Coagulation Tests and Reversal Agents in Patients Treated with Oral Anticoagulants: The Challenging Scenarios of Life-Threatening Bleeding and Unplanned Invasive Procedures

Abstract

In clinical practice, the number of patients treated with direct oral anticoagulants (DOACs) has consistently increased over the years. Since anticoagulant therapy has been associated with an annual incidence of major bleeding (MB) events of approximately 2% to 3.5%, it is of paramount importance to understand how to manage anticoagulated patients with major or life-threatening bleeding. A considerable number of these patients’ conditions necessitate hospitalization, and the administration of reversal agents may be imperative to manage and control bleeding episodes effectively. Importantly, effective strategies for reversing the anticoagulant effects of DOACs have been well recognized. Specifically, idarucizumab has obtained regulatory approval for the reversal of dabigatran, and andexanet alfa has recently been approved for reversing the effects of apixaban or rivaroxaban in patients experiencing life-threatening or uncontrolled bleeding events. Moreover, continuous endeavors are being made to develop supplementary reversal agents. In emergency scenarios where specific reversal agents might not be accessible, non-specific hemostatic agents such as prothrombin complex concentrate can be utilized to neutralize the anticoagulant effects of DOACs. However, it is paramount to emphasize that specific reversal agents, characterized by their efficacy and safety, should be the preferred choice when suitable. Moreover, it is worth noting that adherence to the guidelines for the reversal agents is poor, and there is a notable gap between international recommendations and actual clinical practices in this regard. This narrative review aims to provide physicians with a practical approach to managing specific reversal agents.

Exploring the Perioperative Use of DOACs, off the Beaten Track

“…Acute emergency procedures need to operate within minutes and cannot be delayed. In patients requiring emergency surgery, reversal with idarucizumab for dabigatran and andexanet alfa (“off-label”) for FXa inhibitors is advisable, especially in moderate-to-high hemorrhagic risk procedures or when surgery is required for ongoing bleeding (e.g., spontaneous bleeding or major trauma) [ 72 ]. Idarucizumab 5 g divided into two 2.5 g intravenous doses, given up to 15 min apart, has been shown to achieve normal hemostasis within minutes among patients on dabigatran undergoing urgent procedures [ 50 ].…”

“…The attenuated anti-factor Xa activity persists for up to two hours after the cessation of the infusion. Furthermore, it is noteworthy that andexanet alfa can inhibit tissue factor pathway inhibitor, with this inhibition sustained for a minimum of 22 h post-administration of andexanet alfa [ 72 ].…”

“…Under circumstances where dedicated reversal agents are unavailable, activated prothrombin complex concentrate (aPCC) and prothrombin complex concentrate (PCC) may be considered alternatives, notwithstanding the limited evidence regarding their efficacy and safety [ 72 ]. The supportive data for the utilization of PCCs in patients undergoing DOACs with major bleeding episodes or necessitating urgent surgical interventions are scant and predominantly drawn from retrospective analyses.…”

“…Andexanet alfa is an antidote for FXa inhibitors. It is a modified recombinant FXa, enzymatically rendered inactive through a mutation in its catalytic site, which, however, has retained the ability to bind direct and indirect FXa inhibitors [ 72 ]. This allows it to sequester anticoagulants within the vascular space and neutralize their effect [ 72 ].…”

“…Unlike idarucizumab, andexanet alfa has not been evaluated for reversing anti-FXa activity before urgent surgery. Moreover, specific studies do not exist for PCC/aPCC in this context [ 72 ].…”