Arrhythmia & Electrophysiology Review – A New Era for NOAC Antidotes

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Reviewing recent literature of advances in arrhythmia therapy, I have found most interesting the emergence of antidotes, both general and specific, for the non-vitamin K antagonist oral anticoagulants (NOACs). NOACs offer a relative 50 % reduction in the risk of intracranial haemorrhage and haemorrhagic stroke compared with warfarin that is also maintained in the elderly. There are no clear interactions with food, and no need for frequent laboratory monitoring and dose adjustments.1–3 Their main problems so far have been the lack of antidotes and specific assays to measure anticoagulant effect, and considerably higher cost than warfarin.4 It is, therefore, of major clinical importance to see specific antidotes emerging in phase 1 and 2 trials.

Non-specific procoagulant agents such as 3- or 4-factor prothrombin complex concentrates (PCCs) and activated factor VIIa can be used as antidotes for dabigatran.5–7 Specific antidotes are also under study. Idarucizumab, a fully humanised antibody fragment, or Fab, is investigated as a specific antidote of dabigatran, and also reversed its effects and, unlike PCCs, was not associated with over-correction of thrombin generation.7 Four-factor PCCs are also general antidotes for Xa inhibitors such as apixaban, rivaroxaban
and endoxaban.6 Specific antidotes such as aripazine (PER977, 100–200 mg), a synthetic molecule that
binds specifically to unfractionated heparin and low-molecular-weight heparin, and the recombinant factor
Xa andexanet have been successfully used for edoxaban and rivaroxaban. Aripazine also binds in a similar way to dabigatran, but further clinical experience is needed in this setting.

Clinical experience with the NOACs compared with warfarin is too limited to unequivocally pronounce dead this useful old drug. Nevertheless, a new era has begun, and the results of clinical trials and ‘real-life’ registries are eagerly awaited in this respect.

Dr Demosthenes Katritsis, Editor-in-Chief

Athens Euroclinic, Greece and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, US


  1. De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: Esc working group on thrombosis-task force on anticoagulants in heart disease position paper. J Am Coll Cardiol 2012;59:1413–25
    Crossref | Pubmed
  2. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: A systematic review and meta-analysis of the literature. Circulation 2012;126:2381–91.
    Crossref | Pubmed
  3. Ruff CT GR, Braunwald E, Hoffman EB, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet 2014;383:955–62.
    Crossref | Pubmed
  4. Canestaro WJ PA, Avorn J, Ito K, et al. Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation. Circ Cardiovasc Qual Outcomes 2013;6:724–31.
    Crossref | Pubmed
  5. Eerenberg ES KP, Sijpkens MK, Meijers JC, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9.
    Crossref | Pubmed
  6. Gómez-Outes A, Suarez-Gea ML, Lecumberri R, et al. Specific antidotes in development for reversal of novel anticoagulants: A review. Recent Pat Cardiovasc Drug Discov 2014;9:2–10.
    Crossref | Pubmed
  7. Honickel M TS, van Ryn J, Tillmann S, et al. Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab. Thromb Haemost 2015;113:728–40.
    Crossref | Pubmed