Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Atherosclerosis. 2017 Nov;266:81-86. doi: 10.1016/j.atherosclerosis.2017.09.029. Epub 2017 Sep 28.
Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial. This cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. This study aimed to investigate any direct effect of dronedarone on blood thrombogenicity, independent of its antiarrhythmic effects.
Blood samples from patients with cardiovascular disease (n = 30) taking no anticoagulant or antiplatelet medication except aspirin were incubated with dronedarone's active metabolite (SR35021A) at 66 ng/ml (am-L) and 119 ng/ml (am-H), i.e., minimum and maximum mean C reported after repeated 400 mg BID dosing. A third aliquot of blood was incubated with vehicle (Control). Antithrombotic effects of dronedarone were assessed using Coagulation Time (CT), Clot Formation Rate (CFR) and Maximum Clot Firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to ADP, collagen and TRAP.
Compared to Control, mean CT was prolonged by am-L and am-H (164 ± 25 s vs. 180 ± 22 and 182 ± 32 s, respectively, p<0.01 for both). Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). Platelet aggregation induced by ADP and TRAP was also reduced (p<0.05 for both) by am-H.
Dronedarone exerts direct anticoagulant and antiplatelet effects on human blood in vitro that are independent of its antiarrhythmic actions. This suggests the reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve understanding of the mechanisms involved.
在 ATHENA 试验中，决奈达隆降低了阵发性心房颤动（AF）患者的中风和短暂性脑缺血发作的发生率。这不能仅用其抗心律失常作用来解释，可能涉及其他机制。本研究旨在研究决奈达隆对血液血栓形成的直接作用，而不考虑其抗心律失常作用。
从服用除阿司匹林外无抗凝或抗血小板药物的心血管疾病患者的血液样本中，用决奈达隆的活性代谢物（SR35021A）孵育，浓度为 66ng/ml（am-L）和 119ng/ml（am-H），即重复 400mg 每日两次给药后报告的最低和最高平均 C。第三份血液样本用载体孵育（对照）。使用血栓弹性描记法中的凝血时间（CT）、血栓形成速率（CFR）和最大血栓硬度（MCF）以及对 ADP、胶原和 TRAP 的全血血小板聚集来评估决奈达隆的抗血栓形成作用。
与对照相比，am-L 和 am-H 使平均 CT 延长（分别为 164±25s、180±22s 和 182±32s，两者均 p<0.01）。CFR（am-L 和 am-H）和 MCF（am-H）也略有显著降低。ADP 和 TRAP 诱导的血小板聚集也减少（两者均 p<0.05）。
决奈达隆在体外对人血液产生直接的抗凝和抗血小板作用，独立于其抗心律失常作用。这表明，决奈达隆报告的缺血性事件减少可能不是由于改善了 AF 本身。需要进一步的临床研究来进一步提高对相关机制的理解。
