Ascah K J, Rock G A, Wells P S
Department of Medicine, University of Ottawa, Ontario, Canada.
Ann Pharmacother. 1998 Jul-Aug;32(7-8):765-8. doi: 10.1345/aph.17310.
To determine whether the potentiation of warfarin's anticoagulation effect, which occurred in two patients, was due to an interaction with fenofibrate.
Two patients developed significant potentiation of the anticoagulant effect of warfarin while receiving fenofibrate. In one patient we followed published guidelines to test the potential interaction, including rechallenge twice, and measurements of factors II, V, and VII and liver enzymes to ensure the authenticity of the interaction. We confirmed the interaction by noting that the international normalized ratio (INR) increased with rechallenge, the clotting factor concentrations decreased in concert with the INR, and no other laboratory or clinical factors accounted for this potentiation of the oral anticoagulant affect.
We previously developed criteria specifically for determining the strength of inferred causation in reports of drug interactions with oral anticoagulants; these criteria were adapted from previously described principles of causality assessment. Our observations in two patients suggest a "highly probable" potentiating interaction between fenofibrate and warfarin. Our data do not allow us to draw definitive conclusions on a mechanism of interaction, but fenofibrate is an oral antilipemic agent, similar to clofibrate, that has been described as potentiating oral anticoagulants by affecting coagulation factor synthesis, likely by altering receptor synthesis. Our finding of lower concentrations of coagulation factors suggests a similar mechanism for fenofibrate. Recent data suggest that lipid lowering is effective for primary and secondary prevention of cardiac events. One might therefore expect to see an increase in the use of the various lipid-lowering agents in patients who receive long-term anticoagulation. Our results indicate that the potential for an exaggerated anticoagulant effect occurs within 5-10 days in patients treated with fenofibrate who are receiving long-term anticoagulation with warfarin.
Fenofibrate potentiates the effect of warfarin. Serial monitoring of the INR, at least three times per week, is therefore strongly recommended when initiating fenofibrate therapy in patients receiving warfarin.
确定两名患者中出现的华法林抗凝作用增强是否归因于与非诺贝特的相互作用。
两名患者在接受非诺贝特治疗时，华法林的抗凝作用出现显著增强。在一名患者中，我们遵循已发表的指南来检测潜在的相互作用，包括两次再激发试验，以及对凝血因子II、V和VII及肝酶进行检测，以确保相互作用的真实性。我们通过观察到再激发试验时国际标准化比值（INR）升高、凝血因子浓度与INR同步下降，且没有其他实验室或临床因素可解释这种口服抗凝剂作用的增强，从而证实了这种相互作用。
我们之前专门制定了标准，用于确定口服抗凝剂药物相互作用报告中推断因果关系的强度；这些标准是根据先前描述的因果关系评估原则改编而来。我们对两名患者的观察表明，非诺贝特与华法林之间存在“极有可能”的增强相互作用。我们的数据无法让我们就相互作用机制得出明确结论，但非诺贝特是一种口服降血脂药物，与氯贝丁酯类似，已被描述为通过影响凝血因子合成（可能是通过改变受体合成）来增强口服抗凝剂的作用。我们发现凝血因子浓度较低表明非诺贝特存在类似机制。近期数据表明，降脂对心脏事件的一级和二级预防有效。因此，人们可能预期在接受长期抗凝治疗的患者中，各种降脂药物的使用会增加。我们的结果表明，在接受华法林长期抗凝治疗且同时使用非诺贝特的患者中，5 - 10天内就会出现抗凝作用过度增强的可能性。
非诺贝特可增强华法林的作用。因此，强烈建议在接受华法林治疗的患者开始非诺贝特治疗时，每周至少对INR进行三次连续监测。
