ESC Congress 2016 - 38

sElEcTEd uPdATEs reduced within minutes after the bolus injection of andexanet alfa. This reversal was sustained with a bolus plus an infusion over 2 hours. Thrombin generation was also quickly restored. There were no serious adverse events. In a subgroup of participants, transient increases in levels of d-dimers and prothrombin fragments were observed, but no thrombotic events were reported [Siegal DM et al. N Engl J Med. 2015]. A phase 3b study to evaluate the ability of andexanet alfa to reverse the anticoagulation effect of fXa inhibitors in patients experiencing an acute major bleed (ANNEXA-4) is in progress [NCT02329327]. Ciraparantag is a synthetic, peptide-like small molecule designed for the reversal of oral direct fXa and IIa inhibitors, low-molecular-weight heparins, unfractionated heparin, and fondaparinux [Laulicht et al. AHA 2012]. Ciraparantag competitively binds NOACs restoring blocked coagulation factor activity. It reduces blood loss in NOAC-treated rats to normal levels and reverses rivaroxaban effects in fresh human whole blood ex vivo, but shows no effects on warfarin anticoagulation. A phase 2 ascending dose study in healthy subjects treated with a single dose of edoxaban 60 mg for 4 days is recruiting [NCT02207257]. Freek W. A. Verheugt, MD, Amsterdam, The Netherlands, discussed whether the availability of specific reversal agents might change the use of NOACs. Prof Verheugt believes that the introduction of the reversal agents will cause clinicians who are currently reluctant to prescribe NOACS to do so with greater comfort. Referring to a 2012 meta-analysis, he reminded the audience that there has already been a very significant reduction in fatal bleeding [Ruff CT et al. Lancet. 2014] with the use of NOACs. He sees the requirement for surgery as the most frequent indication for use of the reversal agents. Reviewing each of the 3 reversal agents in turn, he noted that, in his opinion, the most important aspects of idarucizumab are that it is very specific, it is unlikely to cause an allergic (immunologic) reaction, and it has been shown to be safe and effective for patients requiring emergency surgery [Siegal DM et al. N Engl J Med. 2016]. Andexanet alfa is a nonspecific Xa blocker that acts as a decoy and retains high affinity for all direct inhibitors of fXa as well as low molecular weight heparin activated antithrombin [Lu G et al. Nat Med. 2013]. Prof Verheugt noted that while the concept is quite elegant, more data are needed. Prof Verheugt expressed the most uncertainty regarding ciraparantag, primarily because of the limited data on its mechanism of action and clinical efficacy. He also noted that the only currently available data showing restored hemostasis are in young (aged ≤ 45 years) healthy volunteers [Ansell JE et al. N Engl J Med. 2014]. Since their introduction in practice nearly 6 years ago, NOACs have steadily replaced VKAs for several indications, but one of the concerns from some clinicians has been the lack of specific reversal agents for the management of severe bleeding complications. One specific antidote to dabigatran is now available and others to reverse fXa inhibitors are in late-stage development. The totality of evidence to date indicates that these agents are effective to rapidly reversal the anticoagulant effect of NOACs. Whether these antidotes will improve clinical outcomes in bleeding patients remains to be seen. Receive alerts for new Congress Reports Sign up at http://medicom-publishers.com/mcr/register 38 October 2016 www.escardio.org/ESCcongressinreview http://www.medicom-publishers.com/mcr/register http://www.escardio.org/ESCcongressinreview

Table of Contents for the Digital Edition of ESC Congress 2016