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系統識別號 U0026-0208201823321900
論文名稱(中文) 靜脈血栓症使用新型口服抗凝血藥物之有效性及安全性評估:台灣單中心、回溯性世代研究
論文名稱(英文) Effectiveness and Safety of New Oral Anticoagulants for the Treatment of Symptomatic Venous Thromboembolism:a Single Center, Retrospective Cohort Study in Taiwan
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 106
學期 2
出版年 107
研究生(中文) 周冠玗
研究生(英文) Kuan-Yu Chou
學號 S66051057
學位類別 碩士
語文別 中文
論文頁數 112頁
口試委員 指導教授-鄭靜蘭
指導教授-李政翰
口試委員-高雅慧
口試委員-王美文
中文關鍵字 新型口服抗凝血藥物  瓦法靈  靜脈血栓症  重大出血  台灣 
英文關鍵字 NOACs  Warfarin  VTE  Major bleeding  Taiwan 
學科別分類
中文摘要 研究背景
靜脈血栓症(包括深部靜脈血栓及肺栓塞)的治療方式是使用抗凝血劑,除了傳統的Warfarin以外,近年發展了新型口服抗凝血藥物 (New oral anticoagulants; NOACs),包括:Apixaban、Dabigatran、Edoxaban、Rivaroxaban,在上市前的臨床試驗研究顯示,NOACs預防靜脈血栓症再復發的效果不劣於Warfarin,且安全性較高;然而亞洲次族群分析資料有限,且沒有任何亞洲族群使用NOACs之觀察性研究。在台灣族群缺乏靜脈血栓症使用NOACs情況下,執行此研究。

研究目的
本研究的目的為評估台灣靜脈血栓症病患使用NOACs和Warfarin的療效和安全性,包括重大出血、靜脈血栓症、全因死亡、及非重大出血事件。
研究方法
本研究採用病歷回顧的方式進行回溯性的世代研究,納入條件為於成大醫院處方NOACs或Warfarin的靜脈血栓症病患 (需經客觀檢查確診,且大於等於20歲)。主要研究事件為,重大出血;次要研究事件為,靜脈血栓症再復發、全因死亡、及非重大出血事件。為了降低二組間基本特性潛在之不平衡,將執行傾向分數配對分析。本研究經國立成功大學附設醫院人體試驗委員會核淮。

研究結果
本研究收錄2014年1月1日至2017年4月30日之間心臟血管外科及內科之個案。總研究之個案為382人,NOACs組為162人,Warfarin組為220人。
重大出血發生率NOACs組及Warfarin組分別為3.7%與10.91% (HR: 0.282; 95% CI 0.115-0.691; P= 0.0056),NOACs重大出血發生風險顯著比Warfarin少;靜脈血栓症再復發NOACs組及Warfarin組分別為1.23%與0.91% (HR: 0.975; 95% CI 0.137-6.961; P= 0.9802),二組未達統計學上差異;全因死亡率NOACs組及Warfarin組分別為2.47%與10% (HR: 0.195; 95% CI 0.067-0.567; P= 0.0027),NOACs全因死亡風險顯著比Warfarin少;非重大出血比例NOACs組12.35%,Warfarin組20.91%,二組達統計學上差異 (P=0.0293)。
然而Warfarin組有較多Active cancer個案,且Index CrCl小於30 ml/min之個案比例也較多,故執行傾向配對。傾向分數配對後重大出血發生率NOACs組及Warfarin組分別為4.59%與10.09% (HR: 0.967; 95% CI 0.060-15.460; P= 0.9811);靜脈血栓症再復發NOACs組及Warfarin組二組皆為0.92% (HR: 0.443; 95% CI 0.154-1.279; P= 0.1323);全因死亡率NOACs組及Warfarin組分別為2.75%與8.26% (HR: 0.300; 95% CI 0.081-1.107; P= 0.07070),傾向配對後,此三項研究事件二組皆未達統計學上差異。

結論
本研究提供台灣靜脈血栓症病患使用口服抗凝血劑的療效和安全性。在常規臨床處方中,Active cancer或Index CrCl小於30 ml/min,偏向處方Warfarin。傾向分數配對後之結果也確定NOACs在VTE族群中之有效性及安全性。然因本研究樣本數較少,仍有待更大型的研究來證實台灣VTE族群使用NOACs之有效性及安全性。
英文摘要 New oral anticoagulants (NOACs) are now widely used as alternatives to warfarin for management of venous thromboembolism (VTE). The phase Ⅲ trials showed similar rates of recurrent VTE and similar or less rates of major bleeding with NOACs treatment compared with standard anticoagulation (low molecular-weight heparin, overlapping with and followed by a dose-adjusted vitamin K antagonist) for the treatment of VTE. However, subgroup analysis of Asians in phase Ⅲ trials and cohort study enrolling Asians were limited. This study was initiated due to lack of NOACs use in the Taiwanese VTE population. We conducted a retrospective cohort study to assess the effectiveness and safety of NOACs for the treatment of VTE, by chart review in the National Cheng Kung University Hospital. Between January 1, 2014, and April 30, 2017, 382 patients were enrolled in cardiovascular surgery and internal medicine divisions. Compared to Warfarin group, fewer patients in the NOACs group had active cancer or index creatinine clearance (CrCl) less than 30 ml/min. In the propensity score-adjusted population, the frequency of major bleeding was 4.59% (5/109) in the NOACs group and 10.09% (11/109) in the Warfarin group, with a hazard ratio (HR) of 0.967 (95% CI 0.060-15.460; P= 0.9811). The frequency of recurrent VTE was 0.92% (1/109) in the NOACs group and 0.92% (1/109) in the Warfarin group (HR: 0.443; 95% CI 0.154-1.279; P= 0.1323). The frequency of all-cause mortality was 2.75% (3/109) in the NOACs group and 8.26% (9/109) in the Warfarin group (HR: 0.300; 95% CI 0.081-1.107; P= 0.07070). Propensity score-adjusted results confirm that NOACs is a safe and effective alternative to Warfarin. More large-scale studies are warranted to confirm the results due to the limited sample size of this study.
論文目次 中文摘要 I
Extended Abstract III
誌謝 VI
目錄 VIII
表目錄 XII
圖目錄 XIV
縮寫與全名對照表 XV
第一篇、 靜脈血栓症使用新型口服抗凝血藥物之有效性及安全性評估:台灣單中心、回溯性世代研究 1
第1章、 研究背景 1
第2章、 文獻回顧 2
第1節、 靜脈血栓症 2
2.1.1. 疾病簡介 2
2.1.2. 流行病學 2
2.1.3. 危險因子評估 3
2.1.4. 治療藥物及治療時間 4
2.1.5. 出血風險評估 (RIETE Registry bleeding score) 8
第2節、 NOACs於VTE之文獻 9
2.2.1. Phase Ⅲ之樞紐臨床試驗 9
2.2.2. Phase Ⅲ臨床試驗亞洲次群組分析 15
2.2.3. 世代研究 17
2.2.4. NOACs之健保給付規範 22
第3節、 NOACs應用於非瓣膜性心房顫動 23
第4節、 文獻回顧總結 26
第3章、 研究目的 27
第4章、 研究方法 28
第1節、 研究設計 28
4.1.1. 研究類型 28
4.1.2. 研究材料與資料來源 28
4.1.3. 研究藥品 28
4.1.4. 研究對象 28
4.1.5. 研究區間 29
4.1.6. 研究事件 29
4.1.7. 觀察終止 30
4.1.8. 記錄表格 30
4.1.9. 人體試驗委員會核備 31
第2節、 研究名詞、研究變項與操作定義 32
第3節、 研究流程 35
第4節、 統計分析 36
4.4.1. 統計工具 36
4.4.2. 統計分析方法 36
4.4.3. 敏感性分析(sensitivity analysis) 37
第5章、 研究結果 39
第1節、 研究對象納入與排除 39
第2節、 研究對象基本資料分析 41
第3節、 主要研究事件 (Primary outcome) 47
5.3.1. 重大出血事件發生率 47
5.3.2. 重大出血風險描述分析 47
5.3.3. 重大出血事件之單變項分析 47
第4節、 次要研究事件(Secondary outcome) 53
5.4.1. 靜脈血栓症再復發率 53
5.4.2. 全因死亡率 (All-cause mortality) 53
5.4.3. 非重大出血(minor bleeding)事件比例 53
5.4.4. 口服抗凝血劑治療時間 55
5.4.5. Warfarin組之INR控制情形 55
第5節、 敏感性分析 (Sensitivity analysis) 57
5.5.1. Warfarin組依指標日期分二組與NOACs做比較 57
5.5.2. 研究事件依Time-dependent exposure做分析 66
5.5.3. 傾向分數配對 (propensity score matching) 67
第6章、 研究討論 69
第1節、 研究對象納入與排除 69
第2節、 研究對象基本特性分析 69
第3節、 重大出血事件發生率 73
第4節、 次要研究事件(Secondary outcome) 75
6.4.1. 靜脈血栓症再復發率 75
6.4.2. 全因死亡率 75
6.4.3. 非重大出血(minor bleeding)事件比例 76
6.4.4. 口服抗凝血劑治療時間 76
6.4.5. Warfarin組之INR控制情形 76
第5節、 研究限制與優勢 77
第7章、 結論與建議 80
第8章、 未來研究方向 81
第二篇、 臨床藥事服務:手術前後新型口服抗凝血劑之停藥準則 83
第1章、 服務緣起 83
第2章、 服務目的與方法 84
第1節、 目的 84
第2節、 方法 84
第3章、 結果 85
第4章、 感想與建議 91
參考文獻 92
附件 99
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