Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen.

Warfarin is the most commonly prescribed oral anticoagulant in the UK for the treatment and prevention of thromboembolic disorders. Vitamin K administration is an effective way of reversing excessive anticoagulation. Over-anticoagulated patients present with a wide range of international normalized ratio (INR) values and may respond differently to a fixed dose of vitamin K. Current dosing algorithms for vitamin K administration in the non-urgent treatment of over-anticoagulation do not take this variability in response into account. Consequently, over a third of over-anticoagulated patients still remain outside their target INR 24 h after treatment. Such patients are therefore prone to either haemorrhage (if the patient is still over-anticoagulated) or thromboembolism (if the INR reversal is over-corrected). A number of factors such as patient age, body weight, co-morbidity, frailty, warfarin daily dose and CYP2C9 and VKORC1 polymorphism could affect response to vitamin K and thus the rate and extent of INR reversal. There is a need for a more individualized approach to the reversal of over-anticoagulation in asymptomatic or mildly haemorrhagic patients in order to improve the safety of warfarin therapy.

APOE genotype makes a small contribution to warfarin dose requirements.

Alterations in vitamin K availability can significantly influence anticoagulation response to warfarin. Apolipoprotein E (APOE) plays a part in the hepatic uptake of lipid-soluble vitamin K. This study aimed to determine the influence of common polymorphisms in the APOE gene on warfarin dose requirements. patients with stable anticoagulation control and with a target International Normalized Ratio (INR) 2.0-3.0 were genotyped for the APOE epsilon2, epsilon3 and epsilon4 variants. Mean +/- SD daily warfarin doses were significantly lower in patients carrying at least one epsilon4 allele compared to the epsilon3epsilon3 reference genotype (3.3 +/- 1.9 versus 4.0 +/- 1.8; P = 0.03; 95% CI: 0.1-1.2). Multivariate regression analysis showed that patient age, height and CYP2C9, VKORC1 and APOE genotypes significantly contributed to warfarin dose requirement (R = 57%). only the epsilon4 allele of APOE was found to make a significant (P = 0.002) but small contribution to warfarin dose requirement. There was no significant difference in fasted plasma vitamin K concentration between patients with the different APOE genotypes. This study suggests that APOE genotype is unlikely to have a clinically significant effect on warfarin dose requirements.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.