Andexanet alfa for acute major bleeding associated with factor Xa inhibitors.

Anticoagulants are highly effective in reducing thromboembolic complications (mostly stroke in patients with atrial fibrillation) but they increase the risk of haemorrhage, which has become the most common cause of iatrogenic hospital admission. In ‘real-life’ studies, the incidence of the most dreaded complication of vitamin K antagonists (VKAs), i.e. intracranial haemorrhage, is approximately 0.5%/year. The development and marketing authorisation of direct oral anticoagulants (DOACs) has provided patients and physicians with oral anticoagulants that have a predictable effect and thus do not require regular monitoring. Moreover, clinical trials have shown that DOACs have an efficacy at least similar to that of VKAs and a lower risk of intracranial bleeding. Despite evidence of the safety of DOACs, there have been concerns that, unlike VKAs, they did not have antidotes, and thus reports of patients on DOACs with major uncontrolled bleeding were highlighted in many journals. Furthermore, in patients taking DOACs requiring an immediate invasive procedure, most practitioners prefer the availability of a reversing agent.

Recently, andexanet alfa, a recombinant non-coagulant factor Xa molecule that acts as a decoy for anti-Xa DOACs, was designed as an antidote for these drugs (it is also an effective antidote to other anti-factor Xa drugs such as low-molecular-weight heparins and fondaparinux). The study by Connolly et al. demonstrates effective inhibition of anti-Xa effect in patients with acute bleeding on rivaroxaban, apixaban and enoxaparin. Within 12 hours, over 80% of patients had effective haemostasis. Administration of andexanet alfa and associated interruption of anticoagulant treatment after the episode of bleeding was associated with a high thrombosis rate for 30 days following reversal (12 of 67 [18%]).

It is impossible to know whether andexanet alfa had an intrinsic prothrombotic effect and/or the high rate of thrombosis is related to the absence of an antithrombotic agent in a high-risk situation (for major bleeding itself is associated with an increased rate of subsequent VTE). Anyhow, andexanet alfa is most probably represents an effective antidote for patients requiring immediate reversal of the anticoagulation effect of a facotr Xa inhibitor.

– Marcel Levi

Reference

Hunt B, Levi M. Engineering reversal – Finding an antidote for direct oral anticoagulants. N Engl J Med 2016;375:1185-6.