Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial

Robert G Hart¹, Mukul Sharma¹, Hardi Mundl², Ashkan Shoamanesh¹, Scott E Kasner³, Scott D Berkowitz⁴, Guillaume Pare¹, Bodo Kirsch⁵, Janice Pogue⁶, Calin Pater⁷, Gary Peters⁸, Antoni Davalos⁹, Wilfried Lang¹⁰, Yongjun Wang¹¹, Yilong Wang¹¹, Luis Cunha¹², Jens Eckstein¹³, Turgut Tatlisumak¹⁴, Nikolay Shamalov¹⁵, Robert Mikulik¹⁶, Pablo Lavados¹⁷, Graeme J Hankey¹⁸, Anna Czlonkowska¹⁹, Danilo Toni²⁰, Sebastian F Ameriso²¹, Rubens J Gagliardi²², Pierre Amarenco²³, Daniel Bereczki²⁴, Shinichiro Uchiyama²⁵, Arne Lindgren²⁶, Matthias Endres²⁷, Raf Brouns²⁸, Byung-Woo Yoon²⁹, George Ntaios³⁰, Roland Veltkamp³¹, Keith W Muir³², Serefnur Ozturk³³, Antonio Arauz³⁴, Natan Bornstein³⁵, Alan Bryer³⁶, Martin J O'Donnell³⁷, Jeffrey Weitz³⁸, Frank Peacock³⁹, Ellison Themeles⁴⁰, Stuart J Connolly⁴¹

Affiliations

¹ Department of Medicine (Neurology), Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Canada.
² Bayer Pharma AG, Wuppertal, Germany.
³ Department of Neurology, University of Pennsylvania, Philadelphia, USA.
⁴ Bayer Healthcare Pharmaceuticals, Parsippany, USA.
⁵ Bayer Pharma AG, Berlin, Germany.
⁶ Department of Clinical Epidemiology and Biostatistics, Department of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Canada.
⁷ Bayer Vital, Leverkusen, Germany.
⁸ Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.
⁹ Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
¹⁰ Hospital St. John of God, Medical Faculty, Sigmund Freud University, Vienna, Austria.
¹¹ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
¹² Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
¹³ Department of Innere Medizin, Universitätsspital Basel, Basel, Switzerland.
¹⁴ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
¹⁵ Pirogov Russian National Research Medical University, Moscow, Russia.
¹⁶ International Clinical Research Center and Neurology Department, St. Anne's University Hospital, Brno, Czech Republic.
¹⁷ Clinica Alemana de Santiago, Universidad del Desarrollo, Universidad de Chile, Santiago, Chile.
¹⁸ School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia.
¹⁹ 2nd Department of Neurology, Institute of Psychiatry and Neurology, Medical University of Warsaw, Warsaw, Poland.
²⁰ Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.
²¹ Institute for Neurological Research, Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia (FLENI), Buenos Aires, Argentina.
²² Irmandade da Santa Casa de Misericórdia de São Paulo, Sao Paulo, Brazil.
²³ Department of Neurology, Bichat Hospital, Paris, France.
²⁴ Department of Neurology, Semmelweis University, Budapest, Hungary.
²⁵ Sanno Hospital and Sanno Medical Center, Tokyo, Japan.
²⁶ Department of Clinical Sciences (Neurology), Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Lund University, Lund, Sweden.
²⁷ Klinik und Hochschulambulanz für Neurologie, Center for Stroke Research Berlin, Charité-Universitätsmedizin, Berlin, Germany.
²⁸ Universitair Ziekenhuis Brussel, Brussels, Belgium.
²⁹ Department of Neurology, Seoul National University Hospital, Seoul, Korea.
³⁰ Department of Medicine, University of Thessaly, Larissa, Greece.
³¹ Imperial College London, London, UK.
³² Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.
³³ Department of Neurology, Selcuk University, Konya, Turkey.
³⁴ Instituto Nacional de Neurologia y Neurocirugia, Mexico D.F., Mexico.
³⁵ Tel-Aviv Medical Center, Tel-Aviv, Israel.
³⁶ Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
³⁷ National University of Ireland, Galway, Ireland.
³⁸ Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.
³⁹ Baylor College of Medicine, Houston, USA.
⁴⁰ Population Health Research Institute, Hamilton, Canada.
⁴¹ Department of Medicine (Cardiology), Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Canada.

PMID: 31008276
PMCID: PMC6301240
DOI: 10.1177/2396987316663049

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial

Robert G Hart et al. Eur Stroke J. 2016 Sep.

. 2016 Sep;1(3):146-154.

doi: 10.1177/2396987316663049. Epub 2016 Aug 3.

Authors

Affiliations

¹ Department of Medicine (Neurology), Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Canada.
² Bayer Pharma AG, Wuppertal, Germany.
³ Department of Neurology, University of Pennsylvania, Philadelphia, USA.
⁴ Bayer Healthcare Pharmaceuticals, Parsippany, USA.
⁵ Bayer Pharma AG, Berlin, Germany.
⁶ Department of Clinical Epidemiology and Biostatistics, Department of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Canada.
⁷ Bayer Vital, Leverkusen, Germany.
⁸ Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.
⁹ Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
¹⁰ Hospital St. John of God, Medical Faculty, Sigmund Freud University, Vienna, Austria.
¹¹ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
¹² Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
¹³ Department of Innere Medizin, Universitätsspital Basel, Basel, Switzerland.
¹⁴ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
¹⁵ Pirogov Russian National Research Medical University, Moscow, Russia.
¹⁶ International Clinical Research Center and Neurology Department, St. Anne's University Hospital, Brno, Czech Republic.
¹⁷ Clinica Alemana de Santiago, Universidad del Desarrollo, Universidad de Chile, Santiago, Chile.
¹⁸ School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia.
¹⁹ 2nd Department of Neurology, Institute of Psychiatry and Neurology, Medical University of Warsaw, Warsaw, Poland.
²⁰ Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.
²¹ Institute for Neurological Research, Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia (FLENI), Buenos Aires, Argentina.
²² Irmandade da Santa Casa de Misericórdia de São Paulo, Sao Paulo, Brazil.
²³ Department of Neurology, Bichat Hospital, Paris, France.
²⁴ Department of Neurology, Semmelweis University, Budapest, Hungary.
²⁵ Sanno Hospital and Sanno Medical Center, Tokyo, Japan.
²⁶ Department of Clinical Sciences (Neurology), Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Lund University, Lund, Sweden.
²⁷ Klinik und Hochschulambulanz für Neurologie, Center for Stroke Research Berlin, Charité-Universitätsmedizin, Berlin, Germany.
²⁸ Universitair Ziekenhuis Brussel, Brussels, Belgium.
²⁹ Department of Neurology, Seoul National University Hospital, Seoul, Korea.
³⁰ Department of Medicine, University of Thessaly, Larissa, Greece.
³¹ Imperial College London, London, UK.
³² Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.
³³ Department of Neurology, Selcuk University, Konya, Turkey.
³⁴ Instituto Nacional de Neurologia y Neurocirugia, Mexico D.F., Mexico.
³⁵ Tel-Aviv Medical Center, Tel-Aviv, Israel.
³⁶ Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
³⁷ National University of Ireland, Galway, Ireland.
³⁸ Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.
³⁹ Baylor College of Medicine, Houston, USA.
⁴⁰ Population Health Research Institute, Hamilton, Canada.
⁴¹ Department of Medicine (Cardiology), Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Canada.

PMID: 31008276
PMCID: PMC6301240
DOI: 10.1177/2396987316663049

Abstract

Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source.

Main hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily.

Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches.

Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.

Keywords: Stroke; aspirin; cerebral embolism; cryptogenic stroke; embolic stroke of undetermined source; randomized trial; rivaroxaban; stroke prevention.

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Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All of the coauthors have received financial remuneration from Bayer Pharma AG for service on the Steering Committee except H. Mundl, S. Berkowitz, C. Pater, G. Peters, and B. Kirsch who are all employees of the sponsors. All coauthors receive stipend and research support for participation in NAVIGATE ESUS from the industry sponsors.

Figures

**Figure 1.**
NAVIGATE ESUS design overview.

**Figure 2.**
Countries participating in NAVIGATE ESUS.

**Figure 3.**
Conceptual scheme for screening to identify ESUS patients. Prior to diagnostic testing, approximately 15% of strokes would be ESUS. With each additional step in screening, the probability increases toward 100%. *After excluding less uncommon stroke etiologies (e.g. dissections).

See this image and copyright information in PMC

References

1. Hart RG, Diener H-C, Coutts SB, et al. on behalf of the Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–438. - PubMed
1. Li L, Yiin GS, Geraghty OC, et al. Oxford vascular study. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015; 14: 903–913. - PMC - PubMed
1. Fisher CM. Concerning strokes. Canadian Med Assoc J 1953; 69: 257–268. - PMC - PubMed
1. Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989; 25: 382–390. - PubMed
1. Perera KS, Vanassche T, Bosch J, et al. Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry. Int J Stroke 2016; 11: 526–533. - PubMed

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Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial

Affiliations

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Medical