Sié Pierre
Hematology Laboratory, Academic Hospital of Toulouse, Hospital Rangueil, Toulouse, France.
Drug Des Devel Ther. 2016 May 18;10:1683-9. doi: 10.2147/DDDT.S94167. eCollection 2016.
Idarucizumab is the first targeted antidote of dabigatran, a direct oral anticoagulant used for prevention and treatment of venous thromboembolism and prevention of stroke in atrial fibrillation. Idarucizumab is a humanized fragment of a monoclonal antibody, which binds dabigatran reversibly with high affinity and, when administered intravenously, immediately neutralizes its anticoagulant effect. It is rapidly cleared by the kidney with captured dabigatran. In Phase I and II trials, no significant adverse events have been reported. Specifically, idarucizumab has no anticoagulant or procoagulant effect by itself. Idarucizumab is currently being evaluated in an ongoing Phase III trial, in patients treated with dabigatran presenting with severe active bleeding or requiring emergency surgery or an invasive procedure and are at high risk of bleeding. The results of the interim analysis confirm the ability of idarucizumab to neutralize dabigatran instantaneously, without rebound effect, except in rare patients with very high baseline levels of anticoagulant. Although not definitely proving clinical efficacy, due to the noncontrolled design of the trial and the heterogeneity of patient conditions, these promising results on an intermediate criterion with strong rationale have led to the approval of idarucizumab for these indications. However, several questions are unresolved. First, activity measurement of dabigatran in blood, useless in current practice, could be useful to guide the treatment and avoid over- or underutilization of the antidote; but so far, it has not been largely available in real time. Second, the translation of anticoagulant neutralization to an effect on mortality and better outcome is highly dependent on the global management of these patients, especially rapid diagnosis, supportive care, and easy access to antidote administration. Although idarucizumab represents a remarkable achievement in drug design and development, whether it will be an important step toward improved safety of patients treated with dabigatran in the real world will have to be demonstrated in the postmarketing phase.
依达赛珠单抗是达比加群的首个靶向解毒剂，达比加群是一种直接口服抗凝剂，用于预防和治疗静脉血栓栓塞以及预防房颤患者的中风。依达赛珠单抗是一种单克隆抗体的人源化片段，它以高亲和力与达比加群可逆性结合，静脉给药后可立即中和其抗凝作用。它与捕获的达比加群一起被肾脏迅速清除。在I期和II期试验中，未报告显著不良事件。具体而言，依达赛珠单抗本身无抗凝或促凝作用。依达赛珠单抗目前正在一项正在进行的III期试验中进行评估，受试患者为接受达比加群治疗且出现严重活动性出血或需要急诊手术或侵入性操作且出血风险高的患者。中期分析结果证实，依达赛珠单抗能够瞬间中和达比加群，无反弹效应，但极少数抗凝基线水平非常高的患者除外。尽管由于试验的非对照设计和患者情况的异质性，这些结果并未明确证明临床疗效，但基于有力理论依据的中间标准得出的这些有前景的结果已导致依达赛珠单抗获批用于这些适应症。然而，几个问题仍未解决。首先，血液中达比加群的活性测量在当前实践中无用，但可能有助于指导治疗并避免解毒剂的过度或使用不足；但到目前为止，它尚未广泛实时可用。其次，抗凝中和转化为对死亡率和更好结局的影响高度依赖于这些患者的整体管理，尤其是快速诊断、支持性护理以及解毒剂给药的便捷性。尽管依达赛珠单抗在药物设计和开发方面是一项卓越成就，但在现实世界中它是否会成为提高接受达比加群治疗患者安全性的重要一步，还有待上市后阶段予以证明。
