Managing bleeds related to oral factor Xa inhibitors with andexanet alfa or replacement agents

Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study

Coleman CI, Dobesh PP, Danese S, Ulloa J, Lovelace B. Future Cardiol. 2020 Jul;17(1). doi: 10.2217/fca-2020-0073.

As the use of direct oral anticoagulants (DOACs) increases globally, so does the incidence of serious side effects such as intracranial and other types of haemorrhage.

In response, specific reversal agents have been developed. In 2018, the FDA (Food and Drug Administration) approved andexanet alfa to reverse the effects of apixaban and rivaroxaban, two widely used oral factor Xa inhibitors (FXai), in life-threatening or uncontrolled bleeding.

Guidelines now recommend use of specific reversal agents in cases of severe or life-threatening bleeding (Tomaselli et al., 2017, Gibler et al., 2018; Baugh et al., 2020)

How do specific reversal agents perform in the real world alongside older, nonspecific treatments for DOAC-related haemorrhage, for example, four-factor prothrombin complex concentrate (4F-PCC) and fresh frozen plasma? This retrospective, observational study examined outcomes from managing FXai-related major bleeds with andexanet alfa and other nonspecific treatments.

What did the study examine?

The researchers extracted information from the electronic records of 45 US hospitals. They examined hospitalisations from January 2016 to September 2019 for major bleeds related to FXai use (N = 3,030). Data collected included patient demographics, bleed type (intracranial, gastrointestinal, critical compartment, traumatic and other haemorrhage), FXai taken, reversal or replacement agents administered (andexanet alfa, all other agents, no agents), in-hospital mortality, and length of stay, including in intensive care units (ICUs).

The age, gender, FXai use, and bleed type of patients treated with all agents examined were similar at baseline. This included patients treated with andexanet alfa, for whom data was collected only from May 2018 (after FDA approval).

What were the major findings?

Figure 1. In-hospital mortality (%) per bleed type for each reversal or replacement agent administered (Coleman et al., 2021). GI, gastrointestinal; prothrombin complex concentrate. *Values for andexanet alfa are 0%. †All other refers to 3-factor PCCs, recombination factor VIIa, activated 4F-PCC, tranexamic acid, and vitamin K treatments.

The study found:

• In-hospital mortality differed with bleed type (Figure 1):
  • Highest for intracranial haemorrhage (23%, n = 507)
  • Lowest for gastrointestinal bleeds (4%, n = 1,453)
• In-hospital mortality differed with agents administered to manage bleeds (Figure 1):
  • Lowest for andexanet alfa (4%, n = 342) in all (combined) bleed types; sole agent used in 83% of cases
  • 10% (n = 733) for 4F-PCC (nonspecific agent most frequently recommended by guidelines); sole agent used in 72% of cases
• Length of hospital stay (LOS) differed with type of bleed and agent administered:
  • Median LOS highest for intracranial haemorrhage and critical compartment bleeds (that is, non-compressible bleeding in the thorax, abdomen, retroperitoneum or pelvis)
  • Median LOS = 5 days for all agents
• Median stay in ICU = 2 days for andexanet alfa, 3 days for all other agents

What can we conclude from these findings?

The findings suggest that mortality and LOS differ with both bleed type and reversal/replacement agents given. Andexanet alfa resulted in lower mortality in all bleeding types and a shorter stay in ICU. However, because this was a retrospective observational study, the following factors must be considered when interpreting the findings:

• Differences in baseline factors related to patient characteristics (comorbidities, concomitant medications) and bleed size and severity (initial stroke severity and volume) may contribute to apparent differences in mortality and length of stay in ICU among agents
• Reversal or replacement agents may be combined with other agents or procedures such as transfusion, which may affect apparent performance. For example, fresh frozen plasma was used alone in less than half of treated cases
• Data from hospitalisation records are limited to the current admission and do not capture previous medical or prescription history, longitudinal outcomes or patient management after discharge

To confirm clinically relevant differences in mortality among treatment agents, replication with large representative samples is warranted, along with collecting additional data on use of single or multiple agents, functional outcomes, readmission and mortality after discharge, haemostatic efficacy after reversal agent use, and practice patterns related to FXai.

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References

Baugh CW, Levine M, Cornutt D, Wilson JW, Kwun R, Mahan CE, et al. Anticoagulant reversal strategies in the emergency department setting: recommendations of a multidisciplinary expert panel. Ann Emerg Med. 2020;76(4):470–85.

Coleman CI, Dobesh PP, Danese S, Ulloa J, Lovelace B. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: A multicenter study. Future Cardiol. 2021;17(1):127–135.

Gibler WB, Racadio JM, Hirsch AL, Roat TW. Management of severe bleeding in patients treated with oral anticoagulants: Proceedings monograph from the Emergency Medicine Cardiac Research and Education Group–International Multidisciplinary Severe Bleeding Consensus Panel October 20, 2018. Crit Pathw Cardiol. 2019;18(3):143–66.

Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042–67.