Chunxiao Lv1, Changxiao Liu2, Jia Liu1, Ziqiang Li1, Xi Du1, Yanfen Li1, Jinxia Sun1, Lanjun Sun3, Ruihong Fan4, Yuhong Huang5. 1. Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China. 2. State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China. 3. Department of Cardiology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China. 4. Department of Cardiology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China. 5. Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China. Electronic address: hyh101@126.com.
Abstract
PURPOSE: The combination of warfarin and compound Danshen dripping pill (CDDP) is helpful for patients with both coronary heart disease (CHD) and atrial fibrillation (AF). The main adverse drug reaction of warfarin is bleeding because of its narrow therapeutic index. The safety of a combination therapy with warfarin and CDDP is always a concern. Our previous research showed that the combination of warfarin and CDDP improved the quality of life for patients with both CHD and AF. This study describes the changes in dose and concentration of warfarin necessary and evaluates bleeding risk when warfarin is given concomitantly with CDDP. METHODS: An ultra-performance liquid chromatography-MS/MS method with a chiral column was developed to assay the concentration of S-warfarin and R-warfarin in human plasma simultaneously. The method was applied to compare the concentration of warfarin in patients taking warfarin combined with CDDP and without CDDP. International normalized ratio (INR) values were monitored to evaluate bleeding risk. Paired t tests were then used to compare the dose and the concentration in 2 periods. Moreover, patients with VKORC1, CYP2C9*3, CYP4F2, EPHX1, and PROC gene polymorphisms were evaluated to determine interactions. FINDINGS: The results indicate that the dose of warfarin had no significant change with or without CDDP. Also, the peak concentrations of S-warfarin and total warfarin were significantly different in CYP4F2 C/C patients, but there was no significant difference identified in other genetic groups. No bleeding occurred in the study. IMPLICATIONS: The dose of warfarin would be sustainable when combined with CDDP, because CDDP did not affect concentration of warfarin significantly in most patients and the change of INR was not significant. CHINA CLINICAL TRIAL REGISTRY IDENTIFIER: ChiCTR-ONRC-13003523.
PURPOSE: The combination of warfarin and compound Danshen dripping pill (CDDP) is helpful for patients with both coronary heart disease (CHD) and atrial fibrillation (AF). The main adverse drug reaction of warfarin is bleeding because of its narrow therapeutic index. The safety of a combination therapy with warfarin and CDDP is always a concern. Our previous research showed that the combination of warfarin and CDDP improved the quality of life for patients with both CHD and AF. This study describes the changes in dose and concentration of warfarin necessary and evaluates bleeding risk when warfarin is given concomitantly with CDDP. METHODS: An ultra-performance liquid chromatography-MS/MS method with a chiral column was developed to assay the concentration of S-warfarin and R-warfarin in human plasma simultaneously. The method was applied to compare the concentration of warfarin in patients taking warfarin combined with CDDP and without CDDP. International normalized ratio (INR) values were monitored to evaluate bleeding risk. Paired t tests were then used to compare the dose and the concentration in 2 periods. Moreover, patients with VKORC1, CYP2C9*3, CYP4F2, EPHX1, and PROC gene polymorphisms were evaluated to determine interactions. FINDINGS: The results indicate that the dose of warfarin had no significant change with or without CDDP. Also, the peak concentrations of S-warfarin and total warfarin were significantly different in CYP4F2 C/C patients, but there was no significant difference identified in other genetic groups. No bleeding occurred in the study. IMPLICATIONS: The dose of warfarin would be sustainable when combined with CDDP, because CDDP did not affect concentration of warfarin significantly in most patients and the change of INR was not significant. CHINA CLINICAL TRIAL REGISTRY IDENTIFIER: ChiCTR-ONRC-13003523.