Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of hypercoagulability in patients with chronic heart failure

Gheorghiade, Mihai; Thyssen, An; Zolynas, Robert; Nadar, Venkatesh; Greenberg, Barry; Mehra, Mandeep R.; Sun, Xiang; Tian, Hong; Plotnikov, Alexei N.; Burton, Paul

doi:10.1016/j.healun.2010.08.027

Cited by 30 publications

(36 citation statements)

References 25 publications

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“…In 51 patients who had undergone elective hip or knee replacement 6–8 h before receiving either dalteparin (2500–5000 U QD) or rivaroxaban (10 mg QD), effective inhibition of ex vivo thrombin generation was consistently achieved with rivaroxaban, and inhibition was greater than with dalteparin . In 18 HF patients receiving rivaroxaban 10 mg QD or placebo, thrombin generation after 7 days (as measured by prothrombin fragment 1.2) was reduced with rivaroxaban . These data demonstrate that rivaroxaban effectively inhibits thrombin generation across a wide spectrum of doses.…”

Section: Introductionmentioning

confidence: 74%

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Rationale and design of a randomized, double‐blind, event‐driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial

Zannad

Greenberg

Cleland

et al. 2015

European J of Heart Fail

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AimsThrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF‐rEF) and documented coronary artery disease.MethodsThis is an international prospective, multicentre, randomized, double‐blind, placebo‐controlled, event‐driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B‐type natriuretic peptide ≥200 pg/mL or N‐terminal pro–B‐type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all‐cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria.Conclusion COMMANDER HF is the first prospective study of a target‐specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF‐rEF patient population with coronary artery disease.

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Section: Introductionmentioning

confidence: 74%

“…32 In 18 HF patients receiving rivaroxaban 10 mg QD or placebo, thrombin generation after 7 days (as measured by prothrombin fragment 1.2) was reduced with rivaroxaban. 33 These data demonstrate that rivaroxaban effectively inhibits thrombin generation across a wide spectrum of doses.…”

Section: Rivaroxabanmentioning

confidence: 81%

Rationale and design of a randomized, double‐blind, event‐driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial

Zannad

Greenberg

Cleland

et al. 2015

European J of Heart Fail

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“…The pharmacokinetics and pharmacodynamics of rivaroxaban have been investigated in a small study of patients with chronic heart failure [56]. Patients with acute decompensated heart failure or stable, severe, New York Heart Association Class III/IV heart failure received rivaroxaban 10 mg once daily for 6 days.…”

Section: Pharmacokinetics In Patient Populationsmentioning

confidence: 99%

“…Rivaroxaban exhibited similar, predictable pharmacokinetics and pharmacodynamics in patients with acute and stable chronic heart failure. Compared with healthy young and healthy elderly subjects (aged 65–80 years), rivaroxaban exposure (AUC) was increased by 1.8- and 1.2-fold, respectively, in patients with chronic heart failure [56]. …”

Section: Pharmacokinetics In Patient Populationsmentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban

et al. 2013

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Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2–4 h after tablet intake. Oral bioavailability is high (80–100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30–40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5–9 h in healthy young subjects and 11–13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an Emax model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.

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“…28 In the case of asthma, early observations on the association between eosinophil overexpression and asthma severity were made in 1990 by Bousquet et al 29 Multiple studies have since confirmed that blood, tissue, or sputum eosinophil counts can be used to characterize patients with severe asthma and eosinophilic inflammation. [30][31][32][33][34][35][36][37] Through the drug development process for mepolizumab, investigators identified blood eosinophils, rather than sputum eosinophils, as the treatment target for mepolizumab, providing an accessible and multipurpose biomarker for severe eosinophilic asthma. 18,19,38,39 This review will examine how evidence generated during the mepolizumab clinical development program showed that the blood eosinophil count can serve as a pharmacodynamic and predictive biomarker in patients with severe eosinophilic asthma.…”

mentioning

confidence: 99%

Biomarkers for severe eosinophilic asthma

Yancey

Keene

Albers

et al. 2017

Journal of Allergy and Clinical Immunology

200

158

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The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment.

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Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of hypercoagulability in patients with chronic heart failure

Cited by 30 publications

References 25 publications

Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban

Biomarkers for severe eosinophilic asthma

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