Unsafe Oral Blood-Thinner Antidote Andexanet (ANDEXXA) Finally Withdrawn

In December 2025, the Food and Drug Administration (FDA) announced that the intravenous, hospital-only drug andexanet (ANDEXXA) is being voluntarily removed from the U.S. market by its current manufacturer.[1],[2] Seven years earlier, the FDA had approved the drug under the accelerated approval pathway as a specific antidote to reverse the effect of the direct-acting oral blood thinners apixaban (ELIQUIS and generics) and rivaroxaban (XARELTO and generics) in case of life-threatening or uncontrolled bleeding.

The withdrawal decision comes more than 1.5 years after the New England Journal of Medicine published final results of an FDA-required, industry-sponsored post-marketing trial. Called ANNEXA-I, this trial demonstrated that andexanet is associated with an increased risk of blood clots. This finding negates previous claims that this expensive drug (priced in 2020 at $27,000 for a low dose)[3] is a breakthrough.

Public Citizen’s Health Research Group welcomes this belated withdrawal of andexanet; since the February 2021 issue of Worst Pills, Best Pills News, we have designated this drug as Do Not Use.[4],[5] Also, in a November 2024 testimony we urged the FDA to reject an application by andexanet’s manufacturer to convert the drug’s accelerated approval to full approval based on the existing evidence, including findings from the ANNEXA-I trial submitted earlier that year to the agency.[6]

Initial studies

The 2018 accelerated approval of andexanet was based on two small, placebo-controlled pharmacological studies and initial results from what was then an ongoing, open-label, single-group clinical trial called ANNEXA-4. The pharmacological studies enrolled healthy volunteers without bleeding who mainly received either apixaban or rivaroxaban for four days before receiving andexanet. These studies did not include clinical endpoints; instead, they showed that andexanet decreased the activity of direct-acting blood thinner drugs, a surrogate endpoint that was thought to likely predict clinical benefit.

Initial results of the ANNEXA-4 trial showed that, of 67 participants given andexanet to control acute major bleeding within 18 hours of taking a direct-acting oral blood thinner, 18% developed thromboembolic events (including heart attack; ischemic stroke; or blood clot in an artery, a deep vein or the lungs) within 30 days.[7] Therefore, for the accelerated approval, the FDA required a boxed warning, the most prominent warning mandated by the agency, about the risk of thromboembolic events and sudden death on andexanet labels as well as a post-marketing trial to compare andexanet treatment with usual care.

Published in March 2023, the final results of ANNEXA-4 showed that thromboembolic events occurred in 10% of 479 total participants who received andexanet.[8] In addition to lacking a comparison group, this trial had limited generalizability to many patients who might receive the drug in real-world settings. It excluded seriously ill participants who would be most in need of bleeding-reversal treatment, including comatose participants, those with severe bleeding in the brain or those requiring major surgical procedures within 12 hours of andexanet treatment. The trial also excluded participants with a life expectancy of less than one month.

ANNEXA-I trial

This post-marketing, unblinded trial enrolled 530 participants who developed acute intracerebral hemorrhage (bleeding into the brain tissue) within 15 hours of taking a direct-acting oral blood thinner.[9] Of those, 263 were randomized to receive andexanet and 267 were randomized to receive usual care (mostly prothrombin complex concentrate).

The trial showed that the short-term benefits of bleeding cessation due to andexanet are outweighed by its serious blood clot risks.

For the primary effectiveness analysis, researchers used data from only 452 participants. By 12 hours after randomization, 67% of participants treated with andexanet and 53% of those receiving usual care met the criteria for hemostatic effectiveness (bleeding cessation). This endpoint was a composite of three components: 35% or less expansion of hematoma volume in brain tissue (as determined by imaging), use of rescue therapy as well as change from baseline in the National Institutes of Health Stroke Scale.

Although the 14% difference in the hemostatic effectiveness endpoint was statistically significant, its clinical significance is questionable because it was driven by hematoma expansion; the other two components did not differ substantially between the two groups. Additionally, measuring hematoma volume expansion 12 hours after randomization is earlier than recommended by the National Heart, Lung, and Blood Institute guidelines.[10] Because no imaging data were collected beyond 12 hours, delayed hematoma expansion (indicative of long-term benefit) is unknown. Moreover, because hematoma expansion was measured as a dichotomized response, it did not fully capture the treatment effect. Although the FDA had previously raised some of these issues with representatives of andexanet’s manufacturer, the company did not address them.

Although almost 80% of participants treated with andexanet received a low dose of the drug, 10% of those who were included in the final safety analysis experienced thromboembolic events within 30 days of randomization, similar to the rate seen among ANNEXA-4 participants. In contrast, only 6% of participants receiving usual care experienced this serious adverse event. This almost twofold increase in thromboembolic events associated with the use of andexanet was statistically significant. Moreover, ischemic stroke occurred in 7% of participants treated with andexanet, compared with 2% of those receiving usual care.

What You Can Do

If you have a condition for which an oral blood thinner is recommended, discuss with your clinician the fact that there is currently no proven specific antidote for apixaban or rivaroxaban. Although the oral blood thinner warfarin (JANTOVEN and generics) is cumbersome to use because it requires frequent blood testing to monitor its levels, among other issues, it has a proven and affordable antidote (vitamin K).

Unless you experience sudden, severe bleeding, do not stop your blood thinner medication suddenly without talking with your clinician because doing so can increase your risk of blood clots or stroke.

Seek immediate medical help if you fall or injure yourself, or if you experience any signs of bleeding, a blood clot or a stroke while taking any blood thinner.
 

References

[1] Food and Drug Administration. Update on the safety of Andexxa. FDA safety communication. December 18, 2025. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/update-safety-andexxa. Accessed April 9, 2026.

[2] AstraZeneca. Label: andexanet alpha (Andexxa). May 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=2d9d90a6-63e6-46ef-96ff-dd6519ae7b6c&type=display. Accessed April 9, 2026.

[3] Mahan CE. Reply to “key points to consider when evaluating Andexxa for formulary addition.” Neurocrit Care. 2020;33(1):323-326.

[4] Overview of the questionable drug andexanet (ANDEXXA). Worst Pills, Best Pills News. February 2021. https://www.worstpills.org/newsletters/view/1379. Accessed April 9, 2026.

[5] Andexanet (ANDEXXA): A blood thinner reversal agent whose net clinical benefit remains unproven. Worst Pills, Best Pills News. May 2025. https://www.worstpills.org/newsletters/view/1660. Accessed April 9, 2026.

[6] Public Citizen. Testimony before the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee regarding andexanet (Andexxa). November 21, 2024. https://www.citizen.org/wp-content/uploads/2704.pdf. Accessed April 9, 2026.

[7] Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141.

[8] Milling TJ, Middeldorp S, Xu L, et al. Final study report of andexanet alfa for major bleeding with factor Xa inhibitors. Circulation. 2023;147(13):1026-1038.

[9] Connolly SJ, Sharma M, Cohen AT, et al. Andexanet for factor Xa inhibitor–associated acute intracerebral hemorrhage. N Engl J Med. 2024;390(19):1745-1755.

[10] Public Citizen. Testimony before the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee regarding andexanet (Andexxa). November 21, 2024. https://www.citizen.org/wp-content/uploads/2704.pdf. Accessed April 9, 2026.