Clinical analysis of the effects of azole antifungal agents on the anticoagulant activity of warfarin

Abstract

To investigate the frequency and degree of azole antifungal agents that influence the anticoagulant activity of warfarin to reduce the potential bleeding risk and provide a reference for rational administration of warfarin in clinics. Patients with an abnormal international normalized ratio (INR; INR ≥ 4.5) and treated with warfarin plus azole antifungal agents were screened from February 2011 to July 2016, and their data were extracted. Thirty-two patients treated with warfarin plus azole antifungal agents were included. The INR of all the included patients increased by more than 20% of the INR of warfarin alone, and the warfarin sensitivity index showed an upward trend. The INRs of 21 patients treated with fluconazole (FLCZ) and warfarin was closely monitored for 1 week after the combination treatment, and the interaction between warfarin and the azole antifungal agents peaked on the seventh day. The INRs when warfarin was coadministered with azoles (Y) correlated significantly with those in the absence of azoles (X): FLCZ: Y = 1.2515X + 2.1538, R 2 = 0.8128; and voriconazole Y = 2.4144 X + 2.6216, R2 = 0.7828. The combination of FLCZ and voriconazole will enhance the anticoagulant effect of warfarin. Therefore, it is recommended to detect the genotype of CYP2C9 in patients and evaluate the interaction between the 2 drugs to adjust the warfarin dose. It is also recommended to closely monitor INR within 1 week of the addition of azole antifungal agents.

In Vitro Interactions of Antibiotics with Drugs Used in Chronic Diseases

“…In a study conducted by Chen et al in 2020, it was shown that the INR of patient streated in combination with warfarin and azole derivative antifungal agents increased by more than 20% as compared to patients using warfarin alone. According to this study, as the inclusion of azole group drugs in the treatment of patients undergoing warfarin treatment increases the anticoagulant efficacy of warfarin, the INR values need to be closely monitored in these patients (32).…”

Drug interactions of azole antifungals

“…S-isomer is a more potent (more than 5 times) antagonist of Vitamin K, in comparison to R-isomer. [15] Fluconazole will potentiate the anticoagulant effect of warfarin by inhibition of CYP2C9. The interaction between fluconazole and warfarin can occur even if the dose of fluconazole is reduced by 50%.…”

“…[18,19] Patients on warfarin with a high INR are at a greater risk of bleeding, after the introduction of an azole antifungal and need careful monitoring. [15]…”