Abstract：
BACKGROUND: Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding.
METHODS: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process.
RESULTS: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%.
CONCLUSIONS: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given.
CONCLUSIONS: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.
METHODS: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process.
RESULTS: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%.
CONCLUSIONS: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given.
CONCLUSIONS: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.
摘要：
背景：抗凝对于治疗和预防血栓栓塞事件至关重要。目前的指南建议在符合DOAC标准的患者中直接口服抗凝剂（DOAC）而不是维生素K拮抗剂。抗凝的主要并发症是严重或危及生命的出血，这可能需要及时进行止血干预。需要紧急侵入性手术的患者也可能需要逆转DOAC。欧洲麻醉学和重症监护协会（ESAIC）的指南旨在提供循证建议和建议，以了解如何管理接受紧急或急诊手术的DOAC患者，包括治疗DOAC引起的出血。
方法：进行了系统的文献检索，检查四个药物比较器(达比加群，利伐沙班,阿哌沙班,edoxaban)和临床情景，从计划手术到急诊手术，结果为死亡率，血肿生长和血栓栓塞并发症。TheGrade(GradingofRecommendations,评估,开发和评估)方法用于评估纳入研究的方法学质量。德尔菲进程就建议的措辞达成了共识。
结果：到目前为止，目前尚未公布比较两种活性对照物(例如,直接逆转剂和凝血酶原复合物浓缩物:PCC等非特异性止血剂)的前瞻性随机试验的结果,而且大部分出版物都是不受控制的观察性研究.因此，证据的确定性被评估为低或非常低(C级).制定了35项建议和临床实践声明。在Delphi过程中,97.1％的建议达成了强烈共识（>90％同意），2.9％达成了共识（75％至90％同意）。
结论：DOAC特异性凝血监测可能有助于有DOAC水平升高风险的患者，而不建议进行全局凝血测试以排除临床相关的DOAC水平。在紧急情况下，应开始使用直接逆转或非特异性止血剂的止血治疗，而无需等待DOAC水平监测。超过50ngml-1的DOAC水平可以被认为是临床相关的,需要在紧急或紧急程序之前进行止血治疗。在激活的Xa因子（FXa）抑制剂下进行心脏手术之前，由于抑制普通肝素，不推荐使用andexanetalfa，这是体外循环所需要的。在DOAC过量没有出血的情况下，不建议进行止血干预，相反，应采取措施消除DOAC。由于缺乏比较前瞻性的公布结果，随机研究，逆转治疗策略的优越性与非特异性止血治疗对于最紧急和紧急手术和出血尚不清楚.由于缺乏临床数据,没有关于使用重组激活因子VII作为非特异性止血剂的建议.
结论：在紧急手术前服用DOAC和DOAC引起的出血的临床情况下，医师应在开始治疗前评估手术出血的风险和DOAC诱导出血的严重程度.对于大多数临床环境，最佳逆转策略仍有待在未来的试验中确定。
方法：进行了系统的文献检索，检查四个药物比较器(达比加群，利伐沙班,阿哌沙班,edoxaban)和临床情景，从计划手术到急诊手术，结果为死亡率，血肿生长和血栓栓塞并发症。TheGrade(GradingofRecommendations,评估,开发和评估)方法用于评估纳入研究的方法学质量。德尔菲进程就建议的措辞达成了共识。
结果：到目前为止，目前尚未公布比较两种活性对照物(例如,直接逆转剂和凝血酶原复合物浓缩物:PCC等非特异性止血剂)的前瞻性随机试验的结果,而且大部分出版物都是不受控制的观察性研究.因此，证据的确定性被评估为低或非常低(C级).制定了35项建议和临床实践声明。在Delphi过程中,97.1％的建议达成了强烈共识（>90％同意），2.9％达成了共识（75％至90％同意）。
结论：DOAC特异性凝血监测可能有助于有DOAC水平升高风险的患者，而不建议进行全局凝血测试以排除临床相关的DOAC水平。在紧急情况下，应开始使用直接逆转或非特异性止血剂的止血治疗，而无需等待DOAC水平监测。超过50ngml-1的DOAC水平可以被认为是临床相关的,需要在紧急或紧急程序之前进行止血治疗。在激活的Xa因子（FXa）抑制剂下进行心脏手术之前，由于抑制普通肝素，不推荐使用andexanetalfa，这是体外循环所需要的。在DOAC过量没有出血的情况下，不建议进行止血干预，相反，应采取措施消除DOAC。由于缺乏比较前瞻性的公布结果，随机研究，逆转治疗策略的优越性与非特异性止血治疗对于最紧急和紧急手术和出血尚不清楚.由于缺乏临床数据,没有关于使用重组激活因子VII作为非特异性止血剂的建议.
结论：在紧急手术前服用DOAC和DOAC引起的出血的临床情况下，医师应在开始治疗前评估手术出血的风险和DOAC诱导出血的严重程度.对于大多数临床环境，最佳逆转策略仍有待在未来的试验中确定。
