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Archives of Pathology & Laboratory... Jan 2022Assessing direct oral anticoagulant (DOAC) drug levels by reliable laboratory assays is necessary in a number of clinical scenarios.
CONTEXT.—
Assessing direct oral anticoagulant (DOAC) drug levels by reliable laboratory assays is necessary in a number of clinical scenarios.
OBJECTIVE.—
To evaluate the performance of DOAC-specific assays for various concentrations of dabigatran and rivaroxaban, assess the interlaboratory variability in measurement of these DOACs, and investigate the responsiveness of the routine clotting assays to various concentrations of these oral anticoagulants.
DESIGN.—
College of American Pathologists proficiency testing survey data from 2013 to 2016 were summarized and analyzed.
RESULTS.—
For dabigatran, the interlaboratory coefficient of variation (CV) of ecarin chromogenic assay was broad (ranging from 7.5% to 29.1%, 6.3% to 15.5%, and 6.8% to 9.0% for 100-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The CV for diluted thrombin time for dabigatran was better overall (ranging from 11.6% to 17.2%, 9.3% to 12.3, and 7.1% to 11.2% for 100 ng/mL, 200 ng/mL, and 400 ng/mL, respectively). The rivaroxaban-calibrated anti-Xa assay CVs also showed variability (ranging from 11.5% to 22.2%, 7.2% to 10.9%, and 6.4% to 8.1% for 50-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The prothrombin time (PT) and activated partial thromboplastin time (aPTT) showed variable dose- and reagent-dependent responsiveness to DOACs: PT was more responsive to rivaroxaban and aPTT to dabigatran. The undiluted thrombin time showed maximum prolongation across all 3 dabigatran concentrations, making it too sensitive for drug-level monitoring, but supporting its use as a qualitative screening assay.
CONCLUSIONS.—
DOAC-specific assays performed reasonably well. While PT and aPTT cannot be used safely to determine DOAC degree of anticoagulation, a normal thrombin time excludes the presence of dabigatran.
Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation Tests; Dabigatran; Humans; Partial Thromboplastin Time; Pyrazoles; Pyridones; Rivaroxaban
PubMed: 34133726
DOI: 10.5858/arpa.2020-0633-CP -
American Journal of Cardiovascular... May 2021Cardiovascular disease (CVD) remains the leading cause of death in the USA. Several risk factors have been identified, and obesity has become one of prominent concern.... (Review)
Review
Cardiovascular disease (CVD) remains the leading cause of death in the USA. Several risk factors have been identified, and obesity has become one of prominent concern. Excessive weight is considered a risk factor for CVD based on evidence linking it to a hypercoagulable state. Considering the prevalence of CVD and obesity in the USA, along with the increased risk for thrombus-related events, anticoagulation plays a significant role in prevention and treatment. Direct oral anticoagulants have taken the place of many traditional anticoagulants. Considering the recently approved indications and continued postmarketing studies conducted with rivaroxaban, this updated review provides data on the overall impact of obesity on this compound. This includes data obtained from both healthy obese volunteers and obese patients with various CVD conditions enrolled in rivaroxaban clinical trials, along with data obtained from postmarketing real-world evidence studies. Assessment of the clinical pharmacology and population pharmacokinetics in obese individuals revealed no clinically relevant effects of increased weight. Additionally, subgroup analyses from each of the pivotal phase III trials supporting the current approved labeling also demonstrated consistent efficacy and safety results in obese patients. Lastly, these findings are further supported by several recent real-world evidence studies assessing the continued effectiveness and safety of rivaroxaban. In conclusion, rivaroxaban's overall pharmacological and clinical profile remained consistent in obese adults when assessed in both drug development and postmarketing studies, supporting the premise that higher weight does not necessitate adjustment in either dose strength or regimen.
Topics: Anticoagulants; Area Under Curve; Body Weight; Cardiovascular Diseases; Humans; Metabolic Clearance Rate; Obesity; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Venous Thrombosis
PubMed: 32803514
DOI: 10.1007/s40256-020-00434-w -
Basic Research in Cardiology Aug 2023Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation....
Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte-monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.
Topics: Animals; Mice; Bone Marrow; Rivaroxaban; Neutrophils; Hematopoiesis; Leukocytes; Bone Marrow Cells
PubMed: 37580509
DOI: 10.1007/s00395-023-01001-5 -
Biomedicine & Pharmacotherapy =... Sep 2023Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K...
Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower t (2.21 h vs 2.88 h, β = 1.19, R =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC corrected by dose/weight (AUC/DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R =0.250, p = 0.044), higher C/DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, β = 0.245, R =0.320, p = 0.002), and lower t (2.63 vs 3.19 and 4.15 h, β = -0.346, R =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC and C. Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance.
Topics: Humans; Rivaroxaban; Healthy Volunteers; Anticoagulants; Polymorphism, Single Nucleotide; Phenotype; Arylamine N-Acetyltransferase
PubMed: 37385211
DOI: 10.1016/j.biopha.2023.115058 -
Medicina (Kaunas, Lithuania) Feb 2023The administration of an anticoagulant in patients with liver disease (nonalcoholic steatohepatitis-NASH, nonalcoholic fatty liver disease-NAFLD, chronic hepatitis, or... (Review)
Review
The administration of an anticoagulant in patients with liver disease (nonalcoholic steatohepatitis-NASH, nonalcoholic fatty liver disease-NAFLD, chronic hepatitis, or cirrhosis) who have an indication (atrial fibrillation, venous thrombosis, or pulmonary embolism) is challenging because there is an imbalance between thrombosis and bleeding. There is a need to focus our attention on preventing risk factors because diabetes, obesity, dyslipidemia, smoking, and sedentary behavior are risk factors for both NASH/NAFLD and AF, and these patients require anticoagulant treatment. Patients with advanced liver disease (Child-Pugh C) were excluded from studies, so vitamin K antagonists (VKAs) are still recommended. Currently, VKAs are recommended for other conditions (antiphospholipid syndrome, mitral valve stenosis, and mechanical valve prosthesis). Amongst the patients under chronic anticoagulant treatment, especially for the elderly, bleeding as a result of the improper use of warfarin is one of the important causes of emergency admissions due to adverse reactions. DOACs are considered to be efficient and safe, with apixaban offering superior protection against stroke and a good safety profile as far as major bleeding is concerned compared to warfarin. DOACs are safe in the Child-Pugh A and B classes (except rivaroxaban), and in the Child-Pugh C class are contraindicated. Given that there are certain and reliable data for chronic kidney disease regarding the recommendations, in liver function impairment more randomized studies must be carried out, as the current data are still uncertain. In particular, DOACs have a simple administration, minimal medication interactions, a high safety and effectiveness profile, and now a reversal agent is available (for dabigatran and idarucizumab). Patients are also statistically more compliant and do not require INR monitoring.
Topics: Humans; Aged; Warfarin; Non-alcoholic Fatty Liver Disease; Anticoagulants; Rivaroxaban; Stroke; Atrial Fibrillation; Hemorrhage
PubMed: 36837547
DOI: 10.3390/medicina59020346 -
Journal of Comparative Effectiveness... Oct 2022To evaluate the association of comparative effectiveness research with Medicare coverage of direct oral anticoagulants. A literature review for direct oral... (Review)
Review
To evaluate the association of comparative effectiveness research with Medicare coverage of direct oral anticoagulants. A literature review for direct oral anticoagulants was conducted from 2011 to 2017. Monthly prescription drug plan and formulary files (n = 28) were used to conduct change-point analysis and assess each outcome variable. Up to 2013, studies showed that dabigatran was more effective than rivaroxaban. In 2015, apixaban was shown to be the safest and most effective drug in comparison with all direct oral anticoagulants. In 2016-2017, dabigatran and apixaban were shown to have similar efficacy. Approximately 75% of plans covered dabigatran under tier 3 until 2015. From 2011 to 2017, less than 30% of plans required prior authorizations, 50% imposed quantity limits and mean copayment was lowest for rivaroxaban. Consistent with comparative effectiveness research, Medicare plans covered apixaban more favorably and edoxaban less favorably. However, discrepancies in comparative effectiveness research translation were found for rivaroxaban and dabigatran.
Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Comparative Effectiveness Research; Dabigatran; Humans; Medicare; Pyridones; Rivaroxaban; Stroke; United States
PubMed: 36065839
DOI: 10.2217/cer-2021-0307 -
Journal of Thrombosis and Thrombolysis Apr 2023Rivaroxaban is a direct, oral factor Xa inhibitor that is used for the prevention and treatment of various thromboembolic disorders. Several preclinical and clinical... (Review)
Review
Rivaroxaban is a direct, oral factor Xa inhibitor that is used for the prevention and treatment of various thromboembolic disorders. Several preclinical and clinical studies have utilized specific molecules as biomarkers to investigate the potential role of rivaroxaban beyond its anticoagulant activity and across a range of biological processes. The aim of this review is to summarize the existing evidence regarding the use of blood-based biomarkers to characterize the effects of rivaroxaban on coagulation and other pathways, including platelet activation, inflammation and endothelial effects. After a literature search using PubMed, almost 100 preclinical and clinical studies were identified that investigated the effects of rivaroxaban using molecular biomarkers. In agreement with the preclinical data, clinical studies reported a trend for reduction in the blood concentrations of D-dimers, thrombin-antithrombin complex and prothrombin fragment 1 + 2 following treatment with rivaroxaban in both healthy individuals and those with various chronic conditions. Preclinical and also some clinical studies have also reported a potential impact of rivaroxaban on the concentrations of platelet activation biomarkers (von Willebrand factor, P-selectin and thrombomodulin), endothelial activation biomarkers (matrix metalloproteinase-9, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and inflammation biomarkers (interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1). Based on the results of biomarker studies, molecular biomarkers can be used in addition to traditional coagulation assays to increase the understanding of the anticoagulation effects of rivaroxaban. Moreover, there is preliminary evidence to suggest that rivaroxaban may have an impact on the biological pathways of platelet activation, endothelial activation and inflammation; however, owing to paucity of clinical data to investigate the trends reported in preclinical studies, further investigation is required to clarify these observations.
Topics: Humans; Rivaroxaban; Blood Coagulation; Factor Xa Inhibitors; Inflammation; Biomarkers; Anticoagulants
PubMed: 36746885
DOI: 10.1007/s11239-023-02776-z -
Therapeutic Advances in Cardiovascular... Oct 2016Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery.... (Review)
Review
Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights.
Topics: Body Mass Index; Body Weight; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Humans; Rivaroxaban
PubMed: 27090286
DOI: 10.1177/1753944716643645 -
Human Genomics Jul 2023The influence of genetic factors on the pharmacokinetics and clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) is poorly...
BACKGROUND
The influence of genetic factors on the pharmacokinetics and clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) is poorly understood. This study aimed to explore the effects of CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms on the trough concentrations and the bleeding risk of rivaroxaban in NVAF patients.
PATIENTS AND METHODS
This study is a prospective multicenter study. The patient's blood samples were collected to detect the steady-state trough concentrations of rivaroxaban and gene polymorphisms. We visited the patients regularly at month 1, 3, 6, and 12 to record bleeding events and medications.
RESULTS
A total of 95 patients were enrolled in this study, and 9 gene loci were detected. For the dose-adjusted trough concentration ratio (C/D) of rivaroxaban, the homozygous mutant type was significantly lower than wild type at ABCB1 rs4148738 locus (TT vs. CC, P = 0.033), and the mutant type was significantly lower than the wild type at ABCB1 rs4728709 locus (AA + GA vs. GG, P = 0.008). ABCB1 (rs1045642, rs1128503), CYP3A4 (rs2242480, rs4646437), CYP3A5 (rs776746), and ABCG2 (rs2231137, rs2231142) gene polymorphisms had no significant effect on the C/D of rivaroxaban. For the bleeding events, we found that there were no significant differences among genotypes of all gene loci.
CONCLUSION
This study found for the first time that ABCB1 rs4148738 and rs4728709 gene polymorphisms had a significant impact on the C/D of rivaroxaban in NVAF patients. CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms were not associated with the bleeding risk of rivaroxaban.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Atrial Fibrillation; Cytochrome P-450 CYP3A; Neoplasm Proteins; Polymorphism, Genetic; Prospective Studies; Rivaroxaban
PubMed: 37420302
DOI: 10.1186/s40246-023-00506-3 -
Thrombosis Research Dec 2021Direct oral anticoagulants (DOAC) use remains challenging in obese patients treated for Venous-Thrombo-Embolism (VTE) due to the paucity of prospective and dedicated... (Observational Study)
Observational Study
BACKGROUND
Direct oral anticoagulants (DOAC) use remains challenging in obese patients treated for Venous-Thrombo-Embolism (VTE) due to the paucity of prospective and dedicated studies.
OBJECTIVE
To assess rivaroxaban and apixaban concentrations at different time-points after intake, in obese patients followed at a thrombosis center and treated for VTE; to define factors associated with DOAC levels outside the on-therapy ranges; and to evaluate bleeding and thrombosis rates during follow-up.
METHODS
Observational prospective study in two French University hospitals. Apixaban or rivaroxaban concentrations were measured after the first visit, regardless of last intake in obese patients receiving DOAC for VTE. Concentrations were compared to published reference values for non-obese patients. Demographic, clinical, biological and therapeutic data were collected. Univariate and multivariate analyses were performed to identify factors associated to DOAC concentrations outside the on-therapy ranges.
RESULTS
Out of the 146 patients included, 22 (15%) had DOAC concentrations outside the on-therapy ranges, mainly in the rivaroxaban group (n = 17). Age ≤ 63 years, use of rivaroxaban and time since last intake ≤8 h were associated with DOAC concentrations outside the on-therapy ranges, in multivariable analysis. During the median follow-up of 16 months, two (1%) patients receiving apixaban had recurrent VTE. No patient had major bleeding, 11 (8%) patients had minor bleeding.
CONCLUSION
In this specific prospective bi-centric study dedicated to VTE obese patients, use of DOACs at fixed doses led to concentrations similar to those of non-obese patients in a high proportion of patients, without any effect of the BMI, and with risk-benefit profile comparable to non-obese patients.
Topics: Humans; Middle Aged; Obesity; Pharmaceutical Preparations; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism
PubMed: 34689080
DOI: 10.1016/j.thromres.2021.10.009