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系統識別號 U0026-0502201309264100
論文名稱(中文) 臺灣心房顫動病人預防中風之抗血栓劑療效與安全性評估
論文名稱(英文) Effectiveness and safety of antithrombotic agents for thromboembolism prevention among atrial fibrillation patients 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 101
學期 1
出版年 102
研究生(中文) 張家嫺
研究生(英文) Chia-Hsien Chang
學號 tb8971036
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-高雅慧
指導教授-林立人
口試委員-林素真
召集委員-邵文逸
口試委員-李中一
口試委員-張志欽
中文關鍵字 心房顫動  抗血栓劑  中風  臨床效益 
英文關鍵字 Atrial fibrillation  warfarin  stroke  antithrombotic agents  net benefit 
學科別分類
中文摘要 研究背景:
心房顫動為最常見的心律不整之類型,會增加五倍的中風機率,故美國心臟學會及歐洲心臟學會於準則中建議需使用抗血栓劑進行預防。先前研究指出,亞洲族群的顱內出血的發生率較高,故在使用抗凝血劑的治療強度上偏向保守,亦有研究証實臺灣心房顫動病人在抗血栓劑符合準則之使用比例僅24.7%。然而,目前在臺灣心房顫病人於抗血栓劑在治療成效與出血風險之研究尚付之闕如,故本研究欲探討於現行治療環境下,抗凝血劑(warfarin)、抗血小板劑(aspirin)在心房顫動病人之療效與安全性評估。

研究目的:
(1) 抗血栓劑使用是否能預防臺灣心房顫動病人的栓塞風險?
(2) 抗血栓劑使用是否導致臺灣心房顫動病人的出血風險?
(3) 權衡預防中風療效與出血風險之下,抗凝血劑的使用是否具有臨床效益?

研究方法
本回溯性世代研究設計以2000-2008年健保資料庫進行分析,選取2001至2006年間出現二次以上心房顫動診斷碼之病人,為確保醫師評估病人具有需要預防栓塞之特質,指標日期後二年內若有使用warfarin或aspirin等抗血栓劑者才予以納入。病人會依照CHADS2分數及 CHA2DS2–VASc分數進行栓塞風險之分級,而依照 HAS-BLED分數進行在出血風險之分級。由於抗血栓劑的使用會隨時間更動,於追蹤期間以依time-dependent之方式分析抗血栓劑之使用。在療效評估終點部分是觀察栓塞事件和中風事件,在安全性評估終點是任何出血事件及顱內出血事件。在抗血栓劑的比較上,採取Cox proportional hazard model進行分析,而在臨床效益部分,將以warfarin能預防之中風事件與warfarin導致之顱內出血事件之差做為評估指標。

研究結果
本研究共納入80,771人 (合計134,937人年)。追踨期間共發生4,375 (3.2%)之栓塞事件(包含中風和暫時性腦缺血),其中有1,188 (27.2%)的死亡案例。一年間之栓塞和出血的粗發生率各為 3.7%和3.4%。與非warfarin使用者相比,除了低風險族群(亦即CHA2DS2–VASc分數為0者 ),使用warfarin的族群中風發生率較低。若以aspirin組為對照組,warfarin的使用減少37%栓塞事件(hazard ratio [HR]: 0.63 [95% confidence interval (CI): 0.57 to 0.71]), 和36%中風事件的發生 (HR: 0.64 [95% CI: 0.57 to 0.71])。在校正其他出血風險因子之後,warfarin仍會增加約2倍顱內出血的風險。在抗凝血劑的臨床效益部分,本研究發現除了低風險的病人,無論各種出風險使用warfarin都具有其臨床效益,其中本研究也發現CHA2DS2-VASc score在低栓塞風險的病人上具有較佳的鑑別力。

結論
本研究証實warfarin的使用可顯著減少栓塞事件的發生,但顱內出血的風險亦隨之上升。本研究証實除了低栓塞風險的族群之外,warfarin使用具有其臨床效益,故建議臺灣心房顫動病人應使用warfarin做為預防栓塞事件的抗血栓劑。
英文摘要 Background:
Warfarin is suggested as the first choice of antithrombotic agents among atrial fibrillation by ACC/AHA/ESC guideline. The concern on potential intracranial hemorrhage among Asian population might have explained the low INR targeted at clinical practice. Also, the low compliance of anticoagulation in Taiwan was reported to be lower. However, the effectiveness and safety of antithrombotic agents in real world setting warrants assessment but remains lacking in Taiwan.

Objective
This study aimed to determine (1) whether antithrombotic agents would prevent the thromboembolic event among patients with atrial fibrillation, and (2) whether the bleeding risk wound be associated with antithrombotic agents use, and (3) whether clinical benefit of warfarin in patients with atrial fibrillation in terms of risks of ischemic stroke and intracranial hemorrhage.

Methods
This retrospective cohort study was conducted using Taiwan’s National Health Insurance claims database from 2000 to 2008. Patients who were 18 years or older and had at least two diagnoses of atrial fibrillation (AF) within 1 year during January 1, 2001 and December 31, 2006, and eligible to claim any warfarin or aspirin within two years after index date. Patients were stratified according to CHADS2, CHA2DS2–VASc score, and HAS-BLED score to evaluate their thromboembolic and bleeding risk. The treatment with warfarin and aspirin was treated as time-varying covariate during follow-up. The effectiveness endpoints were thromboembolic events and ischemic stroke, and safety endpoints were any bleeding events and intracranial hemorrhage. COX proportional hazard model was conducted for comparing the risk across the treatment. The clinical benefit was defined as number of avoid ischemic strokes with anticoagulation minus the number of excess intracranial bleedings.

Results
80,771 patients aged above 18 years with 134,937 person-years was assembled and met defined AF and claimed any prescription of warfarin and aspirin during follow-up. We identified 4,375 (3.2%) thromboembolic events in the study cohort, of which 1,188 (27.2%) experiencing fatal events. events. Crude incidence rates for thromboembolic events and bleeding events occurred at an annual rate of 3.7% and 3.4%. Compared to non-treated group, the use of antithrombotic agents could lower the risk of ischemic stroke except the real low-risk patients (i.e. CHA2DS2-VASc score equals to 0). Use the aspirin user as the reference, warfarin use was associated with significantly reduced adjusted hazards of thromboembolic event (hazard ratio [HR]: 0.63 [95% confidence interval (CI): 0.57 to 0.71]), and ischemic stroke (HR: 0.64 [95% CI: 0.57 to 0.71]). After conventional bleeding risk factors were accounted for, the risk associated with warfarin use had around two times (HR: 2.08 [95%CI: 1.69 to 2.57]) higher risk of intracranial hemorrhage. With regard to clinical benefits of anticoagulation, there was a positive net clinical benefit with warfarin in patients with the all strata, but CHA2DS2-VASc score had better discrimination in identifying true low-risk patients was found.

Conclusion

Warfarin use was associated with significantly reduced adjusted hazards of thromboembolic event and ischemic stroke, but increased risk of intracranial hemorrhage. . Our finding suggests that the net benefit gained by warfarin so more patients should be offered oral anticoagulation treatment.
論文目次 中文摘要 i
Abstract iii
誌謝 vi
Tables of Content vii
List of Figures ix
List of Tables x
Chapter 1. Introduction 1
1.1 Statement of research question 3
1.2 Specific Aim 5
1.3 Significance of this study 5
Chapter 2. Literature review 6
2.1 Epidemiology of atrial fibrillation 6
2.2 Risk factors of developing atrial fibrillation 10
2.3 Mechanism of thrombogenesis in atrial fibrillation 12
2.4 Risk of embolization in atrial fibrillation 18
2.5 Antithrombotic therapy to prevent embolization in non-valvular atrial fibrillation. 22
2.6. Risk of bleeding in patients treated with warfarin 30
2.7 The benefit and risk of warfarin in nonvalvular atrial fibrillation. 34
2.8 The utilization of warfarin in clinical setting 37
Chapter 3. Objective and Study hypothesis 39
Chapter 4. Method and materials 41
4.1 Data source 41
4.2 Study population 42
4.3 Antithrombotic therapy and the classification of the exposure 43
4.4 Effectiveness endpoint 44
4.5 Safety endpoint 45
4.6 Comorbidities and concomitant medical therapy 46
4.7 Thromboembolic risk stratification: CHADS2 and CHA2DS2-VASc scores 47
4.8 Bleeding risk stratification: HAS-BLED score 48
4.9 Benefit and risk estimation 49
4.10 Statistical Analysis 50
4.11 Subgroup analysis 52
Chapter 5. Results 53
5.1 The characteristics of study cohort 53
5.2 The incidence of thromboembolic events and bleeding events by treatment group 58
5.3 Comparing effectiveness between different treatment and its risk factors 65
5.4 Comparing safety between different treatment and its risk factors 70
5.5 Benefit and risk estimation 76
Chapter 6. Discussion 82
6.1 Summarized the results from this study 82
6.2 Was the incidence rate of ischemic stroke compatible to other studies? 84
6.3 Was the effectiveness of warfarin compatible to other studies? 89
6.4 How was the clinical benefit changed when varying bleeding risk? 92
Chapter 7. Implications for clinical practice 95
Chapter 8. Limitations 97
Chapter 9. Conclusion 99
References 100
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