Improving care for AF Patients: Managing factor Xa inhibitor bleeding risks in urgent surgery

As part of our ongoing commitment to cutting-edge research and patient care, Octapharma has been supporting the PROXY trial, aimed at evaluating whether preoperative 4-factor prothrombin complex concentrate (4F-PCC) can prevent excessive bleeding during emergency surgery in patients on therapeutic levels of oral factor Xa (FXa) inhibitors, without increasing thrombotic risk.

In the rapidly evolving landscape of anticoagulation therapy, direct oral anticoagulants (DOACs) have significantly improved the management of atrial fibrillation (AF). These drugs, which target Factor IIa (in the case of dabigatran) and FXa (in the case of rivaroxaban and apixaban), offer a more predictable dose-response relationship and a broader therapeutic index compared to warfarin.

This advancement means patients can enjoy the convenience of fixed dosing without the frequent need for blood monitoring, thereby enhancing their overall quality of life. However, despite these benefits, DOACs pose challenges, especially in managing bleeding during urgent surgical procedures.1-4

Patients with AF on anticoagulants often require surgery that requires pausing their medication. The RE-LY trial report (2009) showed that 2% of participants needed such procedures over two years5. Dabigatran users benefit from a reversal agent, idarucizumab, which provides a crucial safety net in emergencies.6

For those taking FXa inhibitors, managing bleeding risks becomes more complex. Andexanet alfa, a direct reversal agent, and 4F-PCC have both been used to address major bleeding associated with FXa inhibitors. A recent meta-analysis highlighted similar efficacy and safety profiles for these treatments7. However, the optimal approach before urgent surgery remains uncertain due to limited data and the rare preoperative quantification of FXa inhibitor levels in blood. Most guidelines recommend a “wait and see” strategy whenever possible8, which involves postponing surgery to allow for the clearance of the FXa inhibitor and using a reversal agent if bleeding occurs.

To explore this clinical challenge, Professor Sam Schulman conducted the PROXY trial, a phase 2, investigator-initiated, prospective single-arm study across three Canadian centres, supported by Octapharma9, to evaluate whether preoperative 4F-PCC can prevent excessive bleeding during emergency surgery in patients taking oral FXa inhibitors, without increasing thrombotic risk.

The findings were promising: the majority of patients (16 out of 20) presented normal or near-normal haemostasis during surgery, with only a few presenting moderately (2 out of 20) or severely (2 out of 20) abnormal haemostasis. Notably, only one asymptomatic thrombotic event was identified, the cause of which remains unclear. While larger trials with control groups are necessary to confirm these findings, the results suggest that reversing clinically relevant levels of FXa inhibitors with 4F-PCC could benefit patients prior to their undergoing high-risk urgent surgery.

The leading Journal of Thrombosis and Haemostasis (JTH) has published results from the PROXY study. The results are available online, with open access.

References:

1. Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015;16(1):11–17.

2. Becattini C, Vedovati MC, Agnelli G. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature. Thromb Res. 2012;129(3):392–400.

3. Mueller S, Groth A, Spitzer SG, et al. Real-world effectiveness and safety of oral anticoagulation strategies in atrial fi brillation: a cohort study based on a German claims dataset. Pragmat¬Obs Res. 2018;9:1–10.

4. Rodriguez-Bernal CL, Peiro S, Hurtado I, et al. Primary nonadherence to oral anticoagulants in patients with atrial fi brillation: real-world data from a population-based cohort. J¬Manag Care Spec Pharm. 2018;24(5):440–448.

5. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. PMID: 19717844.

6. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11. PMID: 28693366.

7. Nederpelt CJ, Naar L, Krijnen P, le Cessie S, Kaafarani HMA, Huisman MV, et al. Andexanet alfa or prothrombin complex concentrate for factor Xa inhibitor reversal in acute major bleeding: a systematic review and meta-analysis. Crit Care Med. 2022; 49: e1025-e36

8. Grottke, Oliver; Afshari, Arash; Ahmed, Aamer; Arnaoutoglou, Eleni; Bolliger, Daniel; Fenger-Eriksen, Christian; von Heymann, Christian. Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding. European Journal of Anaesthesiology 41(5):p 327-350, May 2024

9. Schulman S, et al. Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors. J Thromb Haemost. 2024 Jul 11:S1538-7836(24)00386-6