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研究生:張雅嵐
研究生(外文):Ya-Lan Chang
論文名稱:以統合分析比較新一代口服抗凝血藥物與warfarin於併有慢性腎臟疾病之心房顫動患者預防腦中風之療效性與安全性(實證醫學)
論文名稱(外文):Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants versus Warfarin in Atrial Fibrillation Patients with Chronic Kidney Disease.(Evidence-Based Medicine)
指導教授:蔡崇弘蔡崇弘引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:110
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研究背景: 心房顫動( atrial fibrillation, AF)是臨床上常見的一種心律不整疾病,心房顫動患者發生中風機率為正常人的5倍以上,因此心房顫動患者使用適當抗血栓藥物預防中風發生是必要的。心房顫動與慢性腎臟疾病(chronic kidney disease,CKD)具有共病性,約1/3房顫病人同時患有慢性腎臟疾病。
有一研究整合大型隨機對照試驗之統合分析,比較三種新一代口服抗凝血藥(apixaban,dabigatran和rivaroxaban)與傳統藥物warfarin於心房顫動患者之效用與安全性。結果顯示新藥組可減少心房顫動引起腦中風0.78( 95%CI 0.67-0.92),並能顯著降低顱內出血風險0.49( 95% CI 0.36-0.66),重大出血0.88( 95% CI 0.71 - 1.09)及腸胃道出血1.25( 95% CI 0.91-1.72)則無統計學意義。
研究目的: 探討心房顫動合併慢性腎臟疾病患者,使用新一代口服抗凝血藥物相較於warfarin,其預防腦中風效用與重大出血風險之相關研究。
研究方法: 文獻搜尋方法將利用線上實證醫學資料庫Medline OVID、Pubmed等搜尋,經過文獻的評讀,加以篩選適當之文獻資料,再以統合分析軟體加以分析得知結果。本研究將採用統合分析(meta-analysis)的方法,回顧所有相關臨床試驗,並運用統計的方法來
整合所有個別研究結果。本篇研究針對併有慢性腎臟疾病族群之心房顫動患者,收錄過去大型試驗病患資料,以RevMan軟體進行meta-analysis,希望了解在新藥使用上,腎功能不全患者與正常人其有效性與安全性之差異。
研究結果: 共納入 3個隨機對照試驗,整合同質性的研究數據,運用RevMan 軟體得出統計的結果,在輕度慢性腎臟疾病(肌酐酸清除率50-80ml/min)之心房顫動患者,新藥可降低 22%腦中風或全身性栓塞風險( RR 0.78, 95%CI 0.68-0.89),降低19%重大出血風險( RR 0.81, 95%CI 0.74-0.89);中重度慢性腎臟疾病患者(肌酐酸清除率30-49ml/min) 之心房顫動患者,新藥可降低24%腦中風或全身性栓塞風險( RR 0.76, 95%CI 0.69-0.83)與16%重大出血風險( RR 0.84, 95%CI 0.78-0.89)。
結論與建議: 本研究結果於輕度至中重度腎功能不全的心房顫動患者,使用新藥能更有效預防腦中風或全身性栓塞及降低重大出血風險。中重度腎功能不全患者,使用apixaban能顯著降低出血風險,其他新藥重大出血風險與warfarin無顯著差異,建議高出血風險患者,可優先選用 apixaban;較高劑量dabigatran 150mg降低中風風險效用最為顯著,而dabigatran 110mg於效用與安全性皆無顯著優勢。目前尚無新藥間直接比較的臨床試驗,僅能從大型臨床試驗結果擷取數據做分析,希望未來能更進一步收錄更多針對腎功能不全之心房顫動患者使用新型口服抗凝血藥的臨床試驗加以分析研究,為此族群患者帶來更多福音。

Background:
Individuals with atrial fibrillation (AF) is the most common sustained abnormal heart rhythm in adults, have a five-fold increased risk of stroke.Using the appropriate antithrombotic drugs to prevent stroke in patients with atrial fibrillation is necessary. Atrial fibrillation and chronic kidney disease have comorbidity, nearly one-third of atrial fibrillation patients have CKD.
A meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants ( apixaban, dabigatran and rivaroxaban) to those of warfarin in patients with AF. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92) and a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive.
Objective: To research the relevant literatures of compare stroke and major bleeding risk of new oral anticoagulants and warfarin in atrial fibrillation patients with CKD.
Methods: Literature search for evidence-based medicine approach to the use of online databases Medline OVID, Pubmed other search through the literature of the appraisal, to filter appropriate documentation, then meta-analysis software to analyze the results of that.
Results: After screening the relevantly random controlled trials in high
quality after critical appraisal studies, include 3 random controlled trials
finally. Patients with mild renal impairment ( creatinine clearance 50-80 ml/min) randomized to new oral anticoagulants had a decreased risk 22% for stroke and systemic embolism (RR 0.78, 95% CI 0.68-0.89) and decreased risk 19% for major bleeding( RR 0.81, 95%CI 0.74-0.89).
Patients with moderate-severe renal impairment( creatinine clearance 30-49ml/min) randomized to new oral anticoagulants had a decreased risk 24% for stroke and systemic embolism( RR 0.76, 95%CI 0.69-0.83) and decreased risk 16% for major bleeding( RR 0.84, 95%CI 0.78-0.89).
Conclusion and suggestion: In this study conclusion for atrial fibrillation patients with mild to severe renal impairment, new oral anticoagulants are more effective in prevent stroke or systemic embolism and reduces major bleeding risk.
In atrial fibrillation with moderate to severe renal impairment, there was no significant difference between the new anticoagulants and warfarin for major bleeding risk, in addition to apixaban. We suggest that patient with high bleeding risk may select apixaban. It was the most significant that dabigatran 150mg reduce stroke risk, while dabigatran 110mg was no significant advantage for stroke prevention and major bleeding risk.
There is no clinical trials directly comparing between new oral anticoagulants, we can only retrieve data from clinical trial results for analysis. In the future, we hope further include more clinical trials designed for atrial fibrillatin patients with renal insufficiency using novel oral anticoagulants to provide more benefit for CKD patients.

謝誌 I
摘要 II
Abstract V
目錄 VIII
第一章 緒論 1
第一節研究動機 1
第二節研究目的 3
第三節研究背景 4
第二章 文獻探討 5
第一節前言 5
(一) 心房顫動盛行率與發生率 5
(二) 心房顫動的原因及機制 6
(三) 心房顫動診斷及症狀 7
(四) 心房顫動分類 8
(五) 心房顫動患者腦中風風險層級評估 9
(六) 血栓的形成 10
(七) Warfarin之臨床應用 11
(八) 直接凝血酶抑制劑 (direct thrombin inhibitor)..........12
(九) 第十活化凝血因子抑制劑(Xa inhibitors)...................14
(十) 慢性腎臟疾病 (chronic kidney disease,CKD).........16
(十一) 慢性腎臟疾病與心房顫動之共病性..........................18
第二節實證醫學的運用 21
(一) 實證醫學概論 21
(二) 實證醫學的起源 21
(三) 實證醫學的重要性 22
第三節實證醫學之操作步驟 23
(一) 提出一個臨床可以回答的問題 24
(二) 尋找最佳之醫學證據 24
(三) 嚴格評讀相關證據 25
(四) 臨床的應用 26
(五) 對過程進行稽核及評估 26
第四節臨床研究應用之證據等級 27
(一) 實證醫學之統合分析 27
(二) 統合分析的定義 28
(三) 統合分析的目的 28
(四) 統合分析的步驟 29
(五) 統合分析文獻在臨床應用的重要性 30
第三章研究方法 31
第一節研究架構 31
第二節研究設計 32
(一) 研究對象 33
(二) 納入的條件 34
(三) 排除的條件 34
(四) 療效的量測目標 35
第三節 採用本法的原因 35
第四節研究品質的保證 36
第五節研究步驟 37
第六節資料處理與分析 47
第四章 研究結果分析 50
第一節 腦中風或全身性栓塞之比較 50
第二節 重大出血風險之比較 52
第三節 敏感性分析 54
第五章 討論 55
第一節實證醫學PICO的探討 60
第二節文獻搜尋過程的探討 62
第三節證據等級的探討 63
第四節統合分析的探討 64
第五節臨床應用之探討 66
第六節研究限制與建議 67
參考文獻 69


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