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Zhang, Jieying Eunice. "Pharmacogenetics of warfarin." Thesis, University of Liverpool, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569544.
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Warfarin is one of the most commonly used oral anticoagulants worldwide and is highly efficacious for the treatment and prevention of thromboembolic disorders. However, due to its narrow therapeutic index and large interindividual variability, it remains a challenging drug to prescribe. Genetic factors (CYP2C9 and VKORCI), together with clinical factors (age and body weight), account for up to 60% of warfarin dose variance but the remaining ~40% variability remains unexplained. A polymorphism rs2108622 in CYP4F2, a vitamin K oxidase, has previously been associated with increased warfarin stable dose requirements, accounting for 1-7% dose variability. In our cohort of prospectively recruited patients (n = 311), we were unable to confirm these results. Interestingly, after fine mapping of the CYP4F2 gene region, we found a SNP rs2189784, which is in LD with rs2108622, to be associated with time to therapeutic INR (Pc = 0.03). Further fine mapping of the CYP4F gene cluster together with the utilisation a bank of well characterized Caucasian surgical liver samples (n = 149) and data from a genome-wide association study (n = 714), showed that CYP4F2 rs2108622 and rs2189784 SNPs were found to be associated with increasing CYP4F2 and decreasing CYP4FII or CYP4Fl2 mRNA expression, respectively. Interestingly, a CYP4Fll variant rsl060467 (in LD with rs2108622) was associated with reduced CYP4F2 rnRNA expression. Furthermore, rsl060467 contributes to 2.5% of warfarin dose variability and was associated with reduced warfarin dose requirement (~1 mg/day, Pc = 0.003), an effect in the opposite direction previously reported with CYP4F2 rs2108622 by Caldwell et al. (2008) and other studies. Warfarin-resistant patients have been reported to harbour VKORCI missense mutations. Extended regions of VKORCI were sequenced in our patients (n = 65) with resistance to warfarin, defined by clinical and pharmacodynamic criteria. Seven novel heterozygous mutations were identified and in silica analyses predicted the promoter c.-160G>C mutation creates a putative Spl transcription factor binding site and that the missense mutation c.79C>G to be deleterious. To confirm these predictions, in vitro functional studies were carried out using EMSA, transient transfection assays, and DNA methylation. c.-160G>C was found to create a weak binding site for Spl transcription factor, and caused an increase in promoter activity by ~20% (P = 0.003). The c.79C>G mutation reduced levels of PIVKA-II by ~10%. Associations of VKORCI genotypes with DNA methylation did not remain significant after correction for multiple testing. The effect of warfarin on the rate of decline of vitamin K-dependent clotting factors, and the role of SNPs in the clotting factor genes, is not known. Using a large prospective cohort of patients (n = 619), SNPs in F7 and F 10 genes showed association with variability in factor VII levels. The rate at which the plasma levels of factors II, X and protein C decline affect how patients respond to warfarin, in particular the achievement of warfarin stable dose and time to therapeutic INR. Furthermore, the change in clotting factor X level accounted for 1.4% of warfarin dose variability. In conclusion, the results presented in this thesis demonstrate that multiple genetic, clinical and biochemical factors account for the variability in warfarin response. Further understanding of such complex interactions, along with the advent of genomics technologies and development of new computational and conceptual tools, will yield insights to the accurate prediction of drug efficacy and toxicity, which will hopefully translate into improved outcomes for patients.
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Ab, Ghani Azizah. "Pharmacogenetics in warfarin therapy." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/18317/.
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Warfarin is a challenging drug to dose accurately, especially during the initiation phase because of its narrow therapeutic range and large inter-individual variability. Therefore, the aim of this thesis was to investigate the use of pharmacogenetics and clinical data to improve warfarin therapy. Genetic variants in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose. Therefore we developed a pharmacogenetic dosing algorithm to predict warfarin stable dose prospectively in a British population based on 456 patients who started warfarin in a hospital setting and validated it in 262 retrospectively recruited patients from a primary care setting. The pharmacogenetic algorithm which included CYP2C9*2, CYP2C9*3 and VKORC1-1693 together with body surface area, age and concomitant amiodarone use, explained 43% of warfarin dose variability. The mean absolute error of the dose predicted by the algorithm was 1.08 mg/day (95% CI 0.95-1.20). 49.6% of patients were predicted accurately (predicted dose fell within 20% of the actual dose). The HAS-BLED score, a bleeding risk score has recently been suggested for use in the management of patients with atrial fibrillation. We validated HAS-BLED performance in predicting major bleeding using a prospective cohort with 6 months follow-up (n=482) (c-statistic 0.80 95% CI (0.71-0.90). Factors significantly associated with major bleeding in our cohort (p≤0.1) were concurrent amiodarone use, labile INR, concurrent clopidogrel use, bleeding predisposition, concurrent aspirin use and CYP2C9*3. Adding a genetic covariate (CYP2C9*3) to the HAS-BLED score did not significantly improve its performance in predicting major bleeding. Considering CYP2C9*3 is a rare allele, our study was underpowered and requires further investigation in a larger cohort. A retrospective study of 97 Caucasian children was conducted to gain greater understanding of the factors that affect warfarin anticoagulant control and response in children. Results from multiple regression analysis of genetic and non-genetic factors showed that indication for treatment (Fontan or non-Fontan group), VKORC1 -1693, and INR group explained 20.8% of variability in proportion time in which INR measurements fell within the target range (PTTR); CYP2C9*2 explained 6.8% of the variability in INR exceeding target range within the first week of treatment; CYP2C9*2, VKORC1 -1693, age and INR group explained 41.4% of warfarin dose variability and VKORC1 -1693 explained 8.7% of haemorrhagic events. The contributions of CYP2C9 and VKORC1 polymorphism were small in the above outcomes. We therefore went onto explore other genetic markers using genome-wide scanning. Two SNPs on chromosome 5, rs13167496 and rs6882472 were found to be significantly associated at a genome-wide significance level with PTIR. However, none of SNPs were significantly associated with warfarin stable dose, INR values exceeding the target range within the first week of treatment and bleeding complications. Because of our small sample size, these findings will need to be validated in a replication cohort. Finally, we have validated and evaluated the performance of Genie HyBeacon®, a point of care therapy (POCT) instrument to genotype 135 samples for CYP2C9*2, CYP2C9*3 and VKORC1 -1693. We showed that the instrument accuracy was >98% (agreement with ABI Taqman® genotyping), it was relatively simple to use and had a good turn-around time (1.6 hours) making it suitable for clinical use. In conclusion, the results presented in this thesis demonstrate how knowledge of pharmacogenetics may help in assessing improvement in the quality of care of patients on warfarin. However, for personalized medicine to be widely adopted in clinical practice, payers need evidence of clinical- and cost-effectiveness. How such evidence is produced and evaluated varies in different healthcare settings, which further increases the challenge of implementing personalised medicine into the clinic.
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Choiniere, Jennifer. "Content and Uniformity of Mexican Manufactured Lovastatin and Warfarin Versus American Manufactured Lovastatin and Warfarin." The University of Arizona, 2005. http://hdl.handle.net/10150/624720.
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Class of 2005 AbstractObjective: To analyze the quantity of active ingredient as well as the content uniformity of lovastatin and warfarin manufactured in Mexico as compared to the lovastatin and warfarin manufactured in the United States. Methods: High-pressure liquid chromatography assays modified from the U.S. Pharmacopoeia will be used to evaluate the amount of active ingredient found in lovastatin and warfarin manufactured in Mexico and America. Area-under-the-curve analysis was done to evaluate relative quantities of the active ingredients. Results: The amount of lovastatin found in the Mexican manufactured product was found to be 64%, and content uniformity was found to be 73%, both values are outside of the acceptable range of 90%-110% set by the USP-NF guidelines. The amount of warfarin found in the Mexican manufactured product was found to be 84% with a content uniformity of 100%. The average content value is outside of the acceptable range of 90%-110% set by the USP-NF guidelines. Conclusion: The results of this study showed that the amounts of active ingredients found in Mexican manufactured lovastatin and warfarin were significantly different from the amounts found in the American manufactured products.
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Ghaswalla, Parinaz K. "Medication-Related Problems in Older Adults: A Focus on Underuse of Warfarin and Warfarin-Antibiotic Interactions." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2631.
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The work presented in this dissertation focuses on two important medication-related problems in older adults, that is, untreated indication and drug-drug interactions, specifically with respect to a high-risk medication such as warfarin. Warfarin is a challenge to use in clinical practice due to its narrow therapeutic index, variability in dose-response and its interactions with numerous foods and drugs. This dissertation presents the research from two projects. In the first project the prevalence and predictors of warfarin use in nursing home (NH) residents with atrial fibrillation (AF), and use of secondary stroke prevention strategies was determined, in order to understand the patterns of anticoagulant use in frail NH residents and to identify patient characteristics associated with warfarin use. In the second project the effect of oral antibiotics on anticoagulation outcomes, when prescribed concomitantly with warfarin, was determined, in order to provide evidence on the clinical significance of warfarin-antibiotic interactions in older adults. In the first project a cross-sectional analysis of the prescription and resident files from the 2004 National Nursing Home Survey was done to determine the prevalence of AF and rates of use of warfarin and other anti-platelet agents, such as aspirin and clopidogrel. A multiple logistic regression model was used to determine factors associated with warfarin use. In this sample of older NH residents, 13% of residents had a diagnosis of AF, with indications for warfarin use and no contraindications to warfarin. From these patients, 30% received anticoagulant therapy with warfarin and 23% of the remaining patients received either aspirin or clopidogrel, suggesting that more than 50% of residents with AF did not receive any form of anticoagulant therapy. Non-white race, history of bleeding, and use of anti-platelet medications were associated with reduced odds of receiving warfarin. The second project was a retrospective medical record review of older patients from an outpatient anticoagulation clinic at a Veterans Affairs medical center. Results of the repeated measures ANOVA suggested a significant increase in post-antibiotic INR values with fluoroquinolones, azithromycin and amoxicillin. In addition, the percentage of patients with warfarin dose adjustments was significantly greater with fluoroquinolones and azithromycin as compared to cephalexin. No bleeding events were reported for any of these patients. In conclusion, the results of the projects suggest that there is underuse of warfarin in NH settings. Furthermore, antibiotics may be safely prescribed with warfarin in older adults as long as the INR is monitored closely.
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Eriksson, Niclas. "On the Prediction of Warfarin Dose." Doctoral thesis, Uppsala universitet, Klinisk farmakologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-172864.
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Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction. Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available. Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway. The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.
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Chen, Y. Y. "Genetics of the anticoagulant drug warfarin." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597528.
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In this thesis I use the most widely prescribed anticoagulant drug, warfarin, as a model to investigate the effect of genetic determinants on drug efficacy and safety. Following a literature review of all the genes involved in warfarin pharmacokinetics and pharmacodynamics, 35 candidate genes were selected for investigation. Two independent Swedish cohorts of warfarin-treated patients were analysed. First linkage disequilibrium maps were constructed for each gene. Selected SNPs integrated with putative functional variants were genotyped in 201 patients recruited at the Uppsala University. A panel of 216 haplotype tag SNPs were then derived to analyse an independent cohort of 1496 patients from the prospective Warfarin Genetic Study in Sweden. The two studies were analysed separately for genetic association to warfarin dose requirement (single marker and haplotypic tests). Common SNPs in the vitamin K epoxide reductase gene (VKORC1) are significantly associated with dose in the Uppsala and WARG studies (p=1.9 x 10-15 and 6.5 x 10-100, respectively). Cytochrome P450 2C9 (CYP2C9) has been known to affect dose requirement and was confirmed in both Swedish cohorts (p= 2.3 x 10-5 and 4.9 x 10-32). The two genes together explain ~40% of warfarin dose variation. SNPs in microsomal epoxides hydrolase (EPHX1) and orosomucoid 1 (ORM1) genes do not show a broad effect but are associated with dose in both studies. Genes encoding PROC, APOE, CALU, PDIA2 and GGCX showed nominal association with dose in the Uppsala study. Likewise, PROS1, CYP1A1, CYP3A4, PDIA5, PDIA3 and F10 showed nominal association to dose in the WARG study. Most of these minor effects if real are most likely to be population/treatment specific. A model taking in to account genetic factors (VKORC1 and CYP2C9*2/*3) and non genetic factors (age, gender, and drug interaction) together explained more than 50% inter-individual dose variance. We analysed 64 patients from the Uppsala and WARG studies with recorded severe bleeding episodes using the same 216 common SNPs. Case-control analysis found SNPs in PDIA4, P4HB, and NR1I3 to be associated (p≤0.01) with bleeding. Using a recessive model, patients with a gastrointestinal bleeding sub-phenotype in the WARG cohort showed association with common variants in PD1A6 (P=0.0014, odds ratio = 6.98). We sequenced the exons of 11 of the candidate genes in 36 bleeders and 12 non-bleeders (Uppsala study). However, no high prevalence mutation was discovered.
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Khan, Tayyaba Irfan. "Factors affecting anticoagulation response to Warfarin." Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413389.
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Myszka, David Gerard. "Photoaffinity labeling of warfarin binding proteins /." The Ohio State University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487694702785693.
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Msolli, Ines. "Nanosystèmes polymères pour la libération contrôlé de la Warfarine : conception et évaluation biologique." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCD033/document.
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Dans ce travail de thèse, nous avons synthétisé des dérivés de poly(acide (R,S)-3,3-diméthylmalique) (PDMMLA). Les copolymères de PDMMLA sont composésprincipalement de deux monomères: un monomère hydrophobe contenant un groupementhexylique et un monomère hydrophile contenant un groupement acide. Grâce à la proportionde chaque monomère dans le copolymère final, la balance hydrophile/hydrophobe est ajustée.Donc six copolymères ont été obtenus: trois copolymères statistiques PDMMLAHn-co-Hex100-n et trois copolymères à blocs PDMMLAHn-b-Hex100-n. Ces copolymères sont àl’origine de nanoparticules sans et avec un principe actif. La Warfarine a été encapsulée à lafois avec des nanoparticules de PDMMLAHn-co-Hex100-n et de PDMMLAHn-b-Hex100-n.Les nanoparticules formées sont caractérisées afin d'en déterminer la forme, la taille et lacharge de surface. Donc des nanoparticules de forme sphérique, ayant une taille inférieure à100 nm et ayant une charge de surface inférieure à -30 mV ont été obtenues. Lesnanoparticules de PDMMLAH30-co-Hex70, ont été choisies pour étudier la libérationcontrôlée de la warfarine dans des conditions de température et de pH physiologiques. Lesrésultats obtenus montrent une libération lente et progressive de la warfarine à partir dessystèmes nanoparticulaires ainsi conçus et réalisés. De tels systèmes nanoparticulaires à basede dérivés amphiphiles du PDMMLA offriraient ainsi des outils d'intérêt pour l'encapsulationet la libération contrôlée de nombreux principes actifs hydrophobes tels que le dérivécoumarinique inhibiteur de la thrombine (DCBC) dont l'activité antithrombine en systèmepurifié est plus élevée que celle de l'argatrobanIn this work we synthesized derivatives of poly((R,S)-3,3-dimethylmalic acid) (PDMMLA).PDMMLA copolymers are mainly composed of two monomers: a hydrophobic monomercontaining a hydroxyl group and a hydrophilic monomer containing an acid group. Due to theproportion of each monomer in the final copolymer, the hydrophilic / hydrophobic balance ismodulated. Thus, six copolymers were obtained: three random copolymers PDMMLAHn-co-Hex100-n and three block copolymers: PDMMLAHn-b-Hex100-n.These copolymers are at the origin of nanoparticles without and with an active principle.Warfarin, which has been successfully encapsulated with both PDMMLAHn-co-Hex100-nand block, copolymer nanoparticles: PDMMLAHn-b-Hex100-n. The formed nanoparticlesshowed fairly high encapsulation efficiency for both types of copolymers.The PDMMLA nanoparticles are characterized in order to determine their shape, size andsurface charge. Thus nanoparticles of spherical shape, having less than 100 nm size andhaving a surface charge of less than -30 mV have been obtained. The PDMMLAH30-co-Hex70nanoparticles were chosen to study the controlled release of warfarin under physiologicaltemperature and pH conditions. Obtained results show a slow and progressive release ofwarfarin. Such nanoparticulate systems based on amphiphilic derivatives of PDMMLA wouldthus offer tools of interest for the encapsulation and controlled release of many hydrophobicactive principles such as the coumarin derivative thrombin inhibitor (DCBC) whoseantithrombin activity in purified system is higher than that of argatroban
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Hickmott, Helen Ruth. "Factors affecting the pharmacological activity of warfarin." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251170.
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Chan, E. W.-Y. "Warfarin : Stereochemical aspects of pharmacokinetics and response." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374525.
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Choonara, I. A. "Clinical pharmacology of warfarin and vitamin K." Thesis, University of Liverpool, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383440.
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Misra, Devyani. "Warfarin use and risk of osteoporotic fractures." Thesis, Boston University, 2012. https://hdl.handle.net/2144/21219.
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Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.OBJECTIVE: Prior studies examining the association of warfarin use and osteoporotic fractures have found conflicting results and have had methodological problems, such as confounding by indication and confounding by duration of warfarin use. Thus, we studied the association of warfarin use with fractures at the hip, spine and wrist, among older men and women with atrial fibrillation recruited from the general population, using rigorous statistical tools to overcome challenges faced by prior studies. METHODS: We included men and women ≥65 years with incident atrial fibrillation, without history of fracture, followed between 2000-2010 from The Health Improvement Network (THIN). Long-term warfarin use was defined in two ways: 1) warfarin use ≥ 1year; 2) warfarin use ≥3 years. Non-use was defined as no use of warfarin over the follow-up period. Propensity scores (PS) for warfarin use were calculated using logistic regression with long-term use of warfarin as the dependent variable and age, sex, body mass index (BMI), history of multiple falls, deep venous thrombosis, pulmonary embolism, heart failure, neuropsychiatric impairment, hyperthyroidism, estrogen use, beta blockers, corticosteroids, bisphosphonates, smoking and alcoholism as independent variables. Each warfarin user was then matched by PS to a non-user by the “greedy matching” method. Incidence rates were calculated for warfarin users and non-users. The association between long-term warfarin use and risk of hip, spine and wrist fractures was evaluated using Cox-proportional hazards models. RESULTS: Incidence rates of hip fracture were 5.21 and 6.20 per 1000 person-years among subjects with warfarin use >1 (n=20,346) and >3 (n=11,238) years, respectively. The hazard ratios of hip fracture for warfarin use >1 and >3 years were 1.08 (95% CI 0.87, 1.35) and 1.13 (95% CI: 0.84, 1.5), respectively. Similar findings were observed between warfarin use and risk of spine or wrist fracture. CONCLUSIONS: Long-term use of warfarin among older adults with atrial fibrillation is not associated with increased risk of osteoporotic fractures and thus, does not necessitate additional surveillance or prophylaxis.
2031-01-01
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Russomanno, Giusy. "Translational pharmacogenomics: a study of warfarin dosing." Doctoral thesis, Universita degli studi di Salerno, 2016. http://hdl.handle.net/10556/2210.
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2014 - 2015Warfarin is one of the most commonly used oral anticoagulants worldwide and is highly efficacious for the treatment and prevention of thromboembolic disorders. However, due to its narrow therapeutic index, large inter-individual variability in dose requirements, and extensive drug and food interactions, warfarin remains a challenging drug to prescribe. Genetic factors (CYP2C9 and VKORC1), together with clinical factors (age and body weight), account for up to 60% of warfarin dose variance, whereas ~40% variability remains poorly understood. Several warfarin dosing algorithms, comprising genetic and non-genetic covariates have been published over the years. However, none of the published algorithms included patients from Southern Italy. We therefore conducted a candidate-gene study to develop an algorithm for predicting warfarin maintenance dose in patients from the Campania Region (n=266) in Southern Italy. Our pharmacogenetic dosing algorithm consisted of six variables (age, body surface area, amiodarone intake, CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A). It led to the accurate prediction of warfarin maintenance dose in 44% of patients (mean absolute error 7.41 mg/week). The prediction accuracy of the pharmacogenetic algorithm was superior to three previously published pharmacogenetic algorithms derived from patients in Northern and Central Italy. Given that previous studies suggested a role for miR-133a in warfarin response, we conducted a pilot study comparing baseline serum levels of miRNA in patients who achieved warfarin stable dose (n=10) to those who did not achieve warfarin stability (n=10), using the Affymetrix miRNA array. No association was found between miRNA-133a and warfarin response. Interestingly, circulating levels of miR-548a-3p were observed to be higher in patients who did not achieve warfarin stability (P=0.0053, fold change =1.66) compared to patients who achieved stable dose. In silico analyses showed that several target genes of miR-548a-3p are involved in the coagulation pathway. Work is currently underway to validate and replicate these findings in a larger cohort of prospectively recruited patients initiated onto warfarin therapy (n=980) using TaqMan miRNA real-time quantitative PCR. Pharmacogenetic algorithms have shown that common variants in CYP2C9 and VKORC1 genes cannot fully explain the extreme dose requirements in individuals sensitive and resistant to warfarin. To investigate the role of other genetic variants in these patients with extreme phenotypes, we performed a genome-wide association study (GWAS) comprising of warfarin sensitive patients (≤1.5 mg/day, n=55), warfarin resistant patients (≥10 mg/day, n=51), and healthy controls from the National Blood Service (NBS, n=2,501). Our results suggested that an intergenic variant on chromosome 10, rs4918797, could be involved in warfarin sensitivity. Intronic SNPs in MIR6873 on chromosome 6 (rs114213056) and PIGN on chromosome 18 (rs10163900, rs76455916, rs77118150, and rs79434376) showed suggestive association with warfarin resistance. The findings of this thesis showed that a multitude of factors affect warfarin dosing, some of which still need further investigations. Insights of the roles of other factors such as non-coding RNA and rare genetic variants will hopefully improve dose prediction and drug efficacy and ultimately patient outcomes. The work being undertaken with warfarin acts as a pathfinder project, the concepts from which could be applied to other drugs with variable dose requirement. [edited by author]
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Dahlgren, Marie, and Anneli Johansson. "Warfarinbehandlade patienters behov av information." Thesis, Halmstad University, School of Social and Health Sciences (HOS), 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-2956.
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Ett stort antal patienter behandlas med warfarin som förebyggande mot blodpropp. Läkemedlet kräver regelbunden blodprovstagning där INR- värdet mäts för att kunna anpassa dosen individuellt så länge behandling pågår. Indikationen kan till exempel vara förmaksflimmer, mekanisk hjärtklaff eller tromboembolism. Warfarin är ett känt problemläkemedel där interaktionsrisken med andra läkemedel är stor och andra faktorer såsom kost och livsstilsförändringar kan påverka dess effekt. Syftet med litteraturstudien var att beskriva patienters behov av information vid warfarinbehandling. Studien baseras på 12 vetenskapliga artiklar. Resultatet visar att patienter behöver tydlig information om biverkningar som kan uppstå, interaktionsrisk med andra läkemedel och naturläkemedel samt hur kosten och alkoholen påverkar warfarinbehandlingen. Information behövs om vikten av följsamhet vid behandling och vart man bör vända sig vid frågor och problem. Resultatet visar också att vid bristande följsamhet, högre ålder och kommunikationssvårigheter behövs extra resurser för information. Tydligt och individuellt anpassat informationsmaterial på patientens hemspråk, med större text och bilder i bör användas vid behov. Uppföljning av informationen rekommenderas till alla för att behandlingen skall bli så säker som möjligt. Fortsatt forskning behövs om kostens, hälsokostens och alkoholens inverkan på warfarin. Fler kvalitativa studier efterfrågas för att kunna utveckla och förbättra patientinformationen.
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King, Barry Philip. "Genetic factors affecting warfarin dose requirements and clearance." Thesis, University of Newcastle Upon Tyne, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417716.
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Mullan, Judy. "To develop and trial a new warfarin education program." Access electronically, 2005. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20060221.101350/index.html.
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Thesis (Ph.D.)--University of Wollongong, 2005.Typescript. This thesis is subject to a two year embargo until 17/11/2007 and may only be viewed and copied with the permission of the author. For further information please Contact the Archivist. Includes bibliographical references: leaf 226-249.
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Shaw, Kaitlyn. "The pharmacogenomics of warfarin safety and effectiveness in children." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44242.
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Leksell, Sofia. "Är NOAK ett bättre behandlingsalternativ än warfarin vid förmaksflimmer?" Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-53851.
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Bakgrund Förmaksflimmer är en arytmi som uppkommer av att sinusknutan slutar styra hjärtrytmen och impulser initieras istället på flera olika ställen i förmaken. Detta orsakar en snabb och oregelbunden kontraktion med försämrad cirkulation som resultat. Förmaksflimmer är den vanligaste orsaken till stroke och en viktig del i behandlingen av förmaksflimmer är därför att förebygga stroke genom antikoagulerande läkemedel. Warfarin har länge varit förstahandsval, men nya läkemedel, så kallade icke vitamin K antagonist oral antikoagulantia (NOAK) har de senaste åren godkänts som förebyggande behandling vid indikationen förmaksflimmer. Syftet med arbetet var att undersöka effekt, blödningsrisk och kostnad av NOAK som förebyggande behandling av stroke och systemisk emboli hos patienter med förmaksflimmer. Metod och material Arbetet utfördes som en litteraturstudie där fem kliniska studier från databasen PubMed analyserades. I fyra studier jämfördes de tre faktor Xa-hämmarna apixaban, edoxaban och rivaroxaban, samt trombinhämmaren dabigatran med warfarin. I en studie jämfördes apixaban med Aspirin®. Resultat Alla NOAK visades reducera risken att drabbas av stroke och emboli minst likvärdigt med warfarin. Dabigatran 150 mg och edoxaban 60 mg visades även vara effektivare än warfarin (RR=0,66; P<0,001, respektive RK=0,79; P<0,001). Apixaban reducerade risken för stroke och systemisk emboli med mer än 50 % i jämförelse med Aspirin® (RK= 0,45; P<0,001). Uppkomst av större blödning var likvärdigt förekommande i jämförelse mellan NOAK och warfarin. Dabigatran 110 mg, edoxaban 30 mg, edoxaban 60 mg och apixaban 5 mg visade på lägre risk för större blödning. Apixaban och Aspirin® visades vara likvärdiga avseende uppkomst av större blödning. Slutsats Icke vitamin K antagonist oral antikoagulantia är effektiva som förebyggande behandling av stroke och emboli hos patienter med förmaksflimmer, med lägre blödningsrisk än warfarin, men till en högre kostnad.Atrial fibrillation is an arrhythmia characterized by rapid and uncontrolled contraction of the atria. The irregular contractions leads to incomplete circulation, accumulation of blood in the atria and increases the risk of stroke and embolism. An important part in the treatment of atrial fibrillation is to prevent the risk of stroke by use of anticoagulants. The first line treatment is the vitamin K antagonist warfarin. The drug has many side effects such as risk of bleeding, difficulties to adjust the dose and interactions with both drugs and food. In recent years, new drugs, called non vitamin K antagonist oral anticoagulants (NOAC), have been approved as preventive treatment of stroke in patients with atrial fibrillation. These include three factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban, and one thrombin inhibitor: dabigatran. In this study, the efficacy, risk of bleeding and cost of NOAK was investigated for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The study was conducted as a literature study where five clinical trials from the database PubMed was analyzed. In four studies, the three factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran were compared with warfarin. In one study apixaban was compared with Aspirin®. In all studies the prevention of stroke and systemic embolism and risk of bleeding was investigated. All NOAC reduced the risk of stroke and embolism at least equal to warfarin. Dabigatran 150 mg and edoxaban 60 mg was also more effective than warfarin. Apixaban reduced the risk of stroke and systemic embolism with more than 50 % compared with aspirin. The occurrence of major bleeding was similar in comparison of Dabigatran 150 mg, respectively rivaroxaban 20 mg and warfarin. Dabigatran 110 mg, edoxaban 30 mg, edoxaban 60 mg and apixaban 5 mg showed a lower risk of major bleeding than warfarin. Apixaban and Aspirin® appeared to be equivalent regarding the occurrence of major bleeding. Non Vitamin K antagonist oral anticoagulants are effective in the prevention of stroke and embolism in patients with atrial fibrillation, with lower risk of bleeding than warfarin, but with a higher cost.
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Clark, Justin. "An evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/623593.
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Class of 2012 AbstractObjectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case- reports and are of low quality and quantity.
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Clark, Justin, and Daniel Malone. "An Evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/614476.
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Class of 2012 AbstractObjectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case-reports and are of low quality and quantity.
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Smith, Nicole Thomas. "Validation of criteria used to predict warfarin dosing decisions /." Diss., CLICK HERE for online access, 2004. http://contentdm.lib.byu.edu/ETD/image/etd427.pdf.
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Thomas, Nicole. "Validation of Criteria Used to Predict Warfarin Dosing Decisions." BYU ScholarsArchive, 2004. https://scholarsarchive.byu.edu/etd/40.
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People at risk for blood clots are often treated with anticoagulants, warfarin is such an anticoagulant. The dose's effect is measured by comparing the time for blood to clot to a control time called an INR value. Previous anticoagulant studies have addressed agreement between fingerstick (POC) devices and the standard laboratory, however these studies rely on mathematical formulas as criteria for clinical evaluations, i.e. clinical evaluation vs. precision and bias. Fourteen such criteria were found in the literature. There exists little consistency among these criteria for assessing clinical agreement, furthermore whether these methods of assessing agreement are reasonable estimates of clinical decision-making is unknown and has yet to be validated. One previous study compared actual clinical agreement by having two physicians indicate a dosing decision based on patient history and INR values. This analysis attempts to justify previously used mathematical criteria for clinical agreement. Generalized additive models with smoothing spline estimates were calculated for each of the 14 criteria and compared to the smoothing spline estimate for the method using actual physician decisions (considered the "gold standard"). The area between the criteria method spline and the gold standard method spline served as the comparison, using bootstrapping for statistical inference. Although some of the criteria methods performed better than others, none of them matched the gold standard. This stresses the need for clinical assessment of devices.
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Liaghat, Mitra. "Sjuksköterskors erfarenheter och upplevelser av att arbeta inom antikoagulationsmottagning." Thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-219561.
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Background Number of patients treated with medicine that has an anticoagulation character is constantly increasing. Chronic atrial fibrillation is the most common diagnosis being treated, but other diagnoses such as venous thrombosis), pulmonary embolism, stroke, coronary stent thrombosis and arterial thrombosis treated. There are a variety of anticoagulant drugs. In Sweden Warfarin is used as standard medicine for oral anticoagulation therapy. Purpose The purpose of this study is to examine and reflect nurses' experiences of working on anticoagulation clinic, and if he / she claims to have access to the necessary skills and resources to carry out a safe care. Design The study has a qualitative design with semi-structured interviews which were analyzed with an inductive approach. The interviews included six respondents. Findings The results showed that nurses who worked at anticoagulation Clinics had no specific training to operate these clinics. Respondents felt that they had obtained their knowledge through practical experience. However, previous research and Welfare guidelines emphasize the importance of continuous training. Even The National Board of Health and Welfare in Sweden requires that nurses should have significant skills to be able to provide good and safe care with high quality. Conclusion From these results it was concluded that the nurses who worked in anticoagulation clinics felt that they were able to do their work even though they had no specific training. However they considered that a basic theoretical knowledge could contribute to a more secure feeling regarding patient safety. Keywords Wafarinmonitoring, patient safety, Warfarin, Nurse
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Gilbert, Kimberlee Danielle. "Interactions between herbal supplements and warfarin: a patient teaching tool." Montana State University, 2012. http://etd.lib.montana.edu/etd/2012/gilbert/GilbertK0512.pdf.
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Many Americans are using herbal supplements without telling their primary care providers. When a person is taking warfarin, a medication that has a narrow therapeutic window and the potential for interaction with many substances, including food, medications, and supplements, providers must inform them of the risks. A literature review was done to find current literature related to warfarin and herbal interactions. Limited quality data is available, with most literature found being case reports, and small population studies. A patient teaching pamphlet was created and tested using a pre-test/posttest in a convenience sample of 18 patients that use warfarin at an internal medicine clinic in Northern Wyoming. The results showed improvement in posttest scores in 17 of 18 participants. Mean improvement was 10.9%. Providers should include herbal supplements in routine medication history. Providers should teach all patients using warfarin about potential interactions with herbal supplements and about the need to inform their provider about supplements. Lack of standardization of herbal supplements makes it difficult to research the risks and benefits as well as potential interactions. More research is needed to determine risks.
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Hamberg, Anna-Karin. "Pharmacometric Models for Individualisation of Warfarin in Adults and Children." Doctoral thesis, Uppsala universitet, Klinisk farmakogenomik och osteoporos, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-197599.
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Warfarin is one of the most widely used anticoagulants. Therapy is complicated by warfarin’s narrow therapeutic range and pronounced variability in individual dose requirements. Although warfarin therapy is uncommon in children, it is crucial for children with certain congenital or acquired heart diseases. Treatment in children is especially difficult due to the lack of i) a decision support tool for efficient and consistent dose adjustments, and ii) a flexible warfarin formulation for accurate and reproducible dosing. The overall aim of this thesis was to develop a PKPD-based pharmacometric model for warfarin that describes the dose-response relationship over time, and to identify important predictors that influence individual dose requirements both in adults and children. Special emphasis was placed on investigating the contribution of genetic factors to the observed variability. A clinically useful pharmacometric model for warfarin has been developed using NONMEM. The model has been successfully reformulated into a KPD-model that describes the relationship between warfarin dose and INR response, and that is applicable to both adults and children. From a clinical perspective, this is a very important change since it allows the use of information on dose and INR that is available routinely. The model incorporates both patient and clinical characteristics, such as age, weight, CYP2C9 and VKORC1 genotype, and baseline and target INR, for the prediction of an individualised starting dose. It also enables the use of information from previous doses and INR observations to further individualise the dose a posteriori using a Bayesian forecasting method. The NONMEM model has been transferred to a user-friendly, platform independent tool to aid use in clinical practice. The tool can be used for a priori and a posteriori individualisation of warfarin therapy in both adults and children. The tool should ensure consistent dose adjustment practices, and provide more efficient individualisation of warfarin dosing in all patients, irrespective of age, body weight, CYP2C9 or VKORC1 genotype, baseline or target INR. The expected outcome is improved warfarin therapy compared with empirical dosing, with patients achieving a therapeutic and stable INR faster and avoiding high INRs that increase the risk of bleeding.
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Sconce, Elizabeth A. "Improving the stability of anticoagulation in patients on warfarin therapy." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437259.
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Sandén, Per. "Efficacy and safety of warfarin treatment in venous thromboembolic disease." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-133618.
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Background As a major cause of morbidity and mortality treatment of venous thromboembolism is important, with the correct use of anticoagulants it is possible to greatly reduce both mortality and morbidity. Warfarin is among the most widely used anticoagulants being effective in treatment and prevention of venous thromboembolism with few negative side effects other than bleeding complications. With a narrow therapeutic window warfarin treatment requires constant monitoring and adjustments to stay effective without an increased bleeding risk. The aim of this thesis was to study the efficacy and safety of warfarin treatment in venous thromboembolic disease. Methods Using AuriculA, the Swedish national quality register for atrial fibrillation and anticoagulation, a cohort was created of patients registered with warfarin treatment during the study time January 1st 2006 to December 31th 2011, including all different indications for anticoagulation. In all four studies the study design was retrospective with information added to the cohort from the Swedish national patient register about background data and endpoints in form of bleeding complications in all studies and thromboembolic events in study 1 and 2. In study 3 and 4 information was added from the cause of death register about occurrence of death and in study 3 cause of death. In study 3, information from the prescribed drugs register about retrieved prescriptions of acetylsalicylic acid was added. Results In study 1 the mean TTR was found to be high both among patients managed at primary healthcare centres and specialised anticoagulation clinics at 79.6% and 75.7%. There was no significant difference in rate of bleeding between the two types of managing centres being 2.22 and 2.26 per 100 treatment years. In study 2 no reduction in complication rate with increasing centre TTR was seen for patients with atrial fibrillation with few centres having centre TTR below 70% (2.9%), in contrast to previous findings by Wan et al(1). For those with warfarin due to VTE where a larger proportion of the centres had centre TTR below 70% (9.1%) there was a reduction in complication rate with increasing centre TTR. Among the 13859 patients with treatment for VTE in study 3 age (HR 1.02, CI 95% 1.01-1.03), hypertension (HR 1.29, CI 95%1.02-1.64), Cardiac failure (HR 1.55, CI 95% 1.13-2.11), chronic obstructive pulmonary disease (HR 1.43, CI 95% 1.04- 1.96), alcohol abuse (HR 3.35, CI 95% 1.97-5.71), anaemia (HR 1.77, CI 95% 1.29-2.44) and a history of major bleeding (HR 1.75, CI 95% 1.27-2.42) increased the risk of bleeding during warfarin treatment. In study 4 both those with high iTTR and those with low INR variability had a low rate of bleedings at 1.27 (1.14-1.41) or 1.20 (0.94-1.21) per 100 treatment years compared to those with low iTTR and high INR variability having a rate of bleeding at 2.91 (2.61-3.21) or 2.61 (2.36-2.86) respectively. Those with the combination of both low iTTR and high INR variability had an increased risk of bleeding, hazard ratio HR 3.47 (CI 95 % 2.89-4.17). The quartile with both the lowest iTTR and the highest INR variability had an increased risk of bleeding with a hazard ratio 4.03 (3.20-5.08) and 3.80 (CI 95%, 3.01-4.79) compared to the quartile with the highest iTTR and lowest INR variability. Conclusion It is possible to achieve a safe warfarin treatment both in specialised anticoagulation centres and in primary health care. At initiation of treatment some of the patients at high risk of bleeding can be identified using knowledge about their background. With the use of quality indicators as TTR and INR variability during treatment those at high risk of complications can be identified and analysing treatment quality on centre level gives an opportunity to identify improvement areas among managing centres. With the addition of new treatment options warfarin can still be the most suitable option for some patients, being safe and effective when well managed.
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Pisa, Ana Carolina Chaves. "Efeito do controle de morcegos Desmodus rotundus na ocorrência de focos de raiva no estado do Espírito Santo." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/10/10134/tde-25082015-102004/.
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A raiva é uma zoonose nervosa, aguda e fatal que acomete todos os mamíferos e provoca enormes prejuízos para os pecuaristas. No ciclo epidemiológico rural, a doença é transmitida por morcegos hematófagos aos herbívoros e, ainda que haja um esforço por parte dos órgãos de defesa e dos produtores rurais para que se evite a ocorrência da doença, historicamente percebe-se que o combate à raiva com base somente na atuação em focos e vacinação de suscetíveis não elimina eficazmente o problema. Um dos pilares do Programa Nacional de Controle da Raiva dos Herbívoros (PNCRH) do Ministério da Agricultura, Pecuária e Abastecimento (MAPA) é o controle das populações de morcegos hematófagos pelo uso de pasta vampiricida. Porém, apesar dessa medida ser largamente utilizada como forma de controle da raiva rural, há poucas informações a respeito do real impacto que ela causa na ocorrência de focos de raiva no Espírito Santo. Através da análise de dados coletados pelo Instituto de Defesa Animal e Florestal do Espírito Santo (IDAF), pelo Instituto Brasileiro de Geografia e Estatística (IBGE) e pelo Instituto Jones dos Santos Neves (IJSN) determinou-se o efeito do uso da pasta vampiricida em morcegos hematófagos na ocorrência de focos de raiva no Espírito Santo em 2011, 2012 e 2013. Para tal, foram utilizadas as coordenadas de focos de raiva e do uso de pasta vampiricida pelas equipes de captura de morcegos. As coordenadas georreferenciadas foram representadas em um Sistema de Informação Geográfica e analisadas utilizando-se o modelo de interpolação pelo método do “inverso das distâncias” A prevenção da ocorrência de focos de raiva ocorreu quando o impacto do tratamento foi alto e muito alto, porém a área de impacto é espacialmente limitada. Já nas áreas onde o impacto foi baixo ou muito baixo, a doença continuou grassando. Aspectos da biologia e ecologia dos morcegos hematófagos, como o comportamento das colônias após o uso da pasta e a possível dispersão do vírus, precisam ser melhor estudados.Rabies is a nervous, acute and fatal zoonosis that affects mammals and causes enormous economic losses to farmers. In its rural epidemiological cycle, the disease is transmitted by common vampire bats to herbivores. There is a constant effort from cattle breeders and public veterinary services to avoid rabies occurrence. However, it has been reported that only livestock vaccination and outbreak control actions do not effectively control the problem. One of the pillars of the Herbivore Rabies National Control Program (PNCRH) from the the Ministry of Agriculture, Livestock and Supply of Brazil (MAPA) is the control of vampire bat populations through vampiricid gel use. However, even though this measure is largely used as a way to control cattle rabies, there is a lack of information regarding its actual impact in the occurrence of rabies outbreaks in the state of Espírito Santo. Through analysis of data collected by the Forestry and Animal Surveillance Institute of Espírito Santo (IDAF), the Brazilian Statistics and Geography Institute (IBGE) and the Jones dos Santos Neves Institute, we were able to establish the effect of vampiricid gel use on rabies outbreaks in Espírito Santo in 2011, 2012 and 2013. In order to do so, we used the geographic coordinates of rabies occurrence and vampiricid gel use. These references were then represented on a Geographic Information System and analyzed with an in verse distance weighted (IDW) interpolation method. Outbreaks were prevented when impact was high or very high; however, the impact areas in these cases appeared to be spatially limited. In areas where impact was considered low or very low, rabies prevailed. Vampire bat ecology and biology aspects, such as colony behavior after vampiricid gel use and possible virus dispersion, should be investigated further.
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Osman, Abdimajid. "Studies on warfarin treatment with emphasis on inter-individual variations and drug monitoring." Doctoral thesis, Linköping : Linköping University, 2007. http://www.bibl.liu.se/liupubl/disp/disp2007/med1000s.pdf.
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Delaney, Joseph Austin C. "Assessing the risks associated with warfarin therapy and related methodological considerations." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19281.
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Warfarin is an anticoagulant medication that is used for the prevention and treatment of venous and arterial thrombotic complications. The evaluation of the risks associated with warfarin therapy, and its interaction with other drugs, poses important methodological challenges. In this thesis, we studied two of these risks and assessed techniques to address these methodological challenges using data from the United Kingdom's General Practice Research Database (GPRD). First, we conducted a case-control study to examine the risk of gastrointestinal bleeding associated with warfarin use. We identified 4028 cases and 40171 matched controls from 2000 through 2005. Using conditional logistic regression, we found an increased risk of bleeding associated with warfarin use [adjusted odds ratio (OR) 2.15; 95% confidence interval (CI):1.81 to 2.54]. We also observed an increased risk due to drug-drug interactions between warfarin and other anti-thrombotic drugs. We also observed evidence of channelling bias as warfarin users were less likely to be prescribed other anti-thrombotic drugs. Second, as warfarin has many weak interactions, we re-analyzed our case-control study using a marginal structural model to assess the overall impact of effect modification. This analysis produced a different estimate (for the population level instead of the individual level) for the risk of bleeding associated with warfarin [OR 17.2; 95% CI: 6.5 to 37.7] than analysis with conditional logistic regression. The impact of effect modification on these estimates was then assessed with a Monte Carlo simulation study. Third, we created a cohort of patients given their first prescription of warfarin, ibuprofen, statins, or rofecoxib/celecoxib from 2001 through 2003Le traitement par Warfarine est utilisé pour la prévention et le traitement d'événements thrombotiques artériels et veineux. L'évaluation des risques associés au traitement par warfarine et son interaction avec d'autres médicaments représentent des défis méthodologiques importants. Dans cette thèse, nous étudions ces risques et évaluons les techniques pour relever ces défis méthodologiques en utilisant les données de la base de données General Practice Research Database (GPRD). Dans un premier temps, nous avons réalisé une étude cas-témoins pour évaluer le risque de saignement gastro-intestinal associé à l'utilisation de la warfarine. Nous avons identifié 4028 cas et 40171 contrôles appariés, entre 2000 et 2005. En utilisant une régression logistique conditionnelle, nous avons constaté une augmentation du risque de saignement chez les patients sous warfarine [rapport des cotes ajusté (RC) 2.15 (intervalle de confiance à 95 % (IC) :1.81–2.54)]. Nous avons également observé un risque augmenté en raison d'une interaction médicamenteuse entre la warfarine et d'autres médicaments antithrombotiques. Enfin, nous avons mis en évidence un biais d'indication lié à la moindre probabilité de prescription d'autres médicaments antithrombotiques chez les utilisateurs de warfarine. La warfarine ayant de nombreuses faibles interactions, nous avons, dans un deuxième temps analysé notre étude cas-témoins en utilisant un modèle structurel marginal pour évaluer l'impact global d'une modification d'effet. Cette analyse a produit une estimation différente (au niveau de la population et non d'un individu) du risque de saignement associé à la warfarine [RC 17.2 (IC à 95 % : 6.5–37.7)] de celle obt
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Biss, Tina Tracey. "Identification of the factors influencing anticoagulation response to warfarin in children." Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1546.
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The requirement for anticoagulant therapy in children is increasing and warfarin remains the long-term anticoagulant agent of choice. However, little is known about the factors that influence inter-individual variability in response to warfarin among children. The aim of this MD was to gain a greater understanding of the factors that affect warfarin anticoagulant control and response in children. A retrospective study of a cohort of anticoagulated children identified factors contributing to poor anticoagulant control. It also highlighted the importance of the way in which anticoagulant control is assessed in children, with the study results showing that the use of a linear interpolation method may be more appropriate than the proportion of INRs within target range during intermittent periods of instability when INR measurements are carried out more frequently. A multi-centre, cross-sectional study of 120 children with stable anticoagulation with warfarin showed that 72% of the inter-individual variability in warfarin maintenance dose is accounted for by height, VKORC1 and CYP2C9 genotype, and indication for warfarin. The study results were used to develop a pharmacogenetics-based warfarin-dosing algorithm. The latter was demonstrated to have the power to accurately predict maintenance warfarin dose in an unrelated cohort of 23 children. Analysis of data for a subgroup of 51 children showed that VKORC1 and CYP2C9 genotype influence outcome variables during initiation of warfarin therapy, including peak INR response during week 1 and the proportion of supratherapeutic INRs during month 1 of therapy. The above findings have provided us with an insight into the factors influencing anticoagulant control and variability in response to warfarin in children. Application of a pharmacogenetics-based approach to initiation and maintenance warfarin therapy in children has the potential to improve efficacy and safety of warfarin therapy in this challenging patient population.
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Hatch, Ellen. "Variability in response to warfarin : analysis of pharmacogenetic and environmental factors." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500980.
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Anticoagulation response to warfarin is unpredictable because of the wide interindividual variability in dose requirement and the drug's narrow therapeutic index. The aim of my PhD project was to ftirther investigate and identify factors that contribute to the variability in warfarin dose requirements. Identification of the factors contributing to the variability could help toward improving the safety of warfarin through personalized therapy.
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Jorgensen, Andrea Lyn. "Improving the evidence base in pharmacogenetic studies : Warfarin as an example." Thesis, University of Liverpool, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539496.
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Al-Zubiedi, Sameh A. "Investigating warfarin variabilty : the contribution of clinical, genetic, and enviromental factors." Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501741.
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Warfarin is the most widely used oral anticoagulant for the prevention and treatment of various cardiovascular diseases. However, its complications represent an important clinical problem. The drug has a very low therapeutic index and there is significant interpatient and inter-iscmer variability in both pharmacokinetics and pharmacodynamics; these are affected by a large number of genetic and non-genetic factors. Genetic variation in CYP2C9 and VKORCl has been most extensively studied in relation to warfarin dose requirements.
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Barraclough, John. "Pharmacogenetic, clinical and demographic factors in the management of warfarin therapy." Thesis, Sheffield Hallam University, 2012. http://shura.shu.ac.uk/20622/.
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It has been estimated that, at any one time, more than one million people in the U.K. are taking the anticoagulant drug warfarin, for the treatment or prevention of venous thromboembolism. The incidence of life threatening haemorrhage, due to overdose, is approximately two per one hundred patient years. It is well known that there is great inter-individual variability in reaching and maintaining a therapeutic level of oral anticoagulants, in part, due to the combined effect of gender, age, body size and drug interactions. In recent years, single nucleotide polymorphisms (SNPs) have been identified, which significantly reduce the amount of warfarin required for an individual to reach a therapeutic level. Consequently, the optimum dose of warfarin can be predicted in a higher percentage of patients using an algorithm, which includes pharmacogenomic information rather than one with clinical and demographic data alone. The aim of this study was to create two rigorous, composite algorithms, one clinical and one pharmacogenetic, which combined as many influencing factors as possible, in an effort to improve the predictability of warfarin dosing beyond that of other published studies to date. The study was carried out using three groups of subjects, after obtaining ethical committee approval and informed consent. Group 1 subjects (n=12) were healthy, non-warfarin treated laboratory staff, whose DNA was used to optimise the DNA extraction procedure. Group 2 subjects (n=207) consisted of warfarin patients, who had had a stable therapeutic International Normalised Ratio (INR) for at least two months. A comprehensive list of clinical and demographic data was obtained from each patient, as well as DNA samples for SNP analysis of the VKORC1, CYP2C9 and CYP4F2 genes. Group 3 subjects (n=20) comprised of pre-warfarinised patients who provided the same data as in group 2. In addition, venous blood samples were obtained for the measurement of the baseline levels of the vitamin K dependent coagulation factors and albumin. The stable warfarin dose for each of the group 3 patients was obtained retrospectively, after several weeks of warfarin therapy. The two algorithms were then constructed using the data from a random selection of group 2 patients (n=160). These were then used to predict the warfarin dose of the remaining patients in the group (n=47). By plotting the predicted dose against the actual stable dose, the percentage predictability of the new algorithms was calculated. In addition, the predictability of eleven previously published algorithms, eight pharmacogenetic and three clinical, was calculated using the same 47 patients. The clinical algorithm from this study showed the lowest predictability (R2=0.188) when compared to the three published algorithms (R2=0.203-0.268). However, the pharmacogenetic algorithm was able to account for a higher proportion of the warfarin dose (R2=0.553) than any of the other eight published algorithms (R2=0.383-0.525).In the group 3 patients, no relationship was demonstrated between the warfarin dose and either the albumin levels or the baseline levels of the vitamin K-dependent coagulation factors, with the exception of factor IX, which showed a negative correlation.
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Sutcliffe, Frances Anne. "Warfarin metabolism and disposition in anticoagulant-resistant and susceptible mouse strains." Thesis, University of Surrey, 1986. http://epubs.surrey.ac.uk/848073/.
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The differential susceptibilities of warfarin-susceptible LAC-grey and warfarin-resistant HC house mice to the anticoagulant effect of the oral rodenticide 3-(alpha-acetonyl benzyl)-4-hydroxycoumarin (Warfarin) in terms of their blood clotting times, were determined. The hypoprothrombinaemic effect of both the R(+) and S(-) warfarin enantiomers was also investigated, in addition to the standard test for warfarin-resistance in mice, the ability to survive on a diet containing 0.025% warfarin for 21 days. Onto this base of knowledge of the exact hypoprothrombinaemic responses evoked by treatment of both warfarin- susceptible and warfarin-resistant mice with warfarin at various doses, a structured analysis of the biochemical consequence(s) of expression of the major warfarin-resistance gene, War, could be built. Thus, changes in the in vivo pharmacokinetic parameters including half-life (t[1/2]), plasma clearance (Cl[p]), apparent volume of distribution (Vd[app]) and bioavailability (F) were documented for both R(+) and S(-) warfarin in both males and females of the two mouse strains. Similarly, in vitro hepatic microsomal metabolite profiles following pretreatment with warfarin, phenobarbitone, beta-naphthoflavone and clofibrate, excretion of unchanged warfarin enantiomers and warfarin metabolites and finally plasma protein binding parameters were determined in LAC-grey and HC mice. Therefore, it was possible to correlate changes in the pharmacokinetics, metabolism and disposition of warfarin in these mice with their differential anticoagulant sensitivities. Accordingly, the biochemical mechanism(s) of the expression of the major warfarin-resistance gene, War, has (have) been proposed to be due, at least in part, to a combination of a greater plasma clearance of the more potent S(-) warfarin enantiomer in females, a larger hepatic uptake of the same enantiomer in both sexes, and a greater degree of plasma protein binding of both enantiomers of warfarin.
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Podda, G. "PREDICTION OF OPTIMAL WARFARIN MAINTENANCE DOSE USING ADVANCED ARTIFICIAL NEURAL NETWORKS." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/219087.
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Introduction. The individual response to vitamin K antagonists (VKA) is highly variable, being influenced by clinical factors and genetic variants of enzymes that are involved in the metabolism of VKA (CYP2C)) and vitamin K (VKORC1). Currently, the dose of VKA is adjusted based on measurements of the prothrombin time. In the last years, mathematical algorithms were developed for estimating the appropriate VKA dose, based on different mathematical approaches working on clinical and genetic data. Artificial Neural Networks (ANN) are computerized algorithms resembling interactive processes of the human brain, which allow to study very complex non-linear phenomena like biological systems. Aim. To evaluate the performance of new generation ANN on a large data base of patients on chronic VKA treatment. Methods. Clinical and genetic data from 377 patients (186 m; 191 f) treated with a VKA (warfarin) average weekly maintenance dose (WMD) of 23.7 mg (11.5 SD) were used to create a dose algorithm. Forty-eight variables, including demographic, clinical and genetic data (5 CYP2C9 and 3 VKORC1 genetic variants) were entered into Twist® system, which can select fundamental variables during their evolution in search for the best predictive model. The final model, based on 23 variables expressed a functional approximation of the actual dose within a validation protocol based on a tripartite division of the data set (training, testing, validation). Results. In the validation cohort, the pharmacogenetic algorithm reached high accuracy, with an average absolute error of 5.7 mg WMD. In the subset of patients requiring ≤21 mg (45 % of the cohort) and 21-49 mg (51 % of the cohort) the absolute error was 3.86 mg and 5.45 with a high percentage of subjects being correctly identified (72%, 74% respectively). Conclusion. ANN can be applied successfully for VKA maintenance dose prediction and represent a robust basis for a prospective multicentre clinical trial of the efficacy of genetically informed dose estimation for patients who require VKA.
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Ho, Lok-yan. "The clinical efficacy and risk of anticoagulation in Chinese patients /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B3829591X.
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Cholerton, S. "A study of the relationships between the pharmacokinetics and the pharmacodynamics of warfarin and vitamin K1̲." Thesis, University of Liverpool, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381337.
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Chemodurow, Lucy, and Shanna Christensen. "A Pre-‐ Post-‐Evaluation of Implementing an Inpatient Warfarin Monitoring and Education Policy." The University of Arizona, 2010. http://hdl.handle.net/10150/623797.
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Class of 2010 AbstractOBJECTIVES: The objective of this study was to evaluate whether implementation of new anticoagulation policy at a community hospital resulted in better monitoring of warfarin, increased warfarin patient education prior to discharge, and less bleeding complications due to warfarin. METHODS: This study was a pre-‐ post-‐retrospective chart review quality improvement study. A retrospective chart review was conducted of all patients who were inpatients and received warfarin in the time period of April 1, 2008 to July 31, 2008 (historical control group before implementation of the new anticoagulation program) and the time period of April 1, 2009 to July 31, 2009 (after implementation of the new anticoagulation policies). To compare appropriateness of laboratory monitoring, the frequency of warfarin-‐related laboratory orders that included a baseline international normalized ratio (INR), daily INR, baseline complete blood count (CBC), and CBC every 3 days were assessed before and after program implementation. The analysis was repeated for the frequency of patient education that included documentation by pharmacy, nursing, and dietary services. Finally, data was collected to determine frequencies of bleeding complications associated with warfarin. RESULTS: There were 112 patients in the pre-‐policy group and 115 patients in the post-‐policy group. After implementation of the inpatient warfarin policy, obtaining baseline INRs increased from 74% to 90% (p=0.001). In addition, prescriber orders for baseline CBCs increased from 85% to 94% (p=0.026). Obtaining CBCs every 3 days increased from 54% to 74%, (p<0.001). However, there was not a significant increase in orders for daily INR levels (p=0.055). Education by nursing increased from 54% to 80%, (p<0.001). Education by pharmacy increased from 8% to 76%, (p<0.001). Education by dietary increased from 11% to 79%, (p<0.001). Moreover, documentation by all three disciplines in each patient increased significantly from 3.6% to 59%, (p<0.001). There were significantly fewer patients receiving vitamin K and/ or fresh frozen plasma for supratherapeutic INRs with bleeding complications after the policy was initiated compared to baseline (p=0.009). CONCLUSIONS: The implementation of an inpatient warfarin policy led to better monitoring of patients receiving warfarin, and increased patient education. Studies have demonstrated that increased monitoring of warfarin translates to improved patient outcomes. However, a larger and longer assessment is necessary to determine if these changes are maintained and how these changes affect clinical outcomes.
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Hellman, Jacob, and Jonny Dahlberg. "Development of an applicationfor individualized Warfarin treatment : Independent Project in Engineering Physics." Thesis, Uppsala universitet, Institutionen för teknikvetenskaper, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-180358.
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A problem with the widley usedanticoagulant medicine Warfarin hasalways been that the therapeutic dosevaries from person to person and thatthere has not been any methods toestimate individually-based dosingregimens. By using a new populationmodeldescribing the relationship betweenWarfarin dose and INR(internationalnormalized ratio) response fordifferent individuals based on their age,weight and genotypes, a user friendly,dose estimating program has beendeveloped in Java. The applicationestimates the INR given the individualparameters and dosing, but it's alsopossible to estimate the predicted dosegiven the desired INR. The applicationmakes it possible for others to take partof the model, and to give a moreindividualized Warfarin treatment inclinical practice.
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Coleman, Craig I., Jan Beyer-Westendorf, Thomas J. Bunz, Charles E. Mahan, and Alex C. Spyropoulos. "Postthrombotic Syndrome in Patients Treated With Rivaroxaban or Warfarin for Venous Thromboembolism." Sage, 2018. https://tud.qucosa.de/id/qucosa%3A35470.
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Postthrombotic syndrome (PTS) is a frequent complication of venous thromboembolism (VTE). Using MarketScan claims data from January 2012 to June 2015, we identified adults with a primary diagnosis code for VTE during a hospitalization/emergency department visit, ≥6 months of insurance coverage prior to the index event and newly started on rivaroxaban or warfarin within 30 days of the index VTE. Patients with <4-month follow-up postindex event or a claim for any anticoagulant during 6-month baseline period were excluded. Differences in baseline characteristics between rivaroxaban and warfarin users were adjusted for using inverse probability of treatment weights based on propensity scores. Patients were followed for the development of PTS starting 3 months after the index VTE. Cox regression was performed and reported as hazard ratios with 95% confidence intervals (CIs). In total, 10 463 rivaroxaban and 26 494 warfarin users were followed for a mean of 16 ± 9 (range, 4-39) months. Duration of anticoagulation was similar between cohorts (median = 6 months). Rivaroxaban was associated with a 23% (95% CI: 16-30) reduced hazard of PTS versus warfarin. Rivaroxaban was associated with a significant risk reduction in symptoms of PTS compared to warfarin in patients with VTE treated in routine practice.
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Kidd, Robert Scott. "The Development And Validation Of A Novel Genetic-Based Warfarin Dosing Nomogram." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1216306028.
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Mosher, Carrie M. "CYP2C9 binding determinants and activation mechanisms for phenytoin and (S)-warfarin metabolism /." Thesis, Connect to this title online; UW restricted, 2008. http://hdl.handle.net/1773/8170.
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Hermans, Johannes Jozef Robertus Maria. "Comparative metabolism of warfarin and acenocoumarol: stereoselectivity in oxidative and reductive biotransformation routes." [Maastricht : Maastricht : Rijksuniversiteit Limburg] ; University Library, Maastricht University [Host], 1993. http://arno.unimaas.nl/show.cgi?fid=6508.
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Perona, Stephen. "Hemorrhagic Events Lead to an Increase in International Normalized Ratio in Warfarin Patients." The University of Arizona, 2010. http://hdl.handle.net/10150/623790.
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Class of 2010 AbstractOBJECTIVES: The purpose of this study was to demonstrate that an increase in INR is associated with a hemorrhagic event in patients taking the oral anticoagulant warfarin. METHODS: A retrospective review of data from 18 patients previously stable on warfarin therapy with an elevation in INR at the time of a hemorrhagic event. Patients were receiving warfarin treatment in the anticoagulation clinic at the Southern Arizona VA Healthcare system from April 2008 to December 2009. Primary outcome measures included a comparison of INR, warfarin dose, and hematocrit at baseline, within 7 days of the event, and during follow-‐up. RESULTS: A significant increase in INR was observed from baseline to the event (2.5 +/-‐ 0.36 vs 6.2 +/-‐ 3.2; p = 0.0002) but differences in INR during all periods of follow-‐up did not differ from baseline (p = 0.35 – 0.99). When compared with baseline, differences in warfarin dose reached statistical significance when all 12 weeks of follow-‐up were included (34.4 +/-‐ 13.8 mg vs 32.4+/-‐ 15.5 mg; p = 0.01) but were not significant when only the last 8 weeks (p = 0.06) or 4 weeks (p = 0.16) were included. Hematocrit values decreased significantly following hemorrhage (39.8 +/-‐ 3.63 vs 33.5 +/-‐ 5.72; p = 0.0002) before trending toward baseline (39.85 +/-‐ 3.63 vs 37.13 +/-‐ 4.72; p = 0.007). CONCLUSIONS: Hemorrhagic events were associated with an increased INR in previously stable warfarin patients. The mean weekly warfarin dose required to maintain a therapeutic INR returned to baseline within 8 weeks of the hemorrhagic event.
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Hood, Evan, and Jeannie K. Lee. "Postoperative Warfarin Re-Initiation Strategies: an Interview-Based Comparison of Certified Anticoagulation Providers." The University of Arizona, 2013. http://hdl.handle.net/10150/614249.
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Class of 2013 AbstractSpecific Aims: The purpose of this study is to identify a postoperative warfarin re-initiation protocol used most commonly by certified anticoagulation providers. Our main hypothesis is that certified Anticoagulation providers use a postoperative warfarin re-initiation strategy based upon clinical experience/knowledge as opposed to a guideline-based approach. Methods: The Anticoagulation Forum website will be used to select the anticoagulation providers to interview via telephone. The selection process will be as follows: an excel spreadsheet will be created separating every clinic listed on the website by region, then fifty anticoagulation providers will be randomly selected by utilizing a random number generator function in excel for each region. Anticoagulation providers are listed on the website by region, and then further broken down by states in that region. The intention of separating regions is to attain equal representation of anticoagulation providers across the United States that are listed on the Anticoagulation Forum website. Anticoagulation providers will be called during the months of July, August and September 2012. Any anticoagulation provider contacted that is not certified with the National Certification Board for Anticoagulation Providers (NCBAP) as well as services or clinics not listed on the Anticoagulation Forum website will be excluded. An application will be submitted to the University of Arizona Institutional Review Board (IRB) Human Subjects Protection Program for approval of this study. We plan to randomly call 50 anticoagulation providers from each region of the US listed on the Anticoagulation Forum website. Thus, total estimated sample size is approximately 300 providers. The primary dependent variable is the postoperative warfarin re-initiation protocol. Our demographic variables are as follows: # of years in anticoagulation practice, gender of the provider and their credentials. The data extraction form is comprised of 3 parts. Part 1 will focus on questions directly related to the anticoagulation service, part 2 is for describing the patient population served and part 3 will be related to the provider demographic characteristics. Data will be collected by utilizing a telephone interview questionnaire-based approach. Each certified anticoagulation provider randomly selected from the Anticoagulati Main Results: The information about warfarin re-initiation dose and protocol information are shown in Table 2. A majority of certified anticoagulation providers re-initiate warfarin at the same dose (64%) after temporary interruption compared to a relative warfarin dose (36%) following surgery/procedure. Likewise, more certified anticoagulation providers have a protocol in place (59%) compared to no protocol in place (41%). Conclusion: This study displayed strength when certified anticoagulation providers were able to be contacted and take the time to answer the questionnaire. Certified anticoagulation providers utilize a common warfarin re-initiation strategy. Most providers’ re-initiation warfarin at the same dose at which the patient was receiving prior to surgery. However, there are many other factors that may go into making the decision of which warfarin dose to use postoperatively.
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Cove, Christina Lauren. "Severe renal dysfunction among individuals taking warfarin and implications for new oral anticoagulants." Thesis, Boston University, 2014. https://hdl.handle.net/2144/21140.
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Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.BACKGROUND: Although novel anticoagulant drugs have proven safety and efficacy profiles from Phase III clinical trials, those patients with significant kidney disease were excluded. The lack of knowledge about incidence, severity and risk factors for severe renal dysfunction in patients requiring oral anticoagulation impedes development of strategies to mitigate risks of hemorrhage associated with renally-eliminated novel oral anticoagulants. METHODS: Patients taking warfarin for atrial fibrillation (AF) or venous thromboembolism (VTE) were consecutively enrolled from January 2007 to December 2010. Baseline kidney function was assessed and patients were followed to their first decline in Glomerular Filtration Rate (GFR) to < 30 ml/min estimated by the Cockcroft-Gault calculation. Independent risk factors for development of severe kidney dysfunction were assessed by multivariate analysis. RESULTS: Of 787 patients identified, 34 were excluded for baseline eGFR < 30 ml/min. The mean age of the cohort was 71 years. At baseline, 23% (n=174) had moderate renal impairment, or Stage 3 CKD (eGFR 30-59 ml/min), while 31% had mild disease. Overall, those with hypertension, congestive heart failure (CHF), diabetes mellitus (DM), and coronary artery disease (CAD) were 74%, 33%, 31%, 24%, and 9% of the cohort, respectively. A decline in eGFR to < 30 ml/min (the primary outcome) occurred in 91 patients, 25% of which happened within 5.3 months. Of those with baseline Stage 3 CKD, 37% experienced the primary outcome. In multiple logistic regression analysis, a baseline eGFR 30–59 ml/min conferred a greater than 14-fold increased risk in the development of eGFR < 30 ml/min (OR 14.5, 99% CI: 5.3 to 39.8, P<0.001) during the warfarin exposure period. CAD was associated with a greater than two-fold increased risk (OR 2.2, 95% CI 1.1 to 4.4, P=0.004). After adjusting for baseline kidney function, age was not an independent risk factor for a decline in eGFR to < 30 ml/min. CONCLUSIONS: Acute and chronic renal dysfunction is common among individuals on chronic warfarin therapy. Better understanding of the fluctuations in renal function would inform patient selection and monitoring strategies for optimal use of novel anticoagulants.
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Lind, Marcus. "Determinants of adverse events during oral anticoagulant treatment." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-53431.
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Treament with oral anticoagulation is highly effective in reducing the burden of thromboembolic complications in several clinical conditions. The number of patients receiving oral anticoagulation is growing steadily. InSwedenabout 1.5 percent of the population receives treatment. Although the treatment is highly effective in preventing thromboembolic complications, it is also associated with a substantial increase in the risk of bleeding. In clinical practice every physician has to balance the potential benefit of treatment against the risk of bleeding complications in the individual patient. To aid in this decision making, risk scores addressing the likelihood of thromboembolic events, as well as the risk of bleeding complications, have been developed. These scores are imperfect and, to some degree limited by the fact that the risk factors predictive of thromboembolic events are also often associated with bleeding complications. The addition of biomarkers has the potential to increase the predictive ability of risk scores and further enhance the net benefit of oral anticoagulant treatment in the individual patient. In this thesis several potential biomarkers for thromoboembolic and haemorrhagic complications of anticoagulant therapy have been investigated in a longitudinal cohort study of 719 patients with a median follow-up time of 4.2 years. Thrombomodulin is a key component in the generation of activated protein C and hence, a coagulation inhibitor. Conversely, it is also a key component in the inhibition of fibrinolysis by activation of trombin-activated fibrinolysis inhibitor. In warfarin-treated patients we demonstrate that thrombomodulin predicts an increased risk of bleeding complications, but not cardiovascular events. Thus, thrombomodulin has potential as a biomarker specifically for bleeding complications. Von Willebrand factor plays a central and intricate role in the aggregation of platelets and low levels of VWF have been associated with bleeding as a manifestation of von Willebrand’s disease. In our study we noted that high levels of von Willebrand factor predict an increased risk of cardiovascular as well as all-cause mortality, possibly as an expression of endothelial dysfunction. We also noted that high levels of WVF seem to be associated with serious bleeding complications. Decreased renal function is usually measured by an increase in the levels of creatinine and cystatin C, or a decrease in the calculated glomerular filtration rate. A decrease in kidney function is regarded as a marker of an increased risk of bleeding complications. We investigated all the mentioned markers of kidney function and no association with bleeding complications became apparent. However, a clear association between a decrease in kidney function and mortality was noted. Our findings indicate that the emphasis on impaired kidney function as a risk marker needs to be shifted from bleeding complications toward thromboembolic events. Fibrinolysis is important in containing coagulation and several constituents of the fibrinolytic pathway have been shown to predict cardiovascular events and mortality. We found that fibrinolytic factors seem to predict cardiovascular events in patients with oral anticoagulation and that D-dimer also predicts bleeding complications. In conclusion, we have found several biomarkers which exhibit different predictive abilities in patients with oral anticoagulation. It is likely that biomarkers, either alone, in combination, or as ancillary components of risk scores, can contribute to improved risk stratification in patients with oral anticoagulation.