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.

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

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.

Warfarin dose adjustment required after cannabidiol initiation and titration

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.

Mild elevations of international normalized ratio at hospital Day 1 and risk of expansion in warfarin-associated subdural hematomas

2013 ◽  
Vol 119 (4) ◽  
pp. 1050-1057 ◽  
Author(s):  
Marie Roguski ◽  
Kyle Wu ◽  
Ron I. Riesenburger ◽  
Julian K. Wu
Keyword(s):  
Volume Overload ◽  
Neurological Status ◽  
International Normalized Ratio ◽  
Fresh Frozen Plasma ◽  
Increased Risk ◽  
Fresh Frozen ◽  
History Of ◽  
Clinically Significant ◽  
Frozen Plasma ◽  
Increases In Risk

Object A primary goal in the treatment of patients with warfarin-associated subdural hematoma (SDH) is reversal of coagulopathy with fresh-frozen plasma. Achieving the traditional target international normalized ratio (INR) of 1.3 is often difficult and may expose patients to risks of volume overload and of thromboembolic complications. This retrospective study evaluates the risk of mild elevations of INR from 1.31 to 1.69 at 24 hours after admission in patients presenting with warfarin-associated SDH. Methods Sixty-nine patients with warfarin-associated SDH and 197 patients with non–warfarin-associated SDH treated at a single institution between January 2005 and January 2012 were retrospectively identified. Charts were reviewed for patient age, history of trauma, associated injuries, neurological status at presentation, size and chronicity of SDH, associated midline shift, INR at admission and at hospital Day 1 (HD1), concomitant aspirin or Plavix use, platelet count, and medical comorbidities. Patients were stratified according to use of warfarin and by INR at HD1 (INR 0.8–1.3, 1.31–1.69, 1.7–1.99, and ≥ 2). The groups were evaluated for differences the in rate of radiographic expansion of SDH and in the rate of clinically significant SDH expansion resulting in death, unplanned procedure, and/or readmission. Results There was no difference in the rate of radiographic versus clinically significant expansion of SDH between patients not on warfarin and those on warfarin (no warfarin: 22.3% vs 20.3%, p = 0.866; warfarin: 10.7% vs 11.6%, p = 0.825), but the rate of medical complications was significantly higher in the warfarin subgroup (13.3% for patients who did not receive warfarin vs 26.1% for those who did; p = 0.023). For warfarin-associated SDH, there was no difference in the rate of radiographic versus clinically significant expansion between patients reversed to HD1 INRs of 0.8–1.3 and 1.31–1.69 (HD1 INR 0.8–1.3: 22.5% vs 20%, p = 1; HD1 INR 1.31–1.69: 15% vs 10%, p = 0.71). Conclusions Mild INR elevations of 1.31–1.69 in warfarin-associated SDH are not associated with a markedly increased risk of radiographic or clinically significant expansion of SDH. Larger prospective studies are needed to determine if subtherapeutic INR elevations at HD1 are associated with smaller increases in risk of SDH expansion.

Hypoprothrombinemia Associated with Cefmetazole

1997 ◽  
Vol 31 (2) ◽  
pp. 180-184 ◽  
Author(s):  
Gail A Breen ◽  
Wendy L St Peter
Keyword(s):  
At Risk ◽  
Vitamin K ◽  
Clinical Symptoms ◽  
The Elderly ◽  
International Normalized Ratio ◽  
Fresh Frozen Plasma ◽  
Endstage Renal Disease ◽  
Populations At Risk ◽  
Increased Risk ◽  
Patients At Risk

Objective To report a case of hypoprothrombinemia associated with the use of cefmetazole sodium, define patients at risk for this adverse effect, and identify options to prevent this problem. Case Summary A malnourished patient with endstage renal disease received cefmetazole following a below-the-knee amputation of the right leg. Three days later, a prothrombin time (FT) and an international normalized ratio (INR) were obtained and were markedly elevated from baseline; however, the patient had no clinical symptoms of bleeding. Cefmetazole was discontinued. Vitamin K and fresh frozen plasma were administered. The PT and INR normalized within 24 hours and remained normal throughout the remainder of hospitalization. Discussion The incidence of hypoprothrombinemia associated with cefmetazole reported in the literature is conflicting and not consistent. There are three proposed mechanisms of cephalosporin-associated hypoprothrombinemia, two of which involve the N-methylthiotetrazole (NMTT) chain. The most plausible mechanism is NMTT inhibition of vitamin K epoxide reductase in the liver. Patients at an increased risk for this adverse event include those with low vitamin K stores, specifically patients who are malnourished, with low albumin concentrations and poor food intake. The elderly and patients with liver or renal dysfunction are examples of populations at risk. Conclusions Hypoprothrombinemia may occur with cephalosporins and is especially problematic with those containing an NMTT side chain. Clinicians need to identify patients at risk for developing antibiotic-associated hypoprothrombinemia, monitor them closely, and give vitamin K as prophylaxis accordingly.

scholarly journals Should we Test the Prothrombin Time in Anticoagulated Epistaxis Patients?

2013 ◽  
Vol 4 (1) ◽  
pp. ar.2013.4.0049 ◽  
Author(s):  
Michael B. Soyka ◽  
David Holzmann
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Oral Anticoagulation ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Increased Risk

Epistaxis is one of the most frequent emergencies in rhinology. Patients using anticoagulative medication are at increased risk for epistaxis. We evaluated the prothrombin time and the international normalized ratio (INR) in anticoagulated epistaxis patients. Patients suffering from epistaxis were prospectively included in a database and results from prothrombin testing were analyzed in the context of anticoagulation. One hundred sixteen of 591 epistaxis cases were identified to be on oral anticoagulation. The INR was found to be above therapeutic levels in 19 (16%) of these cases. We strongly recommend prothrombin time and INR testing in all epistaxis patients taking any sort of vitamin K antagonists.

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.

Abstract 17328: Novel Oral Anticoagulants in Adult Fontan Patients: A Multi-Site Experience

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Amir Kazerouninia ◽  
Payton Kendsersky ◽  
Ryan Byrne ◽  
Patricia Chu ◽  
Yunfei Wang ◽  
...  
Keyword(s):  
Oral Anticoagulants ◽  
Scoring Systems ◽  
International Normalized Ratio ◽  
Novel Oral Anticoagulants ◽  
Class Iii ◽  
Academic Medical ◽  
Increased Risk ◽  
History Of ◽  
Clinically Significant ◽  
Fontan Patients

Introduction: Adult Fontan patients are typically prescribed antiplatelet or anticoagulant therapy to manage increased risk for thrombotic and embolic complications (TECs). There is a Class III recommendation against the use of novel oral anticoagulants (NOACs) in this population due to a paucity of data. We hypothesized that NOACs are potentially non-inferior to warfarin in adult Fontan patients. Methods: We performed a multi-site retrospective review of adult Fontan patients, evaluated at three major academic medical centers (1995-2018), prescribed NOAC, warfarin, or aspirin therapy. Results: We identified 267 adult Fontan patients: 48 on NOACs, 107 on warfarin, and 180 on aspirin (14.4% to 54.2% cross-over amongst groups). Patients were more likely to have clinically significant bleeds (“bleeds”) if on a NOAC (HR=9.3, CI=3.0-28.4) or warfarin (HR=4.1, CI=1.6-10.5) versus aspirin. Bleed hazard ratio differences between NOAC and warfarin patients were not statistically significant (HR=2.3, CI=0.9-5.9). Patients on NOACs were not more likely to suffer TECs than patients on warfarin (HR=1.7, CI=0.4-6.3) or aspirin (HR=2.8, CI=0.7-10.3). Aspirin patients were younger, healthier, and had more favorable Fontan palliation. The traditional scoring systems to predict bleeds (HAS-BLED) and TECs (CHA 2 DS 2 VASc) were not predictive in this patient population. The only risk factor we identified for bleeds was a history of/predisposition to bleeding (OR=10.2, CI=4.4-23.6). Risk factors we identified for TECs included diabetes mellitus (OR=5.0, CI=2.2-11.4), labile international normalized ratio (OR=3.7, CI=1.1-12.4), and CHF (only in the NOAC/warfarin subgroup, OR=4.4, CI=1.2-16.3). Conclusions: NOACs are a potentially noninferior alternative to warfarin for adult Fontan patients. Our findings have laid the groundwork for a randomized control trial comparing the use of NOACs to warfarin in adult Fontan patients to test noninferiority or equivalence.

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.

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