Use of direct oral anticoagulants: The concerns and interventions

The use of vitamin K antag­onists (VKAs), e.g., Warfarin for anticoagulation therapy is challenged by numerous drug and dietary interac­tions, narrow therapeutic ranges, and routine laboratory monitoring with frequent dose adjustments based on the international normalised ratio (INR). I will be using materials from a paper by Qiao et al. Challenges to Laboratory Monitoring of Direct Oral Anticoagulants. Clinical and Applied Thrombosis/Hemostasis Volume 30: 1-14 (2024).

Direct oral anticoagulants (DOACs) have been gradually introduced in clinical practice worldwide for more than a decade, with comparable or better efficacy and safety profiles than vitamin K antagonist (VKA). DOACs are prescribed for the prevention of stroke and systemic thromboembolic events in non-valvular atrial fibrillation (NVAF), for the treatment and secondary prevention of venous thromboembolic events (VTE) and at lower doses for the pri­mary VTE prevention following orthopedic surgeries or in patients with symptomatic peripheral artery disease following recent lower-extremity revascularisation.

DOACs inhibit directly, specifically, and reversibly activated factor X (FXa, rivarox­aban, apixaban and edoxaban) or thrombin (dabigatran). Direct Factor Xa Inhibitors (DXaI) include rivaroxaban, apixaban, and edoxaban, while dabigatran is the oral direct thrombin inhibitor (DTI). Primary advantages of DOACs, compared to VKAs, include fixed dosing, rapid onsets of action, and fewer reported drug interactions when they entered routine clinical practice. In contrast to VKA, DOACs have predictable pharmacokinetic and pharmacodynamic profiles, wide therapeutic index and limited drug-drug and food-drug interactions: labo­ratory monitoring is thus not needed.

Although DOACs are thought to provide at least similar efficacy and safety profiles to VKAs, there remain unaddressed concerns pertaining to pharmacokinetics and patient risk factors that lead to unprecedented or unexplained bleeding and thrombotic events.

Limitations of traditional coagulation assays

Routine screening coagulation tests such as the prothrombin time (PT), Activated Partial Thromboplastin Clotting Time (aPTT), and thrombin time (TT) are neither sensitive nor specific to the presence of DOACs, and do not reflect a linear, dose-de­pendent response relationships to allow for drug quantification. The PT is affected less by apixaban, when compared to rivarox­aban. Edoxaban shows a concentration dependent prolongation of the PT more so than the aPTT. A normal aPTT excludes therapeutic and supratherapeutic levels but does not exclude drug levels at low-range therapeutic or subtherapeutic levels of dab­igatran. While apixaban shows a dose-de­pendent prolongation of the aPTT at lower drug levels, this only occurs at plasma levels above 200 ng/mL. While rivaroxaban shows better sensitivity to the aPTT when com­pared to apixaban, the aPTT fails to detect rivaroxaban effect at levels less than 50 ng/mL. Edoxaban demonstrates a mod­est increase in aPTT even after treatment with one dose. While a normal screening TT excludes presence of dabigatran, an increased TT cannot differentiate between low or high levels of drug, nor differentiate heparin effect. Finally, PT, aPTT, and TT prolongations may also be attributed to factor deficiencies, inhibitors, and/or global defects of haemostasis.

Limitations of viscoelastic methods

While viscoelastic testing (thromboelas­tography, rotation thromboelastometry, and sonorrheometry) provides comprehensive whole blot clotting ability beyond what the PT and aPTT may offer, test reagents and results lacks specificity especially in the absence of clinical context. This may be problematic in emergency settings where DOAC ingestion history is not readily avail­able. In addition, normal clotting times (CT or R-times) do not exclude all DOACs.

Plasma DOAC levels: “Gold standard”?

Liquid chromatography-mass spectrom­etry (LC-MS) remains the gold standard to determine and quantify plasma drug concentrations, using liquid chromatography as a separation technique coupled to a mass spectrometer, which ionizes molecules and then sorts and identifies the ions accord­ing to their mass-to-charge (m/z) ratios. Recent advancements with instrument automation, increased understanding of clinical relevance, and the increasing number of available instrument platforms have increased the application of LC-MS in a variety of clinical settings, including the use to quantify DOAC plasma concentrations. The major limitation of LC-MS remains the labour intensiveness of the assay; testing is typically performed in batches at reference laboratories rather than clinical and hospital laboratories.

Chromogenic Anti-Xa activity for monitoring of Apixaban, Rivaroxaban, and Edoxaban

Although not yet universally standardised across laboratories, the use of the chromo­genic Anti-Xa activity to detect FXaI DO­ACs has been increasingly reported in recent literature since the 2018 ICSH consensus on DOAC laboratory testing. While the Anti-Xa activity was originally designed to monitor for low-molecular-weight heparin (LMWH) therapy, its use has expanded to unfractionated heparin, as well as FXaIs. When implemented in a similar fashion as LMWH, these assays have a rapid turn­around time (<30 min) and can achieve lower limits of detection of <20 to <30 ng/mL, sufficient for clinical decision-making to rule out the presence of FXaIs, partic­ularly in the ED setting. Anti-Xa is helpful to guide administration of reversal agents, during emergency situations or therapy-re­lated bleeding at critical anatomical sites.

Direct oral anticoagulant–specific point-of-care methods

Qualitative point-of-care (POC) urine dipstick technology has been studied, where a colour change within 10 min provides information on the presence of absence of DOAC effect. The DOAC urine dipstick test has the advantage of reliably excluding plasma DXaI levels <14 ng/mL and DTI levels <19 ng/mL drug.

Reversal of DOACs and monitoring

While the ISTH guideline suggests preop­erative reversal if >30 ng/mL, the PAUSE study shows that properly timed interrup­tion of DOAC therapy provides effective mitigation of perioperative bleeding risk and that residual levels <50 ng/mL or ≥50 ng/mL alone do not appear to predict surgical bleeding.

Justification for emergent drug level monitoring (DLM) using Anti-Xa or DTT includes the use of a specific reversal agent rather than a “broad supplementation” by prothrombin complex concentrates (PCCs), and to exclude DOAC-related bleeding if below levels of detection.

Idarucizumab is a humanised monoclonal antibody fragment that outcompetes by 350-fold endogenous thrombin for binding of dabigatran and its acyglucuronide me­tabolites, effectively neutralising dabigatran anticoagulant effects. It was approved in 2015 for reversal of anticoagulant effect of dabigatran for patients with life-threatening bleeding, as well as in cases where rapid reversal is needed for urgent and emergent surgical procedures.

Both 4 factor PCCs (4F-PCC) and andexanet alfa have been recently studied and compared for DXaI reversal. While 4F-PCC rapidly supplies vitamin K-depen­dent procoagulant factors II, VII, IX, and X, Andexanet alfa is a modified Factor Xa decoy molecule engineered to outcompete endogenous Factor Xa for FXaI binding. While andexanet alfa offers specific, targeted FXaI reversal compared to 4F-PCCs, a re­cent meta-analysis showed similar outcomes pertaining to anticoagulant reversal, mortal­ity, and thromboembolic rates between the two agents. Anti-Xa activity assays provide clinical decision guidance on whether to administer the specific reversal agent of andexanet alfa, as undetectable Anti-Xa activity excludes presence of FXaIs.

The risk of major bleeding while on DOACs therapy is estimated around two per cent per year. Optimal management of these bleeding events is still poorly defined. Measuring DOAC levels is useful to consid­er reversal and to assess the anticoagulant’s potential role in the severity of bleeding. A threshold of 50 ng/mL has been proposed by the subcommittee on control of antico­agulation of the International Society on Thrombosis and Hemostasis (ISTH) and the French Working group on perioperative hemostasis (GIHP) to warrant specific anti­dote administration in case of uncontrolled severe bleeding in DOAC-treated patients.

Every year, 10 to 15 per cent of patients on anticoagulant require emergency surgery or invasive procedure. Algorithms for the management of DOACs patients were proposed by the GIHP and the European Heart Rhythm Association (EHRA). The GIHP also suggested using specific anti­dotes, or at least procoagulant agents such as prothrombin complex concentrate (PCC) for DOAC reversal in case of unknown DOAC plasma level with a time since the last drug intake of less than 24 h or a creat­inine clearance (CrCl) of <50 mL/min. A safety haemostatic threshold of 30 ng/mL is suggested in case of very high bleeding risk urgent surgery (i.e, neurosurgery). DOAC neutralisation should also be considered in case of per- or postoperative bleeding attributable to DOACs with a plasma level above 50 ng/mL as measured in preoper­ative of urgent high bleeding risk invasive procedure.

DR. EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC