Sennesael Anne-Laure, Larock Anne-Sophie, Douxfils Jonathan, Elens Laure, Stillemans Gabriel, Wiesen Martin, Taubert Max, Dogné Jean-Michel, Spinewine Anne, Mullier François
1Louvain Drug Research Institute, Clinical Pharmacy Research Group, Université catholique de Louvain, Brussels, Belgium.
3Namur Research Institute for LIfe Sciences, Namur Thrombosis and Hemostasis Center, Department of Pharmacy, University of Namur, Namur, Belgium.
Thromb J. 2018 Nov 12;16:28. doi: 10.1186/s12959-018-0183-3. eCollection 2018.
Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.
This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and genotype data were collected.
Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).
Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.
服用直接口服抗凝剂（DOAC）的患者中经常出现严重出血事件。在3期试验的二次分析中，DOAC血浆浓度与出血结局相关。本研究旨在描述因出血事件入住急诊科（ED）的患者中利伐沙班的血浆水平。对于每位患者，还调查了发生出血事件的危险因素。
该分析是在两家教学医院的急诊科进行的一项观察性研究的一部分。收集了10例因出血事件入院的接受利伐沙班治疗的患者的血浆样本。利伐沙班血浆浓度通过校准的显色抗Xa测定法测定。然后使用已发表的群体药代动力学（PopPK）模型在谷值时外推测得的利伐沙班水平，并与大型临床试验中观察到的治疗范围内的值进行比较。收集每位患者的临床、用药和基因型数据。
利伐沙班测量值在5至358 ng/ml之间，摄入后延迟时间在9至38小时之间。在谷值时，估计血浆浓度在12至251 ng/ml之间（中位数为94 ng/ml）。4例患者的利伐沙班水平高于预期。在几名患者中观察到剂量方案不当、过量饮酒和缺乏治疗重新评估。一半的患者服用了≥1种具有潜在药代动力学相互作用的药物（如胺碘酮、地尔硫卓），而另一半患者服用了≥1种增加出血风险的药物。所有3例有可用基因分型数据且利伐沙班水平高于预期的患者在1236C>T、2677G>T、3435 C>T和rs4148738单核苷酸多态性（SNP）方面为杂合或纯合突变。
因出血事件入住ED的利伐沙班患者血浆浓度变化很大。该分析强调了快速测定DOAC的有用性以及在摄入后延迟难以控制的情况下PopPK模型用于估计谷值浓度的价值。密切的患者随访，包括肾功能评估和药物相互作用审查，对于将出血风险降至最低至关重要。
