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.

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 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.

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 Factor VII Levels and International Normalized Ratios in the Early Phase of Warfarin Therapy

2010 ◽  
Vol 112 (2) ◽  
pp. 298-304 ◽  
Author(s):  
Honorio T. Benzon ◽  
Michael J. Avram ◽  
Hubert A. Benzon ◽  
Misty Kirby-Nolan ◽  
Antoun Nader
Keyword(s):  
Epidural Catheter ◽  
Early Phase ◽  
Warfarin Therapy ◽  
Warfarin Dose ◽  
Patient Characteristics ◽  
International Normalized Ratio ◽  
Factor Vii ◽  
Clotting Factor ◽  
Epidural Catheter Placement ◽  
Epidural Catheters

Background Factor VII is the most affected clotting factor during the early phase of warfarin therapy. An international normalized ratio (INR) of more than 1.4 is considered unsafe for epidural catheter placement or removal, according to the American Society of Regional Anesthesia and Pain Medicine. The authors tested the hypothesis that factor VII activities would be consistent with safe removal of the epidural catheter on postoperative day (POD) 1 regardless of INR value. Methods Data from 121 patients who took warfarin after undergoing total joint surgery and had INRs and factor VII levels determined were reviewed. Patient characteristics and factor VII activities were compared between patients with INRs of more than 1.4 and those with INRs less than or equal to 1.4 on PODs 1, 2, and 3. Results Eleven patients had INRs of more than 1.4 on POD 1; their mean +/- SD factor VII activities were 60 +/- 28% (normal: 50-160%). On POD 2, 78 patients with INRs more than of 1.4 had factor VII activities of 32 +/- 15%, whereas on POD 3, 84 patients with INRs of more than 1.4 had factor VII activities of 44 +/- 19%. Variables included in the final multiple logistic regression model as predictors of an INR of more than 1.4 on POD 2 were warfarin dose on POD 1 and factor VII activity on POD 2. Conclusions The range of factor VII activities in the patients with INRs of more than 1.4 within 12 h of warfarin therapy was compatible with adequate hemostasis. The authors found no evidence that epidural catheters should not be removed even with INRs up to 1.9, the highest INR on POD 1 noted in their study.

Evaluation of an Initiation Regimen of Warfarin for International Normalized Ratio Target 2.0 to 3.0

2021 ◽  
pp. 875512252110341
Author(s):  
Sahimi Mohamed ◽  
Chan Mei Fong ◽  
Yew Jie Ming ◽  
Ahlam Naila Kori ◽  
Sopian Abdul Wahab ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Warfarin Therapy ◽  
Warfarin Dose ◽  
Asian Population ◽  
International Normalized Ratio ◽  
Efficacy And Safety ◽  
Risk Of Bleeding ◽  
Number Of Patients ◽  
Inpatient Settings ◽  
The Mean

Background: he number of patients on warfarin therapy is rising steadily. Although warfarin is beneficial, it carries a high risk of bleeding, especially if the international normalized ratio (INR) values exceed 3.0. Currently, no warfarin initiation regimens have been developed for the Asian population, especially for Malaysians. Objective: This article describes the efficacy and safety of a new initiation regimen for warfarin among warfarin-naive patients. Method: Data were retrospectively collected from the ambulatory and inpatient settings. Results: A total of 165 patients who each had a target INR of 2.0 to 3.0 were included in the study. The mean age was 57.2 years and 94 patients were male. A total of 108 patients used Regimen 1 (5 mg/5 mg/3mg) and the rest of the patients used Regimen 2 (5 mg/3 mg/3 mg). Most patients used warfarin either for atrial fibrillation (52.1%) or for venous thromboembolism (29.7%). Overall, 88 of the patients had INR values above 50% from the baseline on Day 4. Additionally, 13 patients had INR values of >3.2, which required withholding and lower dose of warfarin. The predicted weekly maintenance warfarin dose (23 ± 0.5 mg/week) was found to have correlated closely with the actual maintenance dose (22.8 ± 0.5 mg/week; r2 = 0.75). Nearly two thirds (70.3%) of the patients achieved the target INR on Day 11. Conclusion: The warfarin initiation regimens in this study was simple, safe, and suitable to be used in both ambulatory and inpatient settings for managing warfarin therapy.

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.

Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype

2005 ◽  
Vol 93 (04) ◽  
pp. 700-705 ◽  
Author(s):  
Deepak Voora ◽  
Charles Eby ◽  
Mark Linder ◽  
Paul Milligan ◽  
Bonny Bukaveckas ◽  
...  
Keyword(s):  
Warfarin Therapy ◽  
Adverse Outcome ◽  
Warfarin Dose ◽  
Controlled Study ◽  
Cyp2c9 Genotype ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Dosing Algorithm ◽  
Orthopedic Patients ◽  
Cytochrome P 450

SummaryCytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4–9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R2 = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.

scholarly journals Validation of Pharmacogenetic Testing Before Initiation of Warfarin Therapy

2019 ◽  
Vol 15 (2) ◽  
pp. 74-78
Author(s):  
MSI Tipu Chowdhury ◽  
Md Fakhrul Islam Khaled ◽  
Sadia Sultana ◽  
Mohammad Walidur Rahman ◽  
MRM Mandal ◽  
...  
Keyword(s):  
Vitamin K ◽  
Warfarin Therapy ◽  
Warfarin Dose ◽  
Bleeding Complications ◽  
Fixed Dose ◽  
Vitamin K Epoxide Reductase ◽  
International Normalization Ratio ◽  
Cytochrome 450 ◽  
Epoxide Reductase ◽  
Cardiac Valve Replacement

Warfarin is an oral anticoagulant used to prevent or treat clotting disorders associated with venous thrombosis, pulmonary embolism, atrial fibrilation, cardiac valve replacement, stroke and acute myocardial infarction. It is a vitamin K antagonist composed of S- and R- isomers. The more potent S-warfarin is metabolized by cytochrome 450 isoenzyme 2C9 (CYP2C9), encoded by CYP2C9 gene. Warfarin exerts its anticoagulants effect by inhibitingits target enzyme vitamin K epoxide reductase (VKOR), encoded by vitamin K epoxide reductase subunit 1 (VKOR1) gene. Genetic variation in the CYP2C9 and VKOR1 gene can affect warfarin efficacy and dose required to achieve stable International Normalization Ratio (INR). Specifically two variants in the CYP2CP gene (CYP2C9*2 and CYP2C9*3) result in an enzyme with reduced activity, leading to increased active warfarin levels. A variant in the VKORC1 gene (VKORC1-1639 G>A) can lead to reduced gene expression resulting in decresed level of VKOR. Together these three variants can account for 40-70% of the variability of warfarin dose. Carriers of variant alleles are at higher risk for bleeding complications, particularly at the induction of warfarin therapy. So, genotype-guided dosing algorithms would be better approximate for maintenance of warfarin dose than fixed-dose algorithms. University Heart Journal Vol. 15, No. 2, Jul 2019; 74-78

scholarly journals GENETIC POLYMORPHISMS OF CYTOCHROME P450 2C9, VITAMIN K EPOXIDE-REDUCTASE SUBUNIT 1 AND WARFARIN DOSING IN PATIENTS WITH PERMANENT ATRIAL FIBRILLATION

2016 ◽  
Vol 1 (4) ◽  
pp. 18-22
Author(s):  
A O Rubanenko ◽  
Yu V Shchukin
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Polymorphisms ◽  
Warfarin Therapy ◽  
Warfarin Dose ◽  
Cytochrome P450 2C9 ◽  
Risk Of Bleeding ◽  
Permanent Atrial Fibrillation ◽  
Epoxide Reductase ◽  
Warfarin Dosing ◽  
Permanent Form

Aim - to assess the influence of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dosing in patients with permanent form of atrial fibrillation. Methods. The study included examination of 100 patients with coronary heart disease and permanent form of atrial fibrillation; mean age 60.5±5.8 years. Conclusion. In patients with permanent form of atrial fibrillation, genotypes CYP2C9*1/*3, TT and GG genotypes of VKORC1 are associated with low warfarin dose, compared to other genotypes. Genotype CYP2C9*1/*3 increases the risk of bleeding complication during warfarin therapy.

scholarly journals Interaction of Warfarin with Herbs Based on Pharmacokinetic and Pharmacodynamic Parameters

2020 ◽  
Vol 2 (2) ◽  
pp. 69
Author(s):  
Amelia Soyata ◽  
Aliya Nur Hasanah ◽  
Taofik Rusdiana
Keyword(s):  
Platelet Aggregation ◽  
Therapeutic Index ◽  
International Normalized Ratio ◽  
Psidium Guajava ◽  
Review Article ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Narrow Therapeutic Index ◽  
St John’S Wort ◽  
St John's Wort

Warfarin is an oral anticoagulant that has been widely used and has strong efficacy, but the use of warfarin is still a concern because of its narrow therapeutic index which cause interactions when co-administration with drugs, herbs or food. This interaction can affect the pharmacokinetics and pharmacodynamics of warfarin and the most fatal effect from warfarin interactions is bleeding. In this review article data on warfarin-herbs interactions were collected based on pharmacokinetic parameters (AUC0-∞, Cmax, T1/2, Cl/F, and V/F), while pharmacodynamic parameters (International normalized ratio (INR), platelet aggregation, AUC INR and Protombine Time). As a result some herbs had significant interactions with warfarin. Herbs that affect warfarin pharmacokinetic were Danshen gegen, echinacea, St. John's wort and caffeine and herbs that affect pharmacodynamic were policosanol, Ginkgo biloba, cranberry, St. John's wort, ginseng, pomegranate, Psidium guajava and curcumin, so co-administration warfarin with herbs need to be considered.Keywords: Warfarin, Interactions, Herbs, Pharmacokinetics, Pharmacodynamics

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