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The largest prospective warfarin-treated cohort supports genetic forecasting.

ABSTRACT: Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

SUBMITTER: Wadelius M

PROVIDER: S-EPMC2630264 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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The largest prospective warfarin-treated cohort supports genetic forecasting.

Wadelius Mia M Chen Leslie Y LY Lindh Jonatan D JD Eriksson Niclas N Ghori Mohammed J R MJ Bumpstead Suzannah S Holm Lennart L McGinnis Ralph R Rane Anders A Deloukas Panos P

Blood 20080623 4

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outsid ...[more]

PMID: 18574025

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Project description:BackgroundPoor anticoagulation management of warfarin may lead to patient admission, prolonged hospital stays, and even death due to anticoagulation-related adverse events. Traditional non-web-based outpatient clinics struggle to provide ideal anticoagulation management services for patients, and there is a need to explore a safer, more effective, and more convenient mode of warfarin management.ObjectiveThis study aimed to compare differences in the quality of anticoagulation management and clinical adverse events between a web-based management model (via a smartphone app) and the conventional non-web-based outpatient management model.MethodsThis study is a prospective cohort research that includes multiple national centers. Patients meeting the nadir criteria were split into a web-based management group using the Alfalfa app or a non-web-based management group with traditional outpatient management, and they were then monitored for a 6-month follow-up period to collect coagulation test results and clinical events. The effectiveness and safety of the 2 management models were assessed by the following indicators: time in therapeutic range (TTR), bleeding events, thromboembolic events, all-cause mortality events, cumulative event rates, and the distribution of the international normalized ratio (INR).ResultsThis national multicenter cohort study enrolled 522 patients between June 2019 and May 2021, with 519 (99%) patients reaching the follow-up end point, including 260 (50%) in the non-web-based management group and 259 (50%) in the web-based management group. There were no observable differences in baseline characteristics between the 2 patient groups. The web-based management group had a significantly higher TTR than the non-web-based management group (82.4% vs 71.6%, P<.001), and a higher proportion of patients received effective anticoagulation management (81.2% vs 63.5%, P<.001). The incidence of minor bleeding events in the non-web-based management group was significantly higher than that in the web-based management group (12.1% vs 6.6%, P=.048). Between the 2 groups, there was no statistically significant difference in the incidence of severe bleeding and thromboembolic and all-cause death events. In addition, compared with the non-web-based management group, the web-based management group had a lower proportion of INR in the extreme subtreatment range (17.6% vs 21.3%) and severe supertreatment range (0% vs 0.8%) and a higher proportion in the treatment range (50.4% vs 43.1%), with statistical significance.ConclusionsCompared with traditional non-web-based outpatient management, web-based management via the Alfalfa app may be more beneficial because it can enhance patient anticoagulation management quality, lower the frequency of small bleeding events, and improve INR distribution.

Project description:BACKGROUND:Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. METHODS:A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. RESULTS:VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. CONCLUSION:Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.

Project description:BackgroundWarfarin, a frequently prescribed oral anticoagulant, is well known for its narrow therapeutic index. Adherence to warfarin may help to achieve a stable international normalized ratio (INR), but little data are available regarding the impact of using a pillbox as a potential adherence aid device.ObjectiveTo evaluate the association between pillbox use and time in therapeutic range (TTR) < 60% and INR instability pattern.MethodsThis study was based on a prospective cohort of 1,069 new warfarin users who initiated warfarin between May 2010 and July 2013 within 17 hospitals in Quebec, Canada. Demographic, lifestyle, and clinical data were collected for 3 months to a year after warfarin initiation, and genetic factors were assessed. Patients usingh self-prepared and pharmacist-prepared pillboxes were compared with nonusers for the 3- to 12-month follow-up period. The primary outcome was a TTR < 60%, which represents a low percentage of time in the INR therapeutic range or an unstable patient. The secondary outcome was the INR instability pattern (unstable below range; unstable over range; unstable with erratic pattern; and stable) to better describe patient INR profiles. A multivariate generalized linear mixed model was used for the primary outcome, along with a multivariate multinomial linear mixed model for the secondary outcome.ResultsThe cohort included patients with a mean age of 70.4 ± 11.7 years; 61.8% of patients were men; 76.3% had atrial fibrillation as warfarin's primary indication; and 35.6% had a previous history of myocardial infarction or angina. Self-prepared and pharmacist-prepared pillbox use was not associated with TTR < 60% or a specific INR instability pattern. A sensitivity analysis showed that self-prepared pillbox users had a higher TTR than nonusers (3.55% ± 1.69%; P = 0.036). This effect was greater among patients aged < 70 years (5.48% ± 2.50%; P = 0.029) than among older patients (1.92% ± 2.31%; P =0.406).ConclusionsPillbox use was not associated with TTR < 60% or a specific INR instability pattern. The impact of self-prepared pillbox use was greater among younger patients, but results were not clinically significant. Future studies adjusting for concomitant drug use are needed to clarify these results.DisclosuresThis study was funded by Canadian Institutes of Health Research (CIHR) and the Centre for Excellence in Personalised Medicine. Both funding sources were not involved in the design, conduct, and reporting of this study. The data used for this study came from the Quebec Warfarin Cohort Study (QWCS), which was supported by the CIHR and the Centre for Excellence in Personalised Medicine. Dumas received a doctoral training award from the CIHR. Perreault and Dubé received a salary award from the Fonds Québécois de Recherche en Santé. Study concept and design were contributed by Talajic, Tardif, Dubé, and Perreault. Dumas, Rouleau-Mailloux, Bouchama, and Lahcene collected the data, which was interpreted by Dumas, Dubé, and Perreault. The manuscript was written and revised by Dumas, Dubé, and Perreault.

Project description:Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice.Pharmacoepidemiological cohort study using observational data.This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and others. The main focus of the study was on outcome events requiring hospitalisation using the HES data.The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal.This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.

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The largest prospective warfarin-treated cohort supports genetic forecasting.

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The largest prospective warfarin-treated cohort supports genetic forecasting.

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