Context: Excessive anticoagulation increases the risk of hemorrhagic complications associated with warfarin therapy. Oral, subcutaneous or parenteral phytonadione is used to reverse both symptomatic and asymptomatic excessive anticoagulation. Multiple reports have addressed the influence of phytonadione dose and route of administration on time course of anticoagulation reversal.

Objective: To determine the influence of CYP2C9 and VKORC1 1173C/T on anticoagulation reversal following phytonadione administration.

Design and Setting: Prospective cohort study of 578 patients newly initiated on warfarin (target INR: 2–3).

Main Outcome measures: INR difference (pre-treatment INR- post-treatment INR) produced by phytonadione after accounting for age, gender, race, CYP2C9 and VKORC1-1173C/T genotype, warfarin dose, comorbidity, concomitant therapy with CYP2C9 inhibitors, phytonadione dose and time (hours) between pre-treatment and post-treatment INR measurement.

Results: During follow-up (August 2003-April 2007) various treatment modalities were used to reverse anticoagulation. Phytonadione monotherapy was administered 28 times to reverse anticoagulation in 24 patients (15 women, 14 African American), mean age 66.4±16.9 yrs. The mean phytonadione dose was 4.1mg (±2.7) and the mean duration between pre-treatment and post-treatment INR measurements was 53.4 (±26.7) hours. Administration of phytonadione produced a median INR decline of 5.5 (range 0.2–10.9). Because 3 of the 24 patients were measured more than one time, a linear mixed model using SAS PROC MIXED was performed in order to account for the dependency in the observations. The mixed model statistically adjusted for age, gender, race, CYP2C9 genotype, warfarin dose, comorbidity, concomitant therapy with CYP2C9 inhibitors, phytonadione dose and time (hours) between pre-treatment and post-treatment INR measurement. The extent of anticoagulation reversal (INR decline in response to phytonadione administration) was significantly smaller among patients with variant VKORC1-1173C/T genotype compared to those with wild-type genotype (p=0.0027). The INR decline was also smaller among patients with variant CYP2C9 genotype, although this finding was of marginal statistical significance (p=0.069).

Conclusion: The efficacy of phytonadione in reversing anticoagulant effect of warfarin is significantly influenced by the individuals VKORC1-1173C/T genotype.

Topics:
anticoagulation reversal, cyp2c9 protein, human, genotype, international normalized ratio, vitamin k, vitamin k 1, vkorc1 gene, warfarin, anticoagulation, anticoagulation treatment, excessive

Author notes

Disclosure: No relevant conflicts of interest to declare.

2007, The American Society of Hematology
2007
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