Anticoagulation reversal for intracranial haemorrhage in the era of the DOACs

Anticoagulation reversal for intracranial haemorrhage in the era of the direct oral anticoagulants

Strein M, May S, Brophy GM. Current Opinion in Critical Care. 2020;26(2):122–128. doi: 10.1097/MCC.0000000000000706

• Direct oral anticoagulant (DOAC) prescribing continues to increase and is now recommended over warfarin for some patients.
• Options for reversal of DOAC-associated intracranial haemorrhage (ICH) are currently available.
• Research is needed to determine whether DOAC-specific reversal agents should be routinely preferred over non-specific reversal agents.

Direct oral anticoagulants (DOACs) have been available for the last 10 years and provide comparable clinical efficacy to warfarin while eliminating the need for frequent laboratory monitoring.

Unlike warfarin, DOACs have more specific targets within the coagulation cascade, and initial approval trials focused on use in venous thromboembolism (VTE) treatment and prevention of stroke or systemic embolism. Since 2010, use of DOACs has expanded significantly, and they are now generally recommended over warfarin.

Although the annual risk of intracranial haemorrhage (ICH) associated with DOAC use is low (approximately 0.5%), outcomes can be devastating with both mortality and functional outcomes worse than for patients not receiving anticoagulation therapy. Increased morbidity and mortality are likely due to larger haemorrhage volumes, increased risk of haematoma expansion, and increased number of comorbidities among anticoagulated patients (Frontera et al., 2016).

How best to reverse the anticoagulant effects of DOACs in patients experiencing ICH is still being determined. Recent clinical trials have demonstrated DOAC-specific reversal agents are effective in this setting. However, a lack of direct comparisons with non-specific reversal agents has hindered determination of clinical superiority.

Table 1. Select pharmacokinetic properties of DOACs

The review by Strein et al. discusses availability of DOAC reversal following ICH, with a focus on DOAC-specific agents.

Non-specific reversal agents

Non-specific reversal agents are used to help restore normal haemostatic activity by acting on various parts of the coagulation cascade, but do not specifically target a drug moiety. Examples of non-specific reversal agents include fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), and 3- and 4-factor prothrombin complex concentrates (PCC).

FFP contains physiological concentrations of inactive coagulation factors but requires thawing before patient administration, and has limited use for DOAC reversal (Christos et al., 2016). The joint guideline from the Neurocritical Care Society and Society of Critical Care Medicine have recommended against the use of FFP in the management of DOAC-associated ICH (Frontera et al., 2016).

rFVIIa enhances thrombin generation via platelet activation. At therapeutic doses, rFVIIa also stimulates Factor X on the platelet surface, producing a thrombin burst and haemostatic plug formation (Monroe et al., 1997). With an inherent risk for thromboembolic complications, current guidelines recommend the use of 4-factor PCC over rFVIIa (Frontera et al., 2016).

Before the development of specific DOAC reversal agents, guidelines recommended off-label use of PCC to manage DOAC-associated ICH (Frontera et al., 2016). PCCs can be administered more rapidly than FFP, as smaller volumes are used and no thawing is required (Levy et al., 2008).

DOAC-specific reversal agents

Three DOAC-specific reversal agents are covered in the review by Strein et al. None has direct effects on the coagulation cascade, and all target the direct anticoagulant mechanism of its associated DOAC.

Idarucizumab

Idarucizumab is a humanized monoclonal antibody fragment, which binds dabigatran with a 350-fold greater affinity than thrombin, providing a rapid, complete, and sustained reversal of anticoagulant activity (Schiele et al., 2013; EMA, 2021a).

The mechanism of action is specific to dabigatran only and the extent of benefit depends on the patient’s overall health and the severity and location of bleeding (EMA, 2021a). Idarucizumab will not reverse the anticoagulant effects of other DOACs.

Andexanet alfa

Andexanet alfa was approved in the US for the reversal of the effects of rivaroxaban and apixaban, and received ‘conditional authorisation’ in the EU for reducing antifactor Xa activity in patients taking FXa DOACs (except for edoxaban) (EMA, 2021b).

Andexanet acts as a molecular decoy by binding to the Factor Xa (FXa) inhibitor, which frees endogenous FXa to participate in the clotting cascade and remain unbound and active - restoring normal FXa activity and anticoagulation (Connolly et al., 2016).

The recommended dosing of andexanet is based on the specific DOAC and duration since the patient’s last dose. However, due to the limited clinical data available and significant treatment costs, widespread use in the treatment of DOAC-associated ICH may be limited.

Ciraparantag

Ciraparantag is a synthetic molecular entity that binds to heparins and all DOACs (Ansell et al., 2017).

Phase I safety and pharmacokinetics trials have demonstrated significant activity for reversal of enoxaparin and edoxaban (Ansell et al., 2016; Ansell et al., 2017), while phase II trials are currently ongoing to assess use in patients receiving apixaban or rivaroxaban.

Although not yet approved for use, ciraparantag has been granted a ‘fast track’ review designation in the US. Ciraparantag may eventually offer anticoagulant reversal across multiple different DOAC classes in a rapid, ready-to-use solution.

Additional treatment considerations
Several clinical factors should be considered before administering DOAC-specific reversal, regardless of the agent used.

- Minimise potential drug interactions – determine which DOAC was taken, what dose, and when

- Medical history – patient comorbidities (for example, renal or hepatic disease) may alter the metabolism of certain DOACs and prolong anticoagulant efficacy

- It is unknown if DOAC-specific reversal agents result in better outcomes compared with non-specific reversal agents

References

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Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res. 2016;146:113–118.

Christos S, Naples R. Anticoagulation reversal and treatment strategies in major bleeding: update. West J Emerg Med. 2016;17:264–270.

Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375:1131–1141.

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Frontera JA, Lewin JJ III, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24:6–46.

Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiol J Am Soc Anesthesiol. 2008;109:918–926.

Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol. 1997;99:542–547.

Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–3562.