Management of Bleeding With Non–Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents

Abstract

Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well.

Reversal Agents: What We Have and What We Can Expect

“…Guidelines and institutional protocols will need to be developed to ensure the appropriate use of reversal agents only for patients with serious or life-threatening bleeding, which may include bleeding causing hemodynamic compromise, intracranial hemorrhage, bleeding into a critical organ or closed space, persistent bleeding despite general supportive measures and local hemostatic support, and/or risk of recurrent bleeding due to excess NOAC drug exposure due to delayed clearance of NOAC (eg, acute renal failure) or overdose. 1 Specific reversal agents are preferred, if available, over non-specific hemostatic agents, as the latter are less effective in reversing coagulation abnormalities, have not been shown to improve outcomes, and are potentially prothrombotic.…”

“…These agents have several distinct advantages in comparison with warfarin, including rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, fewer drug interactions, and the ability to be given in fixed doses without routine coagulation monitoring due to their predictable pharmacokinetic and pharmacodynamic effects. 1 Large phase III trials in patients with AF as well as venous thromboembolism have demonstrated that NOACs have a favorable riskbenefit profile compared with that of warfarin. They are as effective, if not more effective, than warfarin in preventing thromboembolism, and are far safer with respect to serious bleeding, particularly with regard to the risk of intracranial hemorrhage, which is decreased by > 50%.…”

Interventional Spine and Pain Procedures in Patients on Antiplatelet and Anticoagulant Medications (Second Edition)

“…Nonspecific hemostatic agents such as recombinant factor VII, factor VIII inhibitor bypassing activity, or PCCs have been suggested based on clinical need. [321][322][323] A dabigatran-directed neutralizing antibody, idarucizumab, has been approved for use. A prospective study showed that idarucizumab normalized the elevated ECT in 88% to 98% of patients, an effect that was seen within minutes.…”

Use of new anticoagulants for the treatment of venous thromboembolism in the context of the results of the XALIA study — clinical trials and routine clinical practice

“…Currently, a registered antidote against new direct inhibitors of anticoagulation is available only for dabi gatran, but there are ongoing advanced studies related to obtaining clinical confirmation of the possibility of using an antidote for drugs from the group of factor Xa inhibitors, e.g. adnexanet alpha [38][39][40]. While waiting for the results of this studies, it is worth noting that despite the fact that the availability of antidotes seems to be, by all means, justified, according to the earlier observations in most cases bleeding complications reported during the use of new anticoagulant molecules most likely do not require the use of a specific antidote [22,36,39].…”

“…adnexanet alpha [38][39][40]. While waiting for the results of this studies, it is worth noting that despite the fact that the availability of antidotes seems to be, by all means, justified, according to the earlier observations in most cases bleeding complications reported during the use of new anticoagulant molecules most likely do not require the use of a specific antidote [22,36,39]. The above-mentioned observations were mostly made on the basis of the pharmacological properties of new oral anticoagulants and, above all, their relatively short time of action [6][7][8][9][10].…”