臺灣博碩士論文加值系統

研究背景
口服抗凝血劑可以預防急性缺血性中風患者中風復發及血管栓塞，但卻可能會發生出血副作用，而口服抗凝血劑的療效及安全性會受到急性缺血性中風後的用藥時機影響。台灣目前遵循歐洲心律協會建議的「1-3-6-12天法則」，針對具有心房纖維顫動病史的急性缺血性中風患者，依據中風嚴重度分別給予不同的延後口服抗凝血劑使用建議，然而此建議為國際專家共識意見，未於國內以實證研究加以評估。
目的
本研究分析有心房纖維顫動病史的急性缺血性中風患者在中風復發、血管栓塞及出血的風險，作為評估中風後口服抗凝血劑「1-3-6-12 天法則」在療效及安全性上的實證依據。
研究方法
本研究自台灣健保資料庫中納入了2012年1月1日至2016年12月31日中患有心房纖維顫動且首次發生急性缺血性中風的患者約16,108人，在排除性別不詳，中風住院日即被診斷為出血性中風、死亡或發生觀察事件後，依綜合、療效及安全等三種觀察結果，其樣本數分別為10,956人、11,529人及11,709人，且在各觀察結果下，樣本皆會依據中風嚴重度區分為輕度、中度及重度中風，並於2017年12月31日結束追蹤。其中療效結果包括缺血性中風、心肌梗塞、暫時性缺血發作、全身性栓塞、靜脈血栓栓塞及心因性死亡；安全結果包括出血性中風、腸胃道出血及血尿；綜合結果則涵蓋療效與安全結果。本研究以觀察性研究模仿隨機臨床試驗（RCT），將急性缺血性中風後30天內的每一天用藥皆視為一個RCT研究，視當日用藥者為用藥組，缺血性中風後至當日皆無用藥者為無用藥組，進行1：1傾向分數配對以達到近似隨機分配的效果後，分析用藥組與無用藥組的差異。接著將服藥時機符合指引建議延後使用日數的RCT研究歸類為晚期用藥，未遵循者歸類為早期用藥，以網絡統合分析進行早期與晚期用藥的間接比較。
研究結果
在各中風嚴重度下，口服抗凝血劑不論早或晚期使用，皆能降低中風復發、血管栓塞與出血的綜合風險，以及中風復發與血管栓塞的療效風險，部分能達統計顯著，出血風險則僅重度中風早期使用會顯著增加出血風險（HR:1.67, 95%C.I. 1.30~2.13）。
晚期用藥相對早期用藥，在各中風嚴重度下皆不會顯著減少綜合風險，亦不會提高療效風險。然而在出血風險上，晚期用藥普遍能夠降低出血的保護作用，但僅重度中風患者（HR:0.69, 95%C.I. 0.48~1.01）能接近統計顯著。
結論
台灣目前遵循的口服抗凝血劑延後使用日數建議，雖然並不會增加中風復發及血管栓塞的風險，但亦無法有效降低出血風險。就輕中度中風患者而言，提早用藥不僅具療效且不會產生顯著的出血風險，而重度中風則需進一步評估調整臨床建議。

Background
Oral anticoagulants (OAC) prevent stroke recurrence and vascular embolism among acute ischemic stroke (AIS) patients with atrial fibrillation (AF), but it also increases the risk of hemorrhagic transformation or bleeding. Since the timing of OAC use will influence its efficacy and safety, the recommended initiation time of prescription is crucial. However, in Taiwan stroke prevention guideline “1-3-6-12 day rule” recommendation, the delayed initiation time of OAC use was different from stroke severity and was based on empirical consensus, not empirical evidence. This study will examine whether the recommended time of OAC use in the guideline is opportune.
Objective
To evaluate the composite, efficacy, and safety risk about delaying the use of OAC in the “1-3-6-12 day rule” recommended in Taiwan stroke prevention guidelines.
Methods
We prospectively studied AIS patients with AF from January 1, 2012, to December 31, 2016, in Taiwan’s National Health Insurance Research Database, and ended our follow-up on December 31, 2017. Study samples were stratified by stroke severity into mild, moderate, and severe groups to observe the composite (ischemic stroke, myocardial infarction, transient ischemic attack, systemic embolism, venous thromboembolism, cardiovascular death, hemorrhage stroke, gastrointestinal bleeding, and hematuria), efficacy (ischemic stroke, myocardial infarction, transient ischemic attack, systemic embolism, venous thromboembolism, and cardiovascular death), and safety (hemorrhage stroke, gastrointestinal bleeding, and hematuria) outcome. We divided our observational study into thirty day by day trials after AIS and did 1:1 propensity score matching in each trial to mimic the randomized control trial design. In each trial, users were those who didn’t treat with OAC until the trial day, and non-users were those who had not treated with OAC by the trial day. Moreover, late users were defined as patients who initiated OAC followed the recommendation, early users were those who didn’t follow the recommendation. To compare early users and late users in composite, efficacy, and safety outcome, we utilize network meta-analysis to do the indirect comparison after finishing thirty comparisons of users and non-users.
Results
Both early and late OAC users could reduce composite and efficacy risk in each stroke severity and part of the protection effect are significant. Only early users of severe stroke will increase bleeding risk significantly (HR:1.67, 95%C.I. 1.30~2.13). Late OAC use will not reduce the composite risk or increase the efficacy risk in each sample of stroke severity comparing with early users. In safety risk, late OAC use will reduce bleeding risk in each sample of stroke severity but not statistically significant. The severe group (HR:0.69, 95%C.I. 0.48~1.01) was the only one on the borderline.
Conclusion
The current guidelines on the number of days of delayed OAC use are not effective in reducing hemorrhagic transformation or bleeding risk but maintaining the efficacy of preventing stroke recurrence and vascular embolism. It’s acceptable for mild and moderate stroke to use OAC in early phase due to the prevention effect and not significant bleeding risk. However, further researches are needed to evaluate clinical recommendation in severe stroke.

致謝 i
中文摘要 iii
Abstract v
目錄 vii
圖目錄 ix
表目錄 x
第1章 緒論 1
第1節 研究背景與動機 1
第2節 研究目的與問題 3
第3節 研究重要性 4
第4節 重要名詞定義 5
第2章 文獻探討 6
第1節 心房纖維顫動 6
第2節 藥物預防 13
第3節 口服抗凝血劑用藥評估 30
第4節 文獻總結 38
第3章 研究方法 39
第1節 研究架構 39
第2節 研究假說 40
第3節 研究設計概念 41
第4節 研究設計執行細節 43
第5節 研究樣本及分組 48
第6節 資料來源 51
第7節 資料處理及樣本篩選流程 52
第8節 研究變項之定義與測量 53
第9節 統計分析 61
第4章 研究結果 66
第1節 樣本基本特性 66
第2節 結果的描述性統計 105
第3節 多變項分析 129
第5章 討論與限制 133
第1節 研究結果討論 133
第2節 研究限制 137
第6章 結論與建議 138
第1節 結論 138
第2節 建議 138
參考文獻 139
附錄一 150
附錄二 151
附錄三 169
附錄四 175

圖目錄
圖 1 1 1 1-3-6-12天法則 2
圖 2 1 1 心臟中的電位傳導 8
圖 2 1 2 心房纖維顫動患者的動作電位 9
圖 2 1 3 心房纖維顫動導致缺血性中風的機轉 10
圖 2 2 1 抗血小板藥與抗凝血劑的作用機轉 13
圖 2 3 1 導致中風模型 30
圖 2 3 2 亞洲人非瓣膜性房顫的治療流程圖 32
圖 2 3 3 台灣中風防治指引的「1-3-6-12天法則」 35
圖 3 1 1 研究架構圖一：仿RCT中實驗組與控制組的直接比較 39
圖 3 1 2 研究架構圖二：早期用藥與晚期用藥的間接比較 40
圖 3 3 1 研究設計圖 42
圖 3 4 1 本研究的immortal time bias示意圖 43
圖 3 4 2 輕度中風患者以仿RCT比較早與晚期用藥 45
圖 3 4 3 中度中風患者以仿RCT比較早與晚期用藥 45
圖 3 4 4 重度中風患者以仿RCT比較早與晚期用藥 46
圖 3 6 1 資料庫串檔方式 51
圖 3 7 1 樣本選取流程圖 52
圖 4 2 1 輕度患者早期用藥區間之累積發生率比較（綜合結果） 112
圖 4 2 2 輕度患者晚期用藥區間之累積發生率比較（綜合結果） 112
圖 4 2 3 中度患者早期用藥區間之累積發生率比較（綜合結果） 114
圖 4 2 4 中度患者晚期用藥區間之累積發生率比較（綜合結果） 114
圖 4 2 5 重度患者早期用藥區間之累積發生率比較（綜合結果） 116
圖 4 2 6 重度患者晚期用藥區間之累積發生率比較（綜合結果） 116
圖 4 2 7 輕度患者早期用藥區間之累積發生率比較（療效結果） 118
圖 4 2 8 輕度患者晚期用藥區間之累積發生率比較（療效結果） 118
圖 4 2 9 中度患者早期用藥區間之累積發生率比較（療效結果） 120
圖 4 2 10 中度患者晚期用藥區間之累積發生率比較（療效結果） 120
圖 4 2 11 重度患者早期用藥區間之累積發生率比較（療效結果） 122
圖 4 2 12 重度患者晚期用藥區間之累積發生率比較（療效結果） 122
圖 4 2 13 輕度患者早期用藥區間之累積發生率比較（安全結果） 124
圖 4 2 14 輕度患者晚期用藥區間之累積發生率比較（安全結果） 124
圖 4 2 15 中度患者早期用藥區間之累積發生率比較（安全結果） 126
圖 4 2 16 中度患者晚期用藥區間之累積發生率比較（安全結果） 126
圖 4 2 17 重度患者早期用藥區間之累積發生率比較（安全結果） 128
圖 4 2 18 重度患者晚期用藥區間之累積發生率比較（安全結果） 128

表目錄
表 2 2 1 四篇NOAC藥物隨機臨床試驗的相對風險結果 22
表 2 2 2 NOAC藥物不同觀察結果的風險比值 23
表 2 3 1 CHADS2量表的評分項目、分數及中風機率 31
表 2 3 2 CHA2DS2-VASc量表的評分項目、分數及中風機率 31
表 2 3 3 HAS-BLED量表的評分項目、分數及出血機率 33
表 2 3 4 各指引在缺血性中風次級預防的口服抗凝血劑服用時機差異 34
表 2 3 5 心房纖維顫動患者在急性缺血性中風後不同延後用藥日數的文獻 36
表 3 5 1 研究樣本篩選標準 50
表 3 6 1 資料庫簡介 51
表 3 8 1 研究變項及操作型定義-依變項 56
表 3 8 2 研究變項及操作型定義-自變項和分層變項 57
表 3 8 3 研究變項及操作型定義-控制變項 58
表 4 1 1 輕度中風患者之早期用藥與無用藥的基本特性（綜合結果） 69
表 4 1 2 輕度中風患者之晚期用藥與無用藥的基本特性（綜合結果） 71
表 4 1 3 中度中風患者之早期用藥與無用藥的基本特性（綜合結果） 73
表 4 1 4 中度中風患者之晚期用藥與無用藥的基本特性（綜合結果） 75
表 4 1 5 重度中風患者之早期用藥與無用藥的基本特性（綜合結果） 77
表 4 1 6 重度中風患者之晚期用藥與無用藥的基本特性（綜合結果） 79
表 4 1 7 輕度中風患者之早期用藥與無用藥的基本特性（療效結果） 81
表 4 1 8 輕度中風患者之晚期用藥與無用藥的基本特性（療效結果） 83
表 4 1 9 中度中風患者之早期用藥與無用藥的基本特性（療效結果） 85
表 4 1 10 中度中風患者之晚期用藥與無用藥的基本特性（療效結果） 87
表 4 1 11 重度中風患者之早期用藥與無用藥的基本特性（療效結果） 89
表 4 1 12 重度中風患者之晚期用藥與無用藥的基本特性（療效結果） 91
表 4 1 13 輕度中風患者之早期用藥與無用藥的基本特性（安全結果） 93
表 4 1 14 輕度中風患者之晚期用藥與無用藥的基本特性（安全結果） 95
表 4 1 15 中度中風患者之早期用藥與無用藥的基本特性（安全結果） 97
表 4 1 16 中度中風患者之晚期用藥與無用藥的基本特性（安全結果） 99
表 4 1 17 重度中風患者之早期用藥與無用藥的基本特性（安全結果） 101
表 4 1 18 重度中風患者之晚期用藥與無用藥的基本特性（安全結果） 103
表 4 2 1 輕度中風患者之結果描述性統計（綜合結果） 111
表 4 2 2 中度中風患者之結果描述性統計（綜合結果） 113
表 4 2 3 重度中風患者之結果描述性統計（綜合結果） 115
表 4 2 4 輕度中風患者之結果描述性統計（療效結果） 117
表 4 2 5 中度中風患者之結果描述性統計（療效結果） 119
表 4 2 6 重度中風患者之結果描述性統計（療效結果） 121
表 4 2 7 輕度中風患者之結果描述性統計（安全結果） 123
表 4 2 8 中度中風患者之結果描述性統計（安全結果） 125
表 4 2 9 重度中風患者之結果描述性統計（安全結果） 127
表 4 3 1 Cox比例風險模型中「口服抗凝血劑使用時機」在各中風嚴重度及觀察結果下的風險比值，及其間接比較 131
表 4 3 2 藥物分層後之Cox比例風險模型中「口服抗凝血劑使用時機」在各中風嚴重度及觀察結果下的風險比值，及其間接比較 132

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