Updates in Anticoagulation Therapy Monitoring

Updates in Anticoagulation Therapy Monitoring

McRae H, Militello L, Refaai M. Biomedicines. 2021;9(3):262.

• Recommendations for monitoring and reversal of newer anticoagulants such as low molecular weight heparins, factor Xa inhibitors, and direct thrombin inhibitors have evolved in recent years
• The need for specific monitoring and reversal agents for these newer anticoagulants have created a knowledge and resource gap
• Based on the publication by McRae et al. (2021), an overview of the currently available anticoagulants is provided, with a focus on the guidelines and available tests for monitoring and reversal

Anticoagulants are categorised according to their mechanism of action and include heparins, vitamin K antagonists, factor Xa inhibitors and direct thrombin inhibitors, as summarised in Table 1¹.

Clinical indications and monitoring guidelines for each anticoagulant vary due to differences in mechanism of action, clearance and reversal, drug half-life, therapeutic index and risk of adverse events¹

Table 1. Anticoagulants categorised by mechanism of action (Adapted¹). Creative Commons Attribution 4.0 International License.

Vitamin K antagonists

Vitamin K antagonists (VKAs) include warfarin, acenocoumarol and phenprocoumon and are the most commonly prescribed anticoagulants worldwide². VKAs are orally administered, with dose and monitoring frequency being individually adjusted for each patient³.

VKA therapy is affordable, accessible, and easily reversed when compared to other anticoagulants^4,5. However, with delayed onset of action (typically requiring 5–7 days to reach peak therapeutic effect) and variable half-life (40 hours on average, ranging from 20–60 hours), this class of drug can be unpredictable and requires close monitoring^5,6.

A liver function test is recommended to identify potential issues with metabolism of VKA or baseline haemostatic issues before commencing VKA treatment⁷. Monitoring of VKA is done through measuring prothrombin time (PT) and international normalised ratio (INR).

To assess INR after VKA therapy has commenced, the baseline PT, activated partial thromboplastin times (aPTT), and INR values should be obtained to ensure proper calculation of the therapeutic target⁷. The therapeutic index of VKA is narrow, typically within an INR range of 2.0–3.0, though this may be higher with artificial heart valves or conditions such as antiphospholipid syndrome³.

INR measurements should be taken daily in hospitalised patients and 1–3 times a week for outpatients until the therapeutic dose has been attained and stabilised. Once INR has stabilised for at least 1 week, monitoring is required once every 2–4 weeks⁷.

Reversal of VKA is achieved through VKA discontinuation (or abruption), administration of vitamin K, fresh frozen plasma transfusion or infusion of prothrombin complex concentrates^7,8.

Unfractionated heparin

Therapeutic dosing of unfractionated heparin (UFH) is achieved through intravenous (IV) administration of an initial bolus dose, followed by a weight-based or calculated, fixed-dose via continuous IV infusion, modified according to the bleeding risk of the patient^7,9.

The historical gold standard for UFH monitoring is through serial aPTT measurements, taken within 2 hours of initiation and every 6 hours thereafter. The therapeutic range is 1.5–2.5 times the patient’s baseline aPTT score^10–12.

UFH may also be monitored via anti-factor Xa (anti-Xa) activity, with this method demonstrating greater efficiency in achieving the target therapeutic dose. However, there is no evidence to suggest that this is associated with improved clinical outcomes, and aPTT measurements are still considered gold-standard¹³. Monitoring via anti-Xa is not feasible in patients with recent oral factor Xa inhibitor use, as these patients may have residual anti-Xa activity which can result in an incorrect reading⁷.

When administered through continuous IV infusion, the half-life of UFH is 30 minutes, compared to 90 minutes when injected subcutaneously. Reversal is achieved through administration of protamine sulphate, or discontinuation of UFH treatment due to its short half-life¹¹.

Low molecular weight heparin

Multiple preparations of low molecular weight heparin (LMWH) are available worldwide, including enoxaparin, dalteparin, tinzaparin, and nadroparin. Each LMWH preparation is pharmacologically distinct, resulting in different efficacy and safety profiles⁷. LMWH is administered through parenteral subcutaneous injection, once or twice daily^7,11.

When therapeutic monitoring is required for LMWH therapy, anti-Xa is the gold standard because aPTT is not significantly affected by LMWH treatment. Anti-Xa levels should be monitored at 4 hours post-administration, when they should be at peak concentration^14,15.

LMWH is often preferred over UFH due to greater bioavailability and longer half-life (4 hours), resulting in a stronger anticoagulant response and less need for frequent monitoring^7,11. These factors do make urgent reversal more difficult to achieve, and in this instance, protamine sulphate can be administered¹⁶.

Fondaparinux

Fondaparinux is administered through subcutaneous parenteral injection once daily, with dose calculated according to body weight and indication for use. This potent anticoagulant maintains 100% bioavailability after administration, and reaches peak concentration at 1.5–2 hours post-administration^17,18 Therapeutic activity remains for 2–5 days in patients with normal renal function. Therapeutic monitoring is generally not required for this drug, however if levels must be acutely determined, anti-Xa measurements can be used¹⁹.

No reversal agents have been approved for fondaparinux, with protamine sulphate being ineffective for this purpose. In the instance of fondaparinux-induced haemorrhage, administration of recombinant activated factor VII has been shown to stop bleeding¹⁸.

Parenteral direct thrombin inhibitors

Direct thrombin inhibitors (DTIs) include bivalirudin and argatroban. Bivalriudin is frequently used in critically ill patients as an alternative to UFH treatment. DTIs have a half-life of 25–120 minutes depending on the route of administration²⁰.

The most commonly used measurements to monitor DTI concentration are aPTT and activated clotting time (ACT). Alternative measures include thrombin time (TT), dilute thrombin time (dTT), chromogenic anti-IIa, and ecarin clotting time (ECT)²¹.

For aPTT monitoring in patients with heparin-induced thrombocytopenia, the target aPTT ranges for bivalirudin and argatroban are 1.5–3.0 and 1.5–2.5 times the baseline aPTT, respectively²¹.

No reversal agents are available for IV DTIs, although emerging evidence has shown administration of recombinant activated factor VII (FVIIa) to be beneficial for treatment of severe bleeding²².

Direct oral anticoagulants

The four direct oral anticoagulants (DOACs) approved for use in the USA and Europe include rivaroxaban, apixaban, edoxaban (all factor Xa inhibitors) and dabigatran (a DTI)²³. Betrixaban is an additional factor Xa inhibitor which has only been approved in the USA^24,25. DOACs are short-acting, orally administered, and some require twice-daily dosing²⁶.

DOAC therapy usually does not require routine therapeutic monitoring or dose adjustment²⁷. In instances where therapeutic monitoring is necessary, the gold standard for measurement is mass spectrometry calibrated for each individual drug. More rapid, less accurate measures that can be used include PT, aPTT, dTT, ecarin, and anti-Xa assays; however, these must also be calibrated to the individual DOAC being measured²⁸.

Reversal of dabigatran can be achieved through administration of idarucizumab, and reversal of apixaban and rivaroxaban through andexanet alfa²⁶.

-Due to differences in half-life, drug clearance and mechanism of action between anticoagulants, familiarity with the updated guidelines and gold standards of therapeutic monitoring and measurements are necessary.

-The most common tests for anticoagulant therapeutic monitoring include PT, aPTT and anti-Xa. Requirements for therapeutic monitoring vary according to the type of anticoagulant, due to individual drug characteristics such as half-life.

-Reversal is generally more straightforward for anticoagulants with short-half lives when compared to those with long-half lives; and reversal agents include protamine sulphate, prothrombin complex and recombinant activated factor VII.

References

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