© Schattauer 2015 Thrombosis and Haemostasis 114.6/2015 1113 Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants Jeffrey I. Weitz 1 ; Charles V. Pollack Jr 2 1 McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; 2 Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania, USA Summary Non-vitamin K antagonist oral anticoagulants (NOACs) are increas- ingly used in the prevention and treatment of venous thromboembol- ism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, includ- ing consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence sup- ports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in life- threatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anti- coagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers. Keywords Bleeding profiles, bleeding management, non-vitamin K oral antico- agulant, real-world data, reversal agent Correspondence to: Dr. Jeffrey Weitz Thrombosis and Atherosclerosis Research Institute 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada Tel.: +1 905 574 8550, Fax: +1 905 575 2646 E-mail: weitzj@taari.ca Received: March 12, 2015 Accepted after major revision: May 26, 2015 Epub ahead of print: July 9, 2015 http://dx.doi.org/10.1160/TH15-03-0222 Thromb Haemost 2015; 114: 1113–1126 Review Article Introduction Non-vitamin K antagonist (formerly ‘novel’) oral anticoagulants (NOACs), including the direct factor Xa inhibitors rivaroxaban and apixaban and the direct thrombin inhibitor dabigatran etex- ilate, are approved for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, for the treatment and secondary prevention of VTE, and for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF). A third oral factor Xa in- hibitor, edoxaban, has completed phase III studies and has recently been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of VTE and for stroke prevention in patients with non-valvular AF. Although vitamin K antagonists (VKAs), such as warfarin, are effective, inter-individual dose variation and multiple drug–drug and drug–food interactions make patient management difficult, and frequent coagulation monitoring and dose adjustments are required to ensure that the international normalised ratio (INR) remains within the therapeutic range of 2.0–3.0 (1). Such monitor- ing is burdensome for patients and physicians, and is costly for healthcare systems. Even with monitoring, the INR in patients treated with VKAs is often above or below the target range, which places patients at risk of bleeding or thrombotic events, respect- ively (2). Developed to overcome such limitations, the NOACs have a predictable anticoagulant response that allows for fixed doses without routine coagulation monitoring. In phase III trials including more than 150,000 patients, NOACs were at least as effective as VKAs for VTE treatment (3–6) and for stroke preven- tion in patients with AF (7–12), and provided safety advantages. Real-world studies have supported the efficacy and safety of these agents in routine clinical practice (13, 14). Despite their beneficial attributes, some physicians have been slow to embrace the NOACs. A major reason for this is the lack of specific reversal agents for use in patients with serious bleeding or in those who require urgent surgery (15). Thus, there is the per- ception that the management of bleeding events may be more difficult in patients taking a NOAC than in those taking VKAs. For personal or educational use only. No other uses without permission. All rights reserved. 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