新型口服抗凝血劑於靜脈栓塞病人療效與安全性：系統性回顧及統合分析

Systemic review and meta-analysis of direct oral anticoagulants in patients with venous thromboembolism

李美娟(Mei-Chuan Lee) ； 余聰(Tsung Yu) ； 蘇慧真(Hui-Chen Su)

《台灣實證醫學學會會刊》 10卷2期 (2019/12) Pp. 25-40

https://doi.org/10.6864/EC.201912_10(2).0010

摘要

背景：口服抗凝血劑的使用可以減少靜脈栓塞（venous thromboembolism, VTE）的復發。在過去，口服抗凝血劑的使用，僅有warfarin。近年來直接口服抗凝血劑（direct anticoagulants, DOACs）的問世，提供了新的治療選擇。近年來許多大型的世代研究結果問世，目前尚缺乏文獻將這些隨機對照試驗與真實世界中DOACs對於VTE再發與大出血的數據做系統性文獻回顧，以供臨床端參考。目的：本研究的目的為利用系統性回顧與統合分析的方法整理傳統口服抗凝血劑與DOACs在隨機對照試驗與觀察性研究中的在VTE再發與大出血的風險，並利用統合分析的方式整合不同研究設計之結果。方法：利用PubMed和Cochrane databases進行搜尋，使用關鍵字為「（（（（venous thrombosis）OR deep vein thrombosis）OR pulmonary embolism））AND（（new oral anticoagulants）OR direct oral anticoagulants）」，沒有做任何語言的限制，搜尋日至2019年4月。收錄的研究設計為隨機對照試驗與世代研究。為保留原始文章其干擾因子的校正以及考慮原始文獻研究之異質性，我們利用hazard ratio（HR）並選用random-effects model進行統合分析。統計軟體選用Review Manager Version 5.3。結果：共收錄6隨機對照試驗與4篇世代研究。隨機對照試驗中在預防VTE的復發DOACs與warfarin未達統計上的差異（HR: 0.91, 95% CI 0.78-1.06），但在觀察性研究中DOACs有較低VTE復發的風險（HR: 0.81, 95% CI 0.73-0.90），但subgroup differences未達統計上的差異（P=0.20）。在大出血的副作用，隨機對照試驗和世代研究統合分析結果都優於傳統的warfarin（HR: 0.60, 95% CI 0.42-0.86; HR: 0.88, 95% CI 0.80-0.97, subgroup differences P=0.05）。結論:本研究結果DOACs與warfarin相比在隨機對照試驗與世代研究方向一致具有相似的功效甚至更好的功效。此外，在大出血事件DOACs不管在隨機對照試驗或世代研究結果都顯示，DOACs是比warfarin更安全的選擇。

關鍵字

靜脈栓塞 ； 口服抗凝血劑 ； 直接口服抗凝血劑 ； 靜脈栓塞 ； 出血

並列摘要

Background: Venous thromboembolism (VTE) is highly associated with morbidity and mortality. Oral anticoagulants have widely used to reduce the recurrences of VTE. However, there was lacking integrated systemic review of randomized controlled trials (RCTs) and real-world studies for VTE recurrence and major bleeding between traditional regimen and direct oral anticoagulants (DOACs). Objective: The aim of this study was to conduct a systematic review and meta-analysis to integrate the recurrence of VTE and bleeding events of DOACs and warfarin. Methods: We used Medline, Pubmed and Cochrane databases without language restrictions until April 30, 2019. Using the ＂((((venous thrombosis) OR deep vein thrombosis) OR pulmonary embolism)) AND ((new oral anticoagulants) OR direct oral anticoagulants)＂ as our keywords. We enrolled RCTs and observational studies, and then pooled outcomes of different study design respectively. We synthesize data using the random-effects model and expressed results as hazard ratio (HR) with 95% confidence intervals (CIs). Statistical analysis was performed with Review Manager Version 5.3. Results: There were 6 RCTs and 4 cohort studies which was included in our final analysis. Based on the meta-analysis of RCTs, the recurrence of VTE did not have significant difference between DOACs and warfarin (HR: 0.91, 95% CI 0.78-1.06). DOACs had lower risk of recurrence of VTE (HR: 0.81, 95% CI 0.73-0.90) according to the pooling result of cohort studies. In addition, DOACs was represented better safety in major bleeding (RCTs HR: 0.60, 95% CI 0.42-0.86; Cohort studies HR: 0.88, 95% CI 0.80-0.97). Conclusions: This meta-analysis indicated that DOACs may have similar efficacy or even better effectiveness than warfarin. Furthermore, DOACs would be the safer agent according to less major bleeding events. However, the number of cohort studies was still limited, further more studies would be required.

並列關鍵字

Venous thromboembolism ； oral anticoagulants ； direct oral anticoagulants ； VTE recurrence ； bleeding