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

Abstract

Appraisal of current vitamin K dosing algorithms for the reversal of overanticoagulation with warfarin: the need for a more tailored dosing regimen Warfarin has long been utilized for the treatment of thromboembolic disorders and its use has escalated further by recent demonstrations that it effectively prevents strokes in atrial fibrillation (1-3); currently about 1% of the UK population receives warfarin and this is increasing. The clinical effectiveness of warfarin is critically dependent upon maintaining the target anticoagulation, expressed as the international normalized ratio (INR) of the prothrombin time. For most indications the optimal anticoagulation is of moderate intensity, defined as the target INR being between 2.0 and 3.0, with the main exception of prosthetic heart valves where the target INR is at the less safe level of 3.0-4.5 (4).Warfarin has a narrow therapeutic window, and this with an unpredictable anticoagulation response makes it difficult to achieve and maintain optimal anticoagulation. Subgroup analyses of a number of studies have shown a sharp increase in the risk of bleeding when the INR is above the upper limit of the therapeutic range and the risk of thromboembolic events increases when the INR falls below it (5-7). Despite recent improvements in the management of warfarin therapy, over a third of patients fail to stabilize within their target INR range and are thus prone to the adverse effects of the drug (8). The annual frequency of major haemorrhagic events associated with warfarin ranges from 1.3% to 4.2% (1, 7). About half of eligible atrial fibrillation patients are denied warfarin therapy as the risk of haemorrhage is considered to outweigh the potential benefits of the treatment (9).Restoration of the INR towards the target range in over-anticoagulated patients is the logical Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen.Abstract: 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 overanticoagulated 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 ...

Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists?

“…Many factors affect vitamin K reversal of VKA anticoagulation [25]. Advanced age may lead to excessive correction by decreasing hepatic clearance.…”

Pharmacogenomics: Role in Medicines Approval and Clinical Use

“…It is well known that environmental and genetic factors influence the warfarin dose necessary for therapeutic response. Different studies have confirmed that age and weight are the most consistent variables influencing warfarin variability, even if diet and concurrent medication affect dose requirement [10,11,12,13] . Recently it was shown that some of the unexplained variability in the requirement of warfarin dose depends on variants of 2 genes, CYP2C9 and VKORC1 (according to HUGO nomenclature).…”

“…They are also at higher risk for over-anticoagulation and serious bleeding [14,15,16]. Different common polymorphisms and haplotypes have also been identified in the VKORC1 gene, and some of them have been found to be associated with the variability in warfarin dose requirements, explaining a larger percentage of variability compared to CYP2C9 SNPs [5,10,11,12,17,18,19,20,21,22]. The T allele of VKORC1 1173 C>T SNP (c.173+1000, rs9934438) is highly associated with a low mean weekly warfarin dose (MWWD) while the A allele of VKORC1 3730 G>A SNP (c.492+134, rs7294) is associated with a high MWWD [22].…”

“…Moreover, some recently published prospective studies [23,24,25]used specific algorithms, including also information about these genetic variants as proposed by previous papers [10,11], to predict the actual required dose of warfarin. These studies appear to confirm the importance of the VKORC1 and CYP2C9 SNPs/haplotypes as GBs to guide the clinicians in warfarin dose adjustment giving useful indications especially in the initiation of therapy to avoid the risk of adverse events.…”

VKORC1 and CYP2C9 genotypes in Egyptian patients with warfarin resistance

“…Warfarin is one of the most widely used anticoagulants, yet interindividual differences in drug response, a narrow therapeutic range and a high risk of bleeding or thrombosis complicate its clinical use [1][2][3]. Warfarin gains its importance because many people are dependent on this drug (1% of the population in many western countries).…”