Evidence map›Paper›PMID 30274772›Full record

Trial reportThe Lancet. Neurology2018

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.

Scott E Kasner, Balakumar Swaminathan, Pablo Lavados, Mukul Sharma, Keith Muir, Roland Veltkamp, Sebastian F Ameriso, Matthias Endres, Helmi Lutsep, Steven R Messé and 13 more

Erratum issuedOpen access · greenAbstract readClinical Trial, Phase IIIMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The Lancet. Neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 61 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
61citing papers in PubMed, 6 pooled it
20.3field-weighted citation impact, top 1% 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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

61 citing papers in PubMed, 6 syntheses or guidelines pooled it, 177 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Aspirin or anticoagulation after cryptogenic stroke with patent foramen ovale: systematic review and meta-analysis of randomized controlled trials.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2020
    Pooled it
  5. Guideline
  6. Pooled it
  7. Article
  8. Cryptogenic stroke in women: impact of insertable cardiac monitoring in the STROKEWISE cohort study.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026
    Article
  9. Article
  10. Review
  11. Review
  12. Observational
  13. Navigating the Uncertainties of Antithrombotic Therapy After Transcatheter Patent Foramen Ovale Closure: A Comprehensive Review.Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions · 2025
    Review
  14. Review
  15. Review
  16. Article
  17. Review
  18. Review
  19. Review
  20. Article

1 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

23 authors at 18 institutions in 9 countries.

Scott E KasnerDepartment of Neurology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: kasner@pennmedicine.upenn.edu.
Balakumar SwaminathanPopulation Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.
Pablo LavadosClinica Alemana de Santiago, Universidad del Desarrollo, Universidad de Chile, Santiago, Chile.
Mukul SharmaDepartment of Medicine (Neurology), McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.
Keith MuirInstitute of Neuroscience and Psychology, Queen Elizabeth University Hospital, University of Glasgow, Glasgow, Scotland, UK.
Roland VeltkampChefarzt, Neurologische Klinik, Alfried-Krupp Krankenhaus Rüttenscheid, Essen, Germany.
Sebastian F AmerisoInstitute for Neurological Research, Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia (FLENI), Buenos Aires, Argentina.
Matthias EndresDepartment of Neurology, Charité - Universitätsmedizin, Berlin, Germany.
Helmi LutsepDepartment of Neurology, Oregon Health and Science University, Portland, OR, USA.
Steven R MesséDepartment of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
J David SpenceRobarts Research Institute and Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
Krassen NedeltechevDepartment of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
Kanjana PereraPopulation Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.
Gustavo SantoDepartment of Neurology, Hospitais da Universidade de Coimbra, Coimbra, Portugal.
Veronica OlavarriaClinica Alemana de Santiago, Santiago, Chile.
Arne LindgrenDepartment of Clinical Sciences (Neurology), Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Lund University, Lund, Sweden.
Shrikant BangdiwalaDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
Ashkan ShoamaneshDivision of Neurology, McMaster University, Hamilton, ON, Canada.
Scott D BerkowitzVice President and Head, Thrombosis Group, Global Clinical Development, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
Hardi MundlBayer-Pharma AG, Wuppertal, Germany.
Stuart J ConnollyFaculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
Robert G HartDivision of Neurology, McMaster University, Hamilton, ON, Canada.
NAVIGATE ESUS Investigators
McMaster University · CAUniversity of Pennsylvania · USBayer (United States) · USImpact · CAFundación para la Lucha contra las Enfermedades Neurológicas de la Infancia · ARLund University · SEPopulation Health Research Institute · CABayer (Germany) · DEKantonsspital Aarau · CHQueen Elizabeth University Hospital · GBUniversidad del Desarrollo · CLWestern University · CACharité - Universitätsmedizin Berlin · DEOregon Health & Science University · USAlfried Krupp Hospital · DEClínica Alemana · CLHamilton Health Sciences · CAHospitais da Universidade de Coimbra · PT

Funding

A Patient Centered Approach to Restarting Oral Anticoagulant Therapy After Major HemorrhageK23HL127227 · NHLBI · SETON HEALTHCARE · PI MILLING, TRUMAN · 2016 to 2021
$764k
Chief Scientist Office SCAF/17/01NHLBI NIH HHS K23 HL127227
6 · The paper itself

Abstract

backgroundPatent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.

methodsNAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.

findingsBetween Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; p

interpretationAmong patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.

fundingBayer and Janssen.

Indexed as

AgedAspirinCohort StudiesDouble-Blind MethodFactor Xa InhibitorsFemaleForamen Ovale, PatentHumansInternational CooperationMaleMEDLINEMiddle AgedPlatelet Aggregation InhibitorsRivaroxabanStatistics, NonparametricStrokeAspirinFactor Xa InhibitorsPlatelet Aggregation InhibitorsRivaroxaban

Identifiers

PMID30274772
PMCPMC6662613
OpenAlexW2894235280

What OpenQuestion holds

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Registered trials

None linked

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.