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

Existing Reversal Strategies for Non-vitamin K Antagonist Oral Anticoagulants

As there are no specific antidotes available so far, several therapeutic interventions have been used, including activated charcoal, haemodialysis, activated charcoal haemoperfusion, fresh frozen plasma (FFP), and pro-haemostatic agents.[22–25] This section will focus on the potential of the pro-haemostatic CFCs for reversal of NOAC effects encompassing pro-thrombin complex concentrates (PCCs) and recombinant (r)FVIIa (Novoseven®, NiaStase©). The ESC Guidelines for the management of AF have recommended considering these CFCs in case of very severe bleeding.[26] Pro-thrombin complex concentrates, developed for reversal of VKAs, are lyophilized concentrates of vitamin K-dependent coagulation factors available as: (i) non-activated three-factor PCCs (Profilnine® SD, Bebulin® VH) containing similar amounts of factors II, IX, and X, and low factor VII levels; (ii) non-activated four-factor PCCs (Beriplex® P/N, Kanokad®, Octaplex®, Kaskadil®, Cofact®), containing adequate levels of factors II, VII, IX, and X, with varying amounts of heparin and proteins C and S to reduce thrombogenicity; and (iii) activated four-factor PCC (FEIBA®) containing factors II, IX, X, and protein C, mainly in non-activated forms, and factor VII mainly in the activated form. rFVIIa is a potent general haemostatic agent.[27,28] Fresh frozen plasmas containing normal levels of all coagulation factors have practical constraints for the rapid reversal of OACs. A limitation for the use of PCCs is an absolute increase of thromboembolic events of >1%.[29,30] The increase of thromboembolic events associated with the use of rFVIIa may be even higher.[31,32]

As the effect of pro-haemostatic agents on NOACs has not been tested in clinical trials so far, our evidence is based on surrogate endpoints. In comparison, the effect of PCCs on the reversal of VKA effects has been evaluated in patients with major bleeding or requiring urgent surgery. However, this evidence is likewise based on the effect on coagulation tests in small, mostly uncontrolled, retrospective,[33] and prospective clinical trials.[34–37] In Supplementary material online https://academic.oup.com/eurheartj/article/38/22/1710/3056894/Reversal-strategies-for-nonvitamin-K-antagonist#supplementary-data, surrogate endpoints for measuring the reversal of NOAC effects with CFCs are critically appraised. Supplementary material online, Table S3 https://academic.oup.com/eurheartj/article/38/22/1710/3056894/Reversal-strategies-for-nonvitamin-K-antagonist#supplementary-data gives a detailed description of the available data for reversal of NOAC effects with CFCs based on normalization of coagulation tests, ex vivo thrombus generation (TG) or animal bleeding models. In summary, the evidence supporting the efficacy and safety of CFCs in case of severe or life-threatening bleeding is based on laboratory or animal studies, case reports and a Phase I trial using punch biopsies[38] but not on well-designed clinical trials so far. The results are contradictory with regard to an overall reversal of NOAC effects by CFCs and the preference of one specific CFC. Furthermore, they are confusing due to the lack of correlation between the correction of routine laboratory tests, TG, and bleeding in animal models. In particular, animal data suggest that a high dose of CFCs (e.g. 50 IU/kg of four-factor PCC) is necessary for a sufficient reversal effect. Limited animal data suggest that CFCs may ameliorate the effect of NOACs in case of ICH. An important drawback of the use of PCCs and rFVIIa may be an increased risk of thromboembolic complications.[29–32]

Pending the availability of robust clinical evidence of a beneficial effect, if immediate haemostatic support is required due to a life-threatening situation, the choice of CFCs may be based on its least pro-thrombotic effect, favouring PCCs over rFVIIa. If a four-factor PCC is used, a high dose or repeated dose is recommended. Finally, the choice of a CFC must be individually assessed according to drug availability and experience of the centre, institutional transfusion guidelines and available consensus among cardiologists, haemostasis experts, and emergency physicians. Although pro-haemostatic agents may also limit the extent of bleeding in patients with ICH, their effect on mortality and disability is unknown.[39]

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