Warfarin Dose Reduction vs Watchful Waiting for Mild Elevations in the International Normalized Ratio*

Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.

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Inductive Effect of a Ritonavir-Containing Hepatitis C Treatment Regimen on Warfarin in a Patient—A Case Report

Journal of Pharmacy Practice ◽

10.1177/0897190018758541 ◽

2018 ◽

Vol 32 (4) ◽

pp. 470-473 ◽

Cited By ~ 2

Author(s):

Audrey C. Rosene ◽

Jaymee L. Gaspar

Keyword(s):

Hepatitis C ◽

Treatment Regimen ◽

Case Reports ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Close Monitoring ◽

Anticoagulation Management ◽

Hepatitis C Treatment ◽

History Of ◽

Repeated Use

The warfarin management strategy for a mechanical mitral valve patient initiated on a ritonavir-based hepatitis C treatment regimen is described. A 62-year-old male with a past medical history of hepatitis C genotype 1a and stable warfarin dose history was initiated on a concomitant Viekira Pak® (VP) regimen containing ritonavir. Prior to initiation of the VP for hepatitis C treatment, the patient was stable on a warfarin dose of 40 mg/wk for 5 months. During treatment with VP, the patient experienced a markedly decreased international normalized ratio (INR) and warfarin requirements ultimately increased 125% from baseline (90 mg/wk). Effective anticoagulation management throughout and surrounding the treatment period for hepatitis C involved frequent warfarin dose adjustments, including preemptive changes, close monitoring, and repeated use of enoxaparin to ensure adequate thrombotic prophylaxis. This is believed to be the first reported case describing the management of warfarin in a patient with hepatitis C who received VP and required a drastically increased weekly warfarin dose. The possible mechanisms suggestive of this interaction and similar case reports in the literature are discussed.

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Evaluation of dosing and safety outcomes of low-dose prophylactic warfarin in children after cardiothoracic surgery

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxaa111 ◽

2020 ◽

Vol 77 (13) ◽

pp. 1018-1025

Author(s):

Maura Harkin ◽

Brittany Powers Shaddix ◽

Stephen B Neely ◽

Leigh A Peek ◽

Katy Stephens ◽

...

Keyword(s):

Low Dose ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Primary Objective ◽

Cardiothoracic Surgery ◽

Entire Study Period ◽

Entire Study ◽

Frequent Monitoring ◽

Safety Outcomes ◽

Warfarin Dosing

Abstract Purpose Prophylactic warfarin with an International Normalized Ratio (INR) goal of 1.5 to 2.0 is one antithrombotic therapy utilized in children after cardiothoracic surgery (CTS); published sources suggest a dose of 0.1 mg/kg per day to achieve this goal. However, few studies have evaluated dosing in this population. The purpose of this study was to evaluate dosing and safety outcomes in children receiving warfarin after CTS. Methods A descriptive, retrospective review was conducted to evaluate warfarin dosing and INR outcomes in patients 18 years of age or younger who underwent CTS and received prophylactic warfarin with an INR goal of 1.5 to 2.0 from January 2014 through December 2018. The primary objective was to determine the median initial warfarin dose. Secondary objectives included identifying the percentage of documented INR values that were outside the therapeutic range, the percentage of patients with therapeutic INRs at discharge, and the 30-day readmission rate. Results Twenty-six patients were included in the review. The median initial warfarin dosage was 0.07 mg/kg/d (interquartile range [IQR], 0.05-0.10 mg/kg/d). Of the total of 177 INR values collected during the entire study period, 67 (37.9%) were therapeutic, 64 (36.2%) were subtherapeutic, and 46 (26.0%) were supratherapeutic. Eighteen patients (69.2%) had at least 1 supratherapeutic INR at any point during the study period, most frequently on days 2 through 4 of therapy. At discharge, 11 patients (42.3%) had therapeutic INRs. Four patients (15.4%) were readmitted within 30 days, with bleeding documented in 2 patients during their readmission. Conclusion The majority of patients received an initial warfarin dose less than that specified in published recommendations but still had a supratherapeutic INR at least once during the study period. When initiating warfarin after CTS, a dosage of <0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.

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Preliminary outcomes of preemptive warfarin pharmacogenetic testing at a large rural healthcare center

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxy072 ◽

2019 ◽

Vol 76 (6) ◽

pp. 387-397 ◽

Cited By ~ 2

Author(s):

Emili Leary ◽

Murray Brilliant ◽

Peggy Peissig ◽

Sara Griesbach

Keyword(s):

Care Service ◽

Anticoagulation Therapy ◽

Warfarin Dose ◽

Standard Of Care ◽

International Normalized Ratio ◽

Preliminary Evaluation ◽

Thromboembolic Events ◽

Rural Healthcare ◽

Pharmacogenetic Testing ◽

Warfarin Dosing

Abstract Purpose As a preliminary evaluation of the outcomes of implementing pharmacogenetic testing within a large rural healthcare system, patients who received pre-emptive pharmacogenetic testing and warfarin dosing were monitored until June 2017. Summary Over a 20-month period, 749 patients were genotyped for VKORC1 and CYP2C9 as part of the electronic Medical Records and Genomics Pharmacogenetics (eMERGE PGx) study. Of these, 27 were prescribed warfarin and received an alert for pharmacogenetic testing pertinent to warfarin; 20 patients achieved their target international normalized ratio (INR) of 2.0–3.0, and 65% of these patients achieved target dosing within the recommended pharmacogenetic alert dose (± 0.5 mg/day). Of these, 10 patients had never been on warfarin prior to the alert and were further evaluated with regard to time to first stable target INR, bleeds and thromboembolic events, hospitalizations, and mortality. There was a general trend of faster time to first stable target INR when the patient was initiated at a warfarin dose within the alert recommendation versus a dose outside of the alert recommendation with a mean (± SD) of 34 (± 28) days versus 129 (± 117) days, respectively. No trends regarding bleeds, thromboembolic events, hospitalization, or mortality were identified with respect to the pharmacogenetic alert. The pharmacogenetic alert provided pharmacogenetic dosing information to prescribing clinicians and appeared to deploy appropriately with the correct recommendation based upon patient genotype. Conclusion Implementing pharmacogenetic testing as a standard of care service in anticoagulation monitoring programs may improve dosage regimens for patients on anticoagulation therapy.

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The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on Optimal Warfarin Doses After Heart Valve Replacement

Medicina ◽

10.3390/medicina47010004 ◽

2011 ◽

Vol 47 (1) ◽

pp. 4 ◽

Cited By ~ 1

Author(s):

◽

Keyword(s):

Valve Replacement ◽

Heart Valve ◽

Heart Surgery ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Heart Valve Replacement ◽

Warfarin Dosage ◽

Individualize Treatment ◽

The Impact ◽

Vkorc1 Gene

A clinical effect of warfarin depends on highly polymorphic drug-metabolizing (CYP2C9) and drug-target (VKORC1) enzymes. The objective of this study was to investigate the impact of CYP2C9*2, CYP2C9*3, and VKORC1 (G-1639A) polymorphisms on the variability of warfarin dosage requirements in Lithuanian patients after heart valve replacement. Materials and Methods. The study included 83 patients with a mean age of 65.2 years (SD, 13.31) after heart valve replacement with an achieved stable international normalized ratio of 2–3.5. The restriction fragment length polymorphism method was used to identify polymorphisms of VKORC1 and CYP2C9. Results. Daily warfarin dosage significantly correlated with weight (r=0.4087) and height (r=0.3883) of the patients. Patients younger than 60 years required significantly higher daily warfarin dosages than older patients. Two-thirds (66.3%) of the patients had the wild-type (WT) CYP2C9* 1/*1 genotype; 38.6% and 54.2% of the patients had WT VKORC1 (G/G) and VKORC1 (G/A) genotypes, respectively. WT CYP2C9*1/*1 genotype was associated with a higher daily warfarin dosage (5.84 mg [SD, 2.84]) as compared to other CYP2C9 genotypes. Carriers of WT VKORC1 (G/G) required a higher warfarin dose as compared to (A/A) carriers (6.20±2.78 mg and 3.75±1.40 mg, respectively; P=0.04). Patients having CYP2C9*1/*1 or 1/*2 in combination with VKORC1 (G/G) or (G/A) genotypes required the highest daily warfarin dosage in comparison to other combinations of genotypes. Conclusions. The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose. Analysis of combined CYP2C9 and VKORC1 gene variants allows the prediction of warfarin dosage. These results can be used to individualize treatment with warfarin in the field of heart surgery in Lithuania.

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Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

Blood ◽

10.1182/blood-2011-07-365502 ◽

2012 ◽

Vol 119 (3) ◽

pp. 861-867 ◽

Cited By ~ 52

Author(s):

Caroline Moreau ◽

Fanny Bajolle ◽

Virginie Siguret ◽

Dominique Lasne ◽

Jean-Louis Golmard ◽

...

Keyword(s):

Vitamin K ◽

Dose Response ◽

Maintenance Dose ◽

Vitamin K Antagonists ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Individual Variability ◽

Dose Requirement ◽

Warfarin Dose Requirement ◽

Main Determinants

Abstract Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

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Warfarin dose adjustment required after cannabidiol initiation and titration

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxaa268 ◽

2020 ◽

Vol 77 (22) ◽

pp. 1846-1851

Author(s):

Josh Cortopassi

Keyword(s):

Case Report ◽

Interaction Potential ◽

Significant Interaction ◽

Dose Adjustment ◽

Intractable Epilepsy ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Dose Titration ◽

Published Report ◽

Clinically Significant

Abstract Purpose A case of a possible interaction between cannabidiol and warfarin is presented along with a brief overview of cytochrome enzymes involved in these drugs’ metabolism. Summary A 46-year-old male taking warfarin for treatment of a deep venous thrombosis was initiated on a Food and Drug Administration (FDA)–approved cannabidiol product (Epidiolex, Greenwich Biosciences) for intractable epilepsy. The patient’s International Normalized Ratio (INR) was monitored closely during cannabidiol initiation and dose titration. The patient required a nearly 20% warfarin dose reduction to maintain an INR within the goal range after starting therapy with cannabidiol. There is 1 other case report describing a clinically significant interaction between cannabidiol (specifically Epidiolex) and warfarin in a patient receiving warfarin who was enrolled in a study involving the initiation and titration of cannabidiol; that patient developed a supratherapeutic INR of 6.86 and required a 30% reduction in the weekly warfarin dose to reachieve the goal INR. Conclusion A previously published report suggesting an interaction between cannabidiol and warfarin is supported by this case report. INR should be monitored frequently in patients taking warfarin who begin to take FDA-approved cannabidiol. Additional studies should be performed to clarify the interaction potential of cannabidiol and warfarin.

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Patient Factors That Influence Warfarin Dose Response

Journal of Pharmacy Practice ◽

10.1177/0897190010362177 ◽

2010 ◽

Vol 23 (3) ◽

pp. 194-204 ◽

Cited By ~ 19

Author(s):

Pamela J. White

Keyword(s):

Dose Response ◽

Warfarin Therapy ◽

Anticoagulation Therapy ◽

Warfarin Dose ◽

Therapeutic Index ◽

International Normalized Ratio ◽

Patient Factors ◽

Disease States ◽

Treatment And Prevention ◽

Number Of Factors

Warfarin has long been the mainstay of oral anticoagulation therapy for the treatment and prevention of venous and arterial thrombosis. The narrow therapeutic index of warfarin, and the complex number of factors that influence international normalized ratio (INR) response, makes optimization of warfarin therapy challenging. Determination of the appropriate warfarin dose during initiation and maintenance therapy requires an understanding of patient factors that influence dose response: age, body weight, nutritional status, acute and chronic disease states, and changes in concomitant drug therapy and diet. This review will examine specific clinical factors that can affect the pharmacokinetics and pharmacodynamics of warfarin, as well as the role of pharmacogenetics in optimizing warfarin therapy.

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Intrahospital Correlation of the International Normalized Ratio

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029608315167 ◽

2008 ◽

Vol 15 (2) ◽

pp. 220-224 ◽

Cited By ~ 1

Author(s):

Alejandro Lazo-Langner ◽

Rosario Villa-Márquez ◽

Darinel Hernández-Hernández ◽

Sonia Rojas-Maya ◽

Josefa Piedras

Keyword(s):

Oral Anticoagulant Therapy ◽

Warfarin Dose ◽

Correlation Coefficients ◽

Coagulation Factors ◽

International Normalized Ratio ◽

Rabbit Brain ◽

Clinical Use ◽

Altman Analysis ◽

Bland Altman Analysis ◽

Highly Sensitive

Background. Monitoring of oral anticoagulant therapy (OAT) is usually accomplished by measuring prothrombin time and the international normalized ratio (INR). However, thromboplastins have different responsiveness and sensitivity to vitamin K—dependent coagulation factors depletion. Several studies have shown INR variation when low sensitive thromboplastins are used. This study compared INR variability between two laboratories using highly sensitive thromboplastins. Methods. A total of 237 plasmas were tested, half of them from patients under OAT. Samples were tested simultaneously in two laboratories: in laboratory A, a Behring Coagulation Timer instrument and a human recombinant thromboplastin (Innovin, Dade Behring) (ISI 1.01) were used. In laboratory B, a Thrombolyzer Compact (Behnk Elektronik) and a rabbit brain thromboplastin (Simplastin Excel S, Organon Teknika) with an ISI of 1.30 were used. Statistical analysis was carried out according to the method of Bland and Altman. Results. Even though high correlation coefficients were obtained when comparing both laboratories, Bland—Altman analysis showed a variation of INR between laboratories ranging from −0.77 to +1.07. After logarithmic transformation of data, these values yielded a variation of the INR either 25% below or 44% above. Conclusions. These results are clearly inadequate for clinical use because such a variation would most probably induce the clinician to make a change in warfarin dose. Standardization of instruments, reagents, and controls is warranted to decrease this variation.

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Continuous use of low-dose warfarin for gastric endoscopic submucosal dissection: a prospective study

Endoscopy International Open ◽

10.1055/s-0043-105493 ◽

2017 ◽

Vol 05 (05) ◽

pp. E348-E353 ◽

Cited By ~ 11

Author(s):

Hideaki Harada ◽

Satoshi Suehiro ◽

Daisuke Murakami ◽

Takanori Shimizu ◽

Ryotaro Nakahara ◽

...

Keyword(s):

Endoscopic Submucosal Dissection ◽

Low Dose ◽

Postoperative Bleeding ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Safety And Efficacy ◽

Submucosal Dissection ◽

Day Range ◽

Dose Warfarin ◽

Significant Difference

Abstract Background and study aims Patients who receive warfarin usually require heparin bridge therapy (HBT) to prevent thromboembolic events during endoscopic submucosal dissection (ESD); however, clinical evidence demonstrating the safety and efficacy of HBT during gastric ESD is limited. Conversely, warfarin can be continuously used as a substitute for HBT to endoscopic procedures which have a low risk of bleeding. This study aimed to clarify the safety and efficacy of continuous low-dose warfarin (LDW) for gastric ESD. Patients and methods This was a prospective observational study at a single institution. A total of 22 patients who received warfarin between December 2014 and January 2016 were enrolled. The patients were treated with gastric ESD with a low dose of warfarin ( ≤ 4 mg) at approximately 1.6 – 2.6 of the international normalized ratio (INR) levels. Furthermore, we analyzed a total of 23 patients with HBT who underwent gastric ESD between January 2011 and November 2014. Results The average of warfarin dose and the INR level on the day of gastric ESD in the continuous LDW group were 2.3 mg/day (range 0.5 – 4.0) and 1.87 (range 1.41 – 2.75), respectively. Two of the 22 patients (9.1 %) in the continuous LDW group and 5 of the 23 patients (21.7 %) in the HBT group had postoperative bleeding after gastric ESD. Although the postoperative bleeding rate in the continuous LDW group was lower than that in the HBT group, no significant difference was observed between the 2 groups (P = 0.414). Conclusions Gastric ESD with continuous LDW as a substitute for HBT was feasible and may be acceptable.

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