Brem Elizabeth, Koyfman Alex, Foran Mark
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
J Emerg Med. 2013 Jul;45(1):143-9. doi: 10.1016/j.jemermed.2012.11.032. Epub 2013 Jan 30.
Dabigatran and rivaroxaban are novel anticoagulants that have been approved for the prevention of thromboembolic events in atrial fibrillation. These medications are attractive to both patients and clinicians, as, unlike warfarin, they do not require laboratory monitoring or dietary restrictions. However, they carry bleeding risks similar to that of warfarin and are without a reliable reversal agent.
The objectives of this article are to 1) summarize the pivotal trials leading to the U.S. Food and Drug Administration approvals of dabigatran (Pradaxa; Boehringer Ingelheim, Ridgefield, CT) and rivaroxaban (Xarelto; Janssen Pharmaceuticals, Inc., Titusville, NJ); 2) present the limited data available regarding the management of bleeding patients on these agents; and 3) provide suggestions to guide emergency providers given the limited data.
Dabigatran and rivaroxaban were approved based on large, non-inferiority trials comparing the new agents to warfarin with stroke or systemic embolism as the primary outcome. Traditional coagulation studies cannot be used to determine the degree of anti-coagulation produced by these agents. Fresh frozen plasma is unlikely to be effective in patients on these drugs who are acutely bleeding. Prothrombin complex concentrate can be considered in patients on rivaroxaban. Dabigatran is renally cleared, so dabigatran could be removed by hemodialysis. Theoretically, DDAVP (Sanofi-Aventis U.S. LLC, Bridgewater, NJ), aminocaproic acid, tranexamic acid, or recombinant activated factor VII could also be used in an attempt to control bleeding.
There is a need for assays for the degree of anticoagulation produced by drugs such as dabigatran and rivaroxaban. Additionally, studies are needed to evaluate reversal agents that could be effective in the setting of acute bleeding.
达比加群酯和利伐沙班是新型抗凝药物，已被批准用于预防心房颤动中的血栓栓塞事件。与华法林不同，这些药物对患者和临床医生都颇具吸引力，因为它们无需实验室监测或饮食限制。然而，它们的出血风险与华法林相似，且没有可靠的逆转剂。
本文的目的是：1）总结促成美国食品药品监督管理局批准达比加群酯（Pradaxa；勃林格殷格翰公司，美国康涅狄格州里奇菲尔德）和利伐沙班（Xarelto；杨森制药公司，美国新泽西州蒂特斯维尔）的关键试验；2）介绍关于使用这些药物的出血患者管理的有限数据；3）鉴于数据有限，为指导急救人员提供建议。
达比加群酯和利伐沙班基于大型非劣效性试验获批，这些试验将新药物与华法林进行比较，以中风或全身性栓塞作为主要结局。传统凝血研究无法用于确定这些药物产生的抗凝程度。新鲜冰冻血浆对正在服用这些药物且急性出血的患者不太可能有效。服用利伐沙班的患者可考虑使用凝血酶原复合物浓缩剂。达比加群酯经肾脏清除，因此可通过血液透析清除达比加群酯。理论上，去氨加压素（赛诺菲安万特美国有限责任公司，美国新泽西州布里奇沃特）、氨基己酸、氨甲环酸或重组活化因子VII也可用于尝试控制出血。
需要针对达比加群酯和利伐沙班等药物产生的抗凝程度进行检测。此外，需要开展研究以评估在急性出血情况下可能有效的逆转剂。
