Interpatient Variation in Rivaroxaban and Apixaban Plasma Concentrations in Routine Care

Gulilat, Markus; Tang, Anthony; Gryn, Steven E.; Leong‐Sit, Peter; Skanes, Allan C.; Alfonsi, Jeffrey; Dresser, George K.; Henderson, Sara L.; Rose, Rhiannon V.; Lizotte, Daniel J.; Teft, Wendy A.; Schwarz, Ute I.; Tirona, Rommel G.; Kim, Richard B.

doi:10.1016/j.cjca.2017.04.008

Cited by 54 publications

(50 citation statements)

References 32 publications

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“…The results showed differences up to 10 times higher between the minimum and maximum values determined by LC-MS/MS [34]. A subsequent similar study with AF patients found a greater degree of variation in apixaban and rivaroxaban plasma concentrations (50-fold and 60-fold inter-patient variation) [35].…”

Section: Discussionmentioning

confidence: 78%

Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients

Roşian

Kiss

et al. 2020

Genes

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(1) Background: Prescribing apixaban for stroke prevention has significantly increased in patients with non-valvular atrial fibrillation (NVAF). The ABCB1 genotype can influence apixaban absorption and bioavailability. The aim of the present study was to assess the factors that influence apixaban’s plasma level and to establish if a certain relationship has clinical relevance. (2) Methods: Fifty-three NVAF patients were treated with 5 mg apixaban twice/day (70.0 years, range: 65–77, 60.4% men). Trough and peak plasma concentrations of apixaban were determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS), and ABCB1 genotyping was performed. (3) Results: Apixaban plasma concentrations varied considerably. They were higher in women than in men (311.2 ng/dL vs. 252.2 ng/dL; p = 0.05) and were lower in patients with heart failure (149.4 ng/dL vs. 304.5 ng/dL; p < 0.01). Creatinine clearance was inversely correlated with the apixaban plasma level (Spearman correlation: r = −0.365; p = 0.007 for trough concentrations). No statistically significant differences between the genotypic groups of ABCB1 rs1045642 and ABCB1 rs4148738 were found in the trough or peak apixaban plasma concentrations. (4) Conclusions: Pharmacokinetic parameters are influenced by several clinical factors of which renal function is the major determinant. Plasma concentrations measured in women had higher values than those measured in men, and heart failure was associated with decreased plasma levels of apixaban.

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Section: Discussionmentioning

confidence: 78%

Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients

Roşian

Kiss

et al. 2020

Genes

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“…Apixaban and rivaroxaban also demonstrate conserved inhibition of FXa, which inhibits prothrombin activation. In humans, mean plasma concentrations of all 3 inhibitors are in the range of 100-600 nM 30,31 . Similar concentrations of dabigatran and 10-100 fold higher concentrations of rivaroxaban have been shown to impair clot formation following tail bleeds in mice 32,33 .…”

Section: Zebrafish Thrombin Activity Is Inhibited By Direct Oral Antimentioning

confidence: 99%

Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish

Grzegorski

Liu

et al. 2020

Sci Rep

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The ability to prevent blood loss in response to injury is a conserved function of all vertebrates. Complete deficiency of the central clotting enzyme prothrombin has never been observed in humans and is incompatible with postnatal life in mice, thus limiting the ability to study its role in vivo. Zebrafish are able to tolerate severe hemostatic deficiencies that are lethal in mammals. We have generated a targeted genetic deletion in the kringle 1 domain of zebrafish prothrombin. Homozygous mutant embryos develop normally into the mid-juvenile stage but demonstrate complete mortality by 2 months of age primarily due to internal hemorrhage. Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants. Human prothrombin engineered with the equivalent mutation exhibits a severe reduction in secretion, thrombin generation, and fibrinogen cleavage. Together, these data demonstrate the conserved function of thrombin in zebrafish and provide insight into the role of kringle 1 in prothrombin maturation and activity. Understanding how zebrafish are able to develop normally and survive into early adulthood without thrombin activity will provide important insight into its pleiotropic functions as well as the management of patients with bleeding disorders.Maintaining blood flow in a closed circulatory system requires a delicate balance between pro-and anticoagulant factors. Disequilibrium of these factors in either direction can lead to pathology. In response to vascular injury, the balance shifts towards coagulation in an effort to stabilize blood clots and prevent exsanguination. Critical to this clot stabilization is the activation of prothrombin, a vitamin K-dependent clotting factor, to form the central clotting enzyme, thrombin 1 . Thrombin cleaves soluble fibrinogen into fibrin monomers, which then polymerize to form the insoluble fibrin clot 2 . Additionally, thrombin interacts with protease activated receptors (PARs) on the surface of various cells, including platelets, which makes it the most potent endogenous agonist of primary hemostasis 3 . Human prothrombin (F2) variants have been linked to both thrombophilia and bleeding diatheses. The most common variant (~2% in European populations) 4 is a guanine to adenine transition in the 3' untranslated region at position 20210 that leads to increased plasma prothrombin levels and a 2-3 fold elevated risk of deep vein thrombosis 5,6 . Congenital prothrombin deficiencies result in a bleeding diathesis, but are rare. Acquired deficiencies due to liver failure or vitamin K deficiency are more common 7,8 .Structurally, prothrombin consists of six domains: signal peptide, propeptide, Gla, kringle 1, kringle 2, and serine protease; a domain composed of a light and heavy chain 1 . Following translation, the propeptide targets the protein for post-translational gamma-carboxylation of the glutamic acid residues within the Gla domain. This vitamin K-dependent process is necessary...

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“…Finally, a recent Canadian study (Gulilat et al , ) determined rivaroxaban and apixaban plasma concentrations in patients with AF during routine clinic visits. Of the 243 patients reported (rivaroxaban, n = 94; apixaban, n = 149), a 60‐ and 50‐fold interpatient variation in plasma concentration was reported for rivaroxaban and apixaban, respectively.…”

Section: What Is the Inter‐patient Variability Of Doac Concentrations?mentioning

confidence: 99%

Progress in the monitoring of direct oral anticoagulant therapy

et al. 2019

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Summary The availability of direct oral anticoagulants (DOACs) has led to a paradigm shift in the field of anticoagulation, with DOACs increasingly being prescribed for patients in preference to vitamin K antagonists and low molecular weight heparin. Despite good experience with the use of these agents at fixed doses, there are clinical scenarios where monitoring is recommended. Data from phase III studies of the DOACs and small real‐world studies suggest a relationship between DOAC concentration and clinical events. The DOACs have differing impacts on the common tests of haemostasis and it is important that clinicians are familiar with the sensitivity of the reagents used in their laboratory to individual DOACs. The specific DOAC drug concentrations can be assayed in the laboratory, when required, to guide appropriate clinical decision‐making. Studies from the real world with sufficient numbers evaluating the association of DOAC concentrations with outcomes should be a research priority in order to understand if we could do better through dose individualisation.

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Interpatient Variation in Rivaroxaban and Apixaban Plasma Concentrations in Routine Care

Cited by 54 publications

References 32 publications

Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients

Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients

Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish

Progress in the monitoring of direct oral anticoagulant therapy

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