warfarin and Body-Weight

Essentials The association of body weight and patient-important outcomes remains unknown. Phase III randomized controlled trials of direct oral anticoagulants (DOACs) were searched. Risk of outcomes varying among body weight subgroups is not attributable to anticoagulant type. Dose adjustment of DOACs, outside that recommended, is unlikely to improve the outcomes. Click to hear Dr Braunwald's perspective on antithrombotic therapy in cardiovascular disease SUMMARY: Background Concerns have arisen in direct oral anticoagulant (DOAC)-treated patients about safety and efficacy in extremes of body weight. The aims of this systematic review were to investigate the association of body weight and patient-important outcomes in patients treated with DOACs or warfarin, and to demonstrate the fixed-dose effect of DOACs. Methods MEDLINE and EMBASE were searched until November 2016. Phase III randomized controlled trials (RCTs) using DOACs in atrial fibrillation (AF) and acute venous thromboembolism (VTE) were included. Relative risk and 95% confidence interval were calculated. The pooled estimates were performed using a Mantel-Haenszel random effects model. Results A total of 11 phase III RCTs were included. Low body weight was associated with increased risk of thromboembolism compared with non-low body weight (relative risk [RR], 1.57; 95% confidence interval [CI], 1.34-1.85). High body weight was not associated with risk of thromboembolism compared with non-high body weight (RR, 0.88; 95% CI, 0.63-1.23). The subgroup of AF patients with high body weight had a lower risk of thromboembolism compared with non-high body weight (RR, 0.43; 95% CI, 0.28-0.67). Bleeding outcomes were comparable for all body weight comparisons. There were no clear interactions between types of anticoagulant in all outcomes. Conclusion The pooled effect of both the DOAC and comparison arms was likely to be attributable to differences in baseline thrombotic risk in each body weight category, rather than an effect of the type or dose of DOAC used for each indication. Dose adjustment of DOACs, outside that recommended in the package insert, is unlikely to improve safety or efficacy.

Topics: Acute Disease; Anticoagulants; Atrial Fibrillation; Body Weight; Clinical Trials, Phase III as Topic; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Risk; Sensitivity and Specificity; Thromboembolism; Treatment Outcome; Venous Thromboembolism; Warfarin

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.

Topics: Administration, Oral; Anticoagulants; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Gastrointestinal Hemorrhage; Humans; Medication Adherence; Venous Thromboembolism; Vitamin K; Warfarin; Women's Health

Numerous factors are well documented to affect the response to vitamin K antagonists (VKA), including dietary vitamin K, other drugs, age, pharmacogenetics, and disease states. Body weight is perhaps not as well known as a variable affecting VKA dose. Our aim was to review the literature regarding body weight and VKA dose requirements.. We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight.. Among 32 studies conducted since the widespread use of the international normalized ratio, 29 found a correlation with body weight or body surface area and VKA dose requirement. Warfarin was evaluated in 27 studies and acenocoumarol, phenprocoumon, or fluindione were assessed in 5 investigations.. Because of varying study methodologies, further study is warranted. Based on current evidence, clinicians should include body weight, along with other established variables when dosing VKA. Most important, obese and morbidly obese patients may require a 30% to 50% increase with the initial dosing of VKA.

Topics: Acenocoumarol; Anticoagulants; Body Weight; Comorbidity; Drug Dosage Calculations; Humans; Obesity; Obesity, Morbid; Phenindione; Phenprocoumon; Vitamin K; Warfarin

Due to the narrow therapeutic range and high drug-to-drug interactions (DDIs), improving the adequate use of warfarin for the elderly is crucial in clinical practice. This study examines whether the effectiveness of using warfarin among elderly inpatients can be improved when machine learning techniques and data from the laboratory information system are incorporated.. Having employed 288 validated clinical cases in the DDI group and 89 cases in the non-DDI group, we evaluate the prediction performance of seven classification techniques, with and without an Adaptive Boosting (AdaBoost) algorithm. Measures including accuracy, sensitivity, specificity and area under the curve are used to evaluate model performance.. Decision tree-based classifiers outperform other investigated classifiers in all evaluation measures. The classifiers supplemented with AdaBoost can generally improve the performance. In addition, weight, congestive heart failure, and gender are among the top three critical variables affecting prediction accuracy for the non-DDI group, while age, ALT, and warfarin doses are the most influential factors for the DDI group.. Medical decision support systems incorporating decision tree-based approaches improve predicting performance and thus may serve as a supplementary tool in clinical practice. Information from laboratory tests and inpatients' history should not be ignored because related variables are shown to be decisive in our prediction models, especially when the DDIs exist.

Topics: Aged; Aged, 80 and over; Algorithms; Anticoagulants; Artificial Intelligence; Body Weight; Clinical Laboratory Information Systems; Comorbidity; Cross-Cultural Comparison; Decision Trees; Dose-Response Relationship, Drug; Drug Interactions; Ethnicity; Female; Heart Failure; Humans; Male; Medical History Taking; Middle Aged; Quality Improvement; Risk Factors; Taiwan; Thyrotoxicosis; Warfarin

Warfarin has long been the mainstay of oral anticoagulation therapy for the treatment and prevention of venous and arterial thrombosis. The narrow therapeutic index of warfarin, and the complex number of factors that influence international normalized ratio (INR) response, makes optimization of warfarin therapy challenging. Determination of the appropriate warfarin dose during initiation and maintenance therapy requires an understanding of patient factors that influence dose response: age, body weight, nutritional status, acute and chronic disease states, and changes in concomitant drug therapy and diet. This review will examine specific clinical factors that can affect the pharmacokinetics and pharmacodynamics of warfarin, as well as the role of pharmacogenetics in optimizing warfarin therapy.

Topics: Age Factors; Anticoagulants; Body Weight; Comorbidity; Dose-Response Relationship, Drug; Drug Interactions; Humans; International Normalized Ratio; Pharmacogenetics; Thrombosis; Warfarin

Topics: Age Factors; Aged; Anticoagulants; Body Weight; Drug Interactions; Drug Monitoring; Humans; Male; Warfarin

Topics: Adult; Age Factors; Animals; Blood Coagulation Factors; Body Weight; Chickens; Depression, Chemical; Female; Humans; Male; Metabolism; Middle Aged; Prothrombin; Prothrombin Time; Sex Factors; Stimulation, Chemical; Time Factors; Vitamin K; Vitamin K 1; Warfarin

To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups.. While underuse of anticoagulation in high-risk patients with AF remains common, substitution of effective and safer alternatives to warfarin, such as edoxaban, represents an opportunity to improve clinical outcomes.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Body Weight; Factor Xa Inhibitors; Humans; Pyridines; Stroke; Thiazoles; Treatment Outcome; Warfarin

CYP2C9 and VKORC1 genotypes could be used to predict warfarin requirement. The objective was to develop and validate a warfarin dosing algorithm using genetic, clinical and demographic data of Chinese patients from an anticoagulation clinic in Hong Kong. Blood samples were collected from 100 patients on stable maintenance dose of warfarin, recruited from an anticoagulation clinic, for genotyping CYP2C9 and VKORC1. Clinical and demographic data were obtained by face-to-face interview and medical chart review. Data of 80 patients (study cohort) were randomly selected for deriving a dosing algorithm. Comparison between predicted dose and actual stable doses was conducted in a validation cohort (n = 20). Sixty-nine (69%) of all 100 patients were homozygous for VKORC1 1173-TT, 25 (25%) were VKORC1 1173-CT heterozygotes and six (6%) were homozygous for VKORC1 1173-CC. 6 (6%) patients were CYP2C9 1*/3* and 94 (94%) were CYP2C9 1*/1*. CYP2C9 and VKORC1 genotype, age, weight and vitamin K intake were identified by stepwise regression modelling to produce the best model for estimating warfarin dose (R (2) = 68%, P < 0.001). In the validation cohort (n = 20), actual stable dose was significantly associated with predicted dose (R = 0.6, P = 0.005). Five of 11 (45.6%) and 5/9 (55.6%) patients whose mean warfarin requirements were ≤ 3 mg/day and >3 mg/day, respectively, were within <20% of actual doses. In conclusion, a genotype-guided dosing algorithm for warfarin therapy was developed for Chinese patients to explain 68% of dosage variation. The predicted doses differed from the actual doses by no more than 20% in 50% of patients.

Topics: Age Factors; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Asian People; Body Weight; Cross-Sectional Studies; Cytochrome P-450 CYP2C9; Female; Follow-Up Studies; Genotype; Hong Kong; Humans; Male; Middle Aged; Mixed Function Oxygenases; Vitamin K; Vitamin K Epoxide Reductases; Vitamins; Warfarin

The objective of this study was to assess the contribution of the VKORC1 and CYP2C9 genotypes and age, body size, and weight of the patients to the warfarin dose requirement in a Chinese population.. Blood samples were collected from 178 Chinese patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5-3.0). The polymorphisms for the VKORC1 (-1639GA) and CYP2C9*3 genotypes, venous INR, and plasma concentration and unbound concentration of warfarin were then analyzed.. VKORC1 (-1639G>A) genotyping showed that 149 patients were homozygous AA, 28 were heterozygous GA, and one was homozygous for the GG genotype. CYP2C9*3 genotyping showed that 162 patients were *1/*1, and 16 patients were heterozygous *1/*3. Patients with the VKORC1(-1639 GG+GA) (3.32 +/- 1.02 mg/day) and CYP2C9*1/*1 (2.06 +/- 0.82 mg/day) genotypes required a significantly higher warfarin dose than those with the -1639 AA (1.76 +/- 0.57 mg/day; P < 0.001) or CYP2C9*1/*3 (1.60 +/- 1.29 mg/day; P < 0.001), genotype. The multiple linear regression model for warfarin dose indicated significant contributions from age (r (2) = 0.084; P < 0.001), weight (r (2) = 0.063; P < 0.001), VKORC1 genotype (r (2) = 0.494; P < 0.001), and age, weight, and CYP2C9 and VKORC1 genotype together (r (2) = 0.628; P < 0.001).. This study shows that age, weight and the VKORC1 and CYP2C9 polymorphism affect warfarin dose requirements in our sample of Chinese patients receiving long-term therapy and showing stable control of anticoagulation. It is anticipated that the use of dosing regimens modified by taking into account the contribution of age, weight, and the CYP2C9 and VKORC1 genotypes has the potential to improve the safety of warfarin therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Blood Coagulation; Body Weight; China; Cytochrome P-450 CYP2C9; Female; Genotype; Humans; International Normalized Ratio; Male; Middle Aged; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Genetic; Vitamin K Epoxide Reductases; Warfarin

Warfarin is currently considered to be the anticoagulant of choice in the long-term treatment and prevention of thromboembolic events. However, it presents a narrow therapeutic range and a great interindividual dose variability. We investigated the influence of variants of the VKORC1 and CYP2C9 loci on the mean weekly warfarin dose (MWWD) required to reach stabilized therapeutic international normalized ratio, in order to confirm and to estimate the contribution of common genetic variability of these two genes in an Italian population and to search for novel rare VKORC1 alleles.. A total of 148 patients were followed for 6 months and analyzed for VKORC1 and CYP2C9 gene variants. Analysis of variance and multiple linear regression analysis were used to study the contribution of each genetic factor to MWWD requirement.. The complete sequencing of the VKORC1 coding region did not reveal the presence of exonic variants, while two common noncoding SNPs were highly associated: the T allele of VKORC1 1173C>T SNP (tag-SNP of H1-H2 haplotypes) is highly associated with low MWWD (p < 0.0001), while the A allele of VKORC1 3730G>A SNP (tag-SNP of H9 haplotype) is associated with high MWWD (p = 0.001). Also, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) variant alleles were significantly associated with low MWWD (p = 0.003 and 0.027, respectively). According to a multiple linear regression model including, besides VKORC1 and CYP2C9 SNPs, also age and weight, this percentage reaches 56% (gender is not significant).. Our results clearly indicate VKORC1 as the gene with the largest contribution to MWWD. Analyzing only one tag SNP of VKORC1 gene (1173C>T), it is possible to foresee 20% of the total variability. Our results may contribute to give useful indications for clinicians especially in the initiation of therapy so as to avoid the risk of adverse events.

Topics: Age Factors; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Body Weight; Cytochrome P-450 CYP2C9; DNA; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Humans; Italy; Linear Models; Male; Mixed Function Oxygenases; Polymorphism, Single Nucleotide; Thromboembolism; Vitamin K Epoxide Reductases; Warfarin

Negative feedback regulation of pancreatic proteases controls pancreatic secretion in most species and pancreatic growth in rodents. Its mechanism involves the inhibition of intraluminal proteases, resulting in sustained elevation of plasma cholecystokinin (CCK) concentrations, producing a chronic trophic stimulus to the pancreas that leads to the formation of pancreatic nodules and adenomas. Ximelagatran, whose active form, melagatran, inhibits both thrombin and the serine protease trypsin, is under clinical development as an oral anticoagulant. Recent data indicate species differences in the expression of CCK receptor subtypes in the pancreas. CCK1 receptors are abundant in rat pancreas but are either absent or present at very low levels in human pancreas. As part of the clinical studies, we examined whether long-term ximelagatran administration causes CCK release and exerts possible trophic effects on the pancreas in humans.. One hundred thirty patients requiring anticoagulation treatment for atrial fibrillation randomly received, in a double-blind fashion, either 36 mg oral ximelagatran twice daily or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0. Before enrollment and after 12 months of treatment, computed tomography scans of the pancreas were performed, and pancreas volumes were quantified using the summation-of-areas technique. Three months after the initiation of drug treatment, plasma CCK concentrations were measured by radioimmunoassay 120 minutes after the patients drank 240 mL of a mixed liquid meal (Ensure).. After 3 months of treatment, plasma CCK concentrations did not differ between the ximelagatran and warfarin groups, 15 +/- 18 and 11 +/- 17 pmol/L (X +/- SD; P = 0.22), respectively. The initial average pancreas volumes were 82 +/- 31 and 88 +/- 28 mL in the ximelagatran and warfarin groups, respectively, and decreased to 70 +/- 25 and 75 +/- 28 mL, respectively, after 12 months of treatment. Although the decrease in pancreas volume with time was significant in each group (P = 0.0001), the magnitude of the volume reduction was similar in the 2 groups.. In contrast to rats, in which long-term oral administration of ximelagatran stimulates pancreatic growth and adenoma formation, in humans, ximelagatran does not increase plasma CCK concentrations and has no demonstrable trophic effect on the human pancreas.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Body Mass Index; Body Weight; Cholecystokinin; Double-Blind Method; Humans; Pancreas; Tomography, X-Ray Computed; Warfarin

The lack of oral anticoagulant guidelines specific to paediatric practice has led to the adoption of adult regimens, often without scientific evidence of efficacy or safety. A two year prospective study of anticoagulant control was carried out in 45 children aged 9 months to 18 years, the majority of whom were receiving primary prophylactic anticoagulation. The main indication was congenital heart disease, either with (n = 8) or without (n = 34) mechanical valve prosthesis. During a follow up period of 602 patient months the average interval between visits was three weeks. Target international normalised ratios (INRs) were achieved on 62% and 39% of visits for children with low target INR (2.0-3.0) and high target INR (3.0-4.0) respectively. However warfarin dose was altered on only 22% of visits. Warfarin doses required to achieve a stable INR of 2.0-3.0 in 33 children were strongly correlated with weight [dose (mg/d) = 0.07 x weight (kg) + 0.54] but independently influenced by age. No thrombotic complications were recorded, and haemorrhagic events were infrequent (2.1% of visits) and, with one exception, minor. Safe outpatient oral anticoagulation is feasible in children, whose warfarin requirements appear moderately predictable and whose control is no more erratic than that of adults.

Topics: Adolescent; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Child; Child, Preschool; Drug Administration Schedule; Female; Follow-Up Studies; Heart Defects, Congenital; Heart Valve Prosthesis; Humans; Infant; Male; Middle Aged; Prospective Studies; Thromboembolism; Warfarin

Plasma warfarin and its R,S enantiomer concentrations, one-stage prothrombin times, and mean daily warfarin doses were analyzed in 196 patients given warfarin. These individuals were part of a controlled clinical trial that examined the effect of warfarin as an adjuvant to "standard" treatment in a variety of malignancies. Neither the plasma warfarin concentration nor the daily warfarin dose required to produce a given degree of prothrombin-time prolongation was influenced by age or body weight in these subjects. When the data were analyzed by performance status, we noted several variations of interest. Individuals with different tumor types demonstrated disparities in warfarin disposition. Patients with colorectal cancer, for example, required lower mean daily warfarin doses to achieve a given degree of one-stage prothrombin time prolongation. Analysis of warfarin enantiomers (R,S) in a selected group of patients demonstrated a lower-than-normal ratio (2:1) for the colorectal cancer group (1.42:1) because of an apparent decrease in the plasma R component. In contrast, patients with head and neck cancer demonstrated a ratio of 2.85:1, and the R component was elevated. Warfarin disposition and the effect of warfarin on vitamin K-dependent clotting factor production were altered in the patients with cancer reported in this study. The mechanisms for these alterations are complex and not completely understood.

Topics: Aging; Body Weight; Colorectal Neoplasms; Head and Neck Neoplasms; Humans; Neoplasms; Prospective Studies; Prothrombin Time; Psychomotor Performance; Stereoisomerism; United States; United States Department of Veterans Affairs; Warfarin

A prospective randomized trial compared the effectiveness of low-dose warfarin (LDW) to sequential compression devices (SCD) for deep venous thrombosis (DVT) prophylaxis in 95 patients after total hip arthroplasty (THA). Patients were 39 years of age or older, with no history of previous venous disease. Bilateral lower-extremity venography was used for thrombi detection. Venous thrombi occurred in 12 patients (all calf) on LDW (26.6%) and 3 patients with SCDs (one calf, two thigh) (6.0%). The incidence of DVT was significantly higher in the LDW group (P less than .006). In this study of average-risk patients, the use of SCDs significantly outperformed LDW as a prophylactic agent. However, the thrombi that did occur with SCDs were more critical.

Topics: Adult; Aged; Aged, 80 and over; Bandages; Body Weight; Female; Hip Prosthesis; Humans; Male; Middle Aged; Phlebography; Prospective Studies; Thrombophlebitis; Warfarin

In 228 ambulatory patients receiving treatment with warfarin, there was a progressive decline in the dose required to produce an equivalent degree of anticoagulant control with increasing age from the third decade onwards. However, the relationship between age and dose was significant only in patients receiving warfarin after episodes of venous thromboembolism or because of coronary artery disease. Patient weight was also related to warfarin requirements, although it was less important a determinant than age.

Topics: Adult; Aged; Aging; Angina Pectoris; Blood Coagulation Disorders; Body Weight; Clinical Trials as Topic; Drug Administration Schedule; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Prospective Studies; Prothrombin Time; Sex Factors; Thromboembolism; Warfarin

To assess whether Roberts' age-adjusted warfarin loading protocol is effective in Chinese patients and whether the SAMeTT2R2 score can predict international normalized ratio (INR) control. Roberts' protocol for warfarin titration was applied to patients with non-valvular atrial fibrillation (NVAF) complicated with ischemic stroke at the Department of Neurology between 2014 and 2019. Clinical and sociodemographic variables were recorded. A minimum of 1-year follow-up was used to calculate the time in therapeutic range (TTR) of the INR. A total of 94 acute ischemic stroke patients with NVAF were included in the study. Seventy-seven (81.9%) of the patients had attained stable INR (2.0-3.0) at the fifth dose, and 90.0% of the patients had achieved stable INR on the ninth day. Seventeen (18.1%) of the patients had an INR > 4 during dose-adjustment period. Patients with INR > 4 had significantly lower body weight (53.8 vs. 63.1 kg, P = 0.014), lower rate of achievement of stable INR (35.3% vs. 92.2%, P = 0.000), and lower rate of TTR ≥ 65% (23.5% vs. 70.1%, P = 0.001), but with no significant increase in bleeding risk. A total of 89 patients underwent long-term INR follow-up, of which 58 (65.2%) patients achieved TTR ≥ 65%. Patients with poor TTR had significantly lower body weight (56.3 vs. 63.7 kg, P = 0.020) and lower rate of stable INR achievement (64.5% vs. 89.7%, P = 0.002). All 94 patients had SAMeTT2R2 score ≥ 2. There was no linear association between SAMeTT2R2 score and the rate of TTR ≥ 65% (P

Topics: Anticoagulants; Atrial Fibrillation; Body Weight; East Asian People; Humans; International Normalized Ratio; Ischemic Stroke; Retrospective Studies; Stroke; Treatment Outcome; Warfarin

The purpose of this study was to analyse the effects of demographic factors, clinical factors, and genetic polymorphisms of related gene loci on warfarin bleeding-related complications in the Han population.. Retrospective medical record review. The study cases were patients treated at the Fujian Medical University Union Hospital from March 2016 to February 2020, and all received regular warfarin anticoagulation treatment for at least 3 months, and were provided the initial standard dose and stable dose of warfarin.. Data were collected from 451 qualifying patients (47% male, 53% female). The average age of patients was 53.8 ± 12.2 years, and the average body surface area was 1.6 ± 0.18 m. The ApoE (rs429358) gene polymorphism influences bleeding complications in Chinese Han patients treated with warfarin. The sample size of this study was relatively small; hence an international study with a larger sample size is needed in the future.

Topics: Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Apolipoproteins E; Asian People; Body Surface Area; Body Weight; China; Cytochrome P-450 Enzyme Inhibitors; Ethnicity; Female; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Polymorphism, Single Nucleotide; Retrospective Studies; Sociodemographic Factors; Warfarin

Warfarin remains the most widely prescribed oral anticoagulant in sub-Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine-learning techniques in predicting stable warfarin dose in sub-Saharan Black-African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub-Saharan Africa (War-PATH) clinical dose-initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39-13.76) was the best performing machine-learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75-19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine-learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45-14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine-learning techniques. We have also externally validated our previously developed clinical dose-initiation algorithm, which is being prospectively tested for clinical utility.

Topics: Adult; Africa South of the Sahara; Age Factors; Algorithms; Anticoagulants; Body Weight; Drug Dosage Calculations; Female; HIV Infections; Humans; International Normalized Ratio; Machine Learning; Male; Middle Aged; Models, Biological; Reproducibility of Results; Sex Factors; Simvastatin; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Body Weight; Humans; Stroke; Warfarin

To interprete the importance of clinical features and genotypes for warfarin daily dose prediction, we developed a post-hoc interpretable framework based on an ensemble predictive model. This framework includes permutation importance for global interpretation and local interpretable model-agnostic explanation (LIME) and shapley additive explanations (SHAP) for local explanation. The permutation importance globally ranks the importance of features on the whole data set. This can guide us to build a predictive model with less variables and the complexity of final predictive model can be reduced. LIME and SHAP together explain how the predictive model give the predicted dosage for specific samples. This help clinicians prescribe accurate doses to patients using more effective clinical variables. Results showed that both the permutation importance and SHAP demonstrated that VKORC1, age, serum creatinine (SCr), left atrium (LA) size, CYP2C9 and weight were the most important features on the whole data set. In specific samples, both SHAP and LIME discovered that in Chinese patients, wild-type VKORC1-AA, mutant-type CYP2C9*3, age over 60, abnormal LA size, SCr within the normal range, and using amiodarone definitely required dosage reduction, whereas mutant-type VKORC1-AG/GG, small age, SCr out of normal range, normal LA size, diabetes and heavy weight required dosage enhancementt.

Topics: Age Factors; Anticoagulants; Body Weight; China; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Heart Atria; Humans; Polymorphism, Genetic; Vitamin K Epoxide Reductases; Warfarin

Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4-12.8) and 12.5 (95% CI 11.6-13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3-13.7) and 12.7 (95% CI 11.5-13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2-13.0) and 12.2 (95% CI 11.4-13.1) mg/week in the validation cohort. Compared with fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5-13.7%) and 11.9% (7.1-16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Warfarin dosing remains challenging due to a highly variable clinical response for a given dose. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Can a clinical dose-initiation model be developed and validated for sub-Saharan Black-African patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ We have developed the first warfarin dose-initiation clinical model for Black-African patients in Uganda and South Africa. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ We will be implementing and validating this model in a prospective cohort to inform future large-scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Black People; Body Weight; Child; Cohort Studies; Dose-Response Relationship, Drug; Female; HIV Seropositivity; Humans; International Normalized Ratio; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; South Africa; Treatment Outcome; Uganda; Warfarin; Young Adult

Patients who require urgent warfarin reversal often receive four-factor prothrombin complex concentrate (4F-PCC), which is traditionally dosed according to weight and initial INR. Our institution implemented a fixed-dose 4F-PCC strategy, using an initial dose of 1500 units. We evaluated the frequency with which the initial fixed dose 4F-PCC was inadequate, as defined by need for supplemental dosing. As part of the protocol, if the initial fixed-dose 4F-PCC is administered and does not achieve INR goal, then the remainder of the standard weight- and INR-based dosing can be given. During the study period, 63 patients on warfarin received 4F-PCC using the fixed-dose protocol. Based on the INR following 4F-PCC administration, 11 patients (17%) were eligible to receive a supplemental dose based on failure to achieve their specified INR goal. Two of the 11 patients eligible for supplemental 4F-PCC dosing received the second dose, both with initial supratherapeutic INRs > 3.5. We found that most patients given an initial fixed-dose 4F-PCC achieved their INR goals, and of those who did not, most did not receive supplemental dosing, suggesting that clinical providers felt that adequate hemostasis had been achieved. In addition, fixed-dose 4F-PCC was able to be given rapidly, with few dosing errors, suggesting that this is a reasonable option for 4F-PCC delivery.

Topics: Aged, 80 and over; Blood Coagulation Factors; Body Weight; Clinical Protocols; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; International Normalized Ratio; Male; Outcome and Process Assessment, Health Care; Retrospective Studies; Warfarin

Prothrombin Complex Concentrates (PCC) are prescribed for emergent warfarin reversal (EWR). The comparative effectiveness and safety among PCC products are not fully understood.. Patients in an academic level one trauma center who received PCC3 or PCC4 for EWR were identified. Patient characteristics, PCC dose and time of dose, pre- and post-INR and time of measurement, fresh frozen plasma and vitamin K doses, and patient outcomes were collected. Patients whose pre-PCC International Normalized Ratio (INR) was > 6 h before PCC dose or the pre-post PCC INR was > 12 h were excluded. The primary outcome was achieving an INR ≤ 1.5 post PCC. Secondary outcomes were the change in INR over time, post PCC INR, thromboembolic events (TE), and death during hospital stay. Logistic regression modelled the primary outcome with and without a propensity score adjustment accounting for age, sex, actual body weight, dose, initial INR value, and time between INR measurements. Data are reported as median (IQR) or n (%) with p < 0.05 considered significant.. Eighty patients were included (PCC3 = 57, PCC4 = 23). More PCC4 patients achieved goal INR (87.0% vs. 31.6%, odds ratio (OR) = 14.4, 95% CI: 3.80-54.93, p < 0.001). This result remained true after adjusting for possible confounders (AOR = 10.7, 95% CI: 2.17-51.24, p < 0.001). The post-PCC INR was lower in the PCC4 group (1.3 (1.3-1.5) vs. 1.7 (1.5-2.0)). The INR change was greater for PCC4 (2.3 (1.3-3.3) vs. 1.1 (0.6-2.0), p = 0.003). Death during hospital stay (p = 0.52) and TE (p = 1.00) were not significantly different.. PCC4 was associated with a higher achievement of goal INR than PCC3. This relationship was observed in the unadjusted and propensity score adjusted results.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Body Weight; Emergencies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Plasma; Propensity Score; Retrospective Studies; Time Factors; Trauma Centers; Vitamin K; Warfarin

Four-factor PCC is the recommended standard of care for acute warfarin reversal but optimal dosing is unknown. We aim to show that a low-dose strategy is often adequate and may reduce the risk of thromboembolic events when compared to manufacturer-recommended dosing.. A weight-based dosing strategy of 15-25 units/kg was established as the institutional standard of care in May 2015. This retrospective, before-and-after cohort analysis included patients receiving 4F-PCC according to a manufacturer-recommended (n = 122) or a low-dose (n = 83) strategy. The primary efficacy outcome was a combination of INR reversal on first check and hemostatic efficacy at 24 h.. Demographics, indications for warfarin, and presenting INR values were similar between the two groups. Patients in the manufacturer-recommended dose group received significantly more 4F-PCC than the low dose group (2110 units vs. 1530 units). More patients in the manufacturer-recommended dose group achieved the primary endpoint (75.4% vs. 61.4%), with more patients achieving the target INR on recheck in the manufacturer-recommended dose group (95.9% vs. 84.3%) and no difference in hemostatic efficacy between groups (79.5% vs. 74.7%). There was no difference in thromboembolic events at 72 h (4.1% vs. 1.2%) or at 30 days (8.2% vs. 4.8%). Significantly more patients in the manufacturer-recommended dose group died or were transferred to hospice care during hospitalization (21.3% vs. 9.6%).. Utilization of a low-dose 4F-PCC strategy resulted in fewer patients achieving target INR reversal, but no difference in hemostatic efficacy, thromboembolic events, or survival.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Body Weight; Drug Dosage Calculations; Drug Monitoring; Female; Hemorrhage; Hemostasis; Heparin Antagonists; Humans; International Normalized Ratio; Male; Models, Biological; Retrospective Studies; Risk Assessment; Risk Factors; Treatment Outcome; Warfarin

Guidelines caution against the use of non-vitamin K antagonist oral anticoagulants in patients with extremely high (>120 kg) or low (≤60 kg) body weight because of a lack of data in these populations.. In a post hoc analysis of ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201), a randomized trial comparing apixaban with warfarin for the prevention of stroke in patients with atrial fibrillation, we estimated the randomized treatment effect (apixaban versus warfarin) stratified by body weight (≤60, >60-120, >120 kg) using a Cox regression model and tested the interaction between body weight and randomized treatment. The primary efficacy and safety outcomes were stroke or systemic embolism and major bleeding.. Of the 18 139 patients with available weight and outcomes data, 1985 (10.9%) were in the low-weight group (≤60 kg), 15 172 (83.6%) were in the midrange weight group (>60-120 kg), and 982 (5.4%) were in the high-weight group (>120 kg). The treatment effect of apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction was consistent across the weight spectrum (interaction P value>0.05). For major bleeding, apixaban had a better safety profile than warfarin in all weight categories and even showed a greater relative risk reduction in patients in the low (≤60 kg; HR, 0.55; 95% CI, 0.36-0.82) and midrange (>60-120 kg) weight groups (HR, 0.71; 95% CI, 0.61-0.83; interaction P value=0.016).. Our findings provide evidence that apixaban is efficacious and safe across the spectrum of weight, including in low- (≤60 kg) and high-weight patients (>120 kg). The superiority on efficacy and safety outcomes of apixaban compared with warfarin persists across weight groups, with even greater reductions in major bleeding in patients with atrial fibrillation with low to normal weight as compared with high weight. The superiority of apixaban over warfarin in regard to efficacy and safety for stroke prevention seems to be similar in patients with atrial fibrillation across the spectrum of weight, including in low- and very high-weight patients. Thus, apixaban appears to be appropriate for patients with atrial fibrillation irrespective of body weight.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Body Weight; Ethnicity; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Obesity; Proportional Hazards Models; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk; Stroke; Thinness; Thromboembolism; Treatment Outcome; Warfarin

It is unclear whether the overall effectiveness and safety of direct oral anticoagulants (DOACs) are consistent in patients with nonvalvular atrial fibrillation (AF) and extremely low body weight (<50 kg).. This study compared DOACs with warfarin in AF patients with low body weight.. Using data from the Korean National Health Insurance Service database from January 2014 to December 2016, AF patients with body weight ≤60 kg and who were treated with oral anticoagulants (n = 14,013 taking DOACs and n = 7,576 taking warfarin) were included and examined for ischemic stroke, intracranial hemorrhage (ICH), gastrointestinal bleeding, major bleeding, all-cause death, and composite outcome. The propensity score weighting was used to balance the 2 groups.. Baseline characteristics were well balanced between the 2 groups (mean age 73 years, mean CHA. In this real-world Asian AF population with low body weight, DOACs showed better effectiveness and safety than warfarin. These results were consistent in patients with extremely low body weight. Regular dosages of DOACs showed comparable results as reduced dosages of DOACs in both effectiveness and safety.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Body Weight; Brain Ischemia; Dose-Response Relationship, Drug; Dual Anti-Platelet Therapy; Female; Follow-Up Studies; Humans; Incidence; Male; Republic of Korea; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Body Weight; Humans; Warfarin

Topics: Atrial Fibrillation; Body Weight; Humans; Pyrazoles; Pyridones; Warfarin

For reversal of warfarin-induced coagulopathy, FDA labeling of four-factor prothrombin complex concentrate (4F-PCC) endorses a dosing strategy based on body weight and baseline INR. Recent literature suggests lower, fixed doses of 4F-PCC may be equally efficacious. The present evaluation aims to characterize the relationship between 4F-PCC dose and degree of reduction in INR.. This is a retrospective, single-center review of 4F-PCC administrations for warfarin reversal between May 2014 and August 2017. The primary endpoint evaluates the relationship between doses of 4F-PCC and INR measurement after reversal, represented as a linear regression. Exploratory endpoints characterize the relationships of both body weight and baseline INR, the components determining initial 4F-PCC dose, with INR after reversal. Additionally, for records presenting with an INR of 2-3.9, mean INR after reversal was characterized as a function of two 4F-PCC dose cohorts (< 30 and ≥30 IU fIX/kg).. This evaluation found no clinically relevant relationship with 4F-PCC doses and degree of INR reversal. Further prospective study is required to determine optimal dosing schemes of 4F-PCC for warfarin reversal.

Topics: Aged; Aged, 80 and over; Blood Coagulation Disorders; Blood Coagulation Factors; Body Weight; Dose-Response Relationship, Drug; Female; Humans; International Normalized Ratio; Linear Models; Male; Retrospective Studies; Warfarin

Warfarin therapy is recommended in children with giant coronary artery aneurysms (GCAAs) after Kawasaki disease (KD). Large individual variability makes it difficult to predict the warfarin dose. Polymorphisms in the vitamin K expoxide reductase 1 (VKORC1) and cytochrome P4502C9 (CYP2C9) genes have been reported to influence the warfarin dose. We investigated the effects of the VKORC1 and CYP2C9 genotypes on the warfarin dose in pediatric patients with giant CAAs after KD. We attempted to create a dosing algorithm.. The clinical and genetic data of patients were documented. VKORC1 (rs 9923231) and CYP2C9 *3 (rs 1057910) were genotyped using TaqMan real-time polymerase chain reaction. A linear regression analysis was performed to evaluate the contribution of clinical and genetic factors to the warfarin maintenance dose.. Forty-seven patients were enrolled. Patients with the CT or CC genotype of VKORC1 had a relatively higher warfarin dose than did those with the TT genotype (p < 0.05). Three patients with CYP2C9*1/*3 had a lower warfarin dose than did those with the wild CYP2C9*1/*1 genotype, but the difference did not reach significance (p > 0.05). Weight and the VKORC1 genotype predominantly contributed to the warfarin dose, with 33.0% and 11.2% of variability, respectively. The observed warfarin dose was correlated with the predicted dose based on the algorithm used in our study (r = 0.45, p < 0.01).. Weight and the VKORC1 genotype primarily determined the warfarin dose in Chinese pediatric patients with KD. Further studies are warranted to verify the findings of our study.

Topics: Body Weight; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Genotype; Humans; Male; Middle Aged; Mucocutaneous Lymph Node Syndrome; Vitamin K Epoxide Reductases; Warfarin

Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain.. Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation.. Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups.. Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

Topics: Animals; Anticoagulants; Body Weight; Brain; Caspase 3; Collagen; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Plant Lectins; Rats; Rats, Wistar; Receptors, Platelet-Derived Growth Factor; Rivaroxaban; Warfarin

The objective of the present study was to develop an optimal equation for the pediatric dose-response relationship of warfarin using a size parameter with an exponent of body weight (SIZE) which has been proposed for scaling drug clearance. Twenty patients with stable anticoagulation by warfarin were enrolled in the present study. During a mean follow-up period of 7.36 years, 857 data points were obtained. The average patient age and body weight were 8.49 years and 24.5 kg, respectively. The relative response index to warfarin with PT-INR values normalized by daily-dose per SIZE showed fewer systematic changes than those per body weight. The anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 47.3% of that with the 1173TT genotype. Concomitant use of bosentan attenuated the anticoagulant effect of warfarin to 84.1%. In conclusion, the SIZE parameter appeared to be an effective way to describe the pediatric dose-response relationship of warfarin, and consequently, a longitudinal follow-up study design with multiple measurements was useful to detect changes within individual subjects.

Topics: Adolescent; Anticoagulants; Body Weight; Bosentan; Child; Child, Preschool; Cytochrome P450 Family 4; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Genotype; Humans; Japan; Longitudinal Studies; Male; Models, Biological; Retrospective Studies; Sulfonamides; Vitamin K Epoxide Reductases; Warfarin

Chronic kidney disease (CKD) alters dose-effect relationship not only of drugs eliminated by the kidney but also of some drugs metabolized by the liver and not renally excreted. It is not known whether impaired renal function alters dose-effect relationship of warfarin in Asian patients. It is also unknown whether the maintenance dose of warfarin can be predicted more accurately by incorporating renal function in Asians.. This was a cross-sectional study of patients receiving constant doses of warfarin who had PT-INR within 1.5-3.0 for 3 months or longer.. In a total of 137 participants, the estimated creatinine clearance (eCrCl) was 62.5±25.5 [ml/min] and the warfarin dose was 3.21±1.46 [mg/day] (both mean±standard deviation). There was a significant correlation between warfarin dose and eCrCl (p<0.0001, r(2)=0.23). In a stepwise linear regression with the maintenance dose of warfarin as the dependent variable, eCrCl as well as age, body weight, intra-individual average prothrombin time/international normalized ratio (PT-INR), and genotype of VKORC1 -1639 G>A polymorphism were chosen as independent variables. The coefficient of determination (r(2)) of this formula was 0.47. A regression equation with all the same explanatory variables except for eCrCl had an r(2) of 0.41.. The maintenance warfarin dose was positively correlated with kidney function as represented by eCrCl in Japanese patients. Incorporating eCrCl improved accuracy of predicting warfarin maintenance dose in this population.

Topics: Aged; Aged, 80 and over; Anticoagulants; Body Weight; Creatinine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Female; Genotype; Humans; International Normalized Ratio; Japan; Kidney; Maintenance Chemotherapy; Male; Metabolic Clearance Rate; Middle Aged; Polymorphism, Genetic; Prothrombin Time; Vitamin K Epoxide Reductases; Warfarin

This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African-Americans.. Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African-Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African-Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates.. CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m(2)/-10 kg reduction in CL[S], respectively) in African-Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose.. African-Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Anticoagulants; Black or African American; Body Surface Area; Body Weight; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Genotype; Humans; International Normalized Ratio; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Polymorphism, Single Nucleotide; Vitamin K Epoxide Reductases; Warfarin

Optimal dosing of prothrombin complex concentrate (PCC) has yet to be defined and varies widely due to concerns of efficacy and thrombosis. We hypothesized a dose of 15 IU/kg actual body weight of a three-factor PCC would effectively correct coagulopathy in acute care surgery patients. Retrospective review of 41 acute care surgery patients who received 15 IU/kg (± 10%) actual body weight PCC for correction of coagulopathy. Demographics, laboratory results, PCC dose, blood and plasma transfusions, and thrombotic complications were analyzed. We performed subset analyses of trauma patients and those taking warfarin. Mean age was 69 years (18-94 years). Thirty (73%) trauma patients, 8 (20%) emergency surgery patients, 2 (5%) burns, and 1 (2%) nontrauma neurosurgical patient were included. Mean PCC dose was 1305.4 IU (14.2 IU/kg actual body weight). Mean change in INR was 2.52 to 1.42 (p 0.00004). Successful correction (INR <1.5) was seen in 78 per cent. Treatment failures had a higher initial INR (4.3 vs 2.03, p 0.01). Mean plasma transfusion was 1.46 units. Mean blood transfusion was 1.61 units. Patients taking prehospital warfarin (n = 29, 71%) had higher initial INR (2.78 vs 1.92, p 0.05) and received more units of plasma (1.93 vs 0.33, p 0.01) than those not taking warfarin. No statistical differences were seen between trauma and nontrauma patients. One thrombotic event occurred. Administration of low-dose PCC, 15 IU/kg actual body weight, effectively corrects coagulopathy in acute care surgery patients regardless of warfarin use, diagnosis or plasma transfusion.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Body Weight; Burns; Drug Dosage Calculations; Emergencies; Humans; International Normalized Ratio; Middle Aged; Plasma; Retrospective Studies; Surgical Procedures, Operative; Thrombosis; Vitamin K; Warfarin; Wounds and Injuries; Young Adult

Four-factor prothrombin complex concentrates (4FPCCs) are emerging as the standard of care for emergent warfarin reversal due to their ability to rapidly and effectively achieve hemostasis. The ideal dose of this medication is not known. Recently, our hospital instituted a protocol where all doses of 4FPCC were a fixed dose of 1500 IU. This protocol provides 4FPCC rapidly and precludes delay waiting for international normalized ratio (INR) values. The purpose of this study was to evaluate our experience with this fixed dose protocol.. This is a retrospective review of patients who received 1500 IU of 4FPCC for emergent warfarin reversal between March 2014 and January 2015. Demographic and clinical data regarding administration, efficacy, and safety were collected and analyzed.. A total of 39 patients met inclusion criteria. The most common indication for treatment was intracranial hemorrhage (28, 71.8%). The median INR at presentation was 3.3, and the median INR after a single dose of 1500 IU was 1.4 (P < .001). A total of 36 patients (92.3%) achieved successful reversal with a target INR of less than 2.0, and 28 patients (71.8%) achieved successful reversal with a target INR of 1.5 or less. There were no thrombotic adverse events within 7 days.. Administration of a fixed dose of 1500 IU of 4FPCC leads to high rates of successful INR reversal and no related thrombotic adverse events within 7 days, and there was no need to wait for INR at presentation. These findings suggest good efficacy and safety when using 1500 IU of 4FPCC for emergent warfarin reversal.

Topics: Age Factors; Aged; Anticoagulants; Blood Coagulation Factors; Body Weight; Cerebral Hemorrhage; Clinical Protocols; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Retrospective Studies; Treatment Failure; Treatment Outcome; Warfarin

The study aimed to establish a population pharmacokinetic/pharmacodynamic (PPK/PD) model of warfarin. PCR-RFLP technique was used to genotype the CYP2C9 and VKORC1 polymorphisms of 73 patients. RP-HPLC-UV method was used to determine the 190 plasma concentrations of warfarin. Application of NONMEM, the clinical information and 263 international normalized ratio (INR) monitoring data were used to investigate the effect of genetic, physiological, pathological factors, other medication on clearance and anticoagulant response. The final model of warfarin PPK/PD was described as follows: CL = θCL · (WT/60)θWT · θCYP · eηCL (if CYP2C9*1/*1, θCYP = 1; if *1/*3, θCYP = 0.708); EC50 = θEC50 · θVKOR · eηEC50 (if VKORC1- 1639AA, θVKOR = 1; if GA, θVKOR = 2.01; V = θV; K(E0) = θK(E0); Emax = θEmax; E0 = θE0 · eηE0. Among them, the body weight (WT), CYP2C9 and VKORC1 genotype had conspicuous effect on warfarin PK/PD parameters. The goodness diagnosis, Bootstrap, NPDE verification showed that the final model was stable, effective and predictable. It may provide a reference for opitimizing the dose regimen of warfarin.

Topics: Anticoagulants; Body Weight; Cytochrome P-450 CYP2C9; Genotype; Humans; International Normalized Ratio; Nonlinear Dynamics; Polymorphism, Genetic; Vitamin K Epoxide Reductases; Warfarin

To investigate the distribution of Warfarin related genes and the relationship between genotype, gender, weight, age and the administrative dose of Warfarin in Shanghai area.. The clinical data (including sex, age and administrative dose of Warfarin) of 214 patients with stable warfarin dose and the international normalized ratio (INR) between 1.5-3.0 were collected. Polymerase chain reaction-high resolution melting (PCR-HRM) technique was used to detect the single nucleotide polymorphisms (SNPs) of CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, CYP4F2 rs2108622 and VKORC1 rs9934438. The associations of genotype data with clinical material, including gender, age, weight and warfarin dosage were analyzed.. Among 214 patients, 99.53% (213 cases) patients with CC (wild type) of CYP2C9*2 rs1799853 and only 1 case with CT (heterozygous mutation) ; 92.52% (198 cases) with AA (wild type), 7.48% (16 cases) with CA (heterozygous mutation) of CYP2C9*3rs1057910; about 57.94% (124 cases) with CC(wild type) of CYP4F2 rs2108622, the CT and TT (heterozygous and homozygotic mutation) accounted for 42.06% (90 cases). In SNP VKORC1 rs9934438, 82.71% (177cases) were TT (wild type), 17.29% (37 cases) CT (heterozygous mutation). There are no significant difference (P=0.0872) in patients with maintenance dose in CYP2C9*3 between AA and CA gene mutations[(2.816±1.055) mg/d vs (2.352±0.805)mg/d], and no significant difference (P=0.5954) of that in CYP4F2 between CC and CT+TT gene mutations [(2.736±1.062) mg/d vs (2.813±1.034) mg/d]; but the significant differences (P=0.0001) does exist in patients with maintenance dose in VKORC1 between TT and CT variants [(2.597±0.866) mg/d vs (3.660±1.350) mg/d]. The warfarin maintain dosage was negatively correlated with the average age (r=-0.9669) and positively correlated with the body weight (r=0.9022).. It is of great significance to detect the VKORC1 variants for warfarin dosage adjustment in Shanghai population. However, the detection of CYP2C9*2 and CYP4F2 polymorphisms had no significant associations for warfarin dosage adjustment.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Body Weight; China; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Dose-Response Relationship, Drug; Female; Genotype; Heterozygote; Humans; International Normalized Ratio; Male; Middle Aged; Sex Distribution; Vitamin K Epoxide Reductases; Warfarin; Young Adult

Prothrombin complex concentrates (PCC) are recommended for urgent warfarin reversal. However, disagreement exists regarding the proper dosing strategy (i.e. fixed vs. weight-based). We measured the in vitro effect of PCC dosing on international normalised ratio (INR) and factor activity. Plasma from warfarin-anticoagulated patients with stable INRs was collected. PCC doses of 1,000, 2,000 and 3,000 IU were added to the samples, and INR and factor activity were analysed before and after PCC. Twenty-three of thirty subjects enrolled had complete data for analysis. INRs were below 1.5 in all samples post-1,000 IU, and decreased further with subsequent doses (p<0.001). Factors II, VII, and X increased with consecutive doses (p<0.01). Linear correlation was seen between INR and factors II, VII and X. Factor IX did not increase consistently nor show correlation with INR reversal. Weight-based dosing was then estimated; INRs were all <1.2 (0.9-1.2) and activity >0.50 IU for factors II, VII and X (0.96-1.52, 0.51-1.45 and 0.81-1.38, respectively). Factor IX did not uniformly correct above 0.50 IU (0.31-1.31). We confirm in vitro that 1,000 IU of Octaplex(®) is able to correct INR to <1.5 but factors were not uniformly >0.50 IU until 2,000 IU, and not >1.00 IU until 3,000 IU. This suggests that INR correction alone may not accurately reflect factor activity, and lends support for weight-based dosing.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Body Weight; Drug Dosage Calculations; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Warfarin

Warfarin is a clinical anticoagulant that requires periodic monitoring because it is associated with adverse outcomes. Personalized medicine, which is based on pharmacogenetics, holds great promise in solving these types of problems. It aims to provide the tools and knowledge to tailor drug therapy to an individual patient, with the potential of increasing safety and efficacy of medications.. In the present study we analyzed genotypes of 14 SNPs for seven genes using DNA from 297 Han Chinese venous thromboembolism patients treated with warfarin.. Multiple regression analyses revealed that CYP2C9 genotype (p = 0.001), VKORC1 genotype (p < 0.001), age (p < 0.01) and weight (p < 0.001) were all associated with warfarin dose requirements, which can explain 37.4% of the variability of warfarin dose among Han Chinese patients. Meanwhile, in the validation cohort, the predicted warfarin daily dose was calculated using the best model with a 64.5% predicted dose being acceptable (-1 mg/day ≤Δwarfarin dose ≤1 mg/day).. We developed a pharmacogenetic dose algorithm for warfarin treatment that uses genotypes from two genes (VKORC1 and CYP2C9) and clinical variables to predict therapeutic maintenance doses in Chinese patients with venous thromboembolism. The validity of the dosing algorithm was confirmed in a cohort of venous thromboembolism patients on warfarin therapy.

Topics: Age Factors; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Asian People; Body Weight; Cohort Studies; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Genotype; Humans; Male; Middle Aged; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Single Nucleotide; Regression Analysis; Venous Thromboembolism; Vitamin K Epoxide Reductases; Warfarin

Specific guidelines for initial dosing of warfarin in ischaemic stroke patients have not been developed. Therefore, we have developed an age- and weight-adjusted warfarin initiation nomogram (AW-WIN) for ischaemic stroke patients and then evaluated the efficacy and safety of AW-WIN compared with physician-determined warfarin dosing (PDWD).. The age- and weight-adjusted warfarin initiation nomogram was administered to 104 acute ischaemic stroke patients between January 2008 and February 2009. A historical control group (PDWD) of 96 patients was selected from comparable patients who were discharged with warfarin during the previous year. Time-to-therapeutic international normalized ratios (INRs) and the incidence of excessive anticoagulation were compared in the AW-WIN and PDWD groups.. The general characteristics, risk factors, and stroke mechanism of the AW-WIN and PDWD groups did not differ significantly. The mean time to INR ≥ 2.0 was significantly shorter in the AW-WIN than in the PDWD group (4.9 ± 0.7 vs. 6.2 ± 0.8 days, P = 0.0008). After adjustment for potential confounding variables, the AW-WIN group reached target INR faster than the PDWD group (hazard ratio, 1.76; 95% confidence interval, 1.26-2.45; P = 0.001). The time-to-therapeutic INR ≥1.7 was shorter (P = 0.0002), the proportion of patients with therapeutic INR (2-3) at 5 days was higher (P = 0.002), and the rate of excessive anticoagulation of ≥3.5 INR during hospitalization was lower (P = 0.024) in the AW-WIN than in the PDWD group.. AW-WIN reduces the time to target INR and the risk of excessive anticoagulation. AW-WIN may be an efficient and safe method of anticoagulation during the acute phase of ischaemic stroke.

Topics: Age Factors; Aged; Anticoagulants; Body Weight; Female; Humans; International Normalized Ratio; Male; Middle Aged; Nomograms; Risk Factors; Stroke; Warfarin

The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.

Topics: Adolescent; Age Factors; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Asian People; Body Weight; Child; Child, Preschool; Cytochrome P-450 CYP2C9; Drug Interactions; Female; Genotype; Heart Defects, Congenital; Humans; Infant; Likelihood Functions; Male; Mixed Function Oxygenases; Models, Biological; Polymorphism, Single Nucleotide; Prothrombin Time; Regression Analysis; Vitamin K Epoxide Reductases; Warfarin; Young Adult

Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients.. Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule.. Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose (r = 0.88, P < 0.0001). The mean difference between observed and predicted dose was not clinically significant: -0.1 +/- 1.1 mg.. In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.

Topics: Administration, Oral; Adult; Age Factors; Aged; Ambulatory Care; Anticoagulants; Blood Coagulation; Body Weight; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Female; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Nomograms; Phenotype; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and treatment of venous and arterial thromboembolic disorders. Its anticoagulant effect is widely variable between patients because of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors.. This study was conducted to identify the associations between demographic characteristics, warfarin maintenance dose, and genetic polymorphisms of cytochrome P450 (CYP) 2C19, CYP2C9, and vitamin K epoxide reductase complex subunit 1 (VKORC1).. This study was conducted from April 2005 to April 2008 at 3 warfarin clinics affiliated with Shiraz University of Medical Sciences. Blood samples were collected from patients with stable warfarin maintenance dose and a stable target international normalized ratio of 2 to 3. Patients who had a condition (including use of an interacting medication) affecting the metabolism of warfarin were excluded. CYP2C9, CYP2C19, and VKORC1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. The associations between demographic characteristics (eg, age, sex, body surface area, weight, height), genetic factors, and maintenance warfarin dose were examined by multiple linear regression. The probability of F as a criterion for removal of a variable from the multiple linear regression was set at 0.1.. One hundred patients were enrolled in the study; complete data were available for 55, who were included in the regression analysis. Among this smaller group, the mean (SD) age was 53 (11) years (range, 25-80 years) and mean weight was 72 (15) kg (range, 42-125 kg); the mean warfarin dose was 27.2 (13.4) mg/week. The allelic frequencies of CYP2C9*2 and CYP2C9*3 were 27% and 9%, respectively. The allelic frequencies of CYP2C19*2 and CYP2C19*3 were 11% and 1%, respectively. Fifteen percent of our patients carried a VKORC1 genotype GG, whereas the AA and GA genotypes were seen in 18% and 58% of patients, respectively. Multiple linear regression analysis found that sex (P = 0.045), height (P = 0.024), age (P = 0.081), and VKORC1 (P = 0.004) and CYP2C9 (P = 0.011) polymorphism had significant influence on the maintenance dose of warfarin. They were associated with 41.3% of the variability in warfarin maintenance dose requirement. VKORC1 polymorphism (partial R(2) = 20.3%) and height (partial R(2) = 20.3%) had the greatest effects on warfarin maintenance dose requirement.. Among the demographic and genetic factors evaluated in these Iranian patients, sex, height, age, CYP2C9, and VKORC1 had significant effects on warfarin maintenance dose requirements.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Body Height; Body Weight; Cross-Sectional Studies; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Humans; Iran; Male; Middle Aged; Mixed Function Oxygenases; Polymerase Chain Reaction; Polymorphism, Genetic; Regression Analysis; Sex Factors; Socioeconomic Factors; Vitamin K Epoxide Reductases; Warfarin

To investigate the contribution of genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 gene VKORC1-1639G>A, cytochrome P450 2C9 gene (CYP2C9), EPHXI, and clinical factors to warfarin sensitivity in southwest Chinese Han patients with mechanical heart valve prostheses.. A total of 127 patients with mechanical heart valve prostheses who have been followed up at our department during the past 23 years were enrolled in this study and compared to a control group that consisted of 133 randomly selected healthy blood donors. These Chinese patients met stable warfarin dosage requirements and had reached the target international normalized ratio (INR) of 1.5-2.0. PCR and direct sequencing were carried out to identify the polymorphisms of VKORC1-1639G>A (rs9923231), CYP2C9*3 (rs1057910), CYP2C9 IVS3-65G>C (rs9332127), and EPHX1691A>G (rs4653436). In addition, total and free (non-protein-bound) warfarin concentrations were analyzed.. There were great interindividual differences in warfarin maintenance dosage (ranging from 0.6 to 8.4 mg/day) among the 127 patients with mechanical heart valve prostheses. VKORC1-1639G>A, CYP2C9, EPHX1691A>G polymorphism, body weight, and age were found to affect the dose demands. Multiple linear regression models incorporating genetic polymorphisms of VKORC1, CYP2C9, EPHX1691A>G, and the nongenetic factors of age and body weight were developed, and explained up to 76.8% of the total variation (adjusted R (2) of 0.743) in warfarin maintenance doses in southwest Chinese patients with mechanical heart valve prostheses.

Topics: Adult; Age Factors; Aged; Aryl Hydrocarbon Hydroxylases; Asian People; Body Weight; China; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C9; Epoxide Hydrolases; Female; Genotype; Heart Valve Prosthesis; Humans; International Normalized Ratio; Male; Middle Aged; Mixed Function Oxygenases; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Vitamin K Epoxide Reductases; Warfarin

Despite a lack of clear recommendations to guide decision-making, reductions in enoxaparin sodium dosage in the elderly and in patients with mild and moderate renal dysfunction are common in patients with acute coronary syndrome.. To evaluate whether weight, age and renal function are associated with anti-factor Xa activity and with bleeding in elderly patients treated with enoxaparin sodium.. This was a prospective observational study of 156 elderly patients admitted consecutively to a general internal medicine ward with creatinine clearance >30 mL/min who were treated with enoxaparin sodium twice daily. Anti-factor Xa activity and bleeding events were documented in all patients. Statistical analyses were conducted to determine the effects of clinical characteristics such as renal dysfunction, age and bodyweight on these parameters.. 156 patients (60% males, mean age 71.0 +/- 15.98 years) were studied. Therapeutic anti-factor Xa was observed in 85.3% of patients treated with enoxaparin sodium 0.61-0.8 mg/kg/12h, and in 82.6% of patients treated with enoxaparin sodium 0.81-1.1 mg/kg/12h. Minor or major bleeding was observed in 5.8% of patients, and was associated with a lower mean bodyweight (61.89 +/- 13.35 vs 74.30 +/- 13.24 kg for patients with no bleeding; p = 0.014). Bodyweight < or =55 kg was associated with bleeding with an odds ratio of 5.63 (95% CI 1.2, 25, p = 0.025).. Low bodyweight is associated with a greater risk of bleeding despite a reduction in enoxaparin sodium dose according to weight. This finding supports the possibility that low bodyweight is an independent risk factor for enoxaparin sodium-related bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Body Weight; Clopidogrel; Creatinine; Dose-Response Relationship, Drug; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Inpatients; Length of Stay; Logistic Models; Male; Middle Aged; Odds Ratio; Prospective Studies; Risk Factors; Sex Factors; Ticlopidine; Treatment Outcome; Warfarin

To establish individualized warfarin therapy, we investigated the contribution of genetic variations of vitamin K epoxide reductase complex subunit 1 gene (VKORC1) -1639 G>A and Cytochrome P450 2C9 gene (CYP2C9) and clinical factors on warfarin sensitivity in Japanese patients.. Genetic analyses of VKORC1 -1639 G>A and CYP2C9 2, 3, and 4 were performed in 259 Japanese patients and 341 healthy subjects. We selected 259 patients who have been prescribed warfarin with a 1.5-3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months and investigated factors that contribute to individual variability in warfarin dose. Furthermore, multivariate analysis was performed to investigate a warfarin dosing algorithm.. There were great inter-individual differences in warfarin maintenance dose in 259 patients, ranging from a minimum dose of 0.75 mg/day to a maximal dose of 8.00 mg/day. VKORC1 -1639 G>A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variability. The dosing algorithm of warfarin maintenance dose was investigated by multivariate linear regression. The regression equation was able to account for 33.2% (R(2)(Adj)=0.332) of the overall variability in warfarin dose.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Alleles; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Body Weight; Cytochrome P-450 CYP2C9; Female; Gene Frequency; Genotype; Humans; Japan; Linear Models; Male; Middle Aged; Mixed Function Oxygenases; Polymorphism, Genetic; Retrospective Studies; Serum Albumin; Vitamin K Epoxide Reductases; Warfarin

Data evaluating the safety of using weight-based low-molecular-weight heparin in the treatment of obese patients with acute venous thromboembolism are limited. The product monograph of dalteparin suggests the maximum dose should be limited to 18,000 U subcutaneously once daily. There are no specific data regarding the risk of recurrence or bleeding in patients given dalteparin in a weight-based dose of 200 IU kg(-1). We report a retrospective chart review of 193 obese patients who weighed more than 90 kg and who received dalteparin at or near to 200 IU kg(-1) actual body weight for 5-7 days for acute venous thromboembolism with 90 day follow-up information. Of the patients, 77% had idiopathic venous thromboembolism, 16% had an underlying malignancy, and 7% had a transient risk factor. Warfarin was initiated within 2 days with a target International Normalized Ratio range of 2.0-3.0. All patients were followed for 12 weeks post diagnosis. Only two patients had a major hemorrhage, 4 and 8 weeks from diagnosis. This study supports the safety of dosing dalteparin based on actual body weight in obese patients.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Dalteparin; Female; Humans; International Normalized Ratio; Male; Medical Records; Middle Aged; Obesity; Recurrence; Retrospective Studies; Risk Factors; Thromboembolism; Time Factors; Venous Thrombosis; Warfarin

Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R(2)=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R(2)=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.

Topics: Aged; Aging; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Blood Proteins; Body Weight; Cytochrome P-450 CYP2C9; Demography; Drug Interactions; Female; Food-Drug Interactions; Genotype; Heart Valve Prosthesis; Humans; International Normalized Ratio; Male; Polymorphism, Genetic; Regression Analysis; Serum Albumin; Stereoisomerism; Warfarin

The purposes of this study were to clarify that warfarin (WF, vitamin K antagonist) levels that inhibit gamma-carboxylation are different in liver and bone (experiment 1), and to investigate whether the plasma osteocalcin (OC) level reflects bone OC levels (experiments 2 and 3). Four-week-old male rats were treated with 0.2, 0.4, 0.6, 0.8, 1.0, or 1.2 mg/l of WF solution as drinking water for 4 weeks. Blood coagulation activity, an index of gamma-carboxylation of prothrombin in the liver, was significantly decreased in rats receiving 0.8 mg/l or larger doses of WF. A significant decrease of plasma gamma-carboxylated OC (GlaOC), an index of gamma-carboxylation of OC in bone, was shown in rats receiving 0.2 mg/l or larger doses. Significantly lower OC levels in the femoral diaphysis and metaphysis were shown in the 0.2 mg/l and 0.4 mg/l groups. However, femoral bone mineral density (BMD) values in the WF-treated groups were almost the same as those in the intact group. In experiment 2, we evaluated changes in bone OC levels 4 weeks after discontinuing an 8-week WF treatment. Four-week-old male rats received 0.8 mg/l WF as drinking water for 8 or 12 weeks. Recovery of the OC level after discontinuing the WF treatment was shown in the femoral metaphysis, but not in the diaphysis. In experiment 3, 0.3 mg/kg WF was administrated to 25-week-old male rats three times a week for 8, 12, or 16 weeks. In aged rats, decreased bone OC was shown in the femoral metaphysis, but not in the diaphysis. From these findings, it is suggested that the effects of WF on gamma-carboxylation are likely to appear in bone at lower doses than in the liver, that the bone OC level does not always correspond directly to plasma GlaOC, and that the bone OC level is not directly linked with BMD.

Topics: Animals; Anticoagulants; Blood Coagulation; Body Weight; Bone and Bones; Bone Density; Diaphyses; Dose-Response Relationship, Drug; Femur; Liver; Male; Osteocalcin; Rats; Time Factors; Warfarin

Bridging anticoagulation with low-molecular-weight heparin (LMWH) is common in patients who require temporary interruption of warfarin before surgery or a procedure, but whether such patients have a residual anticoagulant effect just before a procedure is not known. Consecutive patients who received bridging anticoagulation with LMWH had anti-Xa levels measured just before a procedure. The proportion of patients with a residual anticoagulant effect, defined as an anti-Xa level > or = 0.10 IU/ml, was determined. Multivariable regression analysis identified predictors of a residual anticoagulant effect, expressed as an odds ratio (OR) and corresponding 95% confidence interval (CI). A pre-procedure residual anticoagulant effect was detected in 12 of 73 (16%) patients overall, in 11 of 37 (30%) patients who received therapeutic-dose LMWH, and in 1 of 36 patients (3%) who received low-dose LMWH. Receiving therapeutic-dose LMWH (OR = 118.8; 95% CI: 5.8, 999.9), and increasing age (OR = 4.0; 95% CI: 1.3, 12.5) were predictors of a residual pre-procedure anticoagulant effect. In patients who require bridging anticoagulation with LMWH, a residual anticoagulant effect from LMWH is detected in 1 of 6 patients, and receiving therapeutic-dose LMWH is the strongest predictor of such an effect.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Disorders; Body Weight; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Preoperative Care; Risk Factors; Surgical Procedures, Operative; Time Factors; Treatment Outcome; Warfarin

To identify patient-specific factors predictive of maintenance warfarin dosage requirements >5 mg/d.. One hundred forty-six adults taking warfarin were identified from a community hospital and an outpatient anticoagulation clinic. Patient demographics and data on warfarin doses, laboratory results, and medication use were obtained by abstracting patient records. Estimates of vitamin K intake were obtained using a questionnaire and structured interview. Multiple logistic regression was used to identify patient characteristics independently predictive of warfarin maintenance requirements >5 mg/d. An assessment tool for estimating an individual patient's likelihood of requiring warfarin maintenance doses >5 mg/d was derived from the logistic regression model and was assessed in both the study cohort and a separate historical validation cohort of 125 patients.. Five factors were independently associated with warfarin requirements >5 mg/d: age <55 years, male gender, African American ethnicity, vitamin K intake >400 micro g/d, and body weight >or=91 kg. The assessment tool derived from these factors correctly classified semiquantitative warfarin requirements as non-high-dose in 84 of 93 study cohort patients and 71 of 78 validation cohort patients, and correctly classified requirements as high-dose in 10 of 13 study cohort patients and 11 of 15 validation cohort patients.. African American ethnicity is a newly identified predictor of warfarin requirements >5 mg/d and is independent of dietary vitamin K intake. An assessment tool incorporating this and other predictors can estimate a patient's likelihood of requiring such dosages.

Topics: Age Factors; Aged; Anticoagulants; Black People; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Multivariate Analysis; Sex Factors; Vitamin K; Warfarin; White People

We succeeded in developing a novel rabbit model of nonsteroid and nontraumatic osteonecrosis (ON) by use of a single- and low-dose lipopolysaccharide (LPS) injection. This model is simple and highly reproducible for the frequent development of multifocal and widespread ON lesions. Male adult Japanese white rabbits intravenously injected with a single injection of 10 microg/kg body weight of LPS were histopathologically examined in the early phase (3 [n = 3], 5 [n = 3], and 24 h [n = 3]) and at 4 weeks (n = 22). Seventy-seven percent of the rabbits developed multifocal ON 4 weeks after LPS injection. ON was also observed in the femoral and humeral condyle. The average percentage of necrotic area/total area examined was 86.7 +/- 29.1% and 78.8 +/- 16.7% in the proximal one third of both the femoral and humeral bones, respectively. Organized thrombi in the intraosseous small-sized arteries and arterioles were frequently seen in and around the necrotic tissues. In the early phase, LPS treatment prominently induced thrombocytopenia, hyperlipidemia, and increased plasma levels of plasminogen activator inhibitor-1 (PAI-1). The plasma level of PAI-1 was significantly higher in the rabbits with ON than in those without ON (p < 0.01). The immunohistochemical expression of tissue factor was exaggerated in monocytes/macrophages and adipocytes in both the femoral and humeral bones of the LPS-treated rabbits. Histologically, marrow necrosis and fibrin thrombi could be observed at 24 h. In addition, pretreatment with an anticoagulant, warfarin potassium, significantly decreased the incidence of LPS-induced ON (33%, n = 9, p < 0.05) associated with elongation of prothrombin time. The results of our study show that a single administration of low-dose lipopolysaccharide induces multifocal and widespread ON characterized by the pathophysiological participation of hypercoagulability in ON development. Therefore, this model would be useful for elucidating the pathogenesis of nonsteroid ON in humans especially inflammatory hypercoagulability-induced as well as for developing preventive and therapeutic strategies.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Femur; Immunohistochemistry; Lipopolysaccharides; Male; Osteonecrosis; Rabbits; Warfarin

Chinese patients are reportedly more sensitive than Caucasians to the anticoagulant effect of warfarin. We examined warfarin dose requirements and their determinants in 151 Chinese out-patients on stable maintenance dose of warfarin with international normalized ratio of 2 to 2.5. Mean daily warfarin requirement was 3.3 +/- 1.4 mg, much lower than reported doses in Caucasian patients. The most important determinant was age (r = -0.43, p < 0.001), with progressively lower warfarin requirement with increasing age (p = 0.0001). There was a weaker association with body weight (r = 0.20, p = 0.01). Patients with chronic rheumatic heart disease tended to require a smaller dose than those with heart valve replacements (2.94 +/- 1.24 vs. 3.69 +/- 1.42 mg, p < 0.01). We confirm that Chinese patients require a smaller dose of warfarin for the same degree of anticoagulation. Age is the most important factor affecting dose requirement, although body weight and underlying disease also play a role.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Asian People; Blood Coagulation Disorders; Body Weight; Cardiovascular Diseases; Drug Administration Schedule; Female; Heart Valve Prosthesis; Hong Kong; Humans; Male; Middle Aged; Rheumatic Heart Disease; Sex Factors; Thrombophlebitis; Warfarin

A pharmacy-managed protocol for warfarin use in orthopedic surgery patients was studied. In 1990 a protocol designed to accommodate either protocol- or physician-determined dosing of warfarin for orthopedic antithrombotic prophylaxis (OAP) was implemented at a community hospital. A "protocol" group consisting of patients treated entirely under the protocol-determined dosing option was prospectively identified over a two-year period. A "physician" group consisting of patients treated by physicians in the 10 months immediately preceding implementation of the protocol was also identified. The ability of the protocol to achieve laboratory-test and clinical goals was assessed by comparing the two groups. The proportion of patients who received OAP increased from 89% for the physician group to 98% for the protocol group. Mean prothrombin times (PTs) were significantly higher in the protocol group only on postoperative day 2; 66% of all PTs beyond post-operative day 1 in the protocol group were within the targeted range, which reflected an International Normalized Ratio of 1.6-3.2. The frequencies of clinically apparent postoperative thrombotic events and bleeding episodes were low in each group and comparable to literature values. Analysis of protocol-group patients with PTs of > 20 seconds indicated that lower weight, female sex, and blood loss during surgery were associated with an elevated PT. The protocol was revised to provide for a lower initial warfarin dose in elderly women. A pharmacy-managed protocol for dosing warfarin achieved therapeutic goals and promoted nearly universal use of OAP in patients undergoing high-risk orthopedic surgery.

Topics: Blood Coagulation Tests; Body Weight; Clinical Protocols; Female; Humans; Male; Montana; Orthopedics; Pharmacists; Pharmacy Service, Hospital; Physicians; Prospective Studies; Prothrombin Time; Sex Factors; Treatment Outcome; Warfarin

The physiologic role of osteocalcin (OC), a vitamin K-dependent protein specific to bone, remains elusive. It has been shown that rats maintained on chronic treatment with vitamin K1 and its antagonist warfarin exhibit a marked decrease in bone osteocalcin because noncarboxylated osteocalcin does not bind to bone hydroxyapatite. To assess the role of OC in bone remodeling, we applied the warfarin model to growing lambs. We analyzed the bone changes after 3 months of concurrent warfarin and vitamin K1 treatment. Four groups of four lambs were constituted at birth and received daily a saline solution (control group, CT), 4 mg/kd/day of vitamin K1 (vitamin K group), 4 mg/kg/day of vitamin K1 + 75 or 150 mg/kg/day of warfarin (W75 and W150 group, respectively). In warfarin-treated animals, bone osteocalcin levels were decreased, both in the metaphysis (9% compared to controls) and the diaphysis (30% compared to controls) of the metacarpals. The fraction of noncarboxylated osteocalcin measured every month in the serum was significantly higher in warfarin-treated lambs than in controls at each timing point (37.6 +/- 2.6% in W75 and 48.7 +/- 5.2% in W150 versus 14.4 +/- 3.8% in controls at 3 months). Compared to non-warfarin-treated animals (NW), the main histomorphometric parameters measured on the iliac crest after tetracycline double labeling were significantly reduced in the warfarin-treated lambs: 12.2 +/- 5.2 versus 18.6 +/- 4.7% in NW (p < 0.03) for the cancellous bone area, which reflects the trabecular bone density; 14.7 +/- 6.1 versus 21.0 +/- 3.6% in NW (p < 0.03) for the eroded perimeter, and 0.315 +/- 0.064 versus 0.561 +/- 0.23 microns 3/microns 2/day in NW (p < 0.02) for the tetracycline-based bone formation rate. In conclusion, the depletion of osteocalcin in the bone of lambs induced within 3 months a marked osteopenia that resulted from a decrease in resorption and a more pronounced decrease in bone formation. Our data suggest that the presence of osteocalcin, the major gla-containing protein of bone, may be important for the maintenance of a normal bone mass and remodeling of trabecular bone.

Topics: Animals; Animals, Newborn; Body Weight; Bone and Bones; Bone Diseases, Metabolic; Bone Remodeling; Calcium; Creatinine; Disease Models, Animal; Male; Osteocalcin; Parathyroid Hormone; Radioimmunoassay; Random Allocation; Sheep; Vitamin K 1; Warfarin

A revised protocol for heparin therapy, in which dosing was based on the patient's weight and the pharmacy staff assumed responsibility for management of the treatment protocol, was evaluated. A fixed-dose protocol for heparin therapy, in which an initial loading dose and infusion rate were specified by physicians and partial thromboplastin times (PTTs) were determined every 12 hours, was revised to determine dosing based on patient weight and diagnosis and to include more levels of dose adjustment and additional laboratory tests. Data on demographic characteristics of patients, heparin therapy, laboratory monitoring, conversion to warfarin therapy, and protocol management were collected for the patients receiving heparin under the revised protocol. Results were compared with those obtained for the old, fixed-dose protocol, which was managed by nursing staff. The revised protocol showed improvements in heparin therapy according to commonly accepted treatment criteria, including dosages, time to achieve a PTT associated with therapeutic anticoagulation, and the time a patient was in the target PTT range. The new protocol was also significantly more effective in avoiding low as well as high PTT ratios. The laboratory monitoring mandated by the revised protocol enhanced the monitoring of heparin therapy, and pharmacy management improved the accuracy and documentation of heparin therapy. Under the revised protocol, anticoagulation goals were attained more rapidly, and dosing changes were more likely to be correct and appropriately documented.

Topics: Adult; Aged; Body Weight; Clinical Protocols; Female; Heparin; Humans; Male; Middle Aged; Montana; Partial Thromboplastin Time; Pharmacy Service, Hospital; Retrospective Studies; Warfarin

Determination of the effects of the vitamin K-dependent anticoagulants, proteins C and S, on warfarin dose requirements and on the prediction error of a bayesian warfarin dose predicting program.. Patients in the study were consecutive inpatients (n = 18) starting treatment with warfarin who were monitored as outpatients for 4 weeks. The following measurements were taken: repeated (n = 8) prothrombin times, expressed as the international normalized ratio (INR), plasma protein C and S antigen levels (percentage of pooled normal plasma), demographic, clinical and biochemical variables.. Maintenance doses (adjusted to INR 2.5) were 6.7 +/- 3.4 mg/day. Protein C decreased to 56.9% +/- 15.3%, protein S to 63.7% +/- 17.3%, INR increased to 2.46 +/- 0.14. Prediction error decreased from 2.84 +/- 2.0 mg/day to 0.95 +/- 0.78 mg/day. Protein C accounted for only 4.2% of the mean maintenance dose but protein C and S levels accounted for 31% of the mean dose prediction error.. Protein C and S levels affect warfarin doses and predictions significantly but not to a clinically meaningful degree.

Topics: Adolescent; Adult; Aged; Bayes Theorem; Body Weight; Drug Monitoring; Female; Glycoproteins; Humans; Male; Middle Aged; Protein C; Protein S; Prothrombin Time; Software; Warfarin

Topics: Animals; Body Weight; Chickens; Lethal Dose 50; Male; Organ Size; Warfarin

Cosmetic surgery of the abdomen is requested frequently by patients and is being performed increasingly at the time of elective gynecologic surgery. However, little information is available regarding the safety of combining these procedures. In this study intraoperative and postoperative morbidity was compared in the following groups of patients: 1) abdominoplasty plus one of five common gynecologic procedures (N = 76); 2) one of the five gynecologic procedures alone, matched for age, weight, and time of operation (N = 76); and 3) abdominoplasty alone (N = 70). Patients in group 1 experienced significantly longer operative time, longer hospital stays, and greater blood loss, which required more transfusions than group 2 or 3. These problems were accentuated in patients who weighed more than 70 kg or were older than age 35. In addition, five patients (6.6%) in group 1 had a documented pulmonary embolus within 18 days of surgery, whereas no pulmonary emboli occurred in group 2 or 3. Because of the increased morbidity, careful patient selection is necessary when abdominoplasty and gynecologic procedures are performed at the same time.

Topics: Abdomen; Adult; Age Factors; Blood Transfusion; Body Weight; Female; Hemorrhage; Heparin; Humans; Hysterectomy; Hysterectomy, Vaginal; Length of Stay; Middle Aged; Postoperative Complications; Pulmonary Embolism; Risk; Surgery, Plastic; Warfarin

The population pharmacokinetics of racemic warfarin was evaluated using 613 measured warfarin plasma concentrations from 32 adult hospitalized patients and 131 adult outpatients. Warfarin concentrations were measured in duplicate using a high-performance liquid chromatographic procedure. The pharmacokinetic model used was a one-compartment open model with first-order absorption (absorption rate constant set equal to 47 day-1) and first-order elimination. The extent of availability was assumed to be one. A linear regression model was used to evaluate the influence of various demographic factors on warfarin oral clearance. Age appeared to be an important determinant of warfarin clearance in this adult population. There was about a 1%/year decrease in oral clearance over the age range of 20-70 years. Smoking appeared to result in a 10% increase in warfarin clearance, while coadministration of the inducers phenytoin or phenobarbital yielded about a 30% increase in clearance. This study has yielded a predictive model that, when combined with appropriate pharmacological response data, may be useful in the design and adjustment of warfarin regimens.

Topics: Adolescent; Adult; Aged; Aging; Body Weight; Drug Interactions; Female; Humans; Kinetics; Male; Middle Aged; Models, Biological; Software; Stereoisomerism; Warfarin

Topics: Age Factors; Aged; Body Surface Area; Body Weight; Female; Humans; Male; Middle Aged; Prothrombin Time; Warfarin

Twenty-two children whose mothers took the oral coumarin anticoagulant warfarin during pregnancy were seen, to assess their physical and mental development; a comparison was made with matched controls. No significant difference was observed between the study group and controls, nor within the study group according to the period of gestation when their mothers took warfarin.

Topics: Body Height; Body Weight; Child Development; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Prenatal Exposure Delayed Effects; Warfarin

Selenium may be related to the hepatic metabolism of the coumarin compounds aflatoxin B1 and warfarin. Selenium evidently increased the pharmacologic activity of warfarin, probably due to a displacement of warfarin from albumin by selenium, the close relationship among selenium, vitamin E, and sulphur-containing groups (eg, glutathione), or the antioxidant effect of selenium. A diet containing selenium in a concentration of 2.5 mg/kg of feed was protective against the toxic effects of both coumarins in pigs given 4 daily oral doses of 0.2 mg/kg of body weight. Selenium, as glutathione peroxidase, at least in part, protects the hepatic cells against the toxic effects of aflatoxin B1 and warfarin. The protection was demonstrated by alteration of clinical responses and hematologic (prothrombin times), electrophoretic, and clinical chemistry values. It also was demonstrated that selenium at 2.5 mg/kg of feed does not produce toxic effects; however, dietary selenium at a concentration of 5 mg/kg (and in the presence of both toxic agents) was toxic for young pigs within the 3-week experimental period. Warfarin was more active as an anticoagulant than aflatoxin B1.

Topics: Aflatoxin B1; Aflatoxins; Animals; Biotransformation; Blood Proteins; Body Weight; Diet; Drug Interactions; Liver; Male; Prothrombin Time; Selenious Acid; Selenium; Swine; Swine Diseases; Warfarin

A survey of patients attending anticoagulant clinics at a District General Hospital showed the maintenance dose of warfarin to increase with weight and decrease with age. A significant correlation was observed between age and weight considered together and the maintenance dose. It is proposed that consideration of age and weight may be of value when prescribing loading or starting doses of warfarin at initiation of therapy.

Topics: Age Factors; Aged; Body Weight; Female; Humans; Male; Middle Aged; Regression Analysis; Warfarin

Prenatal exposure to oral anticoagulants during pregnancy may result in defective fetal development or life-threatening hemorrhage. Fetal exposure during the first eight weeks of pregnancy may cause abnormal development of the facial structures, hypoplastic digits, strippled epiphyses, and mental retardation. Midtrimester exposure may result in optic atrophy, faulty brain growth, and developmental retardation. Third-trimester exposure may produce fetal anticoagulation, predisposing the infant to life-threatening hemorrhage in the perinatal period. Anticoagulation with heparin sodium does not provide a clearly safe alternative, since this therapy has been associated with excessive fetal loss.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Administration, Oral; Adult; Anticoagulants; Body Weight; Chondrodysplasia Punctata; Female; Fetus; Gestational Age; Humans; Infant, Newborn; Maternal-Fetal Exchange; Optic Atrophy; Pregnancy; Pregnancy Complications, Cardiovascular; Rheumatic Heart Disease; Vitamin K; Warfarin

The possibility that anticoagulation with warfarin might inhibit the development of spontaneous metastases from intestinal carcinomas induced by azoxymethane (AOM) was tested in Sprague-Dawley rats with and without 60% distal small-bowel resection (DSBR). Warfarin (0.5 mg/l) was added to the drinking water from 1 week or 12 weeks postoperatively, and thromboplastin times were measured thereafter. AOM was given by 12 weekly s.c. injections (10 mg/kg/week), starting 1 week after DSBR. Besides increasing the sensitivity of rats to warfarin, DSBR itself caused partial anticoagulation, probably because of vitamin K malabsorption: at 30 weeks faecal fat was 59-93% higher, while serum B12 was 40% lower (> 0.05 P > 0.005). Adaptive growth of the jejunum and caecum after DSBR was manifested by 22-76% increases in segmental weight and surface area (P < 0.001). DSBR produced a 4-fold increase in duodenojejunal tumours at 15-25 weeks (P = 0.025) and a 76% increase in colorectal tumours at 25-35 weeks (P < 0.005). Eight of 20 control rats dying after 15 weeks had lymphatic metastases, compared with 0 of 15 rats with DSBR plus warfarin from week 1 (P = 0.005). The overall prevalence of metastases was reduced by both DSBR and warfarin, when assessed independently. Intestinal carcinogenesis induced by AOM is enhanced by the adaptive response to DSBR, but anticoagulation inhibits spontaneous metastases in this model.

Topics: Animals; Blood Coagulation; Body Weight; Ileum; Intestinal Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Postoperative Period; Rats; Warfarin

Topics: alpha-Chlorohydrin; Animals; Body Weight; Chlorohydrins; Epididymis; Male; Rats; Reproduction; Rodent Control; Rodenticides; Warfarin

The potentiality of calciferol (alone and combined with warfarin) for the control of commensal rats and mice has been examined in the laboratory. Nearly all animals fed on 0.1% calciferol for 2 days died. Though illness usually reduced food intake after the first 24 hr. there was no sign of aversion to the poison at 0.1% - which is considered to be the lowest concentration suitable for use against Rattus norvegicus, R. rattus and Mus musculus in the field. There was some indication that resistance to warfarin in R. norvegicus may be correlated with susceptibility to calciferol. Toxicity tests with calciferol combined with warfarin indicated an additive effect between the compounds. No evidence for synergism was found however, although elsewhere there is some evidence for this.

Topics: Animals; Body Weight; Drug Combinations; Drug Resistance; Ergocalciferols; Feeding Behavior; Female; Male; Mice; Rats; Rodent Control; Rodenticides; Warfarin

Topics: Anticoagulants; Blood Pressure; Blood Sedimentation; Body Weight; Drug Interactions; Humans; Medical Records; Outpatient Clinics, Hospital; Pharmacists; Pharmacy Service, Hospital; Pulse; Time Factors; Warfarin

Topics: Administration, Oral; Aged; Anticoagulants; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Male; Mathematics; Middle Aged; Prothrombin Time; Time Factors; Warfarin

Topics: Animals; Blood Proteins; Body Weight; Half-Life; Hypothyroidism; Male; Protein Binding; Prothrombin Time; Rats; Rats, Inbred Strains; Serum Albumin; Thyroidectomy; Time Factors; Warfarin

Individually caged house mice (Mus m. musculus) were fed 0.025% warfarin (3(2-acetyl-1-phenylethyl)-4-hydroxycoumarin) or 0.025% chlorophacinone (2(1-(p-chlorophenyl)-1-phenyl) acetyl-1,3-indandione) for periods varying from 1 to 21 days. In all, 320 mice, 160 of each sex, were tested.A significant difference was found between the mortalities obtained by the two compounds. In feeding periods varying from 1-5 days chlorophacinone produced a mortality of 60-85% and warfarin only 5-75%. Five per cent, however, did survive 21 days feeding on each compound.A great variation in the susceptibility of individual mice was established for chlorophacinone as well as for warfarin.

Topics: Animals; Anticoagulants; Body Weight; Drug Resistance; Female; Indenes; Ketones; Male; Mice; Rodenticides; Time Factors; Warfarin

Topics: Angiocardiography; Animals; Blood Glucose; Blood Proteins; Blood Volume; Body Composition; Body Weight; Cachexia; Calcium; Carbon Dioxide; Chlorides; Creatinine; Dogs; Hydrogen-Ion Concentration; Magnesium; Mitral Valve Stenosis; Penicillins; Potassium; Potassium Isotopes; Sodium; Sodium Isotopes; Streptomycin; Thyroxine; Urea; Warfarin; Water

Topics: Animals; Biological Transport; Body Weight; Cattle; Chromatography, DEAE-Cellulose; Depression, Chemical; Female; Hematocrit; Heparin; Immunodiffusion; Iodine Isotopes; Male; Methods; Models, Biological; Prothrombin; Rabbits; Stimulation, Chemical; Thrombin; Time Factors; Vitamin K; Warfarin

Topics: Acetohexamide; Adult; Agglutination; Angina Pectoris; Anticholesteremic Agents; Arteriosclerosis; Body Weight; Butyrates; Chlorpropamide; Cholesterol; Conjunctiva; Diabetes Complications; Diabetic Neuropathies; Diet, Reducing; Female; Heart Diseases; Humans; Hypercholesterolemia; Hyperlipidemias; Male; Middle Aged; Phenformin; Triglycerides; Warfarin; Xanthomatosis

Topics: Animals; Body Weight; Body Weights and Measures; Drug Tolerance; Mice; Pharmacology; Research; Rodenticides; Toxicology; Warfarin