Kitagawa Fumihiko, Ishii Junnichi, Hiramitsu Shinya, Takahashi Hiroshi, Okuyama Ryuunosuke, Kawai Hideki, Muramatsu Takashi, Harada Masahide, Motoyama Sadako, Naruse Hiroyuki, Matsui Shigeru, Sarai Masayoshi, Hayashi Mutsuharu, Watanabe Eiichi, Izawa Hideo, Ozaki Yukio
Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.
Hiramitsu Heart Clinic, Nagoya, Japan.
Heart Vessels. 2017 May;32(5):609-617. doi: 10.1007/s00380-016-0912-0. Epub 2016 Oct 28.
Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10 mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels, and protein C activities were measured at 0 (baseline), 12 and 24 weeks of rivaroxaban treatment just before the patient's regular dosing time (trough phase). For 49 patients, D-dimer, F1 + 2, and rivaroxaban concentrations were also measured twice between 28 and 32 weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1 + 2 levels were significantly reduced (p < 0.01) from baseline at 12 and 24 weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (p < 0.01) for F1 + 2. Protein C activity was unchanged in the naive group and was increased (p < 0.01) in the warfarin group. Prothrombin time (r = 0.92, p < 0.0001) and activated partial thromboplastin time (r = 0.54, p < 0.0001) correlated with rivaroxaban concentration, but not D-dimer and F1 + 2 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1 + 2 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1 + 2 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.
利伐沙班谷浓度是否能提供足够的抗凝作用还需要更多研究。我们评估了非瓣膜性心房颤动（NVAF）患者在谷浓度阶段的凝血激活标志物水平，以及这些标志物与利伐沙班浓度之间的相关性。55名日本NVAF患者接受了为期24周的利伐沙班治疗，剂量为15毫克或10毫克，每日早晨一次。其中，26名患者无抗凝治疗史（初治组），29名患者从华法林转换而来（华法林组）。在利伐沙班治疗的第0周（基线）、12周和24周，在患者常规给药时间（谷浓度阶段）前测量D-二聚体、凝血酶原片段1+2（F1+2）水平和蛋白C活性。对于49名患者，在利伐沙班治疗的28至32周非谷浓度时间内还进行了两次D-二聚体、F1+2和利伐沙班浓度测量，以获得一系列药物浓度用于相关性分析。对于初治组，D-二聚体和F1+2水平在12周和24周时较基线显著降低（p<0.01）。对于华法林组，D-二聚体的值未改变，但F1+2显著升高（p<0.01）。初治组蛋白C活性未改变，华法林组蛋白C活性升高（p<0.01）。凝血酶原时间（r=0.92，p<0.0001）和活化部分凝血活酶时间（r=0.54，p<0.0001）与利伐沙班浓度相关，但与D-二聚体和F1+2水平无关。总之，谷浓度阶段的利伐沙班在降低D-二聚体水平方面与华法林相当。虽然谷浓度利伐沙班对F1+2的抑制作用小于华法林，但与华法林治疗相比，利伐沙班治疗时蛋白C活性较高可能会抵消这一点。利伐沙班浓度与D-二聚体和F1+2水平缺乏相关性表明，利伐沙班谷浓度与较高浓度一样有效地降低了它们的浓度。
