Clinical Application of Pharmacogenetic-Based Warfarin-Dosing Algorithm in Patients of Han Nationality after Rheumatic Valve Replacement: A Randomized and Controlled Trial

Wang, MingSong; Lang, Xilong; Cui, Shuang; Fei, Ke; Zou, Liang-jian; Cao, Jia; Wang, LiangXu; Zhang, Shenghui; Wu, XinTian; Wang, YiLing; Ji, Qiang

doi:10.7150/ijms.4637

Cited by 46 publications

(57 citation statements)

References 13 publications

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“…Actualmente hay estudios en diversas poblaciones que han demostrado una reducción de efectos adversos serios (40), una menor incidencia de anticoagulación excesiva (INR≥4) (9,40), un menor porcentaje de INR fuera del rango (40) e, incluso, la disminución del tiempo para alcanzar la dosis terapéutica con la consecuente reducción del riesgo de tromboembolia (9,40,41).…”

Section: Discussionunclassified

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

2015

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Contribución de los autores:Ricardo A. Cifuentes: concepción del proyecto, genotipificación y análisis de datos Todos los autores participaron en la captación de los pacientes, la recolección de datos, la interpretación de los resultados y la escritura del manuscrito.Predicción de la sensibilidad a la warfarina con base en polimorfismos de los genes VKORC1 y CYP2C9 en pacientes colombianos Introducción. La validación de los factores predictores de la sensibilidad a la warfarina es importante para evitar las hemorragias asociadas con la terapia anticoagulante. En los estudios previos hechos en Colombia con polimorfismos de los genes VKORC1 y CYP2C9, se reportaban algoritmos con rendimientos diferentes para explicar la variación de las dosis, pero no se evaluaba la predicción de la sensibilidad a la warfarina. Objetivo. Determinar la exactitud del análisis farmacogenético de los polimorfismos *2 y *3 en el gen CYP2C9 y 1639G>A en el gen VKORC1 para predecir la sensibilidad a la warfarina en pacientes del Hospital Militar Central, un centro de referencia que atiende pacientes de diferentes lugares de Colombia. Materiales y métodos. Se recopilaron los datos demográficos y clínicos de 130 pacientes que habían recibido una dosis estable de warfarina durante más de dos meses. Se obtuvieron sus genotipos mediante un análisis de curvas de fusión, y, después de verificar el equilibrio de Hardy-Weinberg de los polimorfismos, se hizo un análisis estadístico con enfoque multivariado y predictivo.Resultados. Se construyó un modelo farmacogenético que explicó el 52,8 % de la variación de la dosis (p<0,001), solo 4 % por encima del rendimiento obtenido con los mismos datos usando el algoritmo del International Warfarin Pharmacogenetics Consortium. El modelo predictivo de sensibilidad logró 77,8 % de exactitud e incluyó como factores la edad (p=0,003), los polimorfismos *2 y *3 (p=0,002) y el polimorfismo 1639G>A (p<0,001). Conclusiones. Estos resultados en una población mestiza colombiana respaldan la validez de la predicción de la sensibilidad a la warfarina basada en los polimorfismos de los genes VKORC1 y CYP2C9. Prediction of sensitivity to warfarin based on VKORC1 and CYP2C9 polymorphisms in patients from different places in Colombia Introduction: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin. Objective: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients' sensitivity to warfarin at the Hospital Militar Central, a reference center for patients born in different parts of Colombia. Materials and methods: Demographic and clinical data were obtained from 130 patients with stable doses of warfari...

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Section: Discussionunclassified

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

2015

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“…18,19,24,29,30 Th e pooled estimates of HRs ( Fig 4 ) showed that the GD resulted in signifi cantly shorter TMD (HR, Fig 5 ). Because of significant heterogeneity, we performed sensitivity analysis excluding the study with lowest Jadad score 29 …”

Section: Time To Maintenance Dosementioning

confidence: 95%

“…Of the 233 studies reviewed for eligibility, we extracted 54 studies for full-text review. We included a total of 10 studies [17][18][19][24][25][26][27][28][29][30] in qualitative and quantitative analysis (meta-analysis).…”

Section: Description Of Included Studiesmentioning

confidence: 99%

“…Dosing algorithm was highly variable. 24,[31][32][33][34][35][36][37][38] Percentage TTR All studies but one 30 reported on this outcome, and all the studies except one used a standard linear interpolation method between successive INR values to calculate % TTR. 21 Hillman et al 25 did not report on the method used to calculate this variable.…”

Section: Description Of Included Studiesmentioning

confidence: 99%

“…Studies reported on TMD as either mean, 26,29,30 median, 19,28 or HR. 18,19,24,29,30 Th e pooled estimates of HRs ( Fig 4 ) showed that the GD resulted in signifi cantly shorter TMD (HR, Fig 5 ).…”

Section: Time To Maintenance Dosementioning

confidence: 99%

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Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin

Dahal

Sharma

Fung

et al. 2015

CHEST

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BACKGROUND:Warfarin is a widely prescribed anticoagulant, and its eff ect depends on various patient factors including genotypes. Randomized controlled trials (RCTs) comparing genotypeguided dosing (GD) of warfarin with standard dosing have shown mixed effi cacy and safety outcomes. We performed a meta-analysis of all published RCTs comparing GD vs standard dosing in adult patients with various indications of warfarin use.

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Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty

Gage

Bass

Lin

et al. 2017

JAMA

207

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IMPORTANCE Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.OBJECTIVE To determine whether genotype-guided dosing improves the safety of warfarin initiation. DESIGN, SETTING, AND PATIENTSThe randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.INTERVENTIONS Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. MAIN OUTCOMES AND MEASURESThe primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. RESULTS Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths.CONCLUSIONS AND RELEVANCE Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing.

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Clinical Application of Pharmacogenetic-Based Warfarin-Dosing Algorithm in Patients of Han Nationality after Rheumatic Valve Replacement: A Randomized and Controlled Trial

Cited by 46 publications

References 13 publications

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty

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