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研究生： 傅裕翔
Fu, Yu-Hsiang
論文名稱： 新型口服抗凝血藥物於非瓣膜性心房顫動病患之出血風險評估
Assessment on Bleeding Risk of Novel Oral Anticoagulants in Patients with Non-valvular Atrial Fibrillation
指導教授： 李政翰
Lee, Cheng-Han
鄭靜蘭
Cheng, Ching-Lan
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2015
畢業學年度： 103
語文別： 中文
論文頁數： 126
中文關鍵詞： 新型口服抗凝血藥物 、dabigatran 、rivaroxaban 、台灣 、出血風險
外文關鍵詞： NOAC, dabigatran, rivaroxaban, Taiwan, bleeding risk
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    • 研究背景
    新型口服抗凝血藥物(novel oral anticoagulants, NOACs)，如Dabigatran與Rivaroxaban，在上市前的臨床試驗皆證實預防中風及全身性栓塞的效果不劣於Warfarin，同時有更好的安全性，然而進一步的次群組分析發現，NOACs在亞洲族群使用的出血風險可能較高。另一方面，觀察性世代研究的結果顯示NOACs的出血風險與臨床試驗並不一致，且目前台灣族群使用的相關研究仍相當有限。
    研究目的
    本研究目的分為兩部分：一、分析台灣非瓣膜性心房顫動病患使用NOACs期間出血事件的發生率。二、比較不同口服抗凝血藥物之新處方者於台灣非瓣膜性心房顫動病患的出血與栓塞風險，分別以NOACs與Warfarin、Dabigatran與Rivaroxaban進行比較。
    研究方法
    本研究為回溯性世代研究，第一部分收錄2013年3月至2015年2月曾於成大醫院處方Dabigatran或Rivaroxaban的心房顫動病患，排除有嚴重瓣膜疾病及過去曾使用過NOACs者，以病歷回顧方式記錄與使用NOACs臨床相關的出血事件(包括重大出血與次要出血)。
    第二部分收錄2012年3月至2015年2月曾於成大醫院新處方Dabigatran、Rivaroxaban或Warfarin之心房顫動病患，排除有嚴重瓣膜疾病及過去曾使用過口服抗凝血藥物者，以病歷回顧方式記錄其重大出血與缺血性中風事件，並利用Cox比例風險模式分別比較NOACs與Warfarin、Dabigatran與Rivaroxaban。
    研究結果
    第一部分共收錄588人，其中Dabigatran組314人，Rivaroxaban組274人。Dabigatran重大出血與次要出血之發生率分別為2.29及12.12 (%/year)；Rivaroxaban分別為2.88及23.85 (%/year)。兩者重大出血皆以胃腸道為主，次要出血則以皮膚瘀斑與血尿較常見。
    第二部分NOACs組共收錄382位新處方者；其中Dabigatran組215人，Rivaroxaban組167人，而Warfarin組有234人。NOACs與Warfarin重大出血發生率分別為2.50及4.80 (%/year)，兩者並未達統計上顯著差異(HR, 0.51; 95% CI, 0.20-1.29; P= .15)；進一步區分，在重大胃腸出血(HR, 0.90; 95% CI, 0.28-2.83; P=.85)及顱內出血(HR, 0.62; 95% CI, 0.04-9.95; P= .74)結果同樣無顯著差異。在缺血性中風方面，NOACs與Warfarin發生率分別為3.75與4.80 %/year，兩者未達顯著差異(HR, 0.85; 95% CI, 0.36-1.99; P= .71)。而Dabigatran及Rivaroxaban的重大出血發生率各為2.65及2.29 (%/year)，兩組相比並無顯著差異(HR, 1.16; 95% CI, 0.27-4.93; P=.84)。在缺血性中風方面，Dabigatran及Rivaroxaban發生率各為3.71 %/year及3.81 %/year，兩組相比同樣無顯著差異(HR, 0.91; 95% CI, 0.29-2.90; P= .87)。
    結論
    本研究提供台灣非瓣膜性心房顫動病患使用NOACs期間出血事件的發生率，由於重大出血事件集中發生在胃腸道，因此使用上必須要特別注意重大胃腸出血的問題。而無論是NOACs與Warfarin或Dabigatran與Rivaroxaban於新處方者的使用，在重大出血及缺血性中風風險皆未達統計上顯著差異，但受限於樣本數不足及僅單一醫學中心的使用經驗，目前仍不足以下定論，因此未來有待更大型研究進一步證實。

    Although novel oral anticoagulants (NOACs) have shown a favorable balance between efficacy and safety compared with warfarin in clinical trial settings, concerns have been raised about the inconsistent bleeding outcomes in real world practice. In addition, Asians and non-Asians seem to have different safety profiles upon receiving NOACs or warfarin, and the data is still limited in Taiwanese population. Thus, we conducted a retrospective cohort study to estimate the incidence of bleeding events associated with NOACs (dabigatran, rivaroxaban) in patients with non-vavular atrial fibrillation (AF) and to evaluate the risks of bleeding and thrombotic events between NOACs and warfarin, dabigatran and rivaroxaban, by using chart review in the National Cheng Kung University Hospital (NCKUH). The incidence of major and minor bleeding associated with dabigatran was 2.29 and 12.12 (%/year) and that associated with rivaroxaban was 2.88 and 23.85 (%/year). No significant differences were found in major bleeding and ischemic stroke between NOACs and warfarin, dabigatran and rivaroxaban. The results were generally consistent across all subgroups examined, with the exception of higher major bleeding risk in estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 and labile international normalized ratio (INR) stratifies for warfarin group. Due to limited sample size and single medical center’s experience, a large scale study is needed to confirm the results in the future.

    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、 新型口服抗凝血藥物於非瓣膜性心房顫動病患之出血風險評估......1 第一章、 研究背景......1 第二章、 文獻回顧......2 第一節、 心房顫動之流行病學......2 2.1.1 簡介......2 2.1.2 盛行率及發生率......2 2.1.3 影響因素......3 2.1.4 疾病負擔......3 第二節、 心房顫動與中風和血栓栓塞......5 2.2.1 簡介......5 2.2.2 流行病學......5 2.2.3 心房顫動導致中風的相關危險因子......6 2.2.4 中風及栓塞風險評估......7 2.2.5 出血風險評估......10 第三節、 Warfarin的療效與安全性......11 2.3.1 簡介......11 2.3.2 Warfarin的療效證據......11 2.3.3 Warfarin使用上的限制......11 第四節、 新型口服抗凝血藥物的療效與安全性......14 2.4.1 簡介......14 2.4.2 Dabigatran的療效與安全性 (RE-LY試驗)......17 2.4.3 Rivaroxaban的療效與安全性 (ROCKET-AF試驗)......18 2.4.4 統合分析(Meta-analysis)......23 2.4.5 間接比較分析(Indirect comparison analysis)......26 2.4.6 世代研究......26 2.4.7 台灣健保給付規定......31 第五節、 口服抗凝血藥物於族群之比較......32 2.5.1 亞洲族群之出血傾向......32 2.5.2 Warfarin使用之族群比較......32 2.5.3 Dabigatran使用之族群比較......33 2.5.4 Rivaroxaban使用之族群比較 ......33 第三章、 研究目的......37 第四章、 研究方法......39 第一節、 研究設計......39 4.1.1 第一部分－NOACs出血事件發生率......39 4.1.2 第二部分－不同口服抗凝血藥物之比較......41 第二節、 研究名詞、研究變項與操作定義......44 第三節、 研究流程......47 4.3.1 第一部分－NOACs出血事件發生率......47 4.3.2 第二部分－不同口服抗凝血藥物之比較......47 第四節、 統計分析......49 4.4.1 統計工具......49 4.4.2 統計模式設定......49 4.4.3 統計分析方法......49 第五章、 研究結果......51 第一節、 第一部分－NOACs出血事件發生率......51 5.1.1 研究對象之納入與排除......51 5.1.2 出血事件發生率......52 5.1.3 導致停、換藥之不良反應事件......55 第二節、 第二部分－不同口服抗凝血藥物之比較......56 5.2.1 研究對象之納入與排除......56 5.2.2 研究對象基本特性分析......58 5.2.3 重大出血風險比較......66 5.2.4 缺血性中風風險比較......72 5.2.5 次群組分析......75 第六章、 研究討論......88 第一節、 第一部分－NOACs出血事件發生率......88 6.1.1 出血事件發生率......88 6.1.2 導致停、換藥之其他不良反應事件......89 第二節、 第二部分－不同口服抗凝血藥物之比較......90 6.2.1 研究對象基本特性分析......90 6.2.2 NOACs重大出血風險之評估......96 6.2.3 NOACs缺血性中風風險之評估......101 6.2.4 Dabigatran與Rivaroxaban缺血性中風與出血風險之比較......102 第三節、 研究限制與優勢......103 第七章、 結論與建議......105 第八章、 未來研究方向......106 第二篇、 臨床藥事服務 急性冠心症住院病人使用新型口服抗血小板藥物之病患用藥指導......108 第一章、 服務緣起......108 第二章、 服務目的與方法......110 第一節、 目的......110 第二節、 方法......110 2.2.1 Ticagrelor用藥指導......110 2.2.2 Ticagrelor用藥手冊......110 第三章、 結果......112 3.1.1 Ticagrelor用藥指導......112 3.1.2 Ticagrelor用藥手冊......112 第四章、 感想與建議......114 參考文獻......115 附件一......123 附件二......126

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