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系統識別號 U0026-2307202017365200
論文名稱(中文) 口服抗凝血劑於心房顫動病人合併慢性腎臟病之腎功能的影響-單中心研究
論文名稱(英文) Renal Effects of Oral Anticoagulants in Atrial Fibrillation Patients with Chronic Kidney Disease - A Single-Center Study
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 108
學期 2
出版年 109
研究生(中文) 張靜萓
研究生(英文) Jing-Yi Chang
學號 S66071031
學位類別 碩士
語文別 中文
論文頁數 124頁
口試委員 指導教授-鄭靜蘭
指導教授-李政翰
指導教授-黃千惠
口試委員-高雅慧
口試委員-許釗凱
中文關鍵字 心房顫動  慢性腎臟病病人  口服抗凝血劑  腎功能惡化事件 
英文關鍵字 Atrial fibrillation  CKD population  NOACs  adverse renal events 
學科別分類
中文摘要 摘要
研究背景與目的

心房顫動(atrial fibrillation,簡稱 AF)是最常見的心律不整,導致栓塞性中風的風險增加 5 倍且復發率高於非心房顫動導致的中風。AF 患者併有慢性腎臟病(chronic kidney disease,簡稱CKD)比起一般 AF 患者有較高風險出現中風、全身性栓塞及大出血,透析病患之風險又為最高。Warfarin 和其他新型口服抗凝血劑(new oral anticoagulants,簡稱NOACs)常用於預防 AF 患者的血栓栓塞事件。
使用口服抗凝血劑預防中風的AF 患者很常發生腎功能下降的問題,而抗凝血劑相關性腎病(anticoagulant-related nephropathy,簡稱 ARN)是由warfarin 或其他抗凝血劑過度抗凝血(如:INR > 3 - 4),導致腎小球出血及紅血球沉積在腎小管阻塞進而發展成 AKI(acute kidney injury,簡稱 AKI),是一種重要但難以確診的抗凝血劑併發症。有些研究指出使用 NOACs 比起 warfarin 有較低的風險引起腎臟
相關不良反應,然而,最近的病例報告和動物研究卻表明NOACs 也可能發生 ARN。
NOACs 上市前臨床試驗因排除嚴重腎功能不全患者(CrCl <15-30 mL/min),所以缺乏 AF 合併第三至四期 CKD 族群之資料,而 warfarin 則因可透過 INR 的監測,被列為 AF 患者合併CrCl <15-30 mL/min 時之建議品項。因此,本研究主要目的是評估AF 合併第三至四期CKD 使用NOACs 與warfarin 對於腎功能之影響及中風事件和出血事件風險差異,於成大醫院進行病歷回顧分析。

研究方法

本研究採用回溯性世代研究法,利用成大醫院電子病歷系統篩選出 2012 年 3 月22 日至 2018 年 12 月 31 日間,新診斷為 AF 之病人,並依據新使用的口服抗凝血劑分組,pooled NOACs 組為研究組(含apixaban、dabigatran、edoxaban、rivaroxaban),warfarin 組為對照組,採治療意向(intention-to-treat,簡稱 ITT)設計,至多追蹤 2年,觀察是否發生腎功能惡化事件,並以多變項 Cox 比例風險模型校正干擾因子,計算風險比。本研究亦執行根據治療(as-treated,簡稱 AT)設計、TTR 分層分析、腎功能監測頻率分層分析以及傾向分數配對之敏感性分析。


研究結果

本研究共收錄100 位新使用NOACs(其中apixaban 佔13%,dabigatran 佔28%,edoxaban 佔4%,rivaroxaban 佔55%)、72 位新使用warfarin 之新診斷 AF 病人。Pooled NOACs 組平均年齡為76.5 歲,warfarin 組為75.4 歲,年齡分布上warfarin 組在 ≤ 64歲及 ≥ 75 歲之比例較pooled NOACs 組高。兩組均男性略多於女性,其中又以warfarin組男性比例更高,而warfarin 組的腎功能比起 pooled NOACs 組較差。
本研究以ITT 設計方式比較pooled NOACs 與warfarin 兩組之間發生腎功能惡化事件的風險差異,未經變項校正時,pooled NOACs 組比起warfarin 組可以降低42.9%發生腎功能惡化事件的風險,但經過CKD 分期、癌症、併用 amiodarone/dronedarone、利尿劑、statins 以及 CHA2DS2-VASc score 變項之校正後兩組並未達到統計學上差異,但方向性仍偏向 pooled NOACs 組有較好的表現(HR = 0.721,95% CI
[ 0.441-1.176 ])。
以 AT 設計方式進行兩組間之比較,未經變項校正時,pooled NOACs 組比起warfarin 組可以降低 47.5%發生腎功能惡化事件的風險,與 ITT 做出的結果方向性一致,經多變項校正後,兩組結果與ITT 相同均未達顯著。進一步對兩組以warfarin 組TTR 控制程度、腎功能監測頻率以及傾向分數配對去進行敏感性分析,方向性均未改變。
療效與安全性部分,無論是中風、重大出血或非重大出血事件之發生比例warfarin組均比pooled NOACs 組高,不過僅有在大出血事件中兩組有達到統計學上顯著差異。

結論

本研究結果發現AF 患者合併第3 至4 期CKD 使用NOACs 發生腎功能惡化事件的風險有低於使用warfarin 的趨勢,但未達統計上顯著差異,有待更大型研究加以證實。

關鍵詞:心房顫動、慢性腎臟病病人、口服抗凝血劑、腎功能惡化事件
英文摘要 SUMMARY

Objective:
Recently, some studies found that the new or non-vitamin K antagonist oral anticoagulants (NOACs) had lower risk of adverse renal effects, compared with warfarin. However, warfarin is the only recommended drug for AF patients with CKD in clinical practice. The evidence about CKD patients with oral anticoagulants treatment and the risk to detailed adverse renal outcomes remain unclear. This cohort study
evaluated the association between different oral anticoagulants use and the risk of adverse renal effects among CKD patients in Taiwan.
Methods:
We conducted a retrospective cohort study using electronic medical record database of National Cheng Kung University Hospital. We performed new-user design, and warfarin
as active comparator. All participants were adults (≥ 20 years old) with newly diagnosis of AF from 2012 through 2018, and followed up until adverse renal endpoints (≥ 30%
decline in eGFR, doubling of the serum creatinine level, AKI, and kidney failure), end of 2-year follow-up, discontinuation or switch of index medication, end of the study period, gap of more than 90 days between treatment episodes, loss of follow-up, or death, whether came first. We estimated the event rate and hazard ratio of adverse renal effects among NOACs users, compared with warfarin users.
Results:
We identified NOACs users (n = 100) and warfarin users (n = 72) from 2012 through 2018. NOACs users had lower risk of composite adverse renal events than warfarin users (37.0% vs. 55.6%; adjusted HR 0.721, 95% CI 0.441-1.176), but did not reach statistical significance; under as-treated design, result was consistent (31.0% vs. 45.8%;
adjusted HR 0.709, 95% CI 0.415-1.210). NOACs users has significantly lower risk of major bleeding events than warfarin (10.0% vs. 23.6%, p = 0.0155).
Conclusion: NOACs users showed a trend with lower risk of adverse renal events in AF patients combined with moderate to severe CKD. However, our study results showed no
significance in adverse renal outcomes, which should be furthermore confirmed by larger-scale studies.
Keywords: Atrial fibrillation, CKD population, NOACs, adverse renal events
論文目次 目錄

摘要 ...................................... I

EXTENDED ABSTRACT ...................... III

誌謝 ...................................... VI

目錄 ............................................... VII

表目錄 ............................................... XI

圖目錄 ............................................ XIII

縮寫與全名對照表 ............................... XIV

第一篇、 口服抗凝血劑於心房顫動病人合併慢性腎臟病之腎功能的影響-單中
心研究 1

第一章、 研究背景 ........................................................................................... 1
第二章、 文獻回顧 ........................................................................................... 2
第一節、 心房顫動患者合併慢性腎臟病 ................................................ 2
一、 疾病簡介 – 慢性腎臟病 ..................................................................... 2
二、 流行病學 – 心房顫動患者合併慢性腎臟病 ..................................... 4
三、 心房顫動患者合併慢性腎臟病之中風及出血風險 ........................... 6
四、 中風及栓塞風險評估 ........................................................................... 7
五、 出血風險評估 ....................................................................................... 9
六、 口服抗凝血劑簡介及臺灣健保給付規範 ......................................... 10
第二節、 口服抗凝血劑與腎功能之相關性 .......................................... 12
一、 口服抗凝血劑對腎功能之影響 – 動物研究 ................................... 12
二、 口服抗凝血劑與腎功能相關性之觀察性研究 ................................. 13
第三節、 AF 病人併有 CKD 之缺血性中風和出血事件 ..................... 17
一、 缺血性中風 ......................................................................................... 17

二、 出血事件 ............................................................................................. 19
第四節、 總結 .......................................................................................... 21
第三章、 研究目的 ......................................................................................... 22
第四章、 研究方法 ......................................................................................... 23
第一節、 研究設計 .................................................................................. 23
一、 研究類型 ............................................................................................. 23
二、 研究材料與資料來源 ......................................................................... 23
三、 研究對象 ............................................................................................. 24
四、 研究區間 ............................................................................................. 25
五、 研究分組 ............................................................................................. 25
六、 結果(Outcome)測量 ...................................................................... 25
七、 觀察中止 ............................................................................................. 26
八、 紀錄表格 ............................................................................................. 26
九、 研究設計及流程 ................................................................................. 27
第二節、 統計分析 .................................................................................. 29
一、 統計工具 ............................................................................................. 29
二、 統計模式設定 ..................................................................................... 29
三、 敘述性分析(Descriptive analysis) ................................................. 29
四、 存活分析(Survival analysis) .......................................................... 29
五、 敏感性分析(Sensitivity analysis) .................................................. 30
第三節、 研究名詞、研究變項與操作定義 .......................................... 31
第四節、 人體試驗委員會核備 .............................................................. 34
第五章、 研究結果 ......................................................................................... 35
第一節、 研究對象之納入與排除 .......................................................... 35
第二節、 研究對象之基本特性分析 ...................................................... 36
第三節、 主要結果 – AF 病人併有 CKD 使用口服抗凝血劑與腎功能惡化
風險 42
一、 不同 CKD 分期之腎功能惡化事件 ................................................... 42
二、 治療意向(ITT)分析 ....................................................................... 46

三、 敏感性分析(Sensitivity analysis) .................................................. 48
第四節、 次要結果 -AF 病人併有 CKD 之缺血性中風和出血事件發生率
59
第六章、 研究討論 ......................................................................................... 62
第一節、 AF 病人併有 CKD 之口服抗凝血劑處方比例 ..................... 62
第二節、 AF 病人併有 CKD 使用口服抗凝血劑與腎功能惡化風險 . 64
一、 AKI 事件 ............................................................................................. 64
二、 其他腎功能惡化事件 ......................................................................... 65
三、 敏感性分析 ......................................................................................... 68
第三節、 AF 病人併有 CKD 之缺血性中風和重大出血事件風險 ..... 68
第四節、 研究優勢與限制 ...................................................................... 69
一、 研究優勢 ............................................................................................. 69
二、 研究限制 ............................................................................................. 69
第七章、 結論 ................................................................................................. 70
第八章、 未來研究方向 ................................................................................. 71

第二篇、 臨床藥事服務:藥師早期介入評估藥物皮膚不良反應 ................. 72

第一章、 前言 ................................................................................................. 72
第二章、 臨床服務目的與方法 ..................................................................... 73
第一節、 服務目的 .................................................................................. 73
第二節、 服務方法 .................................................................................. 73
一、 服務區間 ............................................................................................. 73
二、 服務對象 ............................................................................................. 73
三、 收案方式 ............................................................................................. 73
四、 服務內容與流程 ................................................................................. 73
第三章、 臨床服務結果 ................................................................................. 77
第一節、 本藥事服務與院內評估流程之差異 ...................................... 77
第二節、 本年度藥事服務與前一年度之差異 ...................................... 79
第三節、 結果分析 .................................................................................. 80

一、 藥事服務收案結果分析 ..................................................................... 80
二、 成大醫院 2019 年嚴重型皮膚不良反應案例整理 ........................... 87

第三篇、 臨床藥事服務: EGFR-TKI 標靶治療之副作用、預後與生活品質之研
究 92

第一章、 前言 ................................................................................................. 92
第二章、 臨床服務目的與方法 ..................................................................... 93
第一節、 服務目的 .................................................................................. 93
第二節、 服務方法 .................................................................................. 93
一、 服務區間 ............................................................................................. 93
二、 服務對象 ............................................................................................. 93
三、 收案方式 ............................................................................................. 93
四、 服務內容 ............................................................................................. 93
第三節、 標靶藥物(EGFRI)引起之皮膚不良反應評估表(REDCap)
94
第四節、 臨床藥事服務結果分析 .......................................................... 95
第三章、 未來方向與建議 ............................................................................. 97
第四章、 感想 ................................................................................................. 98

附件 ............................................... 100

附件 1、 REDCap「口服抗凝血劑對心房顫動患者腎功能變化的影響」專案
100
附件 2、 人體試驗委員會「同意人體研究證明書」 ............................... 106
附件 3、 AKI 詳細事件 ............................................................................... 107
附件 4、 FACT-EGFRI-18 授權文件 .......................................................... 109
附件 5、 REDCap「Target therapy and immunotherapy induced skin toxicity」專
案 111

參考文獻 ............................................ 120

表目錄
表1- 1 CKD 定義 ................................................................................................................. 2
表1- 2 CKD 的 GFR 分期 .................................................................................................... 3
表1- 3 AF 與 CKD 共享之危險因子及病理機轉 ............................................................... 5
表1- 4 CHADS2 SCORE .......................................................................................................... 8
表1- 5 CHA2DS2-VASC SCORE ............................................................................................. 8
表1- 6 HAS-BLED SCORE .................................................................................................... 9
表1- 7 臺灣現有之 NOACS .............................................................................................. 11
表1- 8 探討口服抗凝血劑與腎功能相關性之觀察性研究 ............................................ 15
表1- 9 成大醫院 NOACS 進藥時間 .................................................................................. 25
表1- 10 成大醫院 AF 病人併有 CKD 之口服抗凝血劑處方比例 ................................. 37
表1- 11 研究對象之基本特性分布情形 ........................................................................... 38
表1- 12 用藥前後兩組 CKD 分期之分布比例 ................................................................. 43
表1- 13 研究對象觀察終止條件 ....................................................................................... 46
表1- 14 腎功能惡化風險之變項分析 ............................................................................... 47
表1- 15 腎功能惡化事件(綜合性結果)發生率及風險差異 ....................................... 49
表1- 16 追蹤期間腎功能監測次數 .................................................................................. 53
表1- 17 腎功能惡化事件(綜合性結果)風險比較 – 分層分析 ................................. 54
表1- 18 腎功能惡化事件(綜合性結果)發生率及風險差異 – 傾向分數配對 ......... 55
表1- 19 研究對象基本特性分析 – 傾向分數配對 ......................................................... 56
表1- 20 缺血性中風和出血事件發生率 ........................................................................... 59
表1- 21 非重大出血事件分析 .......................................................................................... 60
表1- 22 納入重大出血事件之條件分析 .......................................................................... 61
表1- 23 重大出血事件分析 .............................................................................................. 61
表1- 24 AF 病人併有腎功能不全之口服抗凝血劑處方比例 ....................................... 63
表1- 25 AF 患者使用口服抗凝血劑發生 AKI 事件之研究比較 .................................. 66
表1- 26 AF 患者使用口服抗凝血劑發生其他腎功能惡化事件之研究比較 ............... 67

表2- 1 藥事服務對象之人口學特性 ................................................................................. 81
表2- 2 藥事服務案例之懷疑藥物數 ................................................................................. 82
表2- 3 懷疑單一藥物引起的藥事服務案例之藥物類型 ................................................. 82
表2- 4 藥事服務之 SJS/TEN 案例 .................................................................................... 83
表2- 5 藥事服務之 DRESS 案例 ....................................................................................... 84
表2- 6 藥事服務之 AGEP 案例 ......................................................................................... 84
表2- 7 藥事服務之 GBFDE 案例 ...................................................................................... 85
表2- 8 藥事服務之非嚴重型藥物皮膚不良反應案例 ..................................................... 85
表2- 9 成大醫院 2019 年 SCARS 病人之人口學特性 ..................................................... 87
表2- 10 成大醫院 2019 年SCARS 案例之懷疑藥物數 ................................................... 88
表2- 11 成大醫院 2019 年懷疑單一藥物引起 SCARS 之藥物類型 ............................... 88
表2- 12 成大醫院 2019 年SCARS 病人:SJS/TEN ........................................................ 89
表2- 13 成大醫院 2019 年SCARS 病人:DRESS ........................................................... 90
表2- 14 成大醫院 2019 年SCARS 病人:AGEP ............................................................. 91
表2- 15 成大醫院 2019 年SCARS 病人:GBFDE .......................................................... 91

圖目錄



圖1- 1 研究流程 ................................................................................................................. 27
圖1- 2 研究設計概念圖 ..................................................................................................... 28
圖1- 3 研究對象篩選流程 ................................................................................................ 35
圖1- 4 不同 CKD 分期之腎功能惡化事件發生率 ........................................................... 44
圖1- 5 KAPLAN-MEIER CURVE ............................................................................................ 50
圖1- 6 WARFARIN 組 TTR 分布盒狀圖 ............................................................................. 52
圖1- 7 追蹤兩年之腎功能監測頻率分布盒狀圖 ............................................................ 52
圖1- 8 一年≤7 次之腎功能監測頻率分布盒狀圖 ........................................................... 53
圖2- 1 成大醫院現行之藥物不良反應評估流程 ............................................................. 72
圖2- 2 病患不良反應與用藥史時序圖 ............................................................................ 75
圖2- 3 藥事服務流程與內容 ............................................................................................. 76
圖2- 4 成大醫院現行之流程(左)與本服務之流程(右)比較 ................................. 77
圖2- 5 原皮膚不良反應通報畫面(舊) ........................................................................ 79
圖2- 6 簡化後之皮膚不良反應通報畫面(新) ........................................................... 79
圖3- 1 跨科部合作流程 .................................................................................................... 92
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