Rivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect

Lorenzini, Kuntheavy Ing; Daali, Youssef; Fontana, Pierre; Desmeules, Jules Alexandre; Samer, Caroline Flora

doi:10.3389/fphar.2016.00494

Cited by 57 publications

(75 citation statements)

References 20 publications

(36 reference statements)

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“…20 Likewise, ABCB1 2677G > T and 3435 C > T carriership were associated with higher blood plasma rivaroxaban concentration and bleeding complications. 52 Apart from that, there are studies that report no link between 1236C > T, 2677G > T, 3435 C > T and rivaroxaban pharmacokinetics. 53 The present study has proven that gene polymorphisms, usually associated with clopidogrel-related bleeding, play an important role in combined antithrombotic therapy: CYP2C19*17 carriers twice as often had low residual platelet reactivity (PRU less than 95) 17.2% vs 33.3% (p = 0.059).…”

Section: Discussionmentioning

confidence: 99%

CYP2C19*17 May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban

Sychev

Батурина

Мирзаев

et al. 2020

PGPM

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The aim of this study is to assess the influence of gene CYP2C19, CYP3A4, CYP3A5 and ABCB1 polymorphisms on clopidogrel antiplatelet activity, rivaroxaban concentration equilibrium, and clinical outcomes among patients with acute coronary syndrome and non-valvular atrial fibrillation. Methods: In the multicenter prospective registry study of the efficacy and safety of a combined antithrombotic therapy 103 patients with non-valvular atrial fibrillation both undergoing or not a percutaneous coronary intervention were enrolled. The trial assessed the primary outcomes (major bleeding, in-hospital death, cardiovascular death, stroke\transient ischaemic attack, death/renal insufficiency) and secondary outcomes (platelet reactivity units (PRU), rivaroxaban concentration). Results: For none of the clinical outcomes when combined with other covariates, the carriership of polymorphisms CYP3A5*3 rs776746, CYP2C19*2 rs4244285;*17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738 was significant. None of the markers under study (CYP3A5*3 rs776746, CYP2C19*2 rs4244285, *17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738) has proven to affect rivaroxaban equilibrium concentration in blood plasma among patients with atrial fibrillation and acute coronary syndrome. Conclusion: In situations of double or triple antithrombotic rivaroxaban and clopidogrel therapy among patients with atrial fibrillation and acute coronary syndrome, the genetic factors associated with bleeding complications risk (CYP2C19*17) may prove to be clinically relevant.

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Section: Discussionmentioning

confidence: 99%

CYP2C19*17 May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban

Sychev

Батурина

Мирзаев

et al. 2020

PGPM

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“…The inappropriate use of DOAC has also been highlighted in this respect [ 18 , 19 ]. In addition, ABCB1 genetic polymorphisms have recently been suggested to contribute to high rivaroxaban levels in a patient admitted for gastrointestinal bleeding [ 20 ]. Therefore, a second objective was to investigate and discuss the presence of such risk factors for bleeding events in our rivaroxaban patients.…”

Section: Introductionmentioning

confidence: 99%

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Sennesael

Larock²,

Douxfils

et al. 2018

Thrombosis J

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BackgroundSerious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.MethodsThis analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.ResultsRivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).ConclusionsRivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

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“…On the other hand, since only a third of rivaroxaban is excreted through renal pathway and since the renal impairment was resolved as soon as four days, it is suggested that genotypes on two SNPs of ABCB1 gene might play a role in compromised drug clearance. There are more than 100 SNPs in ABCB1 gene region occurring at frequency higher than 5%, while two markers investigated in this study have inter-racial prevalence range of 2-90%, which points out to the fact that many other ABCB1 variants are still to be studied (Table 1) [33].…”

Section: Rivaroxaban Pharmacogeneticsmentioning

confidence: 72%

Pharmacogenetics of Novel Oral Anticoagulants: A Review of Identified Gene Variants & Future Perspectives

Ašić

Marjanović

Mirat³

et al. 2018

Per. Med.

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Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

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Rivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect

Cited by 57 publications

References 20 publications

<p><em>CYP2C19*17</em> May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban</p>

<p><em>CYP2C19*17</em> May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban</p>

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Pharmacogenetics of Novel Oral Anticoagulants: A Review of Identified Gene Variants & Future Perspectives

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