急性缺血性中風後心房顫動患者的早期或延遲抗凝治療： 系統性回顧和統合分析與臨床試驗計畫書

Abstract

1.研究背景 對於心房顫動 (AF) 患者而言，關於什麼時候以及如何在急性缺血性中風時，開始使用warfarin或新型口服抗凝血劑 (NOAC)，至今仍沒有最佳策略。目前指引對於心房顫動患者於缺血性中風發作後，起始口服抗凝治療的時間和方法仍不一致且缺乏具體建議。儘管一些回顧性和觀察性研究探討了早期使用NOAC的利弊，但這些研究的方法學和結論不盡相同，因此何時需起始口服抗凝血劑此問題仍然存在於臨床實務中，非常需要統合分析及更多大型隨機對照試驗來提供更具說服力的證據。 2.研究方法 由PubMed及Scopus電子資料庫平台收尋相關醫學文獻，共可得到204篇文章。我們依照設定的納入及排除條件後，共獲得4篇隨機的臨床試驗與7篇觀察性研究可進入系統性文獻回顧以進行統合分析。這些隨機分派性臨床試驗及觀察性研究，皆分析給予口服抗凝血劑後之預後，包括複合性預後指標、再次復發的缺血性中風或顱內出血(ICH)的相關風險。 3.研究結果 在包含4個隨機對照試驗及3個觀察性研究的整體分析中，8,874名心房顫動患者於急性缺血性腦中風後接受了NOACs或warfarin 的治療，不論在固定效應模型 (相對風險: 0.74; 95%信賴區間: 0.61-0.89) 或者隨機效應模型 (相對風險: 0.75; 95%信賴區間: 0.58-0.96)的統合分析皆顯示，早期給藥較晚期給藥顯著減少複合式預後指標。而針對次級指標，在4個隨機對照試驗及6個觀察性研究的10,743名心房顫動患者中，不論在固定效應模型 (相對風險: 0.71; 95%信賴區間: 0.58-0.87) 或隨機效應模型 (相對風險: 0.72; 95%信賴區間: 0.51-0.91)的統合分析，亦皆顯示早期給藥較晚期給藥顯著減少復發性缺血性腦中風。而於4個隨機對照試驗及6個觀察性研究的10,002名心房顫動患者，在固定效應模型 (相對風險: 0.87; 95%信賴區間: 0.65-1.18) 或隨機效應模型 (相對風險: 0.91; 95%信賴區間: 0.67-1.22) 的統合分析皆顯示早期給藥和晚期給藥之顱內出血風險相似。 若僅侷限於4個隨機對照試驗進行統合分析，3,172 名心房顫動患者於急性缺血性中風後接受了NOACs 或warfarin的治療，在固定效應模型的統合分析顯示，早期給藥較晚期給藥顯著減少了複合式預後指標 (相對風險: 0.80; 95%信賴區間: 0.64-0.99)；但於隨機效應模型分析上並無顯著 (相對風險: 0.83; 95%信賴區間: 0.67-1.01)。近一步分析，3,134 名心房顫動患者發生復發性缺血性中風的風險，無論在固定效應模型(相對風險: 0.71; 95%信賴區間: 0.53-0.96)或隨機效應模型(相對風險: 0.73; 95%信賴區間: 0.55-0.99)的統合分析，早期給藥皆較晚期給藥顯著減少了復發性缺血性中風的可能性。而於2,246名心房顫動患者中，在固定效應模型(相對風險: 1.07; 95%信賴區間: 0.70-1.65)或隨機效應模型(相對風險: 1.08; 95%信賴區間: 0.71-1.67)的統合分析皆顯示早期給藥和晚期給藥之顱內出血風險相似。 而若僅侷限於7個隨機對照試驗進行統合分析，5,702名心房顫動患者於急性缺血性中風後接受了NOACs或warfarin的治療，在固定效應模型的統合分析顯示，早期給藥較晚期給藥顯著減少了複合式預後指標 (相對風險: 0.63; 95%信賴區間: 0.44-0.90)；但於隨機效應模型分析上並無顯著 (相對風險: 0.63; 95%信賴區間: 0.32-1.24)。而針對次級預後指標，於7,609名心房顫動患者在固定效應模型的統合分析顯示，早期給藥較晚期給藥顯著減少了復發性缺血性腦中風指標 (相對風險: 0.71; 95%信賴區間: 0.54-0.94)，但於隨機效應模型分析上並無顯著 (相對風險: 0.78; 95%信賴區間: 0.51-1.20)。而於7,756名心房顫動患者，在固定效應模型(相對風險: 0.75; 95%信賴區間: 0.49-1.12)或隨機效應模型(相對風險: 0.77; 95%信賴區間: 0.51-1.16)的統合分析皆顯示早期給藥和晚期給藥之顱內出血風險相似。 4.研究結論 在心房顫動的急性缺血性腦中風患者，於中風後早期給予口服抗凝血劑比延後給予藥物治療，可能可以減少整體的不良預後。其中早期給予抗凝血藥物似乎可降低復發性缺血性中風的發生率，且無增加中風後出血發生的機會。

1. Background There is no optimal strategy for when and how to initiate warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) in acute ischemic stroke in patients with atrial fibrillation (AF). Current guidelines are inconsistent and lack specific recommendations for when and how to initiate oral anticoagulant therapy after onset of ischemic stroke in patients with AF. Some retrospective and observational studies discussing early use of anticoagulants in acute stroke have shown inconsistent results; therefore, this clinical relevant issue remains requiring further meta-analysis and large randomized controlled trials to provide more convincing evidence. 2. Method Relevant literature was collected from the PubMed and Scopus electronic database platforms. After obtaining a total of 204 literature, we followed the set inclusion and exclusion criteria, and obtained a total of 4 randomized clinical trials (RCTs) and 7 observational studies for further meta-analysis. They analyzed the outcome after using oral anticoagulants at early or late stage upon acute ischemic stroke, focusing on composite outcome, recurrent ischemic stroke, and intracranial hemorrhage. 3. Results In 4 RCTs and 7 observational studies of 8,874 patients with AF upon acute ischemic stroke, early initiation of NOACs or warfarin showed a significant reduction in composite outcome using the fixed-effects model (RR: 0.74; 95% CI: 0.61-0.89) or the random-effects model (RR: 0.75; 95% CI: 0.58-0.96) as compared to delayed administration of anticoagulants. In 10,743 patients with AF and acute ischemic stroke, early initiation of NOACs or warfarin resulted in a significant reduction in recurrent ischemic stroke using the fixed-effects model (RR: 0.71; 95% CI: 0.58-0.87) and the random-effects model (RR: 0.72; 95% CI: 0.51-0.91) than delayed anticoagulation. On the other hand, in 10,002 patients with AF, there was no significant difference in the risk of intracranial hemorrhage in both fixed-effects model (RR: 0.87; 95% CI: 0.65-1.18) and random-effects model (RR: 0.91; 95% CI: 0.67-1.22). We further analyzed RCTs alone. Among 3,172 participants with AF upon acute ischemic stroke, early administration of anticoagulants showed significantly lower risk to develop events of composite outcome than late administration in the fixed effect model (RR: 0.80; 95% CI: 0.64-0.99) but only a trend toward lower risk for early administration of anticoagulants in the random effects model to achieve composite outcome (RR:0.83; 95% CI: 0.67-1.01). In the secondary outcome, there was lower risk of recurrent ischemic stroke for early than delayed initiation of anticoagulants for 3,134 patients in both fixed effect model (RR: 0.71; 95% CI: 0.53-0.96) and random effects model (RR: 0.73; 95% CI: 0.55-0.99). Notably, in 2,246 patients with AF, there was no significant difference in the risk of intracranial hemorrhage in both fixed-effects model (RR: 1.07; 95% CI: 0.70-1.65) and random-effects model (RR: 1.08; 95% CI: 0.71-1.67). We also analyzed observational studies alone. Among 5,702 participants with AF upon acute ischemic stroke, early initiation of NOACs or warfarin significantly reduced the composite outcome according to the fixed-effects model (RR: 0.63; 95% CI: 0.44-0.90); the random-effects model analysis did not show a statistically significant reduction in the composite outcome for the early initiation group (RR: 0.63; 95% CI: 0.32-1.24). Besides, in 7,609 patients, early compared to delayed initiation of NOACs or warfarin significantly reduced the risk of recurrent ischemic stroke according to the fixed-effects model (RR: 0.71; 95% CI: 0.54-0.94) but not the random-effects model (RR: 0.78; 95% CI: 0.51-1.20). Finally, in 7,756 patients, there was no significant difference in the risk of intracranial hemorrhage in both fixed-effects model (RR: 0.75; 95% CI: 0.49-1.12) and random-effects model (RR: 0.77; 95% CI: 0.51-1.16). 4. Conclusion In patients with AF-related acute ischemic stroke, our meta-analysis demonstrated that early initiation of anticoagulation is likely better than delayed administration regarding composite outcome and secondary outcome of recurrent ischemic stroke without influence on the risk of intracranial hemorrhage.