Reversal of Factor Xa Inhibitor-Associated Acute Major Bleeding

Published - Written by James Yeh, M.D. M.P.H.

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Use of anticoagulants

It is estimated that slightly more than 1 in 7 strokes is due to atrial fibrillation. The use of anticoagulants reduces this risk of thromboembolism. In recent years, a number of direct oral anticoagulants (such as apixaban, rivaroxaban, and edoxaban) that inhibit active coagulation factor X have been approved for stroke prevention in patients with atrial fibrillation, prevention and treatment of venous thromboembolism, and management of acute coronary syndrome. These drugs have more predictable pharmacokinetics than warfarin and obviate the need for prothrombin-time monitoring and multiple dose adjustments. However, many patients and clinicians have expressed the concern that reversal agents are not available, and therefore, have been hesitant to adopt the use of such drugs, despite data from clinical trials showing that factor Xa inhibitors are at least as efficacious as warfarin for prevention and treatment of thromboembolism complications, with lower risk of intracranial bleeding (see N Engl J Med 2011; 365:981; 2010; 363:2487; 2013; 369:799; 2011; 365:883; 2010; 363:2499; 2008; 358:2765; 2013; 369:2093; 2013; 369:1406).

What is the ANNEXA-4 study about?

In a multicenter, open-label, single-group study, investigators evaluated 67 patients who presented with acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients were treated with andexanet, a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. After receiving a bolus of andexanet followed by a 2-hour infusion of the drug, the patients were evaluated for pharmacodynamic outcomes (changes in the reduction of anti-factor Xa activity over time) and clinical outcomes (hemostasis efficacy and safety).

Who participated in the study?

The mean age of the patients was 77 years and the predominant indication for anticoagulation was atrial fibrillation (70%). Of the 67 patients, a majority had received rivaroxaban (n=32) or apixaban (n=31). The primary acute major bleeding sites were GI tract (49%) and intracranial (42%). The time from presentation to andexanet bolus was about 5 hours.

What were the results?

After the administration of andexanet bolus, the median anti-factor Xa activity was reduced by 89% among patients receiving rivaroxaban (95% CI, 58-94) and by 93% among those receiving apixaban (95% CI, 87-94). The reduction of anti-factor Xa activity was stable during the 2-hour infusion. Four hours after the conclusion of the infusion, the median anti-factor Xa activity was reduced by 39% (rivaroxaban) and 30% (apixaban), as compared to baseline measurements.

Twelve hours after the andexanet infusion, clinical hemostasis effectiveness was judged to be excellent or good in about 80% of patients. However, thrombotic events occurred in about 18% of patients at 30-day follow-up.

So, should I worry about safety? Does this potentially change my practice?

In an accompanying editorial, Beverley Hunt (St Thomas’ Hospital, UK) and Marcel Levi (University of Amsterdam, Netherlands) state, “It is impossible to know whether andexanet had an intrinsic prothrombotic effect or whether the high rate of thrombosis was related to the absence of an antithrombotic agent in a high-risk situation, since the presence of major bleeding alone is associated with an increased subsequent rate of venous thromboembolism.”

The editorialists believe that the actual need for antidote is likely to be small: “Because the half-lives of  direct oral anticoagulants are shorter than that of  warfarin, the effects of the drugs  wear off quickly, and unlike the case with warfarin, stopping the drug may be all that is required in most scenarios.”

What is my takeaway?

In patients with acute major bleeding associated with factor Xa inhibitor use, an initial bolus and 2-hour infusion with andexanet subsequently reduced anti-factor Xa activities with effective hemostasis in a vast majority of the patients. It is reassuring to have an effective antidote to the factor Xa inhibitors. Additional work will be necessary to sort out the optimal duration of reversal in patients with underlying increased clotting risk.

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James was a 2015-2016 NEJM Editorial Fellow. He recently completed fellowship in General Internal Medicine at Brigham and Women’s Hospital. He is interested in evidence-based medicine, medical education, knowledge translation, and pharmacoepidemiology.

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