Update: What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors?
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Introduction
In August 2018 and September 2020, the UIC Drug Information group reviewed the literature related to the use of andexanet alfa for the reversal of factor Xa inhibitors.1,2 The initial review can be accessed here and the 2020 update is available here. The purpose of this FAQ is to summarize data on the use of andexanet alfa for the reversal of the factor Xa inhibitors, apixaban or rivaroxaban, that have become available since the previous review.
Background
Andexanet alfa was approved by the United States Food and Drug Administration (FDA) Center for Biologics Evaluation and Research for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, in 2018 under the accelerated approval regulatory pathway.3,4 The accelerated approval for andexanet alfa was based on the change from baseline in anti-factor Xa activity in healthy volunteers; however, improvements in hemostasis have not been established per the drug’s prescribing information.3 In order to be granted full approval by the FDA, the manufacturer of andexanet alfa is required to verify its benefit through the results of studies that demonstrate an improvement in hemostasis in patients.3,4 To fulfill this requirement, the manufacturer conducted a phase 4, open-label, randomized controlled trial to assess the efficacy and safety of andexanet alfa compared to standard of care in acute intracranial hemorrhage (ICH) in patients receiving oral factor Xa inhibitors. The results of this trial, ANNEXA-I, were published in May 2024.5 Additional background and regulatory information on andexanet alfa may be found in the product’s prescribing information and on this FDA webpage.
Summary of new key evidence
In addition to the results of the phase 4 clinical trial ANNEXA-I, an updated literature search identified several meta-analyses published as well as additional results from the phase 3b/4, single-arm study ANNEXA-4.5-9 These studies are summarized in the Table.
The ANNEXA-4 phase 4 study enrolled 530 patients with ICH who were receiving a factor Xa inhibitor with the most recent dose taken within 15 hours of randomization.5 Patients enrolled in the study were randomized to receive either andexanet alfa (n=263), dosed according to the drug’s prescribing information, or usual care (n=267), which may have included prothrombin complex concentrate (PCC). Of the efficacy population analyzed, there were 195 patients who received PCC. Of the 119 patients for whom the type of PCC used was known, 110 received four-factor PCC (4F-PCC), 4 received three-factor PCC, and 5 received activated PCC or factor VIII inhibitor bypass activity. The primary endpoint of this study was hemostatic efficacy and was assessed 12 hours after randomization. Hemostatic efficacy for this trial was defined as having achieved all the following criteria: 1. A change in hematoma volume of 20% or less (excellent hemostatic efficacy) or 35% or less (good hemostatic efficacy) within 12 hours after baseline, 2. An increase in the National Institutes of Health Stroke Scale (NIHSS) of less than 7 points at 12 hours, and 3. No use of any rescue therapies (eg, andexanet alfa, PCC, or surgery) within 3 to 12 hours after randomization. Safety endpoints assessed included thrombotic events and death at 30 days; note that the study was not powered to draw any conclusions on the effect of treatment on death. Hemostatic efficacy was achieved in 67% of patients who received andexanet alfa versus 53.1% of patients who received usual care; however, andexanet alfa was associated with an increased risk of thrombotic events. In addition, the FDA’s 77th Cellular, Tissue, and Gene Therapies Advisory Committee found that the efficacy data did not show a clear, clinically meaningful benefit, despite the achievement of hemostatic efficacy at 12 hours.10 The FDA advisory committee also expressed concerns on the risks of andexanet alfa, including the increased rate of thrombotic events.
Several meta-analyses have also been published on the use of andexanet alfa versus PCC for reversal of factor Xa inhibitor-associated bleeding.6-8 These meta-analyses include several of the same prospective and retrospective studies, with 1 meta-analysis focused on patients with ICH, 2 focused on 4F-PCC as the comparator, and 2 that included data from the ANNEXA-I trial. These meta-analyses have slight differences in the endpoints analyzed. One of the meta-analyses, Sarhan et al 2025, found that andexanet alfa, versus PCC, may have an overall mortality benefit, and another, White et al 2024, found that andexanet alfa may have a 30-day mortality benefit.6,8 Two of these studies (Sarhan et al 2025 and Orso et al 2024) found a significant difference in the risk of thrombotic events with the use of andexanet alfa versus PCC.6,7
A final analysis of the ANNEXA-4 trial, a phase 3b/4 single-arm cohort study, was also published.9 The ANNEXA-4 trial enrolled patients with acute major bleeding within 18 hours of factor Xa inhibitor administration. The updated analysis found that excellent or good hemostasis was attained in 80% of patients, and thrombotic events occurred in 10% of patients.
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| Table. Overview of key studies examining andexanet alfa for factor Xa inhibitor reversal published since August 2020.5-9 | ||||
|---|---|---|---|---|
| Study design and duration | Subjects | Interventions/Comparators | Results | Conclusions |
| Meta-analyses | ||||
| Sarhan et al 20256 MA of controlled trials and observational studies Duration: Not specified | N=16 studies (1 RCT, 15 observational studies) assessing use of andexanet alfa or 4F-PCC for emergent reversal of factor Xa inhibitor (apixaban, rivaroxaban, edoxaban, betrixaban) associated ICH | Andexanet alfa IV at varying low-dose or high-dose regimens 4F-PCC IV at varying dosages | Efficacy: Anticoagulation reversal: 448/598 (80.2%) for andexanet alfa vs. 382/604 (63.2%) for 4F-PCC (risk ratio, 1.10; 95% CI, 1.01 to 1.20, p=0.02, favoring andexanet alfa) Mortality: 243/1384 (17.6%) for andexanet alfa vs. 385/1524 (25.3%) for 4F-PCC (risk ratio 0.72; 95% CI, 0.54 to 0.95; p=0.02, favoring andexanet alfa) In-hospital mortality: 142/938 (15.1%) for andexanet alfa vs. 246/999 (24.6%) for 4F-PCC (risk ratio, 0.67; 95% CI, 0.45 to 0.99, p=0.047, favoring andexanet alfa) 30-day mortality: 101/446 (22.6%) for andexanet alfa vs. 139/525 (26.5%) for 4F-PCC (risk ratio, 0.82; 95% CI, 0.58 to 1.16, p=0.26) Safety: Thromboembolic events: 71/602 (11.8%) for andexanet alfa vs. 48/576 (8.3%) for 4F-PCC (risk ratio, 1.47; 95% CI, 1.01 to 2.15; p=0.05, favoring 4F-PCC) | Andexanet alfa has better hemostatic efficacy and greater reduction in overall and in-hospital mortality rates compared to 4F-PCC; however, is associated with more thrombotic events |
| Orso et al 20247 MA of controlled trials and observational studies Duration: Not specified | N=22 studies (1 RCT, 5 PSM studies, 16 retrospective studies) assessing use of andexanet alpha vs. 4F-PCC for reversal of DOACs (for ICH, non-ICH, or mixed) | Andexanet alfa 4F-PCC | Efficacy: All-cause short-term mortality of RCT and PSM studies using random effects model: risk ratio, 0.71; 95% CI, 0.37 to 1.34 All-cause short-term mortality of 16 retrospective studies using random effects model: risk ratio, 0.82; 95% CI, 0.63 to 1.07 All-cause short-term mortality of ICH studies: risk ratio, 0.94; 95% CI, 0.04 to 20.40 All-cause short-term mortality of non-ICH studies: risk ratio, 0.73; 95% CI, 0.00 to 640.25 Safety: Thromboembolic events of RCT and PSM studies using random effects model: risk ratio, 1.71; 95% CI, 1.01 to 2.89, favoring 4F-PCC | No significant difference was found between andexanet alfa and 4F-PCC in mortality; andexanet alfa had increased risk of thromboembolic events |
| White et al 20248 MA of comparative observational studies Duration: Not specified | N=18 studies assessing use of andexanet alfa vs. PCC for reversal of major bleeding from use of factor Xa inhibitor anticoagulants | Andexanet alfa PCC (including 4F-PCC) | Efficacy: Hemostatic efficacy: OR, 1.36; 95% CI, 1.01 to 1.84, favoring andexanet alfa In hospital mortality: OR, 0.67; 95% CI, 0.40 to 1.10 30-day mortality: OR, 0.53; 95% CI, 0.37 to 0.76, favoring andexanet alfa Safety: Thrombotic events: OR, 1.45; 95% CI, 0.81 to 2.60 | Andexanet alfa has a suggested benefit over PCC in enhancing hemostatic efficacy and in reducing 30-day mortality; there was not a significant difference in thrombotic events between andexanet alfa and PCC |
| Prospective studies | ||||
| Connolly et al 20245 ANNEXA-I Phase 4, OL, MC, prospective, RCT Follow-up: up to 30 days | N=530 patients with ICH and were receiving a factor Xa inhibitor with most recent dose taken within 15 hours before randomization Mean age: 79 years Factor Xa inhibitor: - apixaban (62.5% in andexanet group and 59.2% in usual care group) - rivaroxaban (28.6% in andexanet group and 28.5% in usual care group) - edoxaban (8.9% in andexanet group and 11% in usual care group) | Andexanet alfa IV: High-dose or low-dose bolus over 15 to 30 minutes, followed by continuous infusion over 2 hours, as in accordance with the approved FDA labeling Usual care, as determined by local physicians and could include PCC | Primary: Hemostatic efficacy*: 150/224 (67%) for andexanet alfa vs. 121/228 (53.1%) for usual care (adjusted difference, 13.4%; 95% CI, 4.6 to 22.2; p=0.003) Safety: Thrombotic event (≥1): 27 patients (10.3%) for andexanet alfa vs. 15 patients (5.6%) for usual care (adjusted difference, 4.6%; 95% CI, 0.1 to 9.2; p=0.048) Death: 73 patients (27.8%) for andexanet alfa vs. 68 (25.5%) for usual care (adjusted difference, 2.5%; 95% CI, -5.0 to 10.0; p=0.51) | Use of andexanet alfa vs. usual care in patients with ICH resulted in better hemostatic efficacy, but was associated with increased thrombotic events |
| Milling TJ Jr et al 20239 Final study report of ANNEXA-4, a phase 3b/4, single-group, MC, prospective cohort study Follow-up | N=479 patients with acute major bleeding within 18 hours of factor Xa inhibitor administration Mean age: 78 years Factor Xa inhibitor: apixaban (51%) rivaroxaban (37%) edoxaban (8%) enoxaparin (5%) Sites of bleeding: intracranial (69%) gastrointestinal (23%) other (8%) | Andexanet alfa IV bolus for period of 15 to 30 minutes, followed by 2-hour infusion at either a high-dose or low-dose regimen based on the specific factor Xa inhibitor received, its dose, and time since last dose Low-dose regimen: 400 mg bolus and 480 mg infusion High-dose regimen: 800 mg bolus and 960 mg infusion | Primary: Anti-factor Xa activity decreased by: - 93% (95% CI, 94 to 93) from baseline with apixaban - 94% (95% CI, 95 to 93) with rivaroxaban - 71% (95% CI, 82 to 65) with edoxaban - 75% (95% CI, 79 to 67) with enoxaparin Hemostatic efficacy: Rated as good or excellent in 80% (95% CI, 75 to 84) of patients overall Safety: In a 30-day follow-up period, 50 patients (10.4%) had 1 or more thrombotic events, including 15 DVTs, 7 PEs, 22 ischemic strokes, 3 TIAs, and 10 MIs | In this final analysis of the ANNEXA-4 trial, treatment with andexanet alfa reduced anti-factor Xa levels and was associated with good or excellent hemostatic efficacy |
| *defined as a change in the hematoma volume of 20% or less or 35% or less within 12 hours after baseline, an increase in the NIHSS score of less than 7 points at 12 hours, and receipt of no rescue therapies such as andexanet, PCC, or surgery to decompress hematoma within 3 to 12 hours after randomization. Abbreviations: 4F-PCC=four-factor prothrombin complex concentrate; CI=confidence interval; DOACs=direct oral anticoagulants; DVT=deep-vein thrombosis; FDA=Food and Drug Administration; ICH=intracranial hemorrhage; IV=intravenous; MA=meta-analysis; MC=multicenter; MI=myocardial infarction; NIHSS=National Institutes of Health Stroke Scale; OL=open-label; OR=odds ratio; PCC=prothrombin complex concentrate; PE=pulmonary embolism; PSM=propensity score matching; RCT=randomized controlled trial; TIA=transient ischemic attack. |
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Discussion
The results of the ANNEXA-I trial, the meta-analyses, and the ANNEXA-4 final analysis provide additional data to support its efficacy in achieving hemostatic efficacy. The meta-analyses indicated the potential for benefit in the reduction of risk of mortality with the use of andexanet alfa for major bleeding associated with factor Xa inhibitor use; however, most trials included were retrospective and prone to bias. Additional long-term clinical data on the potential mortality benefit are still needed from prospective, randomized clinical trials. In addition, there is concern with the increased thromboembolic risk with andexanet alfa use.
Guidance from the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH), which includes additional summaries of the ANNEXA-I and ANNEXA-4 studies, lists indications on when to use or avoid use of andexanet.11 Andexanet alfa can be used specifically for the reversal of rivaroxaban and apixaban in situations of life-threatening bleeding, including intracranial hemorrhage, expanding, or uncontrollable bleeding. Andexanet alfa, along with other therapies (ie, PCC), should not be used for urgent or emergency surgery, elective surgery, gastrointestinal bleeds that can be stopped by local supportive measures, high factor Xa inhibitor drug levels without associated bleeding, and need for surgery or intervention that can be delayed long enough to permit clearance of the factor Xa inhibitor. Whether the use of andexanet alfa is preferred over PCC is unclear.
Conclusion
Andexanet alfa appears to be effective for achieving hemostasis for factor Xa inhibitor-associated uncontrolled major bleeding, but has an increased risk of thromboembolic events, and its mortality benefit remains unclear. Additional data are still needed to assess its full benefit and risk profile, as well as its place in therapy.
References
- Coglianese N. What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors? UIC Drug Information Group. Published August 2018. Accessed May 23, 2025. https://dig.pharmacy.uic.edu/faqs/2018-2/august-2018-faqs/
- Koppen L. Update: What data support the use of andexanet alfa (ANDEXXA) for the reversal of factor Xa inhibitors? UIC Drug Information Group. Published September 2020. Accessed May 23, 2025. https://dig.pharmacy.uic.edu/faqs/2020-2/september-2020-faqs/update_what_data_support-the-use-of_andexanet_alfa_andexxa_for_the_reversal_of_factor_xa_inhibitors/
- Andexxa. Package insert. AstraZeneca Pharmaceuticals LP; 2025.
- US Food and Drug Administration. Andexxa. US Food and Drug Administration website. Updated March 29, 2024. Accessed May 23, 2025. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/andexxa
- 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. doi:10.1056/NEJMoa2313040
- Sarhan K, Mohamed RG, Elmahdi RR, et al. Efficacy and safety of andexanet alfa versus four factor prothrombin complex concentrate for emergent reversal of factor Xa inhibitor associated intracranial hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2025;42(2):701-714. doi:10.1007/s12028-024-02130-y
- Orso D, Fonda F, Brussa A, et al. Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis. Crit Care. 2024;28(1):221. doi:10.1186/s13054-024-05014-x
- White CM, Caroti KS, Bessada Y, et al. Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta-analysis. Pharmacotherapy. 2024;44(5):394-408. doi:10.1002/phar.2925
- Milling TJ Jr, 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. doi:10.1161/CIRCULATIONAHA.121.057844
- US Food and Drug Administration. Cellular, tissue, and gene therapies advisory committee November 21, 2024 meeting announcement. US Food and Drug Administration website. Published November 21, 2024. Updated February 14, 2025. Accessed May 26, 2025. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-november-21-2024-meeting-announcement-11212024
- Levy JH, Shaw JR, Castellucci LA, et al. Reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2024;22(10):2889-2899. doi:10.1016/j.jtha.2024.07.009
Prepared by:
Jacqueline Wasynczuk, PharmD
Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy
June 2025
The information presented is current as of May 23, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.