Elsevier

Blood Reviews

Volume 31, Issue 1, January 2017, Pages 77-84
Blood Reviews

REVIEW
Measurement and reversal of the direct oral anticoagulants

https://doi.org/10.1016/j.blre.2016.08.006Get rights and content

Abstract

Direct oral anticoagulants (DOACs) offer noninferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Unlike VKAs, DOACs do not require routine laboratory monitoring of anticoagulant effect and dose adjustment. In certain situations, however, laboratory assessment of anticoagulant effect may be desirable. Here we review the utility of currently available assays for assessment of DOAC effect and recommend an optimal assessment strategy for each drug, including calibrated dilute thrombin time or ecarin-based assays for dabigatran and calibrated anti-Xa activity assays for the factor Xa inhibitors. We also discuss reversal strategies, both specific and nonspecific, for each drug, including the preferential use of idarucizumab for the reversal of dabigatran and two agents, andexanet and ciraparantag, currently under development for the reversal of rivaroxaban, apixaban, and edoxaban.

Introduction

Since 2010, four direct oral anticoagulants (DOACs) have become available in North America, Europe, and elsewhere. Dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, direct factor Xa inhibitors, are approved in various jurisdictions for the treatment and secondary prevention of venous thromboembolism (VTE), the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation (AF), and the prevention of VTE after major orthopedic surgery. DOACs offer noninferior efficacy and a number of advantages over vitamin K antagonists (VKAs), including decreased bleeding [1], lack of requirement for routine laboratory monitoring of anticoagulant effect and dose adjustment based on laboratory measurement, simplified perioperative management, and fewer drug and dietary interactions. On the basis of these advantages, both the American College of Chest Physicians (ACCP) [2] and the Anticoagulation Forum [3] released updated guidelines in 2016 recommending DOACs over VKAs for patients with noncancer associated VTE.

The DOACs are not without limitations, however, including difficulty measuring and interpreting anticoagulant effect and, for the anti-Xa agents, lack of a clear reversal strategy. In this article, we review current data regarding the laboratory measurement of anticoagulant effect and reversal strategies for these agents.

Section snippets

General principles of measurement

Liquid chromatography/tandem mass spectrometry (LC–MS/MS) is the reference standard method for DOAC measurement [4]. LC–MS/MS has been used to define expected steady-state plasma DOAC levels in pharmacokinetic studies (Table 1) [5], [6], [7], [8]. These studies show that DOAC levels vary widely from peak to trough. For twice daily drugs such as dabigatran and apixaban, there is approximately a 2-fold difference between the median peak and trough concentrations. For once daily drugs such as

General principles of reversal

Indications for DOAC reversal include serious bleeding and need for an emergent, unplanned procedure. Appropriate use of any reversal strategy requires careful consideration of risks (including thrombosis) and benefits and should take into consideration the necessity of reversal and time since last dose, as well as drug-specific half-life. For bleeding patients, supportive care measures including local control, hemodynamic support, transfusions and early involvement of interventionalists should

Dabigatran

Dabigatran is a direct thrombin inhibitor. The half-life of dabigatran in individuals with normal renal function is approximately 12–14 h with 80% renal elimination. The standard dose of dabigatran for both AF and VTE in patients with normal renal function is 150 mg BID. In some jurisdictions, a dose reduction to 110 mg BID is recommended in patients judged to be at increased risk for bleeding, including those ≥ 75 years of age. In the US, a dose of 75 mg BID is recommended in AF patients with a

Rivaroxaban

Rivaroxaban is a competitive inhibitor of free and clot-based factor Xa. The half-life is approximately 6–13 h in patients with normal kidney function with 36% renal clearance. On-therapy levels range from 6 to 419 ng/mL in pharmacokinetic studies of patients taking 20 mg daily in steady state (Table 1) [6], [43]. In patients with acute VTE, rivaroxaban is administered at a dose of 15 mg BID for the first 3 weeks of treatment. In patients with AF and in patients with VTE who have completed three or

Summary

DOAC levels vary widely within individual patients from peak to trough and between different patients (Table 1). Although routine laboratory monitoring of anticoagulant activity is not indicated, there are special situations in which laboratory measurement may be desirable. Suggested assays for detection and quantification of DOACs are shown in Table 3. For patients taking dabigatran, a normal TT excludes the presence of clinically relevant levels of drug, although a prolonged TT may occur in

Practice points

  • Calibrated dilute thrombin time and ecarin-based assays are the tests of choice for the measurement of dabigatran.

  • Calibrated anti-Xa activity assays are the tests of choice for the measurement of rivaroxaban, apixaban, and edoxaban.

  • Most DOAC-related bleeding can be managed with supportive care alone.

  • Idarucizumab is the agent of choice if the reversal of dabigatran is required.

  • We suggest PCC 50 IU/kg for the reversal of factor Xa inhibitors, although high-quality evidence is lacking.

  • Specific

Research agenda

  • Develop assays that accurately measure DOACs and can be made widely available.

  • Define the efficacy and safety of specific reversal agents for the DOACs.

Conflict of interest statement

AC has served as a consultant for Amgen and Genzyme and has received research support from Biogen-Idec, Spark Therapeutics, and T2 Biosystems. BTS has no conflicts of interest to disclose.

Acknowledgments

This research was supported in part by the NHLBI under award number T32HL007093 (to BTS). The funding source had no involvement in the collection, analysis, or interpretation of the data or the writing of the manuscript.

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