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

2019 ◽  
Vol 76 (6) ◽  
pp. 387-397 ◽  
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.

scholarly journals An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance

2016 ◽  
Vol 116 (08) ◽  
pp. 337-348 ◽  
Author(s):  
Payman Shahabi ◽  
Laura Scheinfeldt ◽  
Daniel Lynch ◽  
Tara Schmidlen ◽  
Sylvie Perreault ◽  
...  
Keyword(s):  
Standard Dose ◽  
Anticoagulation Therapy ◽  
Standard Of Care ◽  
Clinical Decision ◽  
Drug Label ◽  
Therapy Decision ◽  
Dosing Algorithm ◽  
The Us ◽  
Supplementary Material ◽  
Warfarin Dosing

SummaryPharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar’s two-sided p=0.02; 52 % vs 37 % in the QWC, p<1×10−6). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1×10−6) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label.Supplementary Material to this article is available at www.thrombosis-online.com.

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

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 &lt;0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.

Patient Factors That Influence Warfarin Dose Response

2010 ◽  
Vol 23 (3) ◽  
pp. 194-204 ◽  
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.

Dietary Vitamin K Variability Affects International Normalized Ratio (INR) Coagulation Indices

2006 ◽  
Vol 76 (2) ◽  
pp. 65-74 ◽  
Author(s):  
Rebecca Couris ◽  
Gary Tataronis ◽  
William McCloskey ◽  
Lynn Oertel ◽  
Gerard Dallal ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Vitamin K ◽  
Warfarin Therapy ◽  
Anticoagulation Therapy ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Adverse Outcomes ◽  
Dietary Vitamin ◽  
Prescription Medications ◽  
Oral Warfarin

Background: Changes in daily vitamin K intake may contribute to marked variations in the International Normalized Ratio (INR) coagulation index in patients receiving oral warfarin anticoagulant therapy, with potentially serious adverse outcomes. Thus, patients receiving warfarin therapy are routinely counseled regarding this drug-nutrient interaction and are instructed to maintain consistent vitamin K intakes, though little quantitative information about this relationship is available. Objective: To determine the quantitative impact of variability in dietary vitamin K1 (phylloquinone) intake, assessed by a validated patient self-monitoring instrument, on weekly INR in patients receiving warfarin anticoagulant therapy. Methods: A prospective dietary assessment study was conducted at the Massachusetts General Hospital in Boston. Sixty outpatients (37 males and 23 females) were selected with a mean age 60.3 ± 16.8 years, who began oral warfarin anticoagulant therapy within 14 days prior to their first clinic visit to an outpatient anticoagulation therapy unit. Exclusion criteria included more than 2 drinks of alcohol per day, inability to speak English, and concurrent disease states affecting warfarin therapy such as liver disease and terminal illness. Over the five-week study period, participants recorded daily intakes in specified amounts of all food items appearing on a validated dietary self-assessment tool. Concomitant use of prescription and/or non-prescription medications was also obtained. Concurrent daily warfarin dose and adherence to the drug regimen, concomitant use of prescription and/or non-prescription medications known to interact with warfarin, and weekly INR were obtained. Week-to-week changes in vitamin K intake, warfarin dose, and INR were determined and cross-correlated. Results: Forty-three patients (28 males and 15 females) completed the study and 17 dropped out. Pearson’s correlation coefficient revealed the variability in INR and changes in vitamin K intake were inversely correlated (r = –0.600, p < 0.01). Multiple regression analysis (r = 0.848) indicated that a weekly change of 714 mug dietary vitamin K significantly altered weekly INR by 1 unit (p < 0.01) and a weekly change of 14.5 mg warfarin significantly altered weekly INR by 1 unit (p < 0.01) after adjustment for age, sex, weight, height, and concomitant use of medications known to interact with warfarin. Conclusions: Patients taking warfarin and consuming markedly changing amounts of vitamin K may have a variable weekly INR with potentially unstable anticoagulant outcomes.

scholarly journals Updates on Anticoagulation and Laboratory Tools for Therapy Monitoring of Heparin, Vitamin K Antagonists and Direct Oral Anticoagulants

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 264
Author(s):  
Osamu Kumano ◽  
Kohei Akatsuchi ◽  
Jean Amiral
Keyword(s):  
Dose Adjustment ◽  
Therapy Monitoring ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Monitoring Methods ◽  
Anticoagulant Drugs

Anticoagulant drugs have been used to prevent and treat thrombosis. However, they are associated with risk of hemorrhage. Therefore, prior to their clinical use, it is important to assess the risk of bleeding and thrombosis. In case of older anticoagulant drugs like heparin and warfarin, dose adjustment is required owing to narrow therapeutic ranges. The established monitoring methods for heparin and warfarin are activated partial thromboplastin time (APTT)/anti-Xa assay and prothrombin time – international normalized ratio (PT-INR), respectively. Since 2008, new generation anticoagulant drugs, called direct oral anticoagulants (DOACs), have been widely prescribed to prevent and treat several thromboembolic diseases. Although the use of DOACs without routine monitoring and frequent dose adjustment has been shown to be safe and effective, there may be clinical circumstances in specific patients when measurement of the anticoagulant effects of DOACs is required. Recently, anticoagulation therapy has received attention when treating patients with coronavirus disease 2019 (COVID-19). In this review, we discuss the mechanisms of anticoagulant drugs—heparin, warfarin, and DOACs and describe the methods used for the measurement of their effects. In addition, we discuss the latest findings on thrombosis mechanism in patients with COVID-19 with respect to biological chemistry.

scholarly journals Warfarin Interaction With Hepatic Cytochrome P-450 Enzyme-Inducing Anticonvulsants

2017 ◽  
Vol 24 (1) ◽  
pp. 172-178 ◽  
Author(s):  
Nathan P. Clark ◽  
Kim Hoang ◽  
Thomas Delate ◽  
John R. Horn ◽  
Daniel M. Witt
Keyword(s):  
Warfarin Therapy ◽  
Therapeutic Response ◽  
Warfarin Dose ◽  
Clinical Information ◽  
International Normalized Ratio ◽  
The Mean ◽  
Warfarin Dosing ◽  
Meaningful Interaction ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

Initiation of cytochrome P-450 (CYP)-inducing anticonvulsant medications during warfarin therapy may decrease anticoagulant effect and necessitate frequent warfarin dose adjustments to maintain therapeutic response measured by the international normalized ratio (INR). Clinical information regarding interactions between warfarin and these medications is limited. This study investigated warfarin dose and INR response following CYP-inducing anticonvulsant initiation among chronic warfarin users. This retrospective, pre-post study included patients ≥18 years who were receiving chronic warfarin therapy and who initiated carbamazepine, oxcarbazepine, phenobarbital, or phenytoin between January 1, 2006, and December 31, 2013. Mean weekly warfarin dose/INR ratio and mean weekly warfarin dose were compared in the 90 days pre- and days post-anticonvulsant initiation periods. Of the 57 included patients, 34 (60%), 15 (26%), 6 (11%), and 2 (3%) patients purchased a prescription for carbamazepine, phenytoin, oxcarbazepine, and phenobarbital, respectively. Mean age was 70 years, 59% were female, and the majority were receiving chronic warfarin therapy for atrial fibrillation (39%) or venous thromboembolism (26%). The ratio of mean warfarin dose and INR increased significantly between the pre- and post-anticonvulsant initiation periods (from 13 mg/INR to 18 mg/INR, respectively, P ≤ .001) as did the mean weekly warfarin dose (from 33 mg to 37 mg, P = <.001). Warfarin dose and dose/INR ratio significantly increased after carbamazepine initiation (both P < .001), while oxcarbazepine, phenobarbital, and phenytoin initiation did not significantly affect warfarin dosing. Our results support the presence of a clinically meaningful interaction between warfarin and carbamazepine. Frequent INR monitoring and warfarin dose escalation are recommended in this setting.

scholarly journals Warfarin Dosing in a Patient withCYP2C9*3*3andVKORC1-1639 AAGenotypes

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Mark Johnson ◽  
Craig Richard ◽  
Renee Bogdan ◽  
Robert Kidd
Keyword(s):  
Vitamin K ◽  
Adverse Drug Events ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
White Female ◽  
First Case ◽  
Increased Risk ◽  
Genes Encoding ◽  
Warfarin Dosing ◽  
Clinically Significant

Genetic factors most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR). Patients receiving warfarin who possess one or more genetic variations inCYP2C9andVKORC1are at increased risk of adverse drug events and require significant dose reductions to achieve a therapeutic international normalized ratio (INR). A 74-year-old white female with atrial fibrillation was initiated on a warfarin dose of 2 mg PO daily, which resulted in multiple elevated INR measurements and three clinically significant hemorrhagic events and four vitamin K antidote treatments over a period of less than two weeks. Genetic analysis later revealed that she had the homozygous variant genotypes ofCYP2C9*3*3andVKORC1-1639 AA. Warfarin dosing was subsequently restarted and stabilized at 0.5 mg PO daily with therapeutic INRs. This is the first case report of a white female with these genotypes stabilized on warfarin, and it highlights the value of pharmacogenetic testing prior to the initiation of warfarin therapy to maximize efficacy and minimize the risk of adverse drug events.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2329-2333 ◽  
Author(s):  
Elizabeth A. Sconce ◽  
Tayyaba I. Khan ◽  
Hilary A. Wynne ◽  
Peter Avery ◽  
Louise Monkhouse ◽  
...  
Keyword(s):  
Body Size ◽  
Warfarin Dose ◽  
Patient Characteristics ◽  
International Normalized Ratio ◽  
Dosing Regimen ◽  
Dose Requirement ◽  
Cyp2c9 Genotype ◽  
Daily Dose ◽  
Warfarin Dosing ◽  
The Impact

AbstractCurrent dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P &lt; .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P &lt; .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

scholarly journals Pharmacogenetic Warfarin Dosing Algorithm in the Russian Population

2019 ◽  
Vol 4 (3) ◽  
pp. 40-44
Author(s):  
T. A. Bairova ◽  
A. Yu. Sambyalova ◽  
L. V. Rychkova ◽  
E. A. Novikova ◽  
F. I. Belyalov ◽  
...  
Keyword(s):  
Ethnic Groups ◽  
Predictive Accuracy ◽  
Warfarin Dose ◽  
Absolute Error ◽  
International Normalized Ratio ◽  
Russian Population ◽  
Asian Patients ◽  
Performance Limitation ◽  
The Mean ◽  
Warfarin Dosing

Background. To date, there are many pharmacogenetic algorithms for selecting the dose of warfarin. However, there is very little information about the predictive accuracy of the algorithms. We decided to evaluate the predictive accuracy of the Gage algorithm, using a calculator, located on the web site (http://www.warfarindosing.org) in two ethnic groups (Caucasians and Asians), living in Russia.Aim. To compare the actual warfarin dose (AWD) to the calculated warfarin dose (CWD), using the algorithm in two ethnic groups taking warfarin.Materials and methods. We included 114 patients (66 Caucasians and 48 Asians): the mean age was60.91 ± 12.34 years; 61 (53.51 %) men, and 53 (46.49 %) women. The comparative characteristics of the algorithm were tested using the mean absolute error (MAE) between AWD and CWD, and percentage of patients, whose CWD fell within 20 % of AWD (percentage within 20 %). Genotyping for CYP2C9*2, CYP2C9*3, CYP4F*2 and VKORC1 was performed by real-time polymerase chain reaction (RT-PCR) method using Pharmacogenetics Warfarin reagent kits (DNA technology, Russia).Results. The Gage algorithm produced the predictive accuracy with MAE = 1.02 ± 0.16 mg/day and percentage within 20 % for Asian patients was 39.6 %. We obtained MAE = 1.33 ± 0.16 mg/day and percentage within 20 % for Caucasian patients was 40.9 %. In two ethnic groups (Caucasians and Asians) of the Russian population, overall performance of warfarin pharmacogenetic dosing by the Gage algorithm was similar.Conclusions. Despite the performance limitation of the current warfarin pharmacogenetic dosing Gage algorithm, constant international normalized ratio monitoring is important.

Levofloxacin and Warfarin Interaction

2002 ◽  
Vol 36 (10) ◽  
pp. 1554-1557 ◽  
Author(s):  
Cade B Jones ◽  
Susan E Fugate
Keyword(s):  
Binding Sites ◽  
Warfarin Therapy ◽  
Case Reports ◽  
Anticoagulation Therapy ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Minor Bleeding ◽  
Protein Binding Sites ◽  
Case Summary

OBJECTIVE: To report 4 cases of hypoprothrombotic response resulting from addition of levofloxacin therapy to chronic warfarin therapy and to review related literature to support or refute a warfarin—levofloxacin interaction. CASE SUMMARY: Four patients, 34–81 years old, were prescribed levofloxacin concomitantly with stable warfarin therapy. Three patients had a target international normalized ratio (INR) range of 2.0–3.0 and experienced an increase in INR to 3.5, 8.12, and 11.5 on days 11, 5, and 4 of a 10-day course of levofloxacin, respectively. The fourth patient experienced minor bleeding, with a slightly elevated INR on the second day of levofloxacin therapy that required up to a 19% warfarin dose reduction during levofloxacin treatment. DISCUSSION: An initial premarketing clinical trial concluded that levofloxacin had no effect on warfarin's pharmacokinetics and pharmacodynamic response. Two case reports have since documented an increase in INR in patients taking long-term warfarin on completion of levofloxacin therapy. Our case reports provide further evidence of a significant increase in INR observed during concomitant levofloxacin therapy. The proposed mechanism of this interaction is displacement of warfarin from protein binding sites, reduction in gut flora producing vitamin K, and decreased warfarin metabolism. CONCLUSIONS: Prolonged prothrombin response in patients undergoing chronic warfarin therapy has been well documented with many antibiotics, including fluoroquinolones. Recognition of newer antibiotics' effects on warfarin therapy is important to guide safe use and monitoring of anticoagulation therapy. Our case studies demonstrate significant elevations in INR values during and up to 1 day after levofloxacin therapy in patients undergoing stable warfarin therapy.

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