Institut für Klinische Pharmakologie und Toxikologie, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Institut für Vegetative Physiologie, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
J Thromb Haemost. 2017 Oct;15(10):2017-2028. doi: 10.1111/jth.13801. Epub 2017 Sep 14.
Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time.
Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 μg h L for rivaroxaban and 1860 μg h L for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0-24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban.
目的 比较新型口服直接因子 Xa 抑制剂利伐沙班和阿哌沙班在剂量上的稳定状态药代动力学和抗凝作用，这些剂量以前曾被用于预防非瓣膜性心房颤动患者的中风。
方法 24 名健康的白种男性志愿者参与了这项开放标签、两周期交叉、1 期研究（EudraCT 编号：2015-002612-32）。志愿者随机接受利伐沙班 20mg 每日 1 次或阿哌沙班 5mg 每日 2 次治疗 7 天，然后至少停药 7 天，再接受另一种治疗。在稳定状态和停药后测量血浆浓度和抗凝作用。
结果 两种药物的总体暴露情况相似：利伐沙班 0-24 小时间隔的血浆浓度-时间曲线下面积几何均数为 1830μg·h·L，阿哌沙班为 1860μg·h·L。利伐沙班对内源性凝血酶潜能的抑制作用更大（0-24 小时间隔内相对于基线的曲线下面积几何均数：15.5 小时比 17.5 小时），且与基线相比，凝血酶原时间（PT）（1.66 倍比 1.14 倍）和活化部分凝血活酶时间（APTT）（1.43 倍比 1.16 倍）的最大延长更明显。
结论 尽管两种药物的暴露情况相似，但利伐沙班 20mg 每日 1 次治疗与阿哌沙班 5mg 每日 2 次治疗相比，更能抑制凝血酶生成，且作用更持久。敏感的 PT 和 APTT 检测可用于估计利伐沙班的抗凝作用。
