研究背景
罹患心房顫動的病患建議使用口服抗凝血劑做栓塞風險的預防，除了傳統的warfarin以外，近年來發展了新型口服抗凝血劑（new oral anticoagulants; NOACs），如dabigatran、rivaroxaban，在上市前的臨床試驗研究顯示，NOACs預防中風及全身性栓塞的效果不劣於warfarin，且安全性較高，然而，在次群組分析中發現，亞洲人使用抗凝血劑的出血風險較高，但目前對於台灣族群使用NOACs之安全性的相關研究仍有限。
研究目的
本研究的目的為評估在台灣非瓣膜性心房顫動病患使用dabigatran、rivaroxaban和warfarin的療效和安全性，包括重大出血、非重大出血以及缺血性中風事件，分別以dabigatran和warfarin、rivaroxaban和warfarin、NOACs和warfarin進行比較。
研究方法
本研究採用病歷回顧的方式進行回溯性的世代研究，納入台灣中南部三間醫學中心，於2010年10月至2016年5月間，有心房顫動診斷且為新處方dabigatran、rivaroxaban或warfarin的成年病患，排除有二尖瓣狹窄或曾經接受過人工心臟瓣膜置換者，紀錄在研究區間內是否有發生出血事件和缺血性中風事件，然後進行分析。
研究結果
本研究總共納入2390人，其中warfarin組為1113人、dabigatran組為605人、rivaroxaban組為668人。重大出血及缺血性中風的發生率（%/ year）分別為：warfarin組為6.20及2.10、dabigatran組2.72及1.28、rivaroxaban組為5.85及1.59、NOACs組為4.12及1.43，其中dabigatran和warfarin相比其重大出血發生率有達統計上的顯著差異（HR＝0.492, P value＝0.0066），其餘則無顯著差異。但在進行傾向分數配對後，NOACs組和warfarin相比其缺血性中風的發生率有達統計上的顯著差異（HR＝0.436, P value＝0.0487）。
在重大出血部位的分析顯示胃腸道出血的比例是最高的。在非重大出血的部分，前三大發生出血的部位分別是胃腸道出血、泌尿道出血、皮膚瘀斑，但三組發生的比例略有差異。
 
結論
本研究提供台灣非瓣膜性心房顫動病患使用口服抗凝血劑的療效和安全性，為本土性的研究。台灣族群使用dabigatran和rivaroxaban的重大出血發生率比warfarin低，但僅有dabigatran達到統計學上的差異，而重大出血發生的部位大多在胃腸道，因此，台灣人使用口服抗凝血劑必須特別注意胃腸道出血的問題。在缺血性中風方面，僅在將dabigatran和rivaroxaban兩組合併分析，且進行傾向分數配對後，才達到統計學上的差異。但受限於rivaroxaban組樣本數不足，而未能達統計上顯著差異，且只納入台灣中南部三家醫學中心的個案，是否能代表全台灣心房顫動病患使用口服抗凝血劑的情況，仍有待更大型的研究來證實。

SUMMARY
New oral anticoagulants (NOACs), dabigatran and rivaroxaban, are recommended using for prevention of thromboemobolism in patients with atrial fibrillation. Their efficacy have shown non-inferior to warfarin in the clinical trials, but their safety reports are still inconsistent in prior studies and lack of head-to-head comparison. In addition, Asians and non-Asians seem to have different bleeding risk upon receiving NOACs or warfarin and the relative studies still limited in Taiwanese population. Thus, we conducted a retrospective cohort study to assess the incidence of bleeding and ischemic stroke events associated with NOACs in nonvalvular atrial fibrillation patients in three medical centers in the central and south part of Taiwan. Totally, We included 2,390 patients. The incidence of major bleeding and ischemic stroke events were 6.20 and 2.10 per 100 person-years (%/ year) in warfarin group, 2.72 and 1.28 %/ year in dabigatran group, 5.85 and 1.59 %/ year in rivaroxaban group, and 4.12 and 1.43 %/ year in NOACs group. We compared dabigatran, rivaroxaban, and NOACs with warfarin. There was statistical significance in major bleeding risks between dabigatran and warfarin groups. After propensity score matching for NOACs and warfarin groups, there was statistical significance in ischemic stroke risks. Nevertheless, others were no significant differences among them. Due to the limited sample size of rivaroxaban group and the experience is just in three medical centers in central-south Taiwan, more large-scale studies should be warrented to confirm the result in the future in Taiwanese population.

INTRODUCTION
Atrial fibrillation is a common cardiac arrhythmia and may increase four to five times risk of stoke. For decades, warfarin is the only one oral anticoagulant used to prevent stroke and systemic embolism. In recent years, the development of new oral anticoagulants (NOACs), including dabigatran and rivaroxaban, provide an alternative choice of anticoagulation. Clinical trials, have shown that NOACs were non-inferior to warfarin in efficacy, and had lower risk in some part of major bleeding. However, the bleeding risks upon receiving NOACs or warfarin were different in Asians and non-Asians. Furthermore, the data is limited in Taiwanese population. Based on the current evidence, the objective of our study was to assess safety and efficacy between dabigatran, rivaroxaban and warfarin by comparing bleeding events and ischemic stroke events in Taiwanese population.

MATERIALS AND METHODS
We conducted a retrospective cohort study by using medical chart review. We enrolled patients with nonvalvular atrial fibrillation who were anticoagulat-naïve adults and excluded those who had diagnosed mitral stenosis or ever received mechinical heart valve. The study period was from October 2010 to May 2016 in three medical centers in central and south Taiwan. We set the first date of prescribing dabigatran, rivaroxaban or warfarin during the study period as the index date. The anticoagulat-naïve in our study means there were no records about prescribing any kind of oral anticoagulants during the six months before the index date. Two main outcomes were measured that were major bleeding and ischemic stroke events. We compared dabigatran, rivaroxaban, and NOACs with warfarin. Event rates were presented as % or per 100 person-years (%/ year). Hazard ratios (HR) and confidence intervals (CI) were calculated with Cox proportional hazard model.

RESULTS
Totally, we included 2,390 patients. There were 605 patients in dabigatran group, 670 patients in rivaroxaban group, and 1115 patients in warfarin group. The mean age of dabigatran group was 74.7, rivaroxaban group was 74.4, NOACs group was 74.5, and warfarin group was 70.9. The mean follow-up days were 422.3, 307.3, 343.6 and 343.6 in dabigatran, rivaroxaban, NOACs, and warfarin groups respectively.

The incidence per 100 person-years of major bleeding and ischemic stroke events were 2.72 and 1.28 in dabigatran group, 5.85 and 1.59 in rivaroxaban group, 4.12 and 1.43 in NOACs group, and 6.20 and 2.10 in warfarin group. The major bleeding risks between dabigatran and warfarin groups were statistical significant (HR, 0.492; 95 % CI, 0.295~0.821; P value = 0.0066). After propensity score matching for NOACs and warfarin groups, there was statistical significance in ischemic stroke risks (HR, 0.436; 95 % CI, 0.191~0.995; P value = 0.0487). Nevertheless, others were no significant differences among them. Among these study groups, the highest major bleeding site is gastrointestinal (GI) bleeding. We also assessed the minor bleeding events, and we found that the top three events were GI bleeding, hematuria, and ecchymosis, but the rank of these events were a little bit difference among study groups.

CONCLUSION
This study reported the major bleeding and ischemic stroke rates associated with oral anticoagulants in real-world patients with nonvalvular atrial fibrillation in Taiwan. The Taiwanese population were at GI bleeding risk when receiving anticoagulants. With regard to major bleeding risk, our study found that using dabigatran was favored. Regarding the ischemic stroke risk, using NOACs was possibly less than warfarin. Due to the limited sample size of rivaroxaban group, we could not found statistical significance from these events of rivaroxaban. The results are the experience in three medical centers in central-south Taiwan, if that could stand for all the Taiwanese population is shoud be concerned. Further large-scale studies are needed to confirm the result in the future in Taiwanese population.

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