Are the DOAC plasma level thresholds appropriate for clinical decision‐making? A reappraisal using thrombin generation testing

Evrard, Jonathan; Hardy, Michaël; Dogné, Jean‐Michel; Lessire, Sarah; Maloteau, Vincent; Mullier, François; Douxfils, Jonathan

doi:10.1111/ijlh.13356

Cited by 13 publications

(20 citation statements)

References 11 publications

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“…Global tests such as the TGA have been described as promising to assess the pharmacodynamic profile of anticoagulants. 65,66 Given the known DOAC thrombin generation profiles, the concentration thresholds proposed in the literature may provide highly different anticoagulant activities in a particular patient and TGA may be seen as another way of expressing and assessing the degree of anticoagulation in DOAC-treated patients (►Fig. 2).…”

Section: Doac and Thrombin Generation Assaysmentioning

confidence: 99%

“…2). 24,[66][67][68][69][70][71] The ST Genesia (Diagnostica Stago, Asnières sur Seine Cedex, France), an automated analyzer for thrombin generation testing has the potential for a wide implementation in routine laboratories. Preliminary observations showed that thrombin generation testing is affected by all anticoagulant drugs, suggesting that this assay could be useful in assessing DOAC activity, but this deserves further confirmation in larger cohorts to validate this approach since to date, the role of TGA for clinical decision-making in DOAC-treated patients is not clear.…”

Section: Doac and Thrombin Generation Assaysmentioning

confidence: 99%

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2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Adcock²,

et al. 2021

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In 2018, the International Council for Standardization in Hematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alpha. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author’s personal experience/expert opinion and (3) good laboratory practice.

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Section: Doac and Thrombin Generation Assaysmentioning

confidence: 99%

Section: Doac and Thrombin Generation Assaysmentioning

confidence: 99%

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Adcock²,

et al. 2021

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“…DOAC plasma level measurements can assess the pharmacokinetic response (eg, absorption, distribution, metabolism, and excretion ‐ ADME), while the pharmacodynamic aspect on the coagulation system cannot be described by the plasma level or surrogates such as anti‐Xa‐/IIa levels alone. Finally, the plasma levels of different DOAC cannot be compared in terms of the antithrombotic effect 3 …”

Section: Introductionmentioning

confidence: 99%

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

Metze

Klöter

Stöbe

et al. 2021

Int J Lab Hematology

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Background The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. Objective This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Methods Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC—apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG. Results The baseline TG before DOAC intake showed inter‐individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti‐Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti‐Xa inhibitors. All DOACs showed a nonlinear dose‐response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. Conclusion The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient‐specific baseline TG level and the drug‐specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

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“…The highest dose relationship was seen for both substances for peak thrombin but the effect on the lag time and time to peak was much more pronounced with rivaroxaban than with apixaban. The steep decrease in TG parameters at plasma levels < 100 ng/mL has been recently described by Evrard and colleagues with the CAT system 11 . In that analysis, the inhibition of peak thrombin at 100 ng/mL was comparable between apixaban and rivaroxaban but apixaban had a much lower effect on the time to peak as we have shown for the ceveron TGA in our cohort.…”

Section: Comparison Of the Effect Of Apixaban And Rivaroxaban On Thrombin Generationmentioning

confidence: 60%

“…There are limited data in the literature on thrombin generation measured with the Ceveron TGA in patients on DOACs. Published data about the effect of DOACs on TG were mainly carried out on the semi-automated calibrated thrombin generation assay (CAT) [10][11][12][13] and the ST Genesia system [14][15][16][17] . In a recent survey among laboratories working with TG assays, CAT was used by 56%, while Ceveron Alpha only by 4% 18 .…”

Section: Introductionmentioning

confidence: 99%

The influence of direct oral anticoagulants on thrombin generation on Ceveron TGA

Pfrepper

Behrendt

Bönigk³

et al. 2021

Preprint

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Introduction: Monitoring of direct oral anticoagulants (DOACs) with calibrated anti-Xa assay is limited by the high intra- and interindividual variation of the test results. Thrombin generation (TG) is a global hemostatic assay that reflects the patient´s individual coagulation status. The aim of this study was to investigate the influence of DOACs on TG measured with a fully automated assay system. Methods: All consecutive patients under apixaban and rivaroxaban coming to the outpatient coagulation center MVZ Limbach, Magdeburg, Germany between October 2017 and April 2020 were included. DOAC plasma levels were correlated with TG assessed using the fully automated Ceveron TG analyser. Results: A total of 703 rivaroxaban and 252 apixaban containing plasma samples were included. There was a significant correlation between DOAC plasma levels and all TG parameters except for lag time regarding apixaban. Time to peak and peak thrombin followed an exponential regression curve, while this was linear for the endogenous thrombin potential (ETP). Apixaban showed a lower correlation coefficient for all TG parameters compared to rivaroxaban and thrombin generation was less influenced by apixaban than rivaroxaban at plasma levels > 100 ng/mL. The sensitivity and negative predictive value of normal TG parameters for the prediction of DOAC plasma levels < 30 ng/mL was > 85%. Conclusion: The present data show a moderate predominantly non-linear correlation between TG parameters and plasma levels of apixaban and rivaroxaban. Rivaroxaban has a stronger effect on TG than apixaban.

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Are the DOAC plasma level thresholds appropriate for clinical decision‐making? A reappraisal using thrombin generation testing

Cited by 13 publications

References 11 publications

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

The influence of direct oral anticoagulants on thrombin generation on Ceveron TGA

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