Effect of Genotype on the Pharmacokinetics and Bleeding Events of Direct Oral Anticoagulants: A Systematic Review and Meta‐analysis

This meta-analysis aimed to investigate the effect of the genotype on the pharmacokinetics and bleeding events of direct oral anticoagulants (DOACs) and comprehensively searched electronic databases. Weighted mean difference (WMD) was used to assess the kinetic indicators, odds ratio, and 95% confidence interval (CI) were used to calculate the clinical outcomes. Thirteen articles with 1543 participants were finally included in this study. The peak concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity of individuals with the ABCB1 rs 1045642 CT + TT were higher than that of the CC (WMD = -31.9, 95% CI [-49.94, -12.24], P = .02; WMD = -79.97, 95%CI [-152.38 to -7.56], P = .03, I2 = 0). The Cmax of individuals with mutated genes in ABCB1 2677-3435 is higher than that the wild type (WMD = -19.20, 95%CI [36.62 to -1.79], P = .03, I2 = 0). Carriers of the CYP3A5 rs776746 GG genotype had a higher Cmax than the GA gene (WMD = -51.22, 95%CI [-92.26 to -10.19], P = .01, I2 = 0). Bleeding events were more common in the CES1 rs 2244613 AA + AC than in the CC (odds ratio, 2.62, 95%CI [1.06, 6.47], P = .04; I2 = 0). The Cmax of DOACs was affected by individuals with ABCB1 rs 1045642, ABCB1 2677-343, and cytochrome P450 3A5 rs 776746. Carriers of the ABCB1 rs 1045642 affected the change of area under the plasma concentration-time curve from time 0 to infinity of DOACs. Bleeding events were affected by CES1 rs 2244613.