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Front Cardiovasc Med 2022 10;9:895169. Epub 2022 Jun 10.

Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.

Warfarin has been widely used as an oral anticoagulant agent. In past, efforts have been done to study the contribution of genetic variation on warfarin dose requirements. The possible therapeutic dose determination of warfarin is very challenging, i. Read More

Pharmacogenomics 2022 Jun 24;23(8):475-485. Epub 2022 May 24.

Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Kerala, 695011, India.

Vitamin K antagonists (VKAs) are class I oral anticoagulants that are widely prescribed following surgical heart valve implantation. The objective of this study was to quantify the relative effects of and genotypes in predicting VKA dosing. A total of 506 South Indian patients with mechanical prosthetic heart valves who were prescribed oral VKAs, such as warfarin or acenocoumarol, were genotyped. Read More

BMC Cardiovasc Disord 2022 04 19;22(1):183. Epub 2022 Apr 19.

Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road #2, Beijing, 100029, China.

Objective: To explore the role of genetic testing of VKORC1 and CYP2C9 in determining the dosage of warfarin after aortic valve replacement.

Methods: A total of 172 patients receiving warfarin after aortic valve replacement were divided into a control group (n = 86) and an experimental (n = 86) group based on acceptance of genetic testing. In the experimental group, three loci of VKORC1 and CYP2C9 were tested by polymerase chain reaction-restriction fragment length polymorphism technique, and the initial dose of warfarin was determined based on the genetic testing results and warfarin oral-dose table recommended by U. Read More

Int J Clin Pharm 2022 Jun 5;44(3):599-607. Epub 2022 Mar 5.

School of Pharmacy, University of Florida, Gainesville, USA.

Background For decades, vitamin K antagonists and specifically warfarin, have been the sole agents used orally to manage thromboembolic conditions, including stroke and venous thromboembolism (VTE). Several factors lead to warfarin dose variability, including genetic and non-genetic factors which made warfarin management challenging especially at the initiation phase. To overcome the challenges with warfarin dosing at initiation, strategies other than conventional or fixed dosing were introduced and explored. Read More

Pharmacogenomics 2022 01 10;23(2):85-95. Epub 2022 Jan 10.

Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, Chicago, IL 60612, USA.

We evaluated the clinical acceptance and feasibility of a pharmacist-guided personalized consult service following its transition from a mandatory (mPGx) to optional (oPGx) // genotyping for warfarin. A total of 1105 patients were included. Clinical acceptance and feasibility outcomes were analyzed using bivariate and multivariable analyses. Read More

Genes (Basel) 2021 09 28;12(10). Epub 2021 Sep 28.

Department of Neurology, National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan.

The genotypes of vitamin K epoxide reductase complex 1 () and cytochrome P450 2C9 () can influence therapeutic warfarin doses. Conversely, nongenetic factors, especially renal function, are associated with warfarin maintenance doses; however, the optimal algorithm for considering genes and renal dysfunction has not been established. This single-center prospective cohort study aimed to evaluate the factors affecting warfarin maintenance doses and develop pharmacogenetics-guided algorithms, including the factors of renal impairment and others. Read More

J Thromb Haemost 2021 12 29;19(12):2957-2973. Epub 2021 Sep 29.

Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Background: Warfarin dose variability observed in patients is attributed to variation in genes involved in the warfarin metabolic pathway. Genetic variation in CYP2C9 and VKORC1 has been the traditional focus in evaluating warfarin dose variability, with little focus on other genes.

Objective: We set out to evaluate 27 single nucleotide polymorphisms (SNPs) in the CYP2C cluster loci and 8 genes (VKORC1, ABCB1, CYP2C9, CYP2C19, CYP2C8, CYP1A2, CYP3A4, and CYP3A5) involved in pharmacokinetics of warfarin. Read More

Drug Metab Pharmacokinet 2021 Aug 9;39:100362. Epub 2020 Oct 9.

Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address:

Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. Read More

Eur Heart J Case Rep 2021 Jun 5;5(6):ytab206. Epub 2021 Jun 5.

Service d'hématologie biologique, Hôpital Lariboisière, 2rue Ambroise Pare ´,75010 Paris, Université de Paris, Paris, France.

Background: Severe acute respiratory syndrome coronavirus 2 disease is strongly associated with a high incidence of thrombotic events. Anticoagulation could be a cornerstone in successfully managing severe forms of coronavirus disease 2019 (COVID-19). However, optimal anticoagulant dosing in elderly patients is challenging because of high risk of both thrombosis and bleeding. Read More

Pediatr Cardiol 2021 Jun 10;42(5):1082-1087. Epub 2021 Apr 10.

Heart Failure, Transplant and Mechanical Assistance Program Unit, Bambino Gesù Children Hospital, Rome, Italy.

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. Read More

Pharmacol Rep 2021 Oct 3;73(5):1405-1417. Epub 2021 Apr 3.

RCSI-MUB, Manama, Kingdom of Bahrain.

Background: Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability.

Methods: A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6 months. Read More

J Thromb Haemost 2021 07 21;19(7):1676-1686. Epub 2021 Apr 21.

Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea.

Background: Personalized warfarin dosing is influenced by various factors including genetic and non-genetic factors. Multiple linear regression (LR) is known as a conventional method to develop predictive models. Recently, machine learning approaches have been extensively implemented for warfarin dosing due to the hypothesis of non-linear association between covariates and stable warfarin dose. Read More

Iran J Pharm Res 2020 ;19(3):77-85

Department of Cardiovascular Surgery, Seyyed-al-Shohada Heart Center, Urmia University of Medical Sciences, Urmia, Iran.

The requirement of varying doses of warfarin for different individuals can be explained by environmental and genetic factors. We evaluated the frequency of vitamin K epoxide reductase complex subunit 1 () and cytochrome P450 2C9 () variants together with patientdemographic characteristics and investigated their association with warfarin dose requirement with the objective to suggest a warfarin dosing algorithm. In this study, 185 patients with heart valve replacement from West Azerbaijan, Iran were genotyped for (-1639 G>A) and (*2 and *3 alleles) by PCR-RFLP. Read More

Front Pharmacol 2021 11;12:619339. Epub 2021 Feb 11.

The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Beijing, China.

Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 () and vitamin K epoxide reductase complex subunit 1 () genes among 120 patients taking warfarin. Read More

J Clin Pharm Ther 2021 Jun 21;46(3):640-648. Epub 2020 Dec 21.

Department of Dental Training, Ministry of Health, Manama, Kingdom of Bahrain.

What Is Known And Objectives: Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.

Methods: Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Read More

Pharmacotherapy 2021 03 21;41(3):265-276. Epub 2020 Dec 21.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Introduction: Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian subpopulation numbering over 278,000 in the United States whose participation in genetics-based research is virtually nonexistent. Read More

Br J Clin Pharmacol 2021 04 18;87(4):1717-1729. Epub 2020 Nov 18.

The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, United Kingdom.

Aims: Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms.

Methods: We systematically searched MEDLINE up to 20 May 2020 and selected studies describing the development, external validation or clinical utility of a multivariable warfarin dosing algorithm. Read More

Indian J Thorac Cardiovasc Surg 2019 Oct 22;35(4):539-547. Epub 2019 Apr 22.

Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India.

Purpose: Vitamin K antagonists (VKAs), such as warfarin and acenocoumarol, exert their anti-coagulant effect by inhibiting the subunit 1 of vitamin K epoxide reductase complex (VKORC1). CYP2C9 is a hepatic drug-metabolizing enzyme in the CYP450 superfamily and is the primary metabolizing enzyme of warfarin. Three single nucleotide polymorphisms, two in the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, and one in the VKORC1 gene (c. Read More

Front Pharmacol 2020 14;11:1041. Epub 2020 Jul 14.

Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL, United States.

Background: Tight monitoring of efficacy and safety of anticoagulants such as warfarin is imperative to optimize the benefit-risk ratio of anticoagulants in patients. The standard tests used are measurements of prothrombin time (PT), usually expressed as international normalized ratio (INR), and activated partial thromboplastin time (aPTT).

Objective: To leverage a previously developed quantitative systems pharmacology (QSP) model of the human coagulation network to predict INR and aPTT for warfarin and rivaroxaban, respectively. Read More

Front Pharmacol 2020 10;11:1014. Epub 2020 Jul 10.

Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Objectives: To verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics.

Methods: According to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. Read More

J Clin Pharm Ther 2020 Dec 24;45(6):1466-1473. Epub 2020 Jul 24.

Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China.

What Is Known And Objective: Warfarin is an oral anticoagulant which has been widely used to treat and prevent thromboembolic events. Managing warfarin therapy requires careful monitoring and dose titration. This randomized controlled study was designed to assess the effect of genotype-guided warfarin anticoagulation in Chinese elderly patients with nonvalvular atrial fibrillation. Read More

Curr Med Res Opin 2020 09 28;36(9):1433-1439. Epub 2020 Jul 28.

Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.

Objective: The sex, age, medical history, treatment, tobacco use, race risk (SAMe-TTR) Score; the sex, age, medical history, treatment, tobacco use, genotype combination (SAMe-TTG) Score; and the so-called modified SAMe-TTR scores have been proposed to predict the anticoagulation quality for patients with non-valvular atrial fibrillation (NVAF). The data from a prospective controlled study is used to validate the SAMe-TTR and SAMe-TTG scores in Chinese NVAF patients treated with warfarin and to evaluate the association of factors with time in therapeutic range (TTR) to predict the quality of oral anticoagulation control.

Methods: A total of 379 patients with NVAF under warfarin treatment for a three-month follow-up were included in this prospective, multicenter study. Read More

Pharmacogenomics 2020 08 19;21(12):863-870. Epub 2020 Jun 19.

Department of Electrocardiogram Room, 900 Hospital of The Joint Logistics Team, 156 North Road, West 2nd Ring Road, Fuzhou, Fujian, 350000, PR China.

This study was conducted to investigate the effects of , , and  and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population.  16 variants of , , and were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Read More

Circ Genom Precis Med 2020 08 8;13(4):e002602. Epub 2020 Jun 8.

Department of Cardiology, First People's Hospital of Xiangtan City, China (F.X.).

Background: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients.

Methods: We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Read More

PLoS One 2020 19;15(5):e0233316. Epub 2020 May 19.

Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, United States of America.

Oral anticoagulant (OAC) therapy has been the main treatment approach for stroke prevention for decades. Warfarin is the most widely prescribed OAC in the United States, but is difficult to manage due to variability in dose requirements across individuals. Pharmacogenomics may mitigate risk concerns related to warfarin use by fostering the opportunity to facilitate individualized medicine approaches to warfarin treatment (e. Read More

Sci Rep 2020 04 24;10(1):6988. Epub 2020 Apr 24.

College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea.

This prospective, single-blind, randomized study was designed to evaluate the effect of genotype-based warfarin dosing compared with standard warfarin dosing in Korean patients with mechanical cardiac valves. Patients were assigned to either the genotype-based dosing group or the standard dosing group using stratified block randomization. The genotype-based dosing equation was adopted from a previous study which included VKORC1 rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, and age. Read More

Front Pharmacol 2020 6;11:325. Epub 2020 Apr 6.

Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago, Chile.

Background: Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables. Read More

Clin Transl Sci 2020 09 9;13(5):941-949. Epub 2020 Apr 9.

Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug-drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9-interacting drugs on long-term measures of warfarin anticoagulation. Read More

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620909154

Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago, Chile.

Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. Read More

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Apr;37(4):401-404

Qingdao Fuwai Cardiovascular Hospital, Qingdao, Shandong 266034, China.

Objective: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population.

Methods: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Read More