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.

scholarly journals Genetic-based dosing in orthopedic patients beginning warfarin therapy

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1511-1515 ◽  
Author(s):  
Eric A. Millican ◽  
Petra A. Lenzini ◽  
Paul E. Milligan ◽  
Leonard Grosso ◽  
Charles Eby ◽  
...  
Keyword(s):  
Warfarin Therapy ◽  
Smoking Status ◽  
Warfarin Dose ◽  
Therapeutic Index ◽  
International Normalized Ratio ◽  
Narrow Therapeutic Index ◽  
Therapy Initiation ◽  
Estimated Blood Loss ◽  
Epoxide Reductase ◽  
Orthopedic Patients

AbstractHigh variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and international normalized ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and preoperative and postoperative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression, we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four fifths of the variability in therapeutic dose (R2adj of 79%). Significant (P > .05) predictors were INR value after 3 doses (47% reduction per 0.25-unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (−38% and −17% per allele), estimated blood loss (interacting with INR3), smoking status (+20% in current smokers), and VKORC1 (−11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating 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.

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.

scholarly journals Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 578 ◽  
Author(s):  
Laith AL-Eitan ◽  
Ayah Almasri ◽  
Rame Khasawneh
Keyword(s):  
Warfarin Therapy ◽  
Catalytic Properties ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Cardiovascular Patients ◽  
Cyp2c9 Gene ◽  
Vkorc1 Gene

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.

Decreased Warfarin Effect after Initiation of High-Protein, Low-Carbohydrate Diets

2005 ◽  
Vol 39 (4) ◽  
pp. 744-747 ◽  
Author(s):  
Stuart J Beatty ◽  
Bella H Mehta ◽  
Jennifer L Rodis
Keyword(s):  
Serum Albumin ◽  
Warfarin Therapy ◽  
Anticoagulation Therapy ◽  
Warfarin Dose ◽  
High Protein ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate ◽  
High Protein Diets ◽  
Protein Diets

OBJECTIVE: To report 2 cases of decreased international normalized ratio (INR) after initiation of a high-protein, low-carbohydrate diet. CASE SUMMARIES: Case 1. A 67-year-old white woman had been receiving warfarin for 3 years for venous thromboembolism. After initiation of a high-protein, low-carbohydrate diet, the patient required a 22.2% increase (from 45 to 57.5 mg/wk) in warfarin dose. Her INR remained in the therapeutic range on this dose for 8 weeks. When the patient stopped the high-protein, low-carbohydrate diet, a decrease back to the original warfarin dose was required to return to a therapeutic INR. Case 2. A 58-year-old white man had been receiving warfarin for 8 years for a cerebrovascular accident. Initiation of a high-protein, low-carbohydrate diet resulted in a 30% increase (from 26.25 to 37.5 mg/wk) in warfarin dose. His warfarin dose was reduced to the original dose after he stopped the high-protein, low-carbohydrate diet. DISCUSSION: The Naranjo probability scale indicated a possible adverse effect between warfarin and high-protein diets. High-protein diets have been shown to increase serum albumin levels. This may result in more warfarin binding to serum albumin, thereby decreasing the anticoagulant effect of warfarin. The increase of albumin occurs rapidly after initiation of a high-protein diet and appears to promptly affect anticoagulation therapy with warfarin. CONCLUSIONS: These cases indicate a significant interaction between high-protein, low-carbohydrate diets and warfarin therapy. Patients receiving warfarin therapy should be educated on and monitored for the potential interaction that occurs with warfarin therapy and high-protein, low-carbohydrate diets.

scholarly journals Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

2016 ◽  
Vol 8 (4) ◽  
pp. 100
Author(s):  
Azza A. M. H. Swar Aldahab ◽  
Abdallah. O. Elkhawad
Keyword(s):  
Vitamin K ◽  
Genetic Factors ◽  
Warfarin Therapy ◽  
Anticoagulation Therapy ◽  
Warfarin Dose ◽  
Term Therapy ◽  
P Value ◽  
Retrospective Case ◽  
The Impact

Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G&gt;A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G&gt;A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G&gt;A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G&gt;A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.

International normalized ratio in anticoagulant therapy: understanding the issues

1997 ◽  
Vol 6 (2) ◽  
pp. 88-92 ◽  
Author(s):  
AL Severson ◽  
LR Baldwin ◽  
TG DeLoughery
Keyword(s):  
Anticoagulant Therapy ◽  
Warfarin Therapy ◽  
Healthcare Providers ◽  
Anticoagulation Therapy ◽  
International Normalized Ratio ◽  
Laboratory Methods ◽  
Current Monitoring

Recently, a change in anticoagulation therapy occurred that is still partially ignored by the healthcare community. Understanding the controversy over the use of the internal normalized ratio in monitoring patients receiving warfarin therapy is important for nurses who provide care to these patients. Five questions related to current monitoring of patients treated with anticoagulants are addressed. Nurses must recognize the importance to their practice of changes in laboratory methods and move toward using the most useful measures available to influence patients' outcomes. The international normalized ratio is the most appropriate way to evaluate the effects of warfarin therapy. All healthcare providers should use this ratio as the standard in evaluating the effects of anticoagulation therapy.

De Ritis ratio as a significant prognostic factor of international normalized ratio ≥4 in the initial 10 days of warfarin therapy

2019 ◽  
Vol 13 (18) ◽  
pp. 1599-1607
Author(s):  
Yide Cao ◽  
Ganyi Chen ◽  
Huangshu Li ◽  
Yafeng Liu ◽  
Zhonghao Tao ◽  
...  
Keyword(s):  
Valve Replacement ◽  
Heart Valve ◽  
Warfarin Therapy ◽  
Anticoagulation Therapy ◽  
International Normalized Ratio ◽  
Heart Valve Replacement ◽  
Significant Prognostic Factor ◽  
Replacement Surgery ◽  
The Relationship ◽  
Valve Replacement Surgery

Aim: To assess the relationship between the De Ritis ratio on admission and warfarin sensitivity in the initial 10 days of anticoagulation therapy. Methods: We retrospectively reviewed data from 906 patients who underwent heart valve replacement surgery. Results: A De Ritis ratio of 1.19 was identified as the optimal cutoff according to the ROC curve. Patients with a high De Ritis ratio achieved an international normalized ratio (INR) ≥4 more easily and earlier than those with a low De Ritis ratio in the initial 10 days of warfarin therapy. Multivariate analysis showed that a high De Ritis ratio was an independent predictor of an INR ≥4 (HR: 2.567; p < 0.001). Conclusion: A De Ritis ratio ≥1.19 on admission was significantly associated with an INR ≥4 in the initial 10 days of warfarin therapy among patients underwent heart valve replacement surgery.

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

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 861-867 ◽  
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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