Evidence map›Paper›PMID 33966491›Full record

Trial reportStroke2021

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy.

Andrew M Demchuk, Patrick Yue, Elena Zotova, Juliet Nakamya, Lizhen Xu, Truman J Milling, Tomoyuki Ohara, Joshua N Goldstein, Saskia Middeldorp, Peter Verhamme and 7 more

Erratum issued Registry-linked trialOpen access · bronzeAbstract readClinical Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Stroke, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT02329327 (Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding), which is not on this map. Cited by 30 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed, 4 pooled it
7.4field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02329327 phase3completednot on this map

Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)

TypeinterventionalSponsorAlexion Pharmaceuticals, Inc.Ran2015 to 2020Enrolled479ConditionsBleedingArmsAndexanet
3 · Its place in the literature

Who cites it

30 citing papers in PubMed, 4 syntheses or guidelines pooled it, 64 citations in OpenAlex.

  1. Guideline
  2. Pooled it
  3. Guideline
  4. Pooled it
  5. Article
  6. Article
  7. Real-world clinical decision of andexanet alfa administration for intracranial hemorrhage during anticoagulant therapy using factor Xa inhibitor.Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures) · 2026
    Article
  8. Observational
  9. Clinical Management of Cerebral Amyloid Angiopathy.Journal of clinical medicine · 2025
    Review
  10. Review
  11. Review
  12. Review
  13. Article
  14. Andexanet alfa: trials just leave us with more questions.Research and practice in thrombosis and haemostasis · 2025
    Article
  15. Review
  16. Review
  17. Article
  18. Review
  19. Article
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

17 authors at 9 institutions in 6 countries.

Andrew M DemchukDepartments of Clinical Neurosciences and Radiology, Cumming School of Medicine, University of Calgary, AB, Canada (A.M.D.).
Patrick YuePortola Pharmaceuticals, Inc, now Alexion Pharmaceuticals, Inc, South San Francisco, CA (P.Y., P.B.C., J.T.C.).
Elena ZotovaDepartment of Medicine, McMaster University, Hamilton, ON, Canada (E.Z., J.N., L.X., J.W.E., M.C., S.J.C.).
Juliet NakamyaDepartment of Medicine, McMaster University, Hamilton, ON, Canada (E.Z., J.N., L.X., J.W.E., M.C., S.J.C.).
Lizhen XuDepartment of Medicine, McMaster University, Hamilton, ON, Canada (E.Z., J.N., L.X., J.W.E., M.C., S.J.C.).
Truman J MillingDepartment of Neurology, Seton Dell Medical School Stroke Institute, Austin, TX (T.J.M.).
Tomoyuki OharaDepartment of Neurology, Kyoto Prefectural University of Medicine, Japan (T.O.).
Joshua N GoldsteinDepartment of Emergency Medicine, Massachusetts General Hospital, Boston (J.N.G.).
Saskia MiddeldorpDepartment of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef, the Netherlands (S.M.).
Peter VerhammeCenter for Molecular and Vascular Biology, University of Leuven, Belgium (P.V.).
Jose Luis Lopez-SendonDepartment of Cardiology, Hospital Universitario La Paz, IdiPaz, Universidad Autonoma de Madrid, Spain (J.L.L.-S.).
Pamela B ConleyPortola Pharmaceuticals, Inc, now Alexion Pharmaceuticals, Inc, South San Francisco, CA (P.Y., P.B.C., J.T.C.).
John T CurnuttePortola Pharmaceuticals, Inc, now Alexion Pharmaceuticals, Inc, South San Francisco, CA (P.Y., P.B.C., J.T.C.).
John W EikelboomDepartment of Medicine, McMaster University, Hamilton, ON, Canada (E.Z., J.N., L.X., J.W.E., M.C., S.J.C.).
Mark CrowtherDepartment of Medicine, McMaster University, Hamilton, ON, Canada (E.Z., J.N., L.X., J.W.E., M.C., S.J.C.).
Stuart J ConnollyDepartment of Medicine, McMaster University, Hamilton, ON, Canada (E.Z., J.N., L.X., J.W.E., M.C., S.J.C.).
ANNEXA-4 Investigators
McMaster University · CAPortola Pharmaceuticals (United States) · USHospital Universitario La Paz · ESKyoto Prefectural University of Medicine · JPMassachusetts General Hospital · USSeton Medical Center · USUniversity of Amsterdam · NLUniversity of Calgary · CAVlaams Instituut voor Biotechnologie · BE

Funding

A Patient Centered Approach to Restarting Oral Anticoagulant Therapy After Major HemorrhageK23HL127227 · NHLBI · SETON HEALTHCARE · PI MILLING, TRUMAN · 2016 to 2021
$764k
NHLBI NIH HHS K23 HL127227
6 · The paper itself

Abstract

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Indexed as

HemostasisIntracranial HemorrhagesAgedAged, 80 and overBlood Coagulation Factor InhibitorsFactor XaFemaleHumansMalePyrazolesPyridonesRecombinant ProteinsRivaroxabanapixabanBlood Coagulation Factor InhibitorsFactor XaPRT064445PyrazolesPyridonesRecombinant ProteinsRivaroxabanandexanet alfadirect factor Xa inhibitor reversalintracranial hemorrhage

Identifiers

PMID33966491
PMCPMC8140631
OpenAlexW3162972900

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.