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研究生:陳昱汝
研究生(外文):Yu-Ju Chen
論文名稱:非選擇性乙型阻斷劑對肝硬化合併肝性腦病變病人死亡率之影響
論文名稱(外文):Impact of Non-selective Beta-blockers on the Mortality in Cirrhotic Patients with Hepatic Encephalopathy
指導教授:周月卿周月卿引用關係蘇建維蘇建維引用關係
指導教授(外文):Yueh-Ching ChouChien-Wei Su
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:86
中文關鍵詞:非選擇性乙型阻斷劑失償性肝硬化肝性腦病變全死因死亡率
外文關鍵詞:Non-selective beta blockersDecompensated cirrhosisHepatic encephalopathyAll-cause mortality
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背景與目的:非選擇性乙型阻斷劑 (non-selective beta-blockers,NSBB) 在過去三十多年來,一直被視為是肝硬化患者門脈高壓 (portal hypertention) 藥物治療之重要基石。NSBB可同時抑制第一型乙型交感受體 (beta-1 adrenergic receptor) 降低心輸出量,亦阻斷第二型乙型交感受體 (beta-2 adrenergic receptor) 使內臟血管收縮減少門脈血流,藉此預防胃食道靜脈曲張出血,然而近年來卻有證據開始質疑NSBB用於晚期肝硬化的安全性。由於NSBB在失償性肝硬化 (decompensate cirrhosis) 的使用上仍具爭議,本研究旨在探討NSBB對肝硬化合併肝性腦病變 (hepatic encephalopathy) 病人全死因死亡之影響。
研究方法:我們利用1997年至2011年全民健康保險資料庫之資料進行一以族群為基礎的回溯性世代研究,從中定義2001年至2011年間新診斷肝性腦病變的肝硬化病人,針對NSBB用藥者 (定義為NSBB累計使用90天) 以年齡、性別及傾向分數 (propensity score) 與非用藥者進行1比1配對,持續追蹤至死亡 (退保) 或研究結束 (2011年12月31日),利用時間相依性Cox比例風險模型(time-dependent Cox proportional hazard model) 分析NSBB使用與全死因死亡之關聯性。
研究結果:本研究世代共納入1,946位病人,其中NSBB使用者共743人,而未使用NSBB者共1,203人,而在以年齡、性別及傾向分數1比1配對後兩組人數皆為581人。校正各控制變項後我們發現使用NSBB相較於未使用NSBB顯著下降肝性腦病變病人全死因死亡風險 (adjusted hazard ratios [aHR] 0.61, 95% confidence interval [CI]: 0.50-0.74, p<0.0001),而年齡 (aHR 1.02, 95%CI: 1.01-1.03, p<0.0001)、肝硬化相關醫療資源使用 (aHR 1.02, 95%CI: 1.01-1.03, p<0.0001)、胃食道靜脈曲張 (aHR 1.34, 95%CI: 1.12-1.61, p=0.0017) 及肝細胞癌 (aHR 1.82, 95%CI: 1.45-2.29, p<0.0001) 則顯著增加全死因死亡風險。此外,間接比較顯示propranolol處方劑量和全死因死亡風險相關,其校正後風險比在低處方劑量、中處方劑量及高處方劑量三組病人中分別為0.65 (95%CI 0.45-0.94, p=0.0200)、0.63 (95%CI 0.43-0.92, p=0.0167) 及0.52 (95%CI 0.35-0.77,
p=0.0012)。
結論:本研究首次證實肝性腦病變病人使用NSBB是安全且可顯著降低全死因死亡風險,針對這群病人在停用NSBB前應審慎評估其利弊。
Background: Non-selective beta-blockers (NSBB) remain the cornerstone of medical treatment for portal hypertension in cirrhotic patients in the past three decades. NSBB achieve their therapeutic effects to prevent variceal bleeding through the dual mechanism of reducing cardiac output via beta-1 adrenergic blockade, and reducing portal blood flow through splanchnic vasoconstriction via beta-2 adrenergic blockade. However, in recent years new evidence has cautioned the safety of NSBB in patients with end-stage cirrhosis. As ongoing controversy on the use of NSBB in patients with decompensated cirrhosis, this study aims to determine the impact of NSBB on the all-cause mortality in cirrhotic patients with hepatic encephalopathy.
Method: We conducted a population-based retrospective cohort study using data from the Taiwanese National Health Insurance Research Database (NHIRD) from 1997 to 2011. Cirhotic patients with incident hepatic encephalopathy (HE) between 2001 and 2011 were identified. NSBB users (defined as ≥90 cumulative NSBB prescription days) and a 1:1 ratio age-, gender- and propensity score-matched non-NSBB users were followed up until death (withdrawal from insurance) or December 31, 2011. The association between NSBB use and all-cause mortality was examined using time-dependent Cox proportional hazards models.
Results: Among 1,946 patients included, 743 patients received NSBB and 1,203 patients did not. After 1:1 age, gender and propensity score matching, there were 581 patients in each cohort. We found that NSBB use was associated with reduced all-cause mortality in HE patients (adjusted hazard ratios [aHR] 0.61, 95% confidenceinterval [CI] 0.50-0.74, p<0.0001). On the contrary, older age (aHR 1.02, 95%CI: 1.01-1.03, p<0.0001), cirrhosis-related health service ultilization (aHR 1.02, 95%CI: 1.01-1.03, p<0.0001), esophageal varices (aHR 1.34, 95%CI: 1.12-1.61, p=0.0017) and hepatocellular carcinoma (aHR 1.82, 95%CI: 1.45-2.29, p<0.0001) were associated with an increased risk of all-cause death in patients with HE. In addition, indirect comparison showed that a relationship between prescribed dose of propranolol and all-cause mortality. The aHR were 0.65 (95%CI 0.45-0.94, p=0.0200), 0.63 (95%CI 0.43-0.92, p=0.0167) and 0.52 (95%CI 0.35-0.77, p=0.0012) for patients with low, medium and high prescribed dose, respectively.
Conclusion: This study shows for the first time that treatment with NSBB in HE is safe and significantly reduces the risk of all-cause death. Careful thought
should be given before discountuing NSBB in these patients.
中文摘要......i
英文摘要......ii
目錄......iv
圖目錄......vi
表目錄......vii
縮寫表......viii
第一章 緒論......1
第一節 研究背景與動機......1
第二節 研究目的......6
第二章 文獻探討......7
第三章 研究方法與設計......12
第一節 研究架構與研究假說......12
第二節 研究設計與研究工具......14
第三節 研究對象篩選......17
第四節 研究變項測量......24
第五節 傾向分數配對及次族群分析......29
第六節 統計分析......33
第四章 研究結果......36
第一節 研究族群基本特性......36
第二節 全死因死亡風險......44
第三節 次族群分析......48
第四節 藥品種類及處方型態......53
第五節 處方劑量及處方期間......56
第五章 討論......67
第一節 研究結果討論......67
第二節 研究限制......72
第六章 結論與建議......75
第一節 結論......75
第二節 建議......75
參考文獻......76
附錄一 研究藥品ATC碼及健保代碼......80
附錄二 疾病診斷碼對照表......82
附錄三 都市化程度......84

圖目錄
圖2-1-1 肝硬化病人NSBB治療窗假說......10
圖3-1-1 研究架構......13
圖3-2-2 資料檔案串檔流程......16
圖3-3-1 樣本篩選與配對示意圖......22
圖3-3-2 藥品使用天數校正......23
圖3-4-1 研究變項評估......25
圖3-5-1 藥品處方劑量計算......31
圖4-1-1 傾向分數分佈圖與盒狀圖 (傾向分數配對前)......37
圖4-1-2 傾向分數分佈圖與盒狀圖 (傾向分數配對後)......38
圖4-2-1 使用NSBB與全死因死亡之存活曲線 (傾向分數配對前)......45
圖4-2-2 使用NSBB與全死因死亡之存活曲線 (傾向分數配對後)......45
圖4-3-1 傾向分數配對前全死因死亡風險之次族群分析......49
圖4-3-2 傾向分數配對後全死因死亡風險之次族群分析......51
圖4-4-1 藥品種類與全死因死亡風險之次族群分析(傾向分數配對前)......55
圖4-4-2 藥品種類與全死因死亡風險之次族群分析(傾向分數配對後)......55
圖4-5-1 平均處方劑量與全死因死亡之次族群分析(僅使用propranolol)......57
圖4-5-2 平均暴露劑量與全死因死亡之次族群分析(僅使用propranolol)......57
圖4-5-3 平均暴露時間與全死因死亡之次族群分析(NSBB處方合併計算)......58
圖4-5-4 平均暴露時間與全死因死亡之次族群分析(僅使用propranolol)......58

表目錄
表1-1-1 肝性腦病變臨床分級......3
表1-1-2 胃食道靜脈曲張出血預防之NSBB建議劑量......5
表2-1-1 失償性肝硬化病人使用NSBB對死亡之影響文獻回顧......11
表3-2-1 資料檔案名稱及其擷取變項......15
表3-3-1 研究對象篩選條件與分組依據操作型定義......20
表3-4-1 研究變項測量之操作型定義......26
表3-5-1 探討劑量反應關係之分層操作型定義......32
表3-6-1 傾向分數模型及Cox 比例風險模型之操作型定義......35
表4-1-1 傾向分數配對前後肝性腦病變診斷年分佈情形......39
表4-1-2 傾向分數配對前後基本特質分佈......40
表4-1-3 用以預測NSBB使用傾向分數之邏輯斯迴歸模型......43
表4-2-1 使用NSBB與全死因死亡之風險估計(傾向分數配對前)......46
表4-2-2 各控制變項與全死因死亡之風險估計(傾向分數配對前)......46
表4-2-3 使用NSBB與全死因死亡之風險估計(傾向分數配對後)......47
表4-2-4 各控制變項與全死因死亡之風險估計(傾向分數配對後)......47
表4-4-1 傾向分數配對前後NSBB使用特性......54
表4-5-1 平均處方劑量分組後基本特性分佈(僅使用propranolol)......59
表4-5-2 平均暴露劑量分組後基本特性分佈(僅使用propranolol)......61
表4-5-3 平均暴露時間分組後基本特性分佈(NSBB處方合併計算)......63
表4-5-4 平均暴露時間分組後基本特性分佈(僅使用propranolol)......65
表5-1-1 傾向分數配對前後carvedilol使用分佈......71
表5-2-1 傾向分數配對前後事件分佈......74
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