Laboratory Assessment of Direct Oral Anticoagulants

Douxfils, Jonathan; Gosselin, Robert

doi:10.1055/s-0036-1597296

Cited by 75 publications

(24 citation statements)

References 64 publications

(111 reference statements)

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“…A nationwide Belgian survey has previously highlighted a wide variation in response to rivaroxaban according to the reagent used [ 40 ]. Commercial specific assays are currently available for all DOACs [ 41 ]. They are more accurate but require calibrators and controls.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…INR is the established gold standard to rapidly measure the effect of VKA; whereas laboratory diagnosis is more complex for patients on DOACs. Standard coagulation tests are not sensitive enough for assessment their inhibition on the coagulation process [ 34 ]. Specific tests, which allow quantification of the concentration of Xa inhibitors or dabigatran, are not universally available in all hospitals.…”

Section: Discussionmentioning

confidence: 99%

The impact of direct oral anticoagulants in traumatic brain injury patients greater than 60-years-old

Prexl

Bruckbauer

Voelckel

et al. 2018

Scand J Trauma Resusc Emerg Med

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BackgroundTraumatic brain injury (TBI) is the leading cause of death among trauma patients. Patients under antithrombotic therapy (ATT) carry an increased risk for intracranial haematoma (ICH) formation. There is a paucity of data about the role of direct oral anticoagulants (DOACs) among TBI patients.MethodsIn this retrospective study, we investigated all TBI patients ≥60-years-old who were admitted to the intensive care unit (ICU) from January 2014 until May 2017. Patients were grouped into those receiving vitamin K antagonists (VKA), platelet inhibitors (PI), DOACs and no antithrombotic therapy (no-ATT).ResultsOne-hundred-eighty-six, predominantly male (52.7%) TBI patients with a median age of 79 years (range: 70–85 years) were enrolled in the study. Glasgow Coma Scale and S-100β were not different among the groups. Patients on VKA and DOACs had a higher Charlson Comorbidity Index compared to the PI group and no-ATT group (p = 0.0021). The VKA group received reversal agents significantly more often than the other groups (p < 0.0001). Haematoma progression in the follow-up cranial computed tomography (CCT) was lowest in the DOAC group. The number of CCT and surgical interventions were low with no differences between the groups. No relevant differences in ICU and hospital length of stay were observed. Mortality in the VKA group was significantly higher compared to DOAC, PI and no-ATT group (p = 0.047).DiscussionData from huge registry studies displayed higher efficacy and lower fatal bleeding rates for DOACs compared to VKAs. The current study revealed comparable results. Despite the fact that TBI patients on VKAs received reversal agents more often than patients on DOACs (84.4% vs. 24.2%, p < 0.001), mortality rate was significantly higher in the VKA group (p = 0.047).ConclusionIn patients ≥60 years suffering from TBI, anticoagulation with DOACs appears to be safer than with VKA. Anti-thrombotic therapy with VKA resulted in a worse outcome compared to DOACs and PI. Further studies are warranted to confirm this finding.

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“…Compared to VKA these DOACs share similar pharmacokinetic properties such that elimination half-life is short ranging from 6 to 17 h across agents in patients with normal renal function [32]. Therefore, effective OAC may theoretically not be present on admission, but importantly cannot be timely and validly excluded by routine diagnostics [33, 34]. Using conventional coagulation testing does not provide sufficient sensitivity or specificity, and currently, no data is available suggesting a definite threshold for all DOACs below which one can exclude DOAC effect [33].…”

Section: Direct Oral Anticoagulantsmentioning

confidence: 99%

“…Therefore, effective OAC may theoretically not be present on admission, but importantly cannot be timely and validly excluded by routine diagnostics [33, 34]. Using conventional coagulation testing does not provide sufficient sensitivity or specificity, and currently, no data is available suggesting a definite threshold for all DOACs below which one can exclude DOAC effect [33]. For a rough qualitative estimate of altered hemostasis in DOAC-treated patients in general, thrombin time (TT), prothrombin time (PT), and/or activated partial thromboplastin time may be used.…”

Section: Direct Oral Anticoagulantsmentioning

confidence: 99%

Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage

2019

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In light of an aging population with increased cardiovascular comorbidity, the use of oral anticoagulation (OAC) is steadily expanding. A variety of pharmacological alternatives to vitamin K antagonists (VKA) have emerged over recent years (direct oral anticoagulants, DOAC, i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) which show a reduced risk for the occurrence of intracerebral hemorrhage (ICH). Yet, in the event of ICH under OAC (OAC-ICH), hematoma characteristics are similarly severe and clinical outcomes likewise substantially limited in both patients with VKA-and DOAC-ICH, which is why optimal acute hemostatic treatment in all OAC-ICH needs to be guaranteed. Currently, International Guidelines for the hemostatic management of patients with OAC-ICH are updated as several relevant large-sized observational studies and recent trials have established treatment approaches for both VKA-and DOAC-ICH. While the management of VKA-ICH is mainly based on the immediate reversal of elevated levels of international normalized ratio using prothrombin complex concentrates, hemostatic management of DOAC-associated ICH is challenging requiring specific antidotes, notably idarucizumab and andexanet alfa. This review will provide an overview of the latest studies and trials on hemostatic reversal agents and timing and summarizes the effects on hemorrhage progression and clinical outcomes in patients with OAC-ICH.

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Laboratory Assessment of Direct Oral Anticoagulants

Cited by 75 publications

References 64 publications

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

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

The impact of direct oral anticoagulants in traumatic brain injury patients greater than 60-years-old

Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage

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