慢性腎臟疾病患者使用Tranexamic acid導致嚴重藥物不良反應之探討

The evaluation of severe adverse reaction induced by Tranexamic acid in chronic kidney disease patients

劉閣顯(Ko-Hsien Liu)

指導教授 ： 黃耀斌

共同指導教授 ： 黃尚志(Shang-Jyh Hwang)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2011年)

https://doi.org/10.6832/KMU.2011.00082

摘要

背景：Tranexamic acid（TXA）為一用途廣泛的止血劑，可用於慢性腎臟疾病（Chronic kidney disease, CKD）病人因為尿毒症所引發之出血反應，但該藥主要由腎臟所排泄，當病人腎臟功能受損時，會使得TXA無法順利排除而在體內蓄積造成濃度上升。國外研究顯示TXA較其他同類型止血劑有較高發生癲癇之機率，且此不良反應與病人腎功能與使用劑量有高度相關。目前國內缺乏相關文獻探討此一議題，故本研究之目的為分析國內CKD病人在使用TXA藥品後所產生之癲癇不良反應及導致此不良反應之因素。
方法：本研究採回溯性的觀察性研究，研究分為兩部分，第一部分以從2005年1月1日至2010年6月30日台灣南部某醫學中心資料庫，針對CKD病人在使用TXA後30天內有使用相關抗癲癇藥物（Lorazepam、Diazepam、Valproic acid或Phenytoin）或醫令處置（Computed tomography scan或Electroencephalography），藉由病歷回顧確認這些病人在時間內是否發生癲癇，分析病人之相關基本資料、腎臟功能及TXA藥品處方之開立型態，探討CKD病人在使用TXA後發生嚴重藥物不良反應之關聯性，並探討最適化搜尋方法。第二部分以同樣研究策略應用於國衛院全民健保資料庫的百萬歸人檔，研究期間自1997年1月1日至2008年12月31日，分析合於搜尋條件病人之相關基本資料及相關處置開立型態，並搭配第一部分之最適化搜尋方法，探討全國因TXA所引起之癲癇嚴重藥物不良反應之相關流行病學。
結果： 紙本病歷回顧共計128名病人，男性76人，女性52人。其中共有198件事件與217筆藥品開立筆數，以Lorazepam135筆（62.21%）開立筆數最多，在TXA適應症上，因血尿原因開立筆數最多（27.00%），在藥品開立之科別則以泌尿科與眼科比例最高（19.00%）。從病歷回顧中，研究共計發現8名病人於使用TXA後有發生癲癇之狀況，在發生癲癇與未發生癲癇組別之比較，發生癲癇組的腎臟功能明顯低於未發生癲癇組（p＜0.0001）。在TXA使用劑量上，發生癲癇組使用TXA劑量明顯高於未發生癲癇組（p＜0.0001）。在最適化搜尋方法上，以病人累積事件數3件以下、於住院有使用抗癲癇藥物之注射劑型、同一事件中有多重抗癲癇處置開立及TXA與抗癲癇處置間隔天數22天以內或7天以內這兩方法顯示出有最高之檢出率（60.00%）。而在國衛院全民健保資料庫的百萬歸人檔中，計有1419名病人符合收案條件，其中包含790名（55.67%）男性與629名女性（44.33%），若配合最適化方法，TXA與抗癲癇處置天數間隔22天那組共計29名符合條件，包含18名男性（62.69%）與11名女性（37.93%）；TXA與抗癲癇處置天數間隔7天，共計14名符合條件，包含9名男性（64.29%）與5名女性（35.71%）。
結論：本研究結果發現TXA有導致病人癲癇之情況，且癲癇之發作跟病人腎臟功能與TXA使用劑量呈現高度相關。本研究藉由提供藥物嚴重不良反應資訊，加強相關醫療人員對此不良反應認識，進而降低發生藥物不良反應之機會，增進民眾用藥之安全。

關鍵字

慢性腎臟疾病 ； Tranexamic acid ； 癲癇 ； 藥物不良反應 ； 觀察性研究

並列摘要

Objectives：Tranexamic acid(TXA) is a hemostatic drug which is excreted by kidney. It can be used in chronic kidney disease (CKD) patients for uremic bleeding. However, the research showed that TXA will increase seizure potency. Besides, the data showed that the seizure potency was highly correlated with kidney function and TXA dosage. Moreover, concentration of TXA will rise when TXA was used in CKD patients. Our goal was to investigate occurrence of seizure after administration of TXA in CKD patients.
Methods：A retrospective observational study was conducted using two different sources of data. We used drug prescription (Lorazepam, Diazepam, Valproic acid, Phenytoin) or medical examination (Computed tomography scan, Electroencephalography) as the occurrence of seizure. At the first part of research, the patients were retrieved from medical center during Jan 2005 to June 2010. According to medical record, the patients which were prescribed drugs or examinations within 30 days after TXA were accepted. Patients with occurrence of seizure were identified by chart review. Patients then divided in two parts by seizure occurrence. The characteristics of patients with seizure were pooled together to get information for further investigation. At the second part, the patients were retrieved from Longitudinal Health Insurance Database 2005(LHID) during Jan 1997 to Dec 2008. The characteristic of patients were investigated.
Results：A retrospective medical history of 128 patients with 217 events was reviewed to investigate the occurrence of seizures. Lorazepam was prescribed most within 217 events. Eight patients presented seizures. There were two variables differed significant between patients with and without seizure: kidney function (p＜0.0001) and TXA dosage (p＜0.0001). In LHID, 1419 patients were included in our study. Lorazepam was prescribed most within 2502 events. By further investigation, there were 29 patients having antiepileptic treatment within 22 days and 14 patients having antiepileptic treatment within 7days.
Conclusions：Our result provided information of occurrence of seizure in CKD patients. Results also indicated that high-dose TXA and low kidney function are associated with an increased incidence of seizure in CKD patients. This study gave the information about drug safety and still need further investigation to support this adverse drug reaction.

並列關鍵字

Chronic kidney disease ； Tranexamic acid ； Seizure ； Adverse drug reaction ； Observational study

參考文獻

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