lamotrigine had level A evidence of efficacy for elderly adults with focal seizures. 4 Two small randomized controlled trials in PSE patients showed that lamotrigine and levetiracetam had similar efficacy in seizure control and were better tolerated compared to carbamazepine. [5][6][7] In general, more than 70% of PSE can be well-controlled under AED monotherapy. [6][7][8] Except for seizure control effectiveness, the effects of AEDs on cardiovascular outcomes and mortality are also important issues. A nationwide cohort study in Denmark found that AED-treated epilepsy was associated with a higher risk of myocardial infarction, stroke, cardiovascular death and all-cause death. 9 A range of AEDs, especially firstgeneration of AEDs, have been linked to atherothrombotic risk factors, such as increased level of homocysteine, hyperlipidemia, weight gain, and insulin resistance. 9 Hsieh et al. had found that phenytoin was associated with an increased stroke risk compared to carbamazepine in epilepsy patients. 10 Compared to epilepsy patients without prior stroke history, PSE patients are usually older and having more vascular risk factors, and they are at a higher risk of recurrent stroke and death. [11][12][13] The impact of AEDs on the risk of all-cause death and recurrent stroke should be particularly considered. However, studies about this issue are scarce and diverse. Therefore, we conducted this nationwide cohort study to evaluate the comparative effects of long-term AED monotherapy on the risks of all-cause death and recurrent ischemic stroke in PSE patients.

Data Source
We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database (NHIRD). The Taiwan National Health Insurance program was launched in 1995. It covers 99% of the population and reimburses for outpatient and inpatient services as well as prescription drugs. In the study period, the diagnosis code in NHIRD consists of the 9th revision of the International Classification of Diseases (ICD-9). The diagnoses of acute ischemic stroke and epilepsy have been validated in NHIRD. [14][15][16] This study has been approved by the institutional review board of Chang Gung Memorial Hospital, Chiayi, Taiwan.

Study Population: defining the patients with PSE (Figure 1)
We identified all hospitalized patients (≥20 years) who were admitted with a primary diagnosis of ischemic or hemorrhagic stroke (ICD-9 codes 433.X1, 434.X1, 436, 431) encountered between January 1, 2001 and December 31, 2012. Hospitalizations due to transient ischemic stroke (ICD-9 435.9) or subarachnoid hemorrhage (ICD-9 430) were not included. For each case, the first stroke episode during the study period was defined as the index stroke. We excluded (1) patients without computed tomography or magnetic resonance imaging of brain during the index stroke or within the 3 days before the index stroke (because the diagnosis of stroke may be indefinite), (2) patients with an epilepsy diagnosis (ICD-9 345.00) before the index stroke (because these patients may have other epilepsy syndromes other than PSE), (3) patients who had used any antiepileptic drugs within 180 days before the index stroke (because these patients may use AEDs for indications other than PSE), and (4) patients who died within 2 months after the index stroke (because the early mortality after the stroke is less likely related to AEDs use).
PSE was defined as presence of epilepsy diagnosis (ICD-9 345.00) (once in inpatient or twice in outpatient diagnosis) along with usage of oral AED after 14 days from the index stroke. AEDs in this study included carbamazepine, clobazam, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, sodium valproate, tiagabine, topiramate, vigabatrin, and zonisamide. Intravenous AEDs were not included in our study because we focused on the long-term effects of AEDs.
This was a nationwide study that included all available and eligible patients. The requirement of informed consent from subjects included in this study was waived.

Grouping of antiepileptic drugs (Figure 1)
Among the PSE patients, we identified the patients whose first-line treatment was a single AED for more than 28 days. These patients were grouped according to the first-line AED they used, including phenytoin group, valproic acid group, carbamazepine group and new AED (including monotherapy with clobazam, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, and zonisamide) group. We excluded patients who used phenobarbital as the first AED because the case number was too small. Any gap between AEDs prescription more than 28 days was considered as discontinuing of the AED.

Study design
This was a retrospective cohort study. For each patient, the first date of the AED use was defined as index date of AED use. Each patient was followed from the index date of AED use until one of the following events happened: (1) death from any cause; (2) end of the database (December 31, 2013); (3) switching to or adding on another AEDs; (4) discontinuing the first AED or (5) follow-up for 5 years. The primary study outcome was allcause death and the secondary study outcome was recurrent ischemic stroke. Death was defined by death mark in NHIRD, and recurrent ischemic stroke was defined by new hospitalization with a primary diagnosis of ischemic stroke (ICD-9 codes 433.X1, 434.X1, 436) with brain imaging during or within the 3 days before the hospitalization. Stroke severity of the index stroke was evaluated by the stroke severity index (airway suctioning, bacterial sensitivity test, general ward stays, intensive care unit stay, nasogastric intubation, osmotherapy, and urinary catheterization), developed specifically to evaluate the severity of strokes in Taiwan NHIRD. 17,18 Information about concomitant medication use (including antiplatelets, anticoagulants, antidepressants and statin) from the index date of AED use to the end of the follow-up period was extracted for each case.

Statistical analysis
The differences among the baseline characteristics of the four AED groups were analyzed by Analysis of Variance (ANOVA) for normally distributed variables, and Pearson's Chi Square test for categorical variables.
We employed the Cox regression model to estimate the unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the relative risk of death and recurrent ischemic stroke of the phenytoin group, valproic acid group and carbamazepine group, using the new AED group as the reference. The relative risk of recurrent ischemic stroke in the four AED groups were analyzed by competing risk analysis with death as the competing risk. The model was adjusted for age, gender, index stroke types, all of the abovementioned comorbidities, concomitant medications use (anticoagulants, antidepressants, antiplatelet agents, and statin), and year of index date of AED use. For the groups which had significantly different risk of death or recurrent ischemic stroke compared to the reference group, we further did subgroup analyses. Subgroup analyses were performed to assess the interaction effect between different patient characteristics and AEDs use. We tested the significance of the interaction terms in the regression models using the Wald test for interactions.
Statistical significance was determined using 95% CIs or a P value <0.05. Statistical analysis was performed using the SAS statistical package (release 9.4, SAS Institute Inc, Cary, NC).

RESULTS
In the study period, 320961 stroke patients without previous epilepsy history or previous AEDs use were identified, and 9127 (2.8%) of them had PSE with AED use.
Among these patients, 6962 cases received the first AED monotherapy continuously for more than 28 days, and they were classified according to the first AED they received: 3917 in

DISCUSSION
In this retrospective nationwide cohort study with more than 6000 PSE patients using long-term AED monotherapy, we found that patients who used phenytoin as the first-line AED monotherapy had a higher risk of 5-year all-cause mortality compared to those who were on new AEDs as the first AED monotherapy, after adjustment of confounders.
Subgroup analyses showed that the 5-year all-cause death risk was higher in phenytoin users with hyperlipidemia. To our knowledge, this is the first study investigating the long-term effect of AED monotherapy on the risk of all-cause death in PSE patients.
There is a paucity of studies about the risk of death or vascular events associated with AED use. 9,19,20 Most of these studies restricted to epilepsy patients without prior stroke history. Olesen et al. found that AED-treated epilepsy was associated with a higher risk of myocardial infarction, stroke, cardiovascular death and all-cause death. 9 Bardai et al found AED use was associated with a higher risk of sudden cardiac death. 20 A recent study by Sarycheva et al revealed that AED use was associated with an increased risk of death in patients with Alzheimer disease. 19 Some studies have investigated the comparative effects of different AEDs on the risk of death or vascular events in epilepsy patients without prior stroke. Most of these studies found that older AEDs, such as phenytoin, carbamazepine, valproic acid, or phenobarbital, were linked to a higher risk of death or stroke. 9,10,19 However, older AEDs are still frequently prescribed as the first-line therapy in patients with PSE. In our cohort, 86% of PSE patients used older AEDs as the first-line monotherapy.
There are some potential explanations for our finding that long-term phenytoin monotherapy was associated with a higher death risk in PSE patients. A Sweden study found that the disorders of the circulatory systems were the most common cause of death in the PSE patients. 21 Therefore, the increased death risk in phenytoin user may be contributed from its influences on the circulatory systems. Phenytoin was associated with a higher risk of dyslipidemia, 22,23 increased homocysteine and high sensitivity C-reactive protein, 24 and increased atherosclerosis measured as intima media thickness. 24 Phenytoin is a sodium channel blocker. Sodium channel blocking AEDs were reported to be related to a higher risk of sudden cardiac death and arrhythmogenic ST-T abnormality. 20,25 Decreased cardiac sodium current may increase the risk of ventricular fibrillation and sudden cardiac death. 20 Cases of arrhythmia and sinus arrest has also been reported in phenytoin users. 26 Furthermore, phenytoin has a zero-order metabolism and may easily result in overdose that may present as arrhythmia, respiratory arrest or sinus arrest. Finally, a population-based cohort study in Taiwan found that PSE patients using phenytoin had a higher risk of emergency room visits or hospitalization due to seizures, compared to the PSE patients using new AEDs. 27 Poor control of seizures may also increase the risk of seizure-related death. 27 On the other hand, we did not find a difference in recurrent ischemic stroke risk across the various AEDs groups in PSE patients. But phenytoin has been reported to be related to a higher stroke risk in epilepsy patients without stroke history. 10 We thought that physicians might pay more attention to monitor and to treat the vascular risk factors in PSE patients.
These stroke prevention strategies may mask the small effects of AEDs on recurrent ischemic stroke risk.
The main strength of our study was that it was based on a nationwide database, that provided advantages of large case numbers, long follow-up duration, complete data of the duration and the dosage of AEDs, and less selection bias related to socioeconomic status, job situation or different healthcare institutions. Although the diagnosis of stroke and epilepsy could not be confirmed by medical chart review, the two diagnoses had been validated in NHIRD, with an accuracy of 94% for stroke and 99.83% for epilepsy. 14,16 Another strength of our study was that we focused on first-line AED monotherapy. Previous studies showed that more than 70% of the post-stroke epilepsy patients could achieve seizure freedom under AED monotherapy, 5 and the 5-year retention rate of first AED in post-stroke epilepsy patients was high (55-75%). 28 Therefore, selection of first AED in PSE patients is important in clinical practice, and our study provided an important reference on this issue. This study has limitations. First, some important information, such as the types and the severity of the seizures, reasons to choose or not to choose a specific AED, and the patients' laboratory data, could not be assessed by NHIRD. Second, we did not know the drug compliance and the serum concentration of the AEDs in each patient. Inadequate dosage of AEDs may result in poor seizures control or more severe side effects. Third, we could not ascertain the cause of death from our database, and we could not evaluate if there were any differences in the cause of death in different AED groups. Fourth, although our study design included adequate control of numerous confounding factors, unmeasured or unknown confounders may have generated a bias. For example, we were not able to account for effects of smoking, physical activity, alcohol intake, diet habits, a family history of cardiovascular diseases, or body mass index. Finally, this study was performed in Taiwan, and the result of the study may not be generalizable to other populations. The generalizability of the current results needs to be confirmed by further studies conducted in other countries and populations.
In conclusion, our study showed that using phenytoin as the first-line AED monotherapy, compared with using new AEDs, was associated with an increase in 5-year death risk among PSE patients. This finding provides potentially vital information for clinicians to improve the long-term survival of PSE patients. Still, prospectively designed cohort studies and randomized controlled trials are warranted, to identify the most optimal AED regimen(s) for PSE patients.

Declarations
Ethics approval and consent to participate: Institutional review board of Chang Gung Memorial Hospital, Chiayi, Taiwan did the ethics approval and waived the need for informed consent.

Consent for publication: None
Availability of data and materials: The datasets generated and/or analysed during the current study are not publicly available because this was a national insurance database but are available from the corresponding author on reasonable request.