Guidelines on anticoagulation reversal across different clinical scenarios

A review of guidelines on anticoagulation reversal across different clinical scenarios – Is there a general consensus?

Milling TJ and Pollack CV. American Journal of Emergency Medicine. 2020;38:1890–1903. DOI: 10.1016/j.ajem.2020.05.086. 

This review of guidelines for reversal of oral anticoagulant therapy found they are generally consistent in their recommendations for reversal of both vitamin K antagonists and direct oral anticoagulants, but reversal is recommended only in serious or life-threatening clinical situations.

Anticoagulant therapy is the cornerstone of both preventing and treating thromboembolic events. The two main therapeutic options are vitamin K antagonists (VKAs); primarily warfarin and the newer direct oral anticoagulants (DOACs). The DOACs include dabigatran (a thrombin inhibitor) and rivaroxaban, apixaban, edoxaban and betrixaban (four direct Factor Xa inhibitors). The major risk for both treatment options is serious or life-threatening haemorrhage, although this risk may be lower for DOAC therapy in some patient groups (Milling & Ziebell, 2020).

Severe or life-threatening bleeding events may require prompt reversal of anticoagulation, and/or other management strategies. The decision to institute reversal therapy should weigh the benefit–risk ratio of supporting haemostasis and potentially promoting thrombosis after reversal.

Prothrombin complex concentrates (PCCs), including 3- or 4-factor PCCs (3F-PCC or 4F-PCC), are now used for VKA reversal, rather than administering fresh frozen plasma (Frontera et al., 2016).

Two specific reversal agents are currently available to reverse DOACs: idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban. However, andexanet alfa is not mentioned in some current guidelines because it has been approved only relatively recently.

What was reviewed?

The authors conducted a narrative review of international guidelines on management and reversal of anticoagulation that were published before April 2020. They used PubMed and internet searches of key terms to identify the guidelines. In addition, they identified and included relevant clinical studies, reviews and meta-analyses published after January 2018 to ensure they considered important information reported after the guidelines were published.

The authors identified guidelines from 25 societies or groups. Guidelines were evaluated for the two groups of anticoagulants: Vitamin K antagonists and direct-acting oral anticoagulants. The authors note that most guideline developers acknowledged their recommendations were not fully supported by solid evidence – the guidelines were often developed either before or recently after specific reversal agents were available.

Are the guidelines consistent?

The guidelines generally recommend anticoagulation reversal only in the clinical scenarios of intracranial haemorrhage, other life-threatening bleeding, and before emergency or urgent surgery.

Reversal of Vitamin K antagonists (VKAs)

Generally, guidelines are consistent in their recommendations for VKA reversal:

• all guidelines recommend or suggest administering PCCs for VKA reversal, but only in serious clinical situations (intracranial haemorrhage, life-threatening bleeding, emergency surgery)
• PCCs (mostly 4-F PCCs) in combination with vitamin K (10 mg IV) recommended
• PCC dose is weight-based but varies according to PCC type and admission INR
• use fresh frozen plasma only if PCCs are unavailable or contraindicated
• recombinant Factor VIIa (rFVIIa) and activated PCC (aPCC) use not recommended

Reversal of direct oral anticoagulants (DOACs)

Most guidelines support specific reversal agents for DOACs, if they are available, and especially in life-threatening situations. If specific agents are not available, several guidelines recommend PCCs for nonspecific reversal of DOACs. None of the guidelines reviewed recommended fresh frozen plasma for DOAC reversal.

For intracranial haemorrhage:

• idarucizumab generally recommended for dabigatran reversal
• if idarucizumab not available for dabigatran reversal, consider haemodialysis (Neurocritical Care Society/Society of Critical Care Medicine [NCS/SCCM] guidelines). Note: haemodialysis may be ineffective for rivaroxaban and apixaban
• NCS/SCCM guidelines also recommend aPCC (50 IU/kg) or 4F-PCC (50 IU/kg) for all DOACs
• charcoal may reduce effects of all DOACs for patients presenting within 2 hours of dosing
• NCS/SCCM guidelines do not discuss andexanet alfa (guidelines developed before approval)
• rFVIIa not recommended in NCS/SCCM guidelines

For life-threatening bleeding or before emergency surgery, management is broadly similar to that for intracranial haemorrhage:

• use idarucizumab (5 g IV) for dabigatran reversal
• consider haemodialysis and charcoal as above
• andexanet alfa: less guidance available on use but suggested for rivaroxaban and apixaban reversal by American College of Cardiology and Anticoagulation Forum; dose depends on DOAC dose and time of administration. Note: FDA & Europe labels do not specify andexanet alfa for pre-surgical use
• edoxaban reversal: several guidelines still recommend PCCs, but Anticoagulation Forum recommends off-label treatment with high-dose andexanet alfa/4F-PCC
• no role for vitamin K
• most guidelines suggest/consider aPCC or 3-/4F-PCC (25–50 IU/kg) if specific reversal agents not available (off-label use)
• some guidelines recommend rFVIIa, but only consider if other measures ineffective

Table 1 provides a simplified summary of the overall recommendations of the guidelines; for more information please refer to the relevant guidelines for your discipline in your geographic region.

Table 1. Recommended treatments for reversal of oral anticoagulation therapy

Does recent evidence affect the recommendations?

Recent evidence from various studies on anticoagulant reversal mostly supports the effectiveness of 4F-PCC for both VKA reversal and nonspecific DOAC reversal. In addition, several large and smaller studies support the effectiveness of the specific reversal agents for DOAC reversal. For example, idarucizumab reversed dabigatran in patients with uncontrollable/life-threatening bleeding, and those requiring urgent surgical procedures (Pollack et al., 2017); and andexanet alfa was effective in treating acute major bleeding associated with rivaroxaban or apixaban administration (Connolly et al., 2019).

The challenge of keeping guidelines up to date with emerging clinical data means that anticoagulation reversal guidelines will continue to evolve as more evidence becomes available. This especially applies to the use of specific agents for DOAC reversal; for example, andexanet alfa was approved after several current guidelines were published.

Summary

The guidelines on reversal of oral anticoagulants are generally consistent. They recommend prothrombin complex concentrates (especially 4F-PCC) for reversal of vitamin k antagonists and nonspecific (off-label) reversal of direct oral anticoagulants (DOACs). Where available, specific reversal agents are recommended for DOACs. Guidelines will likely change as more evidence emerges, especially regarding specific reversal agents such as andexanet alfa, which was either newly or not approved when several guidelines were published.

For more information on the options available for oral anticoagulation, follow this link.

References

Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380:1326–35.

Frontera JA, Lewin Iii JJ, Rabinstein AA, 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.

Milling Jr TJ, Ziebell CM. A review of reversal of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery. Trends Cardiovasc Med. 2020;30:86–90.

Pollack Jr CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377:431–41.