Case Vignette
A 72-year-old male with a history of atrial fibrillation on apixaban 5 mg BID presents to the ED with altered mental status and right-sided weakness following a fall. A CT scan reveals a large intraparenchymal hemorrhage, and his last dose of apixaban was four hours ago. Given the severity of the bleed and recent Factor Xa inhibitor use, the team must decide between Kcentra versus Andexxa for urgent reversal.
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ACEP Now: October 2025 (Digital)When?
When should the emergency clinician consider giving this drug? Factor Xa reversal is indicated in patients with:
- Life-threatening bleeding: Intracranial hemorrhage, expanding hemorrhage.
- Bleeding in a closed space or critical organ: Intracranial, intraocular, pericardial, retroperitoneal, etc.
- Persistent major bleeding despite local hemostatic measures.
- Need for emergent surgery or procedures with high bleeding risk (e.g., neurosurgery, cardiac surgery).
Guideline Recommendations:
- First-line: Andexanet alfa (Andexxa) for apixaban/rivaroxaban reversal if available.
- Alternative: Prothrombin complex concentrate (Kcentra) if andexanet alfa is unavailable.
- Edoxaban reversal: Not FDA-approved, but ACC guidelines recommend high-dose Andexxa.
Why?
In what way does this drug affect the target condition?
| Parameter | Kcentra (PCC) | Andexanet Alfa (Andexxa) |
|---|---|---|
| Mechanism of Action | Replaces vitamin K-dependent clotting factors (II, VII, IX, X) | Binds and sequesters Factor Xa inhibitors, restoring thrombin generation |
| Pharmacokinetics | Rapid onset, prolonged duration (6-12 hours) | Immediate onset, anti-Xa activity normalizes within two hours post-infusion |
| Efficacy | Provides clotting factors but does not directly bind Factor Xa inhibitors | Greater reduction in anti-Xa activity and better hemostatic efficacy |
| Risks | Thrombotic risk, asthenia | Higher thromboembolic risk (stroke, MI), possible procoagulant effects |
Overview of Evidence
| Study | Design & Sample Size | Intervention & Comparison | Key Findings |
|---|---|---|---|
| Connolly SJ, et al (2024) | RCT (N=530) | Andexanet Alfa versus PCC | Hemostatic Efficacy: 67 percent with Andexxa versus 53.1 percent with PCC (p=0.003). Thrombotic Events: Higher with Andexxa (10.3 percent versus 5.6 percent, p=0.048). Mortality: No difference at 30 days. |
| Oliverira Ferreira L, et al (2024) | Systematic Review (N=1996) | Andexxa versus four-factor PCC | Hemostatic Efficacy: No difference. Thrombotic Events: Higher with Andexxa in four studies. Mortality: No difference. |
| Dobesh PP, et al (2023) | Observational Cohort (N=4395) | Andexxa versus four-factor PCC | Mortality: 50 percent lower for Andexxa (OR 0.5, 95 percent CI 0.39-0.65). Consistent benefit in ICH and GI bleeds. |
| Ammar AA, et al (2021) | Retrospective Review (N=44) | Andexxa versus four-factor PCC | ICH Stability on CT: No difference at 6h and 24h. Functional Outcome: Similar (36 percent versus 38 percent, p=0.81). Thrombosis: No difference (7 percent versus 0 percent, p=0.53). |
| Connolly SJ, et al (2019) | Retrospective (N=352) | Andexxa | Anti-Xa Reduction: 92 percent for apixaban and rivaroxaban. Hemostatic Efficacy: 82 percent at 12h. Thrombosis: 10 percent. Mortality: 14 percent at 30 days. |
| Song Y, et al (2017) | Open-label RCT (N=15) | PCC (Cofact versus Beriplex versus Saline) | Thrombin Potential: PCC reversed apixaban’s effect within 4h versus 45h for placebo. ETP Peaked at 21h post-infusion. |
| Siegal DM, et al (2015) | RCT (N=33) | Andexxa versus Placebo | Anti-Xa Reduction: 94 percent (apixaban) & 92 percent (rivaroxaban) with Andexxa (p<0.001). Thrombin Generation: Fully restored in 96 percent with Andexxa versus 7 percent with placebo. |
Summary
- Andexxa has higher hemostatic efficacy but increased thrombotic risk.
- No significant mortality differences between Andexxa and PCC.
- PCC remains a viable alternative, especially in settings where thrombotic risk is a concern.
References
- Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 15, 2024, from http://www.micromedexsolutions.com/
- 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;Jul 14:[Epub ahead of print].
- Baugh CW, Levine M, Cornutt D, et al. Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel. Ann Emerg Med. 2020;76(4):470-485. doi:10.1016/j.annemergmed.2019.09.001
- Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. doi:10.1007/s12028-015-0222-x
- Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018;154(5):1121- 1201. doi:10.1016/j.chest.2018.07.040
- Levy JH, Ageno W, Chan NC, et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(3):623-627. doi:10.1111/jth.13227
- Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi:10.1111/j.1538-7836.2005.01204.x
- 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
- Ferreira LO, Oldemburg RAL, Leitão Filho JM, et al. Andexanet Alfa versus Four-Factor Prothrombin Complex Concentrate for the Reversal of Factor Xa (FXa) Inhibitor-Associated Intracranial Hemorrhage: A Systematic Review of Retrospective Studies. J Clin Med. 2024;13(11):3077. Published 2024 May 24. doi:10.3390/jcm13113077
- Dobesh PP, Fermann GJ, Christoph MJ, et al. Lower mortality with andexanet alfa vs 4-factor prothrombin complex concentrate for factor Xa inhibitor-related major bleeding in a U.S. hospital-based observational study. Res Pract Thromb Haemost. 2023;7(6):102192. Published 2023 Aug 30. doi:10.1016/j.rpth.2023.102192
- Ammar AA, Ammar MA, Owusu KA, et al. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Neurocrit Care. 2021;35(1):255-261. doi:10.1007/s12028-020-01161-5
- Song Y, Wang Z, Perlstein I, et al. Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study. J Thromb Haemost. 2017;15(11):2125-2137. doi:10.1111/jth.13815
- Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380(14):1326-1335. doi:10.1056/NEJMoa1814051
- Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413- 2424. doi:10.1056/NEJMoa1510991
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