Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism

Arachchillage, DJ; Efthymiou, Maria; Mackie, Ian; Lawrie, Andrew; Machin, Samuel J.; Cohen, Hannah

doi:10.1016/j.thromres.2014.11.037

Cited by 29 publications

(40 citation statements)

References 35 publications

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“…Rivaroxaban and warfarin both inhibit thrombin generation in patients with venous thromboembolism who do not have antiphospholipid syndrome, 23 indicating effective anticoagulation. Inhibition of thrombin generation, which indicates effective anticoagulation, has also been shown in patients with antiphospholipid syndrome when taking warfarin 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Warfarin, therefore, affects all phases of thrombin generation equally, whereas rivaroxaban mainly affects the initiation and propagation of thrombin generation, leading to a delay in formation of the prothrombinase complex 30 . As a result, the thrombin generation curve becomes protracted, which in turn lengthens the lag time and time to peak thrombin generation,23, 30 and leads to greater ETP than would be expected for the degree of anticoagulation 23 …”

Section: Discussionmentioning

confidence: 99%

“…Thrombin generation testing was done with the Calibrated Automated Thrombogram 9 and PPP Reagent (Diagnostica Stago, Asnières sur Seine, France) 23 . ETP and peak thrombin generation results were normalised by use of thrombin generation test reference plasma (National Institute for Biological Standards, Potters Bar, UK) to reduce interassay variability 24 .…”

Section: Methodsmentioning

confidence: 99%

“…Rivaroxaban concentrations were measured with the Biophen DiXaI amidolytic anti-Xa assay (Hyphen BioMed) on the CS-2000 i analyser 23 . Intra-assay coefficients of variation were 1·3% at 300 μg/L and 8·0% at 100 μg/L.…”

Section: Methodsmentioning

confidence: 99%

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Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial

Cohen

Hunt

Efthymiou

et al. 2016

The Lancet Haematology

363

252

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SummaryBackgroundRivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain.MethodsThis randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5. Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801.FindingsOf 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957–1233 vs 548, 484–621, treatment effect 2·0, 95% CI 1·7–2·4, p<0·0001). Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47–66 vs 86 nmol/L, 72–102, treatment effect 0·6, 95% CI 0·5–0·8, p=0·0006). No thrombosis or major bleeding were seen. Serious adverse events occurred in four patients in each group.InterpretationETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism.FundingArthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial

Cohen

Hunt

Efthymiou

et al. 2016

The Lancet Haematology

363

252

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“…Rivaroxaban affects various parameters of thrombin generation (TG) ex vivo, measured using calibrated automated thrombography (CAT) [18]. The specific effects of aPL on the anticoagulant action of rivaroxaban have not been defined.…”

mentioning

confidence: 99%

Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome

Arachchillage

Mackie

Efthymiou

et al. 2015

Journal of Thrombosis and Haemostasis

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but not with TVT/ECT at peak rivaroxaban levels, and remained LA-ve with both DRVVT reagents and TVT/ ECT at trough levels. aPL positive IgG spiking of PNP had no effect on rivaroxaban's anticoagulant action on thrombin generation or rivaroxaban anti-Xa levels. Conclusions: The TVT/ECT ratio and Textarin time were not affected even at peak rivaroxaban levels, enabling detection of LA ex vivo. aPL had no effects on rivaroxaban's anticoagulant action in vitro.

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The effect of rivaroxaban on biomarkers in blood and plasma: a review of preclinical and clinical evidence

Schiffer

Schwers

Heitmeier

2023

J Thromb Thrombolysis

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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.

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Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism

Cited by 29 publications

References 35 publications

Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial

Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial

Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome

The effect of rivaroxaban on biomarkers in blood and plasma: a review of preclinical and clinical evidence

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