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Revised guidelines that address management of acute bleeding in patients treated with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKA) offer advice on the best assays for qualifying or quantifying these drugs, indicating which tests are in limited supply and offering some alternative testing venues.
The American College of Cardiology (ACC) published its 2020 Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants (ECDP) online. Introduction of new reversal strategies for factor Xa (FXa) inhibitors and new OACs to prevent venous thromboembolism prompted this update to 2017 guidelines, ACC announced in a statement. Guideline authors advise on managing bleeding episodes, therapy interruptions, decision support on treating patients with a reversal agent, and indications and timing for reinstituting treatment.
Measuring anticoagulant activity in patients who require an unplanned procedure or who present with clinically relevant bleeding is a critical step in evaluation, stressed the authors. All patients should receive a prothrombin time (PT) and/or an activated partial thromboplastin time (aPTT) test. “Interpretation of the PT and aPTT as well as the potential need to request specialized coagulation tests will depend on the clinical situation, the anticoagulant, and test availability,” the panelists suggested.
The PT/international normalized ratio is useful for evaluating patients taking VKA to guide perioperative or bleeding management—unless a clinician suspects a concomitant defect in coagulation. Evaluating anticoagulant activity of DOACs is more difficult, however, as it’s unknown what minimum levels lead to bleeding or surgical bleeding risk.
The International Society on Thrombosis and Haemostasis recommends that clinicians consider anticoagulant reversal in patients with serious bleeding and a DOAC level >50 ng/mL, and in those who require an invasive procedure with high bleeding risk and a DOAC level >30 ng/mL. “Assays suitable for quantitation are specialized and are not widely available. More accessible tests such as the PT and aPTT have important limitations,” cautioned the guideline authors.
The panelists summarized which assays are optimal for measuring DOACs based on availability and explain why they paired certain tests to different drugs.
For dabigatran, the authors recommended four tests: liquid chromatography-tandem mass spectrometry (LC/MS), dilute thrombin time, ecarin clotting time, and ecarin chromogenic assay. Availability of these assays is limited, especially in emergent situations. For apixaban, betrixaban, edoxaban, or rivaroxaban, recommended tests include LC/MS and anti-FXa calibrated with the drug of interest. Clinical labs may need to modify their methods to achieve adequate sensitivity in the anti-FXa test for quantitating betrixaban.
When such assays aren’t available, the authors made other suggestions for qualitatively assessing DOACs. For example, a clinical lab could use a thrombin time (TT) or aPTT test to exclude clinically relevant drug levels for dabigatran, or an aPTT test to assess whether on-therapy or above on-therapy levels are present. The authors explained that “TT is exquisitely sensitive to dabigatran, even at very low drug concentrations. Thus, a normal TT excludes clinically relevant dabigatran levels, but a prolonged TT does not discriminate between clinically important and insignificant drug concentrations.”
For apixaban, betrixaban, edoxaban, or rivaroxaban, they recommended anti-FXa calibrated with unfractionated heparin or low-molecular-weight heparin to exclude clinically relevant drug levels, and a PT test to determine the presence of on-therapy or above on-therapy levels. While prolonged PT may indicate on-therapy or above on-therapy levels for these drugs, a normal PT might not exclude on-therapy levels. It all depends on how sensitive the reagent is, the authors indicated.
Gordon F. Tomaselli, MD, FACC, and Kenneth W. Mahaffey, MD, FACC, chair and vice chair of the guidelines’ writing committee, suggested that clinical labs could support cardiologists in managing patients on DOACs in the following areas, depending on local practice patterns and laboratorian responsibilities:
- Educating clinicians about DOAC pharmacokinetic/pharmacodynamic parameters.
- Educating clinicians about laboratory testing as laid out in the guidelines and implications for DOAC management and therapeutic options.
- Educating patients about DOACs.
- Integrating with clinical care teams on rounds or in clinic (face to face or electronically).