Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Clin Pharmacokinet. 2020 Aug;59(8):967-980. doi: 10.1007/s40262-020-00879-x.
A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug-drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug-disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.
大量证据表明，不仅直接抗凝作用，而且大出血事件和卒中预防都依赖于直接口服抗凝剂（DOAC）的血浆浓度。同时使用导致药物相互作用（DDI）的药物会通过增加或减少 DOAC 的生物利用度和/或清除率来改变 DOAC 的暴露情况；因此，它们可能会影响 DOAC 治疗的疗效和安全性。由于避免升高的 DOAC 暴露可能会预防严重的出血事件，因此肾功能损害的患者已经接受较小的 DOAC 维持剂量。对于其他原因引起的暴露增加，如 DDI，管理通常不太明确。考虑到 DOAC 患者通常年龄较大且合并多种疾病，联合用药非常普遍。然而，多种药物对 DOAC 暴露的影响，特别是在肾功能损害中观察到的与药物-疾病相互作用同时存在的 DDI 的影响，尚未得到充分阐明。为了提供有效的和安全的 DOAC 抗凝治疗，了解 DDI 的机制和程度似乎很重要。与其避免与 DOAC 联合用药，不如进行更多的 DDI 试验，并研究新的策略，例如基于治疗药物监测的剂量调整。然而，目前不能推荐基于浓度测量的剂量调整，因为缺乏基于证据的数据。
