Statins影響中風後癲癇風險之探討

Abstract

研究背景 中風後癲癇（post-stroke epilepsy，PSE）可能會增加失能的風險以及死亡率。但由於抗癲癇藥物（anti-epileptic drugs，AEDs）有許多的副作用以及與其他藥品的交互作用，因此不建議預防性給予AEDs。另一方面，statin被發現除了降血脂的作用外，陸續有體外試驗、臨床研究證據顯示其在中樞神經上的保護作用，不過針對中風後癲癇預防效果的臨床資料仍不足。 研究目的 本研究欲分析其中風前後statins的處方型態，並評估statins使用與PSE發生風險之相關性。次要目的為進一步分析statins在不同品項、累積劑量及中風一個月內開始使用或停用對預防PSE發生的效果差異。 研究材料及方法 本研究為一回溯性世代研究，利用全民健康保險資料庫2000年、2005年及2010年共三百萬人之抽樣歸人檔，分別分析自2004年至2012年初次發生出血性或缺血性中風之病例，追蹤直到有癲癇診斷、追蹤達三年、至2013年12月31日、或是退保。本研究之time-dependent變項，包括中風後statins的使用及相關併用藥品，採用extended Cox regression model評估各變項與PSE發生的影響。此外，更進一步依statins之脂溶性、藥效強度（intensity，降低low-density lipoprotein cholesterol效果）分類，並探討各statin品項之PSE預防效果與差異。本研究亦對中風前未使用statins之病人，計算中風後statins的累積定義日劑量（cumulative defined daily dose，cDDD），並視為time-dependent變項，依各期間statins使用之cDDD分為四分位（quartile），評估statins與PSE發生風險是否具劑量相關性。次分組分析則探討statins在中風後一個月內開始使用或完全停用，對PSE發生風險的影響。 研究結果 本研究共納入28,293位初次中風病患，包括缺血性中風20,858人（73.7%）、出血性中風7,435人（26.3%）。缺血性中風群之追蹤時間中位數為31.7個月，有954人（4.0%）符合本研究PSE診斷條件；而出血性中風群追蹤時間中位數為17.6個月，計709人（8.8%）符合PSE診斷條件。 在缺血性及出血性中風後statins的使用皆發現能降低發生PSE的風險（分別為adjusted hazard ratio [aHR] 0.55, 95% confidence interval [CI] 0.46-0.61, p < 0.001；aHR 0.62, 95% CI 0.42-0.91, p = 0.014）；不過在中風前statins的使用與PSE發生風險並無相關（aHR 1.06, 95% CI 0.84-1.47, p = 0.464；aHR 1.32, 95% CI 0.89-1.96, p = 0.174）。缺血性中風群中，不論statins的脂溶性（脂溶性statins：aHR 0.55, 95% CI 0.44-0.68, p < 0.001；水溶性statins：aHR 0.58, 95% CI 0.43-0.79, p < 0.001）以及降低LDL-C的強度（低強度：aHR 0.56, 95% CI 0.42-0.74, p < 0.001；中至高強度：aHR 0.53, 95% CI 0.41-0.68, p < 0.001）均能顯著降低PSE發生風險。但出血性中風病患中，僅有脂溶性statins（脂溶性statins：aHR 0.63, 95% CI 0.40-0.99, p = 0.044）以及中至高強度之statins的使用能降低PSE發生的風險（低強度：aHR 0.93, 95% CI 0.58-1.51, p = 0.781；中至高強度：aHR 0.37, 95% CI 0.18-0.75, p = 0.006）。在兩組病人中皆發現statins與預防PSE呈劑量相關性，都有累積劑量越高，保護效果越好的趨勢。 次分組分析中發現，不論缺血性或出血性中風，對原本未使用statins的病患，在中風一個月內開始使用statins並不會影響PSE發生的風險（aHR 0.81, 95% CI 0.64-1.01, p = 0.066；HR 0.80, 95% CI 0.47-1.35, p = 0.401）；以及對原本正在使用statins，但在中風後一個月皆未使用亦不會影響PSE發生的風險（aHR 0.71, 95% CI 0.29-1.71, p = 0.443；HR 0.80, 95% CI 0.47-1.35, p = 0.401）。

結論 中風後使用statins，無論於缺血性中風或出血性中風，均能降低PSE發生的風險，且呈劑量相關性。其中statins本身脂溶性及降低LDL-C的強度在出血性中風降低PSE的發生有明顯影響，但對缺血性中風病人僅有些微影響。本研究受限於觀察性研究及資料庫內容的限制，尚待進一步的基礎及臨床研究以更完整了解statins用於PSE預防的效果。

Background and Objective Epilepsy after stroke may increase the risk of disability and affect patient’s quality of life. Due to concerns of drug-drug interactions and adverse effects of antiepileptic drugs (AEDs), prophylactic AED treatment is not recommended in the guidelines. HMG-CoA reductase inhibitors (statins) have been found to possess neuroprotective and antithrombotic effects other than lipid lowering. However, the evidence for epilepsy prevention of statins among stroke patients is limited. This study aimed to examine the relationship between pre- and post- stroke statin use and the risk of post-stroke epilepsy (PSE). Methods In this retrospective cohort study, patients with new-onset stroke between 2004 and 2012 were identified from the National Health Insurance Research Database of Taiwan, with a maximum follow-up period of 3 years. Cox regression model with time-dependent variable of post-stroke statin use was utilized to estimate the hazard ratio of PSE, while adjusting for pre-stroke statin use and other covariates. Cumulative dose of post-stroke statin use (in quartiles) among prior-to-stroke nonusers was also evaluated as a time-varying determinant to understand if a dose effect exists. Statins was further classified by lipophilicity (lipophilic: atorvastatin, fluvastatin, lovastatin, pitavastatin and simvastatin; hydrophilic: pravastatin and rosuvastatin) and intensity of lipid-lowering effect. The effect of statin initiation and withdrawal within the first month after stroke was then analyzed in the subgroup analysis. Results In this study, 20,858 patients with new-onset ischemic stroke and 7,435 hemorrhagic stroke patients were enrolled. Median follow-up time was 31.7 months and 17.6 months respectively. Among ischemic stroke patients, 954 (4.0%) patients developed PSE within 3 years after stroke. Statin use after stroke was associated with a reduced risk of PSE (adjusted hazard ratio [aHR] 0.55, 95% confidence interval [CI] 0.46-0.61, p < 0.001), but not for prior-to-stroke statin use. Moreover, the risk of PSE was significantly lower regardless of statin lipophilicity or intensity. Among hemorrhagic stroke patients, 709 (9.5%) patients developed PSE within 3 years after stroke. Post-stroke statin use was also associated with a reduced risk of PSE (aHR 0.65, 95% CI 0.42-0.91, p = 0.014) and prior-to-stroke statin use was not associated with rate reduction of PSE. Moreover, the risk of PSE was lower in users of lipophilic statins (aHR 0.63, 95% CI 0.41-0.99, p = 0.044) and moderate-to-high intensity statin therapy (aHR 0.37, 95% CI 0.18-0.75, p = 0.006), but not significant in those with hydrophilic statins (aHR 0.59, 95% CI 0.30-1.16, p = 0.128) and low-intensity statin therapy (aHR 0.93, 95% CI 0.58-1.51, p = 0.781). Dose-response relationship were observed in both groups, with a significantly decreased risk for high cumulative statin dose. In the subgroup analysis, neither statin initiated within the first month among prior-to-stroke nonusers nor statin free for one month after stroke among prior-to-stroke current users were associated with the risk of PSE. Conclusions This study found that use of statins after either ischemic or hemorrhagic stroke were associated with a reduced risk of PSE. Further research is needed to understand the mechanism of its neuroprotective effect in this patient population.