Written By Katrina Mountfort, Medical Writer, Radcliffe Cardiology
Reviewers - John Camm, Marco Alings, Raffaele De Caterina, Paulus Kirchhof, Jean-Yves Le Heuzey, Freek W A Verheugt
Professor Camm began by stating that whenever asked about NOACs, the matter of reversibility is always mentioned, because anticoagulant drugs may cause serious haemorrhage. At present, the management of bleeding can be largely managed by standard procedures such as pressure on the bleeding point, and in cases of major bleeding, replacement of blood volume, etc. (see Figure 2). However, reversal strategies may be needed in cases of life-threatening bleeding or if the action of the drug is long and needs to be antagonised in emergency situations.26 It should be remembered that the half-life of these drugs is relatively short (around 12 hours) and the anticoagulant effect of the drug will diminish much more quickly than that of warfarin, which often requires much more active intervention. While specific antidotes would be desirable, the major clinical trials of NOACs took place without the availability of antidotes.
Specific reversal agents for NOACs are currently under clinical investigation. These include andexanet alfa (Portola Pharmaceuticals) administered alone or with factor Xa (fXa) inhibitors, (phase II completed27,28 and phase III trials recruiting),29,30 idarucizumab, (Boehringer Ingelheim) administered alone or with dabigatran (phase I competed31 and phase III recruiting)32 and PER977 (aripazine, Perosphere Inc.) administered alone or with edoxaban (phase I study completed).33 Andexanet alfa is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct fXa inhibitors and is a universal factor Xa inhibitor reversal agent. Phase II studies in healthy volunteers have provided rapid, sustained and dose-related reversal of apixaban and rivaroxaban.28 Idarucizumab is a fully humanised monoclonal antibody fragment (FAb) against dabigatran.34 In vitro characterisation and PK analyses showed that the Fab has very tight binding affinity to dabigatran, with rapid onset and slow offset.35 Idarucizumab had no effect on bleeding in rats receiving VKA.
The phase III trial will evaluate the reversal of dabigatran by intravenous administration of idarucizumab in patients who have uncontrolled bleeding or require emergency surgery or procedures.32 Aripazine is a small synthetic molecule with activity against all NOACs and is in early stage clinical development.33
In the panel discussion, Professor Verheugt mentioned first that the NOACs – for which there is no antidote as yet – showed in their trials a reduction in fatal bleeding. He stated that it is important that reversibility agents are effective in bleeding situations – while warfarin can be reversed, this does not stop the bleeding – and it is difficult to conduct clinical trials on bleeding patients. It was also pointed out by Prof Kirchhoff that in a comparison between apixaban and aspirin, the rate of major bleeds was the same despite presumably equal plasma coagulation in the aspirin group.5 He also stated that we [doctors] want to have control about the harm we cause ourselves. Prevention of bleeding is easier than cure. The antidote will not stop the accident and haemostasis will still be required. Availability of antidotes is, however, a serious concern and the availability of an antidote may make NOACs more acceptable to patients and general practitioners, according to Professor Le Heuzey.
The consensus of the panel was that transferring knowledge to patients and the lay press is more important than the availability of an antidote. The panellists would like to have an inexpensive antidote for patient reassurance, even if in clinical practice it might not be much needed, but it should have a long shelf life as it would be used infrequently. Prevention of bleeding is more important than using an antidote, and the short half-lives of NOACs ensures a relatively low rate of major bleeding episodes.
For a full written summary of discussions please click here:
A. John Camm, Professor of Clinical Cardiology and Head of the Department of Cardiac and Vascular Sciences, St. George's Hospital Medical Centre, London, UK
Marco Alings, Director of the Cardiology Training Program, Amphia Ziekenhuis, Breda, The Netherlands
Raffaele De Caterina, Professor of Cardiology and Director of the University Cardiology Division, "G. d'Annunzio" University, Chieti, Italy
Paulus Kirchhof, Chair in Cardiovascular Medicine Cardiovascular and Respiratory Sciences, University of Birmingham, UK
Jean-Yves Le Heuzey, Professor of Cardiology and Head of the Arrhythmia Department, Georges Pompidou Hospital, Paris, France
Freek Verheugt, Chairman, Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands
Professor Camm has disclosed the following financial relationships:
Consultant/Advisor/Speaker: Actelion, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Biotronik, BMS, ChanRX, Daiichi Sankyo, Gilead, GSK, InfoBionic, Incarda, Johnson and Johnson, Medtronic, Menarini, Merck, Mitsubishi, Novartis, Otsuka, Pfizer, Sanofi, Servier, St. Jude Medical, Takeda, Xention
Doctor Alings has disclosed the following financial relationships:
Consultant/Advisor: Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo
Professor De Caterina has disclosed the following financial relationships:
Research grants: Boehringer Ingelheim
Consultant/Advisor/Speaker: Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Novartis
Professor Kirchhof has disclosed the following financial relationships:
Research grants: BMS/Pfizer, Cardiovascular Therapeutics, Daiichi Sankyo, Sanofi, St. Jude Medical.
Consultant/Advisor/Speaker: Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Johnson & Johnson, Medtronic, MSD, Pfizer, Servier
Professor Le Heuzey has disclosed the following financial relationships:
Consultant/Advisor: Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sanyo
Professor Verheugt has disclosed the following financial relationships:
Consultant/Advisor: Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo
The assigned learning objectives for this roundtable are listed for your information:
- To review the established evidence-base for non-VKA thromboprophylaxis in atrial fibrillation (AF)
- To consider recent and emerging data on non-VKA oral anticoagulants in AF trials and registries
- To discuss on-going non-VKA oral anticoagulant research in patients with AF
- To identify and refine the indications for specific non-VKA oral anticoagulants in AF
- To establish the nature of further non-VKA oral anticoagulant research needed for new AF indications
This educational activity is intended for an international audience of non-US healthcare professionals, specifically electrophysiologists and cardiologists. However, neurologists, internal medicine specialists, primary care physicians, and other healthcare professionals involved in the diagnosis and management of patients with atrial fibrillation (AF) will also find this topical.
This course is accredited by the European Board for Accreditation in Cardiology (EBAC) for 1 CME credit hour. The CME e-learning modules can be accessed here.
The CME element of this educational module has been managed by Siyemi Learning and is powered by CME-CPD Academy.
The Novel Oral Anti-Coagulants (NOACs): Hot Topics & Current Issues roundtable was supported by an unrestricted educational grant by Daiichi-Sankyo.