The new oral anticoagulants: clinical use and reversal agent development

Warfarin has been the centre of oral anticoagulant therapy for over 60 years. Recent development of new oral anticoagulants (NOACs) has provided a safe and effective alternative for stroke prevention in patients with atrial fibrillation and for prevention of venous thromboembolism. Determination of their use in acute coronary syndrome has been hampered by increases in bleeding events in most large trials, especially when used with antiplatelet therapy. NOACs have equal or superior efficacy and safety profiles compared to warfarin, fewer drug interactions; no dietary restrictions; predictable responses that eliminates monitoring; a rapid onset eliminates bridging with parenteral anticoagulants; and a potential reduction in mortality in patients with atrial fibrillation. There are reports of bleeding events and deaths associated with NOACs. Haemorrhage associated with dabigatran and warfarin were the most common safety issues for anticoagulants reported to the United States Food and Drug Administration in 2012. The lack of a NOAC reversal agent is a significant clinical concern for many physicians. Current reversal agents for unfractionated heparin, low molecular weight heparins and warfarin are less than optimal, and there are no effective reversal agents for NOACs. Development programs for anticoagulant reversal of the NOACs have three approaches: multiple coagulation factor replacement, large molecules (recombinant antibodies or altered coagulation factors) that either bind to or substitute for the coagulation factor while the anticoagulant itself is either being excreted or metabolized, and a small molecule specifically designed to bind to the NOACs and heparins and prevent them from binding to the coagulation factor targets.