Factor Xa inhibitor antidote provides clinical hemostasis of acute GI bleeding

In a post-hoc analysis of ANNEXA-4, 82% of the patients with factor Xa inhibitor–associated acute major gastrointestinal (GI) bleeding showed good to excellent hemostatic efficacy 12 hours after andexanet alfa treatment, although the 30-day mortality rate was 12%.

This summary is based on the publication of Siegal DM, Forbes N, Eikelboom J, et al. - The Efficacy and Safety of Andexanet Alfa in Patients With Acute Gastrointestinal Bleeding While Taking Factor Xa Inhibitors: An ANNEXA-4 Subanalysis. Circulation. 2024 Apr 16;149(16):1315-1318. doi: 10.1161/CIRCULATIONAHA.123.066933

Introduction and methods

Background

Although the efficacy and safety profiles of factor Xa inhibitors are favorable, ~9% of patients treated with these agents die within 30 days of an associated major extracranial bleeding [1], mostly one in the gastrointestinal (GI) tract [2]. Andexanet alfa is a modified recombinant inactive form of human factor Xa that rapidly reverses the anticoagulant effects induced by factor Xa inhibitors. The ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) study showed that treatment with andexanet alfa resulted in good to excellent hemostatic efficacy after 12 hours in 80% of the patients with factor Xa inhibitor–associated acute major bleeding [3,4].

Aim of the study

In a post-hoc analysis of the ANNEXA-4 study, the authors evaluated the effects of andexanet alfa on anti–factor Xa activity and hemostatic efficacy and examined clinical outcomes in patients with a GI bleeding.

Methods

The ANNEXA-4 study was an international, prospective, single-arm, open-label, phase 3b/4 study of andexanet alfa treatment in 479 patients with factor Xa inhibitor–associated acute major bleeding. At enrollment, factor Xa inhibitors were discontinued in all patients. In the current analysis, 109 patients with a GI bleeding were included, of whom 52 (47.7%) had received rivaroxaban, 43 (39.4%) apixaban, 7 (6.4%) edoxaban, and 7 (6.4%) enoxaparin. The efficacy population included patients with baseline anti–factor Xa activity ≥75 ng/mL (or ≥0.25 IU/mL for enoxaparin and ≥40 ng/mL for edoxaban) and adjudicated major bleeding at presentation.

Outcomes

The 2 coprimary efficacy endpoints were percent change from baseline in anti–factor Xa activity after andexanet alfa treatment and percentage of patients with adjudicated good to excellent hemostatic efficacy 12 hours after andexanet alfa infusion. For GI bleedings, good and excellent hemostatic efficacy were defined as a decrease in corrected hemoglobin or hematocrit levels from baseline to 12 hours of ≤20% and ≤10%, respectively. Primary safety endpoints included 30-day all-cause mortality and thrombotic events.

Main results

Anti–factor Xa activity and hemostatic efficacy

• In the efficacy population, the median percent reduction in anti–factor Xa activity from baseline to the end of infusion was ≥90% for patients who had received apixaban or rivaroxaban.
• The median percent reduction in anti–factor Xa activity from baseline to 12 hours was 40.2% (95%CI: 30.1%–48.3%) in patients who had received apixaban and 64.1% (95%CI: 52.8%–66.2%) in those previously taking rivaroxaban.
• At 12 hours, 61 of 74 patients (82.4%; 95%CI: 71.8%–90.3%) in the efficacy population showed good to excellent hemostatic efficacy. No additional interventions, such as embolization or surgery, were required to control the major GI bleeding.

Clinical outcomes

• In the safety population (n=109), 88 patients (80.7%) received packed red blood cell transfusion. • During the 30-day follow-up, 8 patients (7.3%) experienced a thromboembolic event and 13 (11.9%) died (of whom 6 from CV cause, 6 from non-CV cause, and 1 from unknown cause).
• Anticoagulation was reinitiated in 64 patients (58.7%) within 30 days of andexanet alfa treatment, and 50 patients (45.9%) received oral anticoagulation within 30 days. No thrombotic events were recorded after restarting oral anticoagulation.

Conclusion

In this post-hoc analysis of the single-arm, open-label ANNEXA-4 study among 109 patients with factor Xa inhibitor–associated acute major GI bleeding, 82% of the patients showed good to excellent hemostatic efficacy 12 hours after andexanet alfa treatment. “[T]he 12% mortality rate within 30 days of anticoagulant-related major GI bleeding [suggested] that these events are not trivial complications of therapy,” according to the authors.

Find this article online at Circulation.

References

1. Held C, Hylek EM, Alexander JH, Hanna M, Lopes RD, Wojdyla DM, Thomas L, Al-Khalidi H, Alings M, Xavier D, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015;36:1264–1272. doi: 10.1093/eurheartj/ehu463
2. Xu Y, Siegal DM. Anticoagulant-associated gastrointestinal bleeding: framework for decisions about whether, when and how to resume anticoagulants. J Thromb Haemost. 2021;19:2383–2393. doi: 10.1111/jth.15466
3. Milling TJ Jr, Middeldorp S, Xu L, Koch B, Demchuk A, Eikelboom JW, Verhamme P, Cohen AT, Beyer-Westendorf J, Michael Gibson C, et al. Final study report of andexanet alfa for major bleeding with factor Xa inhibitors. Circulation. 2023;147:1026–1038. doi: 10.1161/CIRCULATIONAHA.121.057844 4.
4. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380:1326–1335. doi: 10.1056/NEJMoa1814051