Title: Reversal of over-anticoagulation using a ‘tailored’ vitamin K dosing regimen: towards a better management of anticoagulation therapy
Funder: Department of Health (England)

Abstract: Background About 50% of patients on warfarin deviate from their target anticoagulation range making them liable to bleed. Current guidelines advocate using oral vitamin K to reverse over-anticoagulation in patients either asymptomatic or with minor bleeds. Over-anticoagulated patients present with a wide range of INR values and response to a fixed dose of vitamin K varies. Consequently about 45% of such patients remain outside their target INR 24 hours after vitamin K administration making them prone to either haemorrhage or thromboembolism. The proposed project will assess the performance of a novel tailored vitamin K dosing regimen against a currently used fixed dose regimen in terms of the proportion of over-anticoagulated patients returning to their target INR 24h after vitamin K administration. Aims In a recent pilot study we showed that individualised vitamin K dosing significanlty increased the proportion of patients returning to their target INR range compared to a fixed-dose regimen. The study results also led to the development of an improved tailored vitamin K dosing regimen, based on patient INR on presentation, target INR and body surface area. The proposed study aims to assess the effectiveness of the improved ‘tailored’ vitamin K dosing regimen in the reversal of warfarin over-anticoagulation. It will also investigate, retrospectively, the impact of factors such as patient age, gender, co-morbidity, warfarin daily dose and polymorphisms in VKORC1 and CYP2C9 genes on the extent of INR reversal, in order to further refine the accuracy of tailored vitamin K dosing. Plan of Investigation 186 patients with excessive anticoagulation will be randomised to two groups. One group will be treated with fixed-dose oral vitamin K according to the guidelines in the Northern Region Trust Hospitals and the other according to the ‘tailored’ vitamin K dosing algorithm. Demographic data and possible reasons for over-anticoagulation will be collected. 5ml blood will be collected for genotyping of the VKORC1 and CYP2C9 genes. The proportion of patients reaching the target INR range within 24 hours of receiving oral vitamin K between the two groups will be compared. We will investigate retrospectively the impact of factors such as patient age, gender, co-morbidity, warfarin daily dose and polymorphisms in VKORC1 and CYP2C9 genes on the extent of INR reversal. Potential Impact The risk of bleeding due to excessive anticoagulation is a major problem associated with warfarin therapy. Vitamin K is used as an antidote to lower INR. Response to vitamin K varies among patients and current fixed dose regimens do not take into account individual patient INR or demography at the time of admission to hospital. Therefore, patients are still at risk of either thromboembolism or bleeding if the antidote fails to return the patient’s INR to within its target value. The use of the tailored dosing algorithm and any refinements derived as a result of the current study could lead to a more accurate reversal of over-anticoagulation, resulting in a higher percentage of patients returning to an INR within their target range and save the NHS costs associated with treatment failure.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR