Seiffge David, Polymeris Alexandros, Pfeilschifter Waltraud, Apostolaki-Hansson Trine, Ip Bonaventure, Kristoffersen Espen Saxhaug, Kuramatsu Joji B, Siepen Bernhard M
Department of Neurology, Inselspital University Hospital and University of Bern, Bern, Switzerland.
Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.
Eur Stroke J. 2025 Apr;10(1_suppl):14-23. doi: 10.1177/23969873241281477. Epub 2025 May 22.
About 20%-25% of all intracerebral haemorrhages are associated with oral anticoagulation therapy. Reflecting changings prescription patterns in the general population, the spectrum of oral anticoagulation-associated intracerebral haemorrhage has substantially changed in the last decade. In many European countries, direct oral anticoagulant-associated intracerebral haemorrhage is now more frequent than vitamin K antagonist-associated intracerebral haemorrhage. Outcome in patients with anticoagulation-associated intracerebral haemorrhage is poor, likely mediated by a high incidence of haematoma expansion. Reversal of anticoagulation is an essential part of current care pathways for hyperacute treatment of intracerebral haemorrhage aiming to limit haematoma expansion and thereby improving outcome.
In this review, we summarise the latest evidence regarding reversal therapy for vitamin K antagonist-, direct thrombin inhibitor- and factor Xa inhibitor-associated intracerebral haemorrhage.
Two randomised controlled trials have shown that the use of prothrombin complex concentrate (compared to fresh frozen plasma) for reversing vitamin K antagonist-associated intracerebral haemorrhage and andexanet alfa (compared to usual care, mainly prothrombin complex concentrate) for factor Xa inhibitor-associated intracerebral haemorrhage had superior haemostatic efficacy. However, the incidence of thromboembolic complications was high in both trials. For reversal of Vitamin K antagonist-associated intracerebral haemorrhage, the overall rate was 18% but due to crossovers, it is impossible to determine the rate for any specific treatment. For factor-Xa inhibitor associated intracerebral haemorrhage, andexanet alfa led to an increase in the incidence of thromboembolic events. Moreover, these two randomised controlled trials were not powered to detect differences in mortality or functional outcomes and lacked long-term follow-up. Idarucizumab has shown promising results in a single-arm case series of patients with intracerebral haemorrhage associated with the direct thrombin inhibitor dabigatran, yet no randomised controlled trial is available to support these findings.
Given that haematoma expansion is strongly associated with poor outcome, current evidence underlines the importance of rapid, targeted and effective reversal of anticoagulation in patients with anticoagulation-associated intracerebral haemorrhage. While haematoma expansion is a key prognostic factor, no randomised controlled trial has demonstrated a clear improvement in functional outcome. Future research should weigh the advantages of preventing haematoma expansion against the risks of increased thromboembolic events, and aim to identify the patients who would derive the most benefit from reversal treatments.
在所有脑出血病例中，约20%-25%与口服抗凝治疗有关。随着普通人群处方模式的变化，口服抗凝相关脑出血的类型在过去十年中发生了显著变化。在许多欧洲国家，直接口服抗凝剂相关脑出血现在比维生素K拮抗剂相关脑出血更为常见。抗凝相关脑出血患者的预后较差，可能是由血肿扩大的高发生率所致。逆转抗凝是目前脑出血超急性治疗护理途径的重要组成部分，旨在限制血肿扩大，从而改善预后。
在本综述中，我们总结了关于维生素K拮抗剂、直接凝血酶抑制剂和Xa因子抑制剂相关脑出血逆转治疗的最新证据。
两项随机对照试验表明，使用凝血酶原复合物浓缩物（与新鲜冰冻血浆相比）逆转维生素K拮抗剂相关脑出血，以及使用andexanet alfa（与常规治疗相比，主要是凝血酶原复合物浓缩物）逆转Xa因子抑制剂相关脑出血，具有更高的止血效果。然而，两项试验中血栓栓塞并发症的发生率都很高。对于逆转维生素K拮抗剂相关脑出血，总体发生率为18%，但由于交叉情况，无法确定任何特定治疗的发生率。对于Xa因子抑制剂相关脑出血，andexanet alfa导致血栓栓塞事件发生率增加。此外，这两项随机对照试验没有足够的能力检测死亡率或功能结局的差异，且缺乏长期随访。依达赛珠单抗在一项与直接凝血酶抑制剂达比加群相关的脑出血患者单臂病例系列中显示出有前景的结果，但尚无随机对照试验支持这些发现。
鉴于血肿扩大与不良预后密切相关，当前证据强调了在抗凝相关脑出血患者中快速、有针对性和有效逆转抗凝的重要性。虽然血肿扩大是一个关键的预后因素，但尚无随机对照试验证明功能结局有明显改善。未来的研究应权衡预防血肿扩大的益处与血栓栓塞事件增加的风险，并旨在确定从逆转治疗中获益最大的患者。
