Purpose: The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes.
Methods: We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0.
Findings: A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P = 0.016).
Implications: Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.
Keywords: Han Taiwanese; Kaplan-Meier estimation; international normalized ratio; pharmacogenetics; warfarin.
Copyright © 2023. Published by Elsevier Inc.