scholarly journals The Creating an Optimal Warfarin Nomogram (CROWN) Study

2012 ◽  
Vol 107 (01) ◽  
pp. 59-68 ◽  
Author(s):  
Todd S. Perlstein ◽  
Samuel Z. Goldhaber ◽  
Kerrie Nelson ◽  
Victoria Joshi ◽  
T. Morgan ◽  
...  
Keyword(s):  
Therapeutic Range ◽  
Significant Proportion ◽  
Warfarin Dose ◽  
Clinical Trial Registration ◽  
Therapeutic Anticoagulation ◽  
Dosing Algorithm ◽  
Epoxide Reductase ◽  
Secondary Endpoints ◽  
Warfarin Dosing ◽  
Dose Variability

SummaryA significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, –1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3, 1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2. A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A to Algorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion.Clinical Trial Registration: ClinicalTrials.gov (NCT00401414)

Predicting the Dose of Warfarin for Therapeutic Anticoagulation

1982 ◽  
Vol 47 (03) ◽  
pp. 230-231 ◽  
Author(s):  
N K Sharma ◽  
P A Routledge ◽  
M D Rawlins ◽  
D M Davies
Keyword(s):  
Therapeutic Range ◽  
Significant Relationship ◽  
Maintenance Dose ◽  
Warfarin Dose ◽  
Loading Dose ◽  
Intravenous Injections ◽  
Therapeutic Anticoagulation ◽  
Close Relationship ◽  
The Relationship ◽  
Anticoagulant Response

SummaryThe validity of a previously described technique for predicting warfarin requirements based on the anticoagulant response to a fixed loading dose was assessed prospectively in 57 patients. There was a close relationship between the predicted and initially observed daily warfarin dose required to maintain the patient within the therapeutic range for anticoagulation. The significant relationship between predicted and observed maintenance dose persisted at 4 and 12 weeks although it decreased with increasing time.The relationship between observed and predicted maintenance requirement of warfarin was not affected by the concomitant use of intermittent intravenous injections of heparin when 9 hr was allowed to elapse between the previous dose of heparin and the thrombotest estimation on which the prediction was based.It is concluded that the method is valuable in predicting an individual’s warfarin requirement, although it does not obviate the need for regular monitoring of anticoagulant control.

scholarly journals Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3827-3834 ◽  
Author(s):  
Nita A. Limdi ◽  
Mia Wadelius ◽  
Larisa Cavallari ◽  
Niclas Eriksson ◽  
Dana C. Crawford ◽  
...  
Keyword(s):  
Linear Regression ◽  
Warfarin Dose ◽  
Population Level ◽  
Racial Groups ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Dose Prediction ◽  
Similar Dose ◽  
Warfarin Dosing ◽  
Dose Variability

Abstract Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

Systematic Review to Identify Validated Manual Warfarin Maintenance Dosing Tools.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3800-3800
Author(s):  
Robby Nieuwlaat ◽  
Ben Connolly ◽  
John Eikelboom ◽  
Stuart Connolly ◽  
Scott Kaatz
Keyword(s):  
Patient Outcomes ◽  
Therapeutic Range ◽  
Self Management ◽  
Control Group ◽  
Computer Assisted ◽  
Inclusion Criteria ◽  
Time In Therapeutic Range ◽  
Dosing Algorithm ◽  
Anticoagulation Clinics ◽  
Warfarin Dosing

Abstract Abstract 3800 Rationale: Vitamin K antagonists, of which warfarin is the most widely used in North America, are some of the most difficult medications to control and require careful monitoring to keep the international normalized ratio (INR) in the therapeutic range. Anticoagulation clinics and computer-assisted decision support systems have been associated with an improved time patients spend in the therapeutic INR range, but these systems can be expensive. Also, patient self-management delivers the best INR control, but is only useful for patients who are capable to perform self testing and management. Simple, inexpensive and easy to use dosing algorithms have the potential to overcome some of these logistical barriers and offer a tool that could be used without the infrastructure of a formal anticoagulation clinic. We performed a systematic review to identify validated manual warfarin maintenance dosing algorithms that do not require computer support. Methods: MEDLINE was searched, without language restriction, by two independent reviewers for observational and experimental reports of warfarin dosing algorithms, nomograms or formulas. Studies that reported efficacy of anticoagulation clinics, patient self management and computer assisted warfarin dosing were reviewed for references for an underlying dosing process. Inclusion criteria for studies for this review were: 1) the tool needed to provide advice on maintenance dose adjustment and next INR testing, 2) the manual dosing tool needed to be compared to a control group, 3) time in therapeutic range or patient outcomes were reported, 4) the effect of the dosing method could be separated from other interventional aspects of warfarin management. Inter-rater agreement for inclusion of candidate studies was measured with the kappa statistic and disagreement was resolved by consensus. Results: Twenty-five studies were identified and 23 either did not report a manually useful tool (computer-based algorithm or complex formula), did not have a control comparator, did not report the time in therapeutic range or patient outcomes, or the effect of the tool could not be separated from other interventional aspects of anticoagulation clinics, computer systems or self-management. Only 2 studies fulfilled all of the inclusion criteria and there was 100% agreement between the two independent reviewers for their selection. Both studies were single center studies and used practice performance before implementation of the dosing tool as the comparator. One study (n=72) showed an improvement in the proportion of INRs in the therapeutic range from 32% to 46% (p < 0.05). The other study (n=1961) showed an improvement in the time in therapeutic range in patients with a target INR range of 2–3 from 67% to 73% (p < 0.001) and in patients with a range of 2.5–3.5, form 50% to 64% (p < 0.001). Data of the two studies were not pooled due to differences in the dosing tool, quality level of care and calculation of the primary outcome, and the negligible effect of the smaller study. Conclusion: We identified only 2 manually useful VKA maintenance dosing tools that have been compared with a control group. Both studies showed an improvement in the quality of INR control with a simple dosing algorithm, but the studies were limited by their pre/post interventional design. Our results stress the need for a randomized trial to validate the usefulness of a manual dosing algorithm which could yield a simple and inexpensive evidence-based method for many physicians managing patients taking a vitamin K antagonist. Disclosures: No relevant conflicts of interest to declare.

Effects of rare CYP2C9 alleles on stable warfarin doses in Chinese Han patients with atrial fibrillation

2020 ◽  
Vol 21 (14) ◽  
pp. 1021-1031
Author(s):  
Dongxu Wang ◽  
Da-Peng Dai ◽  
Hualan Wu ◽  
Jia Chong ◽  
You Lü ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Predictive Power ◽  
Warfarin Dose ◽  
Multivariate Regression Analysis ◽  
Chinese Patients ◽  
Chinese Han ◽  
Dosing Algorithm ◽  
Warfarin Dosing ◽  
Univariate Analyses

Aim: Gene polymorphisms are critical in warfarin dosing variation. Here, the role of rare CYP2C9 alleles on warfarin doses in Chinese Han patients was investigated. Methods: A retrospective study recruited 681 warfarin treated atrial fibrillation patients. The genetic and clinical data were collected. Dose-related variables were selected by univariate analyses and the warfarin-dosing algorithm was derived by multivariate regression analysis. Results: Three rare CYP2C9 alleles ( CYP2C9*13, *16 and *60) were associated with lower stable doses. Inclusion of the rare CYP2C9 alleles in the prediction model added an extra 3.7% warfarin dose predictive power. Conclusion: CYP2C9*13, *16 and *60 was associated with lower stable warfarin doses in Chinese patients. The algorithm including rare CYP2C9 alleles tends to more accurately predict stable warfarin doses.

scholarly journals GENETIC POLYMORPHISMS OF CYTOCHROME P450 2C9, VITAMIN K EPOXIDE-REDUCTASE SUBUNIT 1 AND WARFARIN DOSING IN PATIENTS WITH PERMANENT ATRIAL FIBRILLATION

2016 ◽  
Vol 1 (4) ◽  
pp. 18-22
Author(s):  
A O Rubanenko ◽  
Yu V Shchukin
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Polymorphisms ◽  
Warfarin Therapy ◽  
Warfarin Dose ◽  
Cytochrome P450 2C9 ◽  
Risk Of Bleeding ◽  
Permanent Atrial Fibrillation ◽  
Epoxide Reductase ◽  
Warfarin Dosing ◽  
Permanent Form

Aim - to assess the influence of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dosing in patients with permanent form of atrial fibrillation. Methods. The study included examination of 100 patients with coronary heart disease and permanent form of atrial fibrillation; mean age 60.5±5.8 years. Conclusion. In patients with permanent form of atrial fibrillation, genotypes CYP2C9*1/*3, TT and GG genotypes of VKORC1 are associated with low warfarin dose, compared to other genotypes. Genotype CYP2C9*1/*3 increases the risk of bleeding complication during warfarin therapy.

Prioritizing rs7294 as a mirSNP contributing to warfarin dosing variability

2020 ◽  
Vol 21 (4) ◽  
pp. 257-267
Author(s):  
Linda Koshy ◽  
S Harikrishnan ◽  
PR Sudhakaran
Keyword(s):  
Linkage Disequilibrium ◽  
Association Studies ◽  
Meta Analysis ◽  
Warfarin Dose ◽  
In Silico Analysis ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Warfarin Dosing ◽  
Dosing Accuracy ◽  
Dose Variability

Aim: The role of mirSNPs in the 3′UTR of VKORC1, CYP2C9 and CYP4F2 genes that could influence warfarin dose variability via a discrete miRNA-mediated mechanism remains unexplained. Methods: Genotypic data in the 1000 Genomes dataset were analyzed for pair-wise linkage disequilibrium and allelic enrichment. Results: MirSNP rs7294 in the 3′UTR of VKORC1 gene displayed varying strengths of linkage disequilibrium with rs9923231 and rs9934438 across populations, albeit consistently associated with higher warfarin dose requirements based on genome-wide association studies, meta-analysis and population-based association studies. In silico analysis predicted altered hybrid stability for the hsa-miR-133a-3p conserved binding site, providing evidence for miRNA-mediated gene regulation. Conclusion: The results support the inclusion of rs7294 as a functional variable for population-specific dosing algorithms to improve dosing accuracy.

Pharmacogenetic Warfarin Dosing Algorithms: Validity in Egyptian Patients

2018 ◽  
Vol 139 (4) ◽  
pp. 255-262 ◽  
Author(s):  
Tarek E. Selim ◽  
Hanan A. Azzam ◽  
Hayam R. Ghoneim ◽  
Ahmed A. Mohamed ◽  
Hossam El Wakeel ◽  
...  
Keyword(s):  
Genetic Algorithm ◽  
Warfarin Therapy ◽  
Linear Regression Analysis ◽  
Warfarin Dose ◽  
Clinical Algorithm ◽  
Dosing Algorithm ◽  
Egyptian Patients ◽  
Warfarin Dosing ◽  
Stable Maintenance ◽  
Clinical Algorithms

Background/Aims: Data from previous reports, addressing the significance of genotype-guided dosing of warfarin in Egyptian patients, are infrequent and controversial. This study is aimed at demonstrating the validity of genetic dosing algorithms in Egyptian patients on warfarin therapy. Methods: A total of 100 Egyptian patients on a stable maintenance daily dose of warfarin were enrolled. The predicted warfarin dose for each patient was calculated using the warfarin dosing table, the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) clinical algorithms and the Gage and the IWPC genetic algorithms and compared to the actual dose. The accuracy of warfarin dosing algorithms was assessed by using the linear regression analysis. Results: The most accurate model in predicting the ideal dose was the Gage genetic algorithm by R2 of 50.4% and the IWPC genetic algorithm by R2 of 42.3%, followed by the warfarin dosing table by R2 of 19.1%, and the Gage clinical algorithm by R2 of 18.9% and the least accurate was the IWPC clinical algorithm by R2 of 9.4%. Conclusions: The Gage ­genetic warfarin dosing algorithm is the best model that could be implemented in Egyptian patients starting warfarin therapy.

Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy

2012 ◽  
Vol 108 (12) ◽  
pp. 1228-1235 ◽  
Author(s):  
Lowiek Hubers ◽  
Alex Spyropoulos ◽  
John Eikelboom ◽  
Benjamin Connolly ◽  
Harriette Van Spall ◽  
...  
Keyword(s):  
Management System ◽  
Randomised Trial ◽  
Warfarin Dose ◽  
P Value ◽  
Anticoagulation Management ◽  
Dosing Algorithm ◽  
Anticoagulation Clinics ◽  
One Step ◽  
Excellent Control ◽  
Warfarin Dosing

SummaryExcellent control of the international normalised ratio (INR) is associated with improved clinical outcomes in patients receiving warfarin, and can be achieved by anticoagulation clinics but is difficult in general practice. Anticoagulation clinics have often used validated commercial computer systems to manage the INR, but these are not usually available to general practitioners. It was the objective of this study to perform a randomised trial of a simple one-step warfarin dosing algorithm against a widely used computerised dosing system. During the period of introduction of a commercial computerised warfarin dosing system (DAWN AC) to an anticoagulation clinic, patients were randomised to have warfarin dose adjustment done according to recommendations of the existing warfarin dosing algorithm or to those of the computerised system. The study tested if the computerised system was non-inferior to the existing algorithm for the primary outcome of time in therapeutic INR range of 2.0–3.0 (TTR), with a one-sided non-inferiority margin of 4.5%. There were 541 patients randomised to commercial computerised system and 527 to the algorithm. Median follow-up was 159 days. A dose recommendation was provided and followed in 91% of occasions for the computerised system and in 90% for the algorithm (p=0.03). The mean TTR was 71.0% (standard deviation [SD] 23.2) for the computerised system and 71.9% (SD 22.9) for the algorithm (difference 0.9% [95% confidence interval: –1.4% to 4.1%];p-value for noninferiority=0.002;p-value for superiority=0.34). In conclusion, similar maintenance control of the INR was achieved with a simple one-step dosing algorithm and a commercial computerised management system.

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