Patient-Specific Factors Predictive of Warfarin Dosage Requirements

Summary. Background: The vitamin K epoxide reductase complex subunit 1 (VKORC1) recycles endogenous vitamin K, a cofactor for vitamin K-dependent coagulation factor synthesis. Common polymorphisms in VKORC1, the gene coding for VKORC1, have been found to affect the dose response to vitamin K antagonists, and to confer an increased risk of vascular diseases in a Chinese population. The aim of this study was to evaluate the association between the VKORC1 1173C > T polymorphism and venous thromboembolism (VTE). Methods: We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We studied 439 cases hospitalized with a first venous thromboembolic event that was not related to a major acquired risk factor for VTE, and 439 matched controls. The VKORC1 1173C > T polymorphism was selected for genotyping as the tagging single-nucleotide polymorphism for previously identified VKORC1 haplotypes. Results: The relationship between VTE and the VKORCI 1173C > T polymorphism was consistent with a recessive model. The frequency of the VKORCI TT genotype was lower in cases than in controls. The odds ratio (OR) (95% CI) was 0.62 (0.41-0.94) for the TT genotype as compared to CT/CC genotypes. Adjustment on cardiovascular diseases, body mass index, factor V (FV) and prothrombin gene mutations did not alter the results. Conclusions: In this case-control study, the frequency of the VKORCI TT genotype was lower in patients with VTE than in matched controls. The clinical consequence of these results remains to be determined, but gives new perspectives for exploration of the role of VKORCI polymorphism in the pathogenesis of VTE.

Section: Discussionsupporting

confidence: 88%

Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study

Lacut¹,

Larramendy-Gozalo²,

Gal³

et al. 2007

“…For example, although ethnicity may differ between two study subjects , it obviously remains constant within the same individual before and after carbamazepine initiation. Similarly, although body weight and body surface area may affect warfarin doses , they are likely to remain stable during the relatively short study period.…”

Section: Discussionmentioning

confidence: 99%

The effect of carbamazepine on warfarin anticoagulation: a register‐based nationwide cohort study involving the Swedish population

Mannheimer

Andersson

Järnbert-Pettersson

et al. 2016

Essentials• The clinical impact of the carbamazepine-warfarin drug interaction is largely unknown.• We studied the interaction in 166 patients, using data from three nationwide registries.• Co-treatment with carbamazepine increased warfarin dose requirements by 49%.• International normalized ratio remained reduced for months, indicating poor control.Summary. Background: There are data indicating that the interaction between warfarin and carbamazepine results in decreased warfarin efficacy. However, the evidence on the magnitude of and interindividual differences in susceptibility to this interaction has remained scarce. Objectives: To investigate the effect of carbamazepine on warfarin anticoagulation and warfarin maintenance doses by the use of data from three nationwide registries. Patients/Methods: In a retrospective cohort study including 166 patients, warfarin doses were compared 2-4 weeks before and 10-13 weeks after initiation of cotreatment with carbamazepine. In addition, warfarin doses and International Normalized Ratio (INR) values were calculated week-by-week during cotreatment. Data on prescribed warfarin doses and INR measurements were obtained from two large Swedish warfarin registers. Data on carbamazepine use were retrieved from the Swedish Prescribed Drug Register. Results: The average warfarin doses were 49% (95% confidence interval 43-56) higher during carbamazepine treatment. The INR decreased upon carbamazepine initiation, and subtherapeutic INR levels were observed in 79% of all patients during the fifth week of cotreatment. Warfarin maintenance dose increases exceeding 50% and 100% were observed in 59% and 17% of patients, respectively. Conclusions: Four of five warfarin-treated patients in whom cotreatment with carbamazepine was initiated experienced subtherapeutic anticoagulative effect within 3-5 weeks. The warfarin dose was subsequently increased by 49%, a change that differed widely between patients. In order to avoid thrombosis and ischemic stroke, carbamazepine initiation should be accompanied by close INR monitoring to better meet the anticipated increase in dose demand.

“…While it has long been recognized that race influences warfarin dose requirements [8–10] and therefore potentially affects dose prediction, race has only recently been incorporated as a variable into algorithms proposed for clinical use [38]. The fact that the addition of race/ethnicity did not improve performance implies that its influence on warfarin dose requirements is already captured by clinical or genetic variables included in the algorithms.…”

Section: Discussionmentioning

confidence: 99%

“…These discoveries have prompted calls for testing individuals for variants in these genes prior to initiating warfarin therapy [7], leading to several gene‐based dosing algorithms aimed at improving efficacy and reducing adverse effects that occur during traditional anticoagulant therapy guided by clinical variables. Warfarin dose requirements often vary between races [8–10], yet published algorithms were developed largely in racially homogenous populations and their generalizability has not been established.…”

mentioning

confidence: 99%

Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population

Lubitz

Scott

Rothlauf

et al. 2010

Summary Background Gene-based warfarin dosing algorithms have largely been developed in homogeneous populations, and their generalizability has not been established. Objectives We sought to assess the performance of published algorithms in a racially diverse and multiethnic sample, and determine if additional clinical variables or genetic variants associated with dose could enhance algorithm performance. Patients and methods In 145 compliant patients on warfarin with a goal international normalized ratio (INR) of 2–3, stable, therapeutic doses were compared with predicted doses using 12 reported algorithms that incorporated CYP2C9 and VKORC1 variants. Additional covariates tested with each model included race, concurrent medications, medications known to interact with warfarin and previously described CYP4F2, CALU and GGCX variants. Results The mean patient age was 67 ± 14 years; 90 (62%) were male. Eighty-two (57%) were Caucasian, 28 (19%) African-American, 20 (14%) Hispanic and 15 (10%) Asian. The median warfarin dose was 35 mg per week (interquartile range 23–53 mg per week). Gene-based dosing algorithms explained 37–55% of the variation in warfarin dose requirements. Neither the addition of race, number of concurrent medications nor the number of concurrent medications interacting with warfarin enhanced algorithm performance. Similarly, consideration of CYP4F2, CALU or GGCX variant genotypes did not improve algorithms. Conclusions Existing gene-based dosing algorithms explained between approximately one-third and one-half of the variability in warfarin dose requirements in this racially and ethnically diverse cohort. Additional clinical and recently described genetic variants associated with warfarin dose did not enhance prediction in our patient population.