International Normalized Ratio Is Significantly Elevated With Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study

Ofek, Fanny; Chaim, Samuel Bar; Kronenfeld, Nirit; Ziv‐Baran, Tomer; Berkovitch, Matitiahu

doi:10.1016/j.clinthera.2017.04.007

Cited by 28 publications

(43 citation statements)

References 18 publications

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“…2). International normalized ratio values were elevated (INR: 1.58, 3 h after drug intake, and 1.45 after 12 h; upper limit of normal: < 1.2), whereas and as expected aPTT levels were within normal limits (33.3 and 30.8 s, reference range < 35 s) [13, 21]. Other laboratory results at admission revealed rhabdomyolysis (creatine kinase 31,269 U/l (normal < 170 U/l), ASAT 863 U/l (< 37 U/l)), moderate renal impairment (creatinine 1.36 mg/dl (0.5–1.1 mg/dl); estimated creatinine clearance 40 ml/min (Cockcroft-Gault formula with the adjusted body weight [22, 23]), and moderately elevated ALAT (186 U/l (< 35 U/l)) (Figs.…”

Section: Case Presentationmentioning

confidence: 68%

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways

Huppertz

Grond‐Ginsbach

Dumschat

et al. 2019

BMC Pharmacol Toxicol

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Background Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making. Case presentation We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91–321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41–230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249–463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5–1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5 *3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways. Conclusions This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.

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Section: Case Presentationmentioning

confidence: 68%

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways

Huppertz

Grond‐Ginsbach

Dumschat

et al. 2019

BMC Pharmacol Toxicol

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“…As a direct factor Xa inhibitor, rivaroxaban may prolong prothrombin time and thereby increase INR. In a retrospective study, INR was elevated above upper limit of normal in 84.2% of 158 rivaroxaban‐treated patients, and median INR was 1.7 [IQR, 1.3‐2.5] 5 . Although INR (or prothrombin time) may provide some qualitative measure of rivaroxaban treatment, low sensitivity and significant variation make INR unreliable for the evaluation of rivaroxaban activity 1 .…”

Section: Discussionmentioning

confidence: 99%

Supratheraputic rivaroxaban levels: A persistent drug‐drug interaction after discontinuation of amiodarone

Skov

Falskov

Jensen

et al. 2020

Basic Clin Pharma Tox

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We report the case of an 88‐year old woman referred for evaluation of increased INR. Surprisingly supratherapeutic levels of rivaroxaban was detected. Upon scrutiny of the patient's medical history, a drug‐drug interaction between amiodarone and rivaroxaban persisting 3 weeks after cessation of amiodaron remains the prime suspect causing the clinical picture. Both INR and rivaroxaban levels returned to normal within 3 days of cessation of rivaroxaban. The case highlights that rivaroxaban, although highly variably, does affect INR. Furthermore, it highlights that the potential for DDIs involving amiodarone may persists for weeks or months after discontinuation. Amiodarone is predicted to increase rivaroxaban exposure, through inhibition of rivaroxaban elimination via CYP3A4 and P‐gp. Elderly patients and patients with declining renal function are especially at risk of increased rivaroxaban exposure when a DDI with amiodarone occurs.

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“…Thus, monitoring coagulation routinely is not usually required to guide dosing. However, the use of a reliable assay to assess anti-FXa activity may be needed in several clinical conditions such as major bleeding or thrombotic events, need for an urgent procedure, AF patients presenting with acute ischemic stroke prior to administration of thrombolytic therapy, potential drug–drug interactions, impaired renal or hepatic function, and suspected overdosing or incompliance (Ofek et al, 2017). Assessment of the anticoagulation activity in special populations to avoid intracranial hemorrhage or major bleeding due to overdose may also be desirable.…”

Section: Introductionmentioning

confidence: 99%

International Normalized Ratio as a Screening Test for Assessment of Anticoagulant Activity for Patients Treated With Rivaroxaban or Apixaban: A Pilot Study

et al. 2019

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Introduction: In patients treated with direct oral anti activated factor X (anti-FXa) anticoagulants such as apixaban and rivaroxaban, there are several emergency and non-emergency conditions in which anticoagulation activity should be measured. The validity of the common global clotting tests, prothrombin time and international normalized ratio (PT/INR) for determination of blood levels of these drugs, has been widely investigated. As the anticoagulation activity evaluation “calibrated anti-FXa” of these drugs is relatively more expensive and less available, we aimed to build a prediction model for anticoagulation activity assessment based on INR values. Methods and Findings: One hundred sixty samples from 80 hospitalized patients treated with apixaban or rivaroxaban were tested using PT/INR and Anti-FXa chromogenic assay. Two blood samples, trough and peak, were collected from each subject. Participants were randomly divided into two equal groups. One group (n = 40) was used to build the model, which was validated by the second group (n = 40). There was a strong correlation between anti-FXa concentrations and INR in rivaroxaban treated patients (r = 0.899, p < 0.001). Therefore, we were able to build a formula for rivaroxaban patient group which reliably represent the relationship between these two parameters. The correlation in apixaban treated patients was less predictive (r = 0.798, p < 0.001) and the formula suggested could not be validated. Conclusions: In our study, we developed a formula that estimates the anticoagulant activity of rivaroxaban by obtaining INR values. Where anti-FXa assay is unavailable, our proposed formula may be considered as a screening test for rivaroxaban.

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International Normalized Ratio Is Significantly Elevated With Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study

Cited by 28 publications

References 18 publications

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways

Supratheraputic rivaroxaban levels: A persistent drug‐drug interaction after discontinuation of amiodarone

International Normalized Ratio as a Screening Test for Assessment of Anticoagulant Activity for Patients Treated With Rivaroxaban or Apixaban: A Pilot Study

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