Reversal Strategies for Non-vitamin K Antagonist Oral Anticoagulants: A Critical Appraisal of Available Evidence and Recommendations for Clinical Management

A Joint Position Paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Working Group on Thrombosis

Alexander Niessner; Juan Tamargo; João Morais; Lorenz Koller; Sven Wassmann; Steen Elkjær Husted; Christian Torp-Pedersen; Keld Kjeldsen; Basil S. Lewis; Heinz Drexel; Juan Carlos Kaski; Dan Atar; Robert F. Storey; Gregory Y. H. Lip; Freek W. A. Verheugt; Stefan Agewall

Disclosures

Eur Heart J. 2017;38(22):1710-1716. 

In This Article

Conclusions

While available clinical data for specific antidotes of NOACs are limited, it is very likely that these agents will successfully reverse the effect of NOACs as measured by specific coagulation tests. Another perceived advantage is the lack of a pro-thrombotic effect of the agent itself. However, uncontrolled studies will not give a definite answer to the question whether the clinical outcome will be improved. In the absence of specific antidotes, CFCs and/or haemodialysis for dabigatran may be a valuable alternative and may be used in addition to specific reversal agents in case of liver or renal failure. Before considering the use of a reversal agent for NOACs, a comprehensive pharmacological and clinical assessment of the usually complex situation of a critically ill patient is essential (Table 3). Furthermore, a set of general measures should precede the use of a reversal agent, as depicted in Figure 1. While the availability of specific reversal agents will increase the confidence in the benefit of NOACs in clinical practice, an overuse of specific reversal agents (beyond the tested indications) is of unclear advantage for patients. Prevention of bleeding in patients with NOACs by managing the bleeding risk of the patient and by respecting dose-reduction criteria[61] and contraindications remains essential. Even in patients who have survived life-threatening bleeding, restarting anticoagulation therapy is associated with reduced risks of thromboembolic events and mortality without increasing the risk of bleeding.[62] Thus, a timely restart of anticoagulant therapy (or alternative therapeutic strategies such as left atrial appendage occlusion) should be considered depending on the cause and the reversibility of the index bleeding event.

Consensus Statements

  • Global coagulation tests are not appropriate for measuring successful reversal of NOAC effects (ex vivo studies). Specific coagulation tests for the respective NOAC should be used.

  • CFCs should be used in case of life-threatening bleeding or emergency surgery in NOAC-treated patients when a specific reversal agent is not available or there are signs of systemic coagulopathy. There is no consistent superior effect of a specific CFC (ex vivo studies and animal studies). Pro-thrombin complex concentrates should be preferred over rFVIIa based on the inherent pro-thrombotic risk.

  • Idarucizumab, the first reversal agent tested in critically ill patients, is effective in reversing the effect of dabigatran measured by specific coagulation tests (uncontrolled clinical study) and has been approved by the European Medicines Agency and the U.S. Food and Drug Administration. Andexanet α targets the effect of direct and indirect FXa inhibitors and has been successfully tested in healthy volunteers so far. Ciraparantag (PER977) is designed to antagonize direct and indirect FXa inhibitors as well as dabigatran. In a Phase I study, PER977 was safe and well tolerated. Once approved by regulatory authorities, the use of specific antidotes for NOACs should be restricted to life-threatening bleeding or emergency surgery. Discontinuation of NOACs may be sufficient due to their rather short half-life for other situations requiring improved haemostasis. The effect of reversal agents on the clinical outcome in critically ill patients can only be assessed in controlled trials.

  • While specific antidotes for NOACs may not have an inherent pro-thrombotic effect, the sudden termination of anticoagulation in patients with a significant pro-thrombotic risk may cause thromboembolic events (Phase III study). The time point of restarting anticoagulation may therefore be crucial for the net clinical benefit.

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