Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
J Thromb Haemost. 2022 Jan;20(1):92-103. doi: 10.1111/jth.15563. Epub 2021 Nov 4.
Direct oral anticoagulants (DOACs) do not require concentration monitoring. However, whether DOAC concentrations are stable and their variation between and within patients is not well studied.
Patients on vitamin K antagonists (VKA) who switched to rivaroxaban, apixaban, or dabigatran were included between 2018 and 2020. Blood was drawn at DOAC trough and peak concentrations at week 0, 2, and 8. Plasma drug concentrations were determined by anti-factor Xa concentrations (rivaroxaban, apixaban) or diluted thrombin time (dabigatran). Inter- and intra-individual variability was assessed by calculating the coefficient of variation (CV). Linear regression models were employed to evaluate associations between DOAC trough concentrations and previous VKA dosage, creatinine clearance, and body mass index (BMI).
One hundred fifty-two patients were included, of whom 96 (63%) were male and with a mean age of 73.9 ± 8.4 years. For the inter-individual variability, the CV ranged between 48% and 81% for trough values and between 25% and 69% for peak values among patients using the recommended DOAC dose. Intra-individual variability was substantially lower, as here the CV ranged between 18% and 33% for trough values and between 15% and 29% for peak values among patients using the recommended DOAC dose. Previous VKA dosage and creatinine clearance were inversely associated with DOAC trough concentrations. No association was found between BMI and DOAC trough concentrations.
Inter-individual variability of DOAC concentrations was higher than intra-individual variability. Lower previous VKA dosage and creatinine clearance were associated with higher DOAC trough concentrations. These findings support further study into an optimal target range, in which the risks of both bleeding and thrombosis are minimal.
直接口服抗凝剂（DOACs）无需进行浓度监测。然而，DOAC 浓度是否稳定以及其在患者间和患者内的变化情况尚未得到充分研究。
纳入 2018 年至 2020 年期间从维生素 K 拮抗剂（VKA）转换为利伐沙班、阿哌沙班或达比加群的患者。在 DOAC 谷浓度和峰浓度时于第 0、2 和 8 周采血。通过抗因子 Xa 浓度（利伐沙班、阿哌沙班）或稀释凝血酶时间（达比加群）测定血浆药物浓度。通过计算变异系数（CV）评估个体内和个体间的变异性。采用线性回归模型评估 DOAC 谷浓度与之前 VKA 剂量、肌酐清除率和体重指数（BMI）之间的相关性。
共纳入 152 例患者，其中 96 例（63%）为男性，平均年龄为 73.9±8.4 岁。对于个体间的变异性，在使用推荐 DOAC 剂量的患者中，谷值的 CV 范围为 48%至 81%，峰值的 CV 范围为 25%至 69%。个体内的变异性要低得多，在使用推荐 DOAC 剂量的患者中，谷值的 CV 范围为 18%至 33%，峰值的 CV 范围为 15%至 29%。之前的 VKA 剂量和肌酐清除率与 DOAC 谷浓度呈负相关。BMI 与 DOAC 谷浓度之间未发现相关性。
DOAC 浓度的个体间变异性高于个体内变异性。较低的之前 VKA 剂量和肌酐清除率与较高的 DOAC 谷浓度相关。这些发现支持进一步研究最佳目标范围，在此范围内，出血和血栓形成的风险最小。
