Despite a high rate of effective hemostasis with reversal agents following major bleeding tied to direct oral anticoagulant (DOAC) use, mortality is still substantial, according to a new systematic review and meta-analysis.

As Dr. Antonio Gomez-Outes told Reuters Health by email, “DOAC-related major bleedings are relatively common nowadays in the U.S. and the European Union. Approximately half of them are severe cases requiring hospitalization and potentially requiring the administration of a reversal agent.”

These agents include “idarucizumab for dabigatran reversal and prothrombin complex concentrates or andexanet for reversal of direct FXa inhibitors like rivaroxaban, apixaban and edoxaban,” he noted.

For their analysis, published in the Journal of the American College of Cardiology, Dr. Gomez-Outes of the Spanish Agency of Medicines and Medical Devices, in Madrid, and colleagues evaluated 60 studies involving 4,735 patients.

All patients had severe DOAC-related bleeding and were treated with the four-factor prothrombin complex concentrates, idarucizumab or andexanet. Half of the studies, noted Dr. Gomez-Outes, were published in 2020. “Therefore,” he said, “the results are quite reflective of current practice.”

The team found a high overall rate of effective hemostasis (78.5 percent), with no significant differences between the various reversal agents. The mortality rate overall was 17.7 percent and was higher in patients with intracranial versus extracranial bleedings (20.2 percent vs. 15.4 percent).

“Not achieving effective hemostasis,” said Dr. Gomez-Outes, “was strongly correlated with a more than 3-fold increase in the risk of death. Therefore, in the event of insufficient hemostatic response, additional attempts and/or combination with other treatment modalities aimed at achieving effective hemostasis should be considered.”

He noted that mortality is still significant despite the use of reversal agents, adding that “approximately half of patients with DOAC-related severe bleeding survived with long-term moderate-severe disability. We also found a relatively high rate of thromboembolic events after the administration of andexanet (11 percent) compared with prothrombin complex concentrates or idarucizumab (approximately 4 percent), which deserves further investigation.”

In an accompanying editorial, Drs. Christopher B. Granger and Sean D. Pokorney of Duke University Medical Center, in Durham, North Carolina, note, “This study is a welcome overview of the available evidence of who is getting which reversal agents and related outcomes.”

They point out that the “morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with atrial fibrillation (AF) continue to dwarf the bleeding-related mortality among patients with AF and on DOACs.”

In an email to Reuters Health, Dr. Granger added that “while bleeding can occur with anticoagulation for AF, serious bleeding (like intracranial bleeding) is far less common than with warfarin, and the benefits of preventing stroke far outweigh the risk of bleeding for nearly all patients. For patients on anticoagulation, measures to reduce bleeding risk (like avoiding aspirin) are important. When bleeding does occur, reversal agents are available, although how to best use them is uncertain.”
The study had no specific funding. One of Dr. Gomez-Outes’ coauthors reports financial ties to drugmakers.