Anticoagulant Effect Of Rivaroxaban Research Articles

Clot time ratio (CTR) and relation to treatment outcome in patients with atrial fibrillation treated with Rivaroxaban

BackgroundThere are situations where information about the anticoagulant effects of Rivaroxaban could be clinically useful. Methods for measuring Rivaroxaban concentrations are not available at all medical laboratories while the test MRX PT DOAC for measuring the functional effects of Rivaroxaban, in CTR (Clot Time Ratio), can be made available around the clock. The objectives of this study were to investigate CTR in trough and peak samples during Rivaroxaban treatment of atrial fibrillation and to correlate the findings to bleeding episodes.Methods3 trough- and 3 peak samples from 60 patients (30 on 20 mg daily and 30 on 15 mg daily) were analyzed with PT DOAC. Patients were monitored for 20 months, and bleeding and thrombotic events were documented. Descriptive statistics were used to summarize the data and non-parametric t-test for comparison between groups. ROC curves for the prediction of DOAC plasma levels > 50 ng/mL as determined with LC-MS/MS and anti-FXa methods were computed.ResultsThere was a significant difference between trough and peak CTR (median CTR 1.33 vs. 3.57, p < 0.001). 28 patients suffered bleeds. Patients on 20 mg Rivaroxaban with bleeds had higher mean peak CTR than patients without bleeds (CTR 4.11 vs. CTR 3.47, p = 0.040). There was no significant difference in mean CTR between patients on 15 mg Rivaroxaban with or without bleeds (CTR 3.81 vs. 3.21, p = 0.803), or when considering all patients (CTR 3.63 vs. 3.56, p = 0.445). Five out of seven patients on Rivaroxaban 20 with mean peak CTR above the dose specific first to third quartile range (Q1-Q3) suffered bleeds, while 7/16 patients with mean peak CTR within, and 1/7 patients with mean peak CTR below the Q1-Q3 suffered bleeds. The area under the ROC curve was > 0.98 at the upper limit of the PT DOAC reference interval and the negative predictive value of PT DOAC for the prediction of DOAC plasma levels > 50 ng/mL was > 0.96.ConclusionsThe sample size was too low to draw any firm conclusions but is seems that MRX PT DOAC might be a useful laboratory test in situations where the effect of Rivaroxaban needs evaluation.

Poor Correlation of Rivaroxaban Concentration with the Routine Coagulation Screening Test in Chinese Patients with Atrial Fibrillation

Aims. The aim of this study is to assess the relationship between rivaroxaban plasma concentration quantified by the gold standard and anticoagulant activities measured by routine coagulation assays in Chinese atrial fibrillation (AF) patients. Whether the normal results of these tests were reliable to rule out clinically relevant rivaroxaban levels at various thresholds was also explored. The effect of clinical drug-drug interactions (DDIs) on the exposure and anticoagulant effect of rivaroxaban were further evaluated. Methods. 116 patients receiving rivaroxaban for the management of nonvalvular AF were recruited. Rivaroxaban concentrations and coagulation tests were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a blood coagulation analyzer, respectively. Results. The correlation of trough concentration (Ctrough) and prothrombin time (PT) or international normalized ratio (INR) was moderate with Spearman’s correlation coefficient of 0.495 and 0.506, respectively. A normal PT/INR was unable to rule out Ctrough levels of &gt;30 ng/mL and &gt;50 ng/mL, but the negative predictive value reached 100% to exclude Ctrough of &gt;100 ng/mL. Ctrough showed a small correlation with activated partial thromboplastin time (aPTT) (Spearman’s correlation coefficient: 0.241) and no correlation with thrombin time (TT) (Spearman’s correlation coefficient: 0.074). Neither aPTT nor TT accurately predicted Ctrough at any concentration. Peak concentration (Cpeak) did not correlate with any coagulation parameters. The presence of digoxin and febuxostat significantly increased rivaroxaban Ctrough by 2.18 fold and prolonged PT and INR by 44.16% and 43.60%, respectively. Conclusions. Normal routine coagulation assays were insufficient to monitor therapy with rivaroxaban. Poor correlations between rivaroxaban concentration and routine coagulation assays were observed in Chinese AF patients. The use of digoxin/febuxostat alone had no effect on rivaroxaban concentrations; however, combined strong breast cancer resistance protein inhibitor (febuxostat) and P-glycoprotein probe (digoxin) in patients with renal impairment is likely to cause clinically significant DDI with rivaroxaban. More studies are needed to establish routine therapeutic drug monitoring of rivaroxaban in clinical practice.

Anticoagulant effects of rivaroxaban, prednisone, alone and in combination, in healthy dogs.

The potential effects of glucocorticoid administration on rivaroxaban's anticoagulant bioactivity in dogs, and an appropriate rivaroxaban dosage regimen for dogs receiving glucocorticoid therapy are unknown. The objective was to determine whether glucocorticoid administration influences the anticoagulant effects of rivaroxaban in healthy dogs. We hypothesized that administration of rivaroxaban and prednisone would reduce the anticoagulant intensity compared with rivaroxaban alone. Nine healthy dogs. Randomized, cross-over study. Dogs were administered prednisone (2mg/kg, PO, q24h), rivaroxaban (1.5mg/kg, PO, q24h), or prednisone and rivaroxaban, and the coagulation status was evaluated using prothrombin time (PT), and rivaroxaban-calibrated anti-Xa activity (RIVA, results were log10 transformed for analysis), before drug administration and on days 2, 4, and 8. Linear mixed models and correlation were used to evaluate associations in variables (P < .05 was considered significant). There were no differences in RIVA results for the rivaroxaban and prednisone/rivaroxaban groups on day 8 (P = .599, median 87 [range 45-156] to 167 [56-333], respectively, median difference 90 ng/mL [95% CI:87.3-161.8]) There was a strong correlation between RIVA and PT results when days 2, 4, and 8 were combined (r=.846, P < .001), and increased during drug administration, day 2 (r=.810, P < .001), day 4 (r=.863, P < .001), and day 8 (r=.885, P < .001). Clotting times in the PT correlate with rivaroxaban levels and may prove useful for drug monitoring. Prednisone administration had no apparent influence on the anticoagulant effects of rivaroxaban in healthy dogs, suggesting that combined therapy will not require dosage adjustments.

In Vitro Analysis of Unfractionated Heparin and Enoxaparin on the Anticoagulant Effect of Rivaroxaban by Time

In Vitro Analysis of Unfractionated Heparin and Enoxaparin on the Anticoagulant Effect of Rivaroxaban by Time

Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study

BackgroundThe EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.MethodsThis was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.ResultsFifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.ConclusionsBodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.Trial registrationClinicalTrials.gov number, NCT01145859.

Dosing-time-dependent effect of rivaroxaban on coagulation activity in rats

The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase. A similar chronopharmacological effect was seen in a quantitative model of venous stasis thrombosis. In comparison, the dosing time had minimal influence on the pharmacokinetics of rivaroxaban. These data indicate that the anticoagulant effect of rivaroxaban is influenced by the dosing time. Further studies should confirm this finding in a clinical setting.

Prothrombin Time Tests for the Monitoring of Direct Oral Anticoagulants and Their Evaluation as Indicators of the Reversal Effect.

The prompt assessment and the reversal of direct oral anticoagulants (DOACs) are urgent matters in the emergency care setting. Thus, we planned to elucidate the adequate prothrombin time (PT) test for the evaluation of the anticoagulant effects of various DOACs. The anticoagulant effects of rivaroxaban, apixaban, and edoxaban were measured with 3 PT tests (Triniclot PT Excel S, Neoplastin R, and Thromborel S). Human plasma was spiked with each DOAC at a range of 0 to 1000 ng/mL, and the PT was measured using each PT test. In another series, the reversal effect of either 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC) was evaluated with each PT test. All PT reagents correlated with the concentrations of each DOAC, however, the reactivity was considerably different between the DOACs and the PT tests. A prolonged PT with DOACs was reversed both by PCC and aPCC in a dose-dependent manner; however, Triniclot PT Excel S showed reprolongation of the PT with a higher dose of PCC. The proper choice of PT test is necessary for the assessments of the anticoagulant activity of DOACs. It is also important to understand the different characteristics of each PT test for the assessment of the reversal effects of PCC.

Evaluation of the Antithrombotic Effects of Rivaroxaban and Apixaban Using the Total Thrombus-Formation Analysis System®: In Vitro and Ex Vivo Studies.

BackgroundThe usefulness of the Total Thrombus-Formation Analysis System® (T-TAS®) for monitoring the anticoagulant effects of non-vitamin K oral anticoagulants (NOACs) in clinical practice has been poorly addressed.MethodsNOACs (rivaroxaban and apixaban) were added to whole blood from healthy subjects in an in vitro study, and their effects on thrombus formation were evaluated by the T-TAS®. We also evaluated antithrombotic effects using ex vivo samples of whole blood from patients given rivaroxaban or apixaban at the respective trough and peak drug concentrations.ResultsT-TAS® could determine anticoagulant effects in whole blood treated with rivaroxaban or apixaban in vitro. The increases in the anticoagulant effects of rivaroxaban and apixaban from the trough to peak concentrations in whole blood were successfully monitored by the T-TAS® using ex vivo samples. The antithrombotic effects of rivaroxaban and apixaban (in terms of factor Xa inhibition) at the peak were strongly linked to those at the trough.ConclusionT-TAS® could be a clinically useful tool for monitoring the anticoagulant effects of factor Xa inhibitors, and may represent an accurate quantitative analysis.

CHANGE OF ANTICOAGULANT EFFECT OF RIVAROXABAN DURING A DAY

The article presents an assessment of anticoagulant effect of rivaroxaban in 35 patients with thromboembolic diseases. The results of expressed anticoagulant effect of rivaroxaban were obtained during a day (or more). The data of increase in sensitivity to thrombomodulin indicated about work enchancement of protein C system against the background of rivaroxaban therapy.

IN VIVO REVERSAL OF THE ANTICOAGULANT EFFECT OF RIVAROXABAN WITH 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE

Rivaroxaban lacks a specific reversal agent. Fifty units/kg of 4-factor prothrombin complex concentrate (PCC, Cofact®) completely reversed the anticoagulant effect of rivaroxaban in healthy subjects (Eerenberg, Circulation 2011;124:1573). We hypothesized that infusion with doses of 37.5 or 25 units

In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban

Rivaroxaban has been approved as an antithrombotic agent for prevention of venous thromboembolism with specific indications. At present no antidote is appointed and no guidelines have been formulated for the measurement of Rivaroxaban reversal. In the present study, we have evaluated the influence of prothrombin complex concentrate (PCC) on the anticoagulant effects of Rivaroxaban as measured by prothrombin time (PT) and thrombin generation tests (TGTs). Plasma and whole blood samples from healthy volunteers were spiked with Rivaroxaban (up to 800 μg L(-1) ) and PCC was added to these samples in concentration ranges as used clinically to reverse the effects of vitamin K antagonists. PT, endogenous thrombin potential (ETP) and calibrated automated thrombography (CAT) assays were performed with varying tissue factor (TF) concentrations. Addition of PCC to Rivaroxaban-spiked samples did not result in normalization of PT and TGT lag time/T-Lag in ETP and CAT, respectively. In contrast, normalization of ETP and CAT area under the curve did occur. However, the response to PCC addition was strongly TF concentration dependent and in whole blood less PCC was required for Rivaroxaban reversal as compared with plasma. Prothrombin complex concentrate does not neutralize the lengthening effect on PT and TGT lag time/T-Lag of Rivaroxaban anticoagulated blood in vitro; however, total thrombin potential could be normalized. Response of the different TGTs in this respect is assay condition dependent. Therefore, prospective studies are needed to clarify which assay condition and parameter describes in vivo hemostasis best in patients on Rivaroxaban who are treated with PCC.

Reversing the action of newer oral anticoagulants

We appreciate the remarks of Dr. Fagan and colleagues. As stated in our review, while the studies on the reversal of factor Xa inhibitors were conducted in animal models and healthy volunteers, and the effects of such prohemostatic agents were evaluated with surrogate markers,1–8 the best option in the setting of hemorrhage is unknown. Presently, no published studies have addressed the use of prohemostatic agents in patients with hemorrhage. Likewise, no comparative or combination-treatment trials are available. Recently, Marlu et al.9 used thrombin-generation tests to assess the effect of four-factor prothrombin complex concentrate (PCC), activated PCC (aPCC), and recombinant factor VIIa (rFVIIa) on the anticoagulant effect of rivaroxaban. In this ex vivo study, 10 healthy white male participants received one oral dose of rivaroxaban 20 mg. Blood samples were taken before and two hours after rivaroxaban administration. The anticoagulant-reversal effects of the prohemostatic agents were investigated in vitro at dose-ranging concentrations. Rivaroxaban significantly prolonged pro-thrombin time, reduced the quantitative parameters of thrombin peak and endogenous thrombin potential (ETP), and increased the pharmacokinetic measures of lag time (LT) and time to reach the maximum concentration of thrombin (TTP).

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes

• Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.