Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source

NAVIGATE ESUS Investigators; Stefan Oberndorfer

doi:10.1056/NEJMoa1802686

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source

NAVIGATE ESUS Investigators, Stefan Oberndorfer

Division of Neurology (University Hospital St. Pölten)

Research output: Journal article (peer-reviewed) › Journal article

692 Citations (Scopus)

Abstract

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.

METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.

RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).

CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Original language	English
Pages (from-to)	2191-2201
Number of pages	11
Journal	New England Journal of Medicine
Volume	378
Issue number	23
DOIs	https://doi.org/10.1056/NEJMoa1802686
Publication status	Published - 07 Jun 2018

Keywords

Aged
Aspirin/adverse effects
Brain Ischemia/prevention & control
Factor Xa Inhibitors/adverse effects
Female
Hemorrhage/chemically induced
Humans
Intracranial Embolism/drug therapy
Kaplan-Meier Estimate
Male
Middle Aged
Platelet Aggregation Inhibitors/adverse effects
Rivaroxaban/adverse effects
Secondary Prevention/methods
Stroke/etiology

ASJC Scopus subject areas

General Medicine

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10.1056/NEJMoa1802686

Cite this

@article{d6b64146bd9b481cb663f223582b0576,

title = "Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source",

abstract = "BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).",

keywords = "Aged, Aspirin/adverse effects, Brain Ischemia/prevention & control, Factor Xa Inhibitors/adverse effects, Female, Hemorrhage/chemically induced, Humans, Intracranial Embolism/drug therapy, Kaplan-Meier Estimate, Male, Middle Aged, Platelet Aggregation Inhibitors/adverse effects, Rivaroxaban/adverse effects, Secondary Prevention/methods, Stroke/etiology",

author = "{NAVIGATE ESUS Investigators} and Hart, {Robert G} and Mukul Sharma and Hardi Mundl and Kasner, {Scott E} and Bangdiwala, {Shrikant I} and Berkowitz, {Scott D} and Balakumar Swaminathan and Pablo Lavados and Yongjun Wang and Yilong Wang and Antonio Davalos and Nikolay Shamalov and Robert Mikulik and Luis Cunha and Arne Lindgren and Antonio Arauz and Wilfried Lang and Anna Czlonkowska and Jens Eckstein and Gagliardi, {Rubens J} and Pierre Amarenco and Ameriso, {Sebastian F} and Turgut Tatlisumak and Roland Veltkamp and Hankey, {Graeme J} and Danilo Toni and Daniel Bereczki and Shinichiro Uchiyama and George Ntaios and Byung-Woo Yoon and Raf Brouns and Matthias Endres and Muir, {Keith W} and Natan Bornstein and Serefnur Ozturk and O'Donnell, {Martin J} and {De Vries Basson}, {Matthys M} and Guillaume Pare and Calin Pater and Bodo Kirsch and Patrick Sheridan and Gary Peters and Weitz, {Jeffrey I} and Peacock, {W Frank} and Ashkan Shoamanesh and Benavente, {Oscar R} and Campbell Joyner and Ellison Themeles and Connolly, {Stuart J} and Stefan Oberndorfer",

note = "Funding Information: The trial was conducted and reported in accordance with the protocol (available with the full text of this article at NEJM.org) and the statistical analysis plan. The trial was initiated by the two principal investigators, who designed the trial with input from a steering committee (which included representatives of the trial sponsors, Bayer and Janssen Research and Development). The Population Health Research Institute at McMaster University selected the trial sites, collected and managed the data, and performed the data analysis, with financial support from the sponsors. The trial sponsors provided trial medications, contracted with and paid the members of the steering committee and the trial sites, and provided site monitoring. Publisher Copyright: {\textcopyright} 2018 Massachussetts Medical Society. All rights reserved.",

year = "2018",

month = jun,

day = "7",

doi = "10.1056/NEJMoa1802686",

language = "English",

volume = "378",

pages = "2191--2201",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "23",

}

TY - JOUR

T1 - Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source

AU - NAVIGATE ESUS Investigators

AU - Hart, Robert G

AU - Sharma, Mukul

AU - Mundl, Hardi

AU - Kasner, Scott E

AU - Bangdiwala, Shrikant I

AU - Berkowitz, Scott D

AU - Swaminathan, Balakumar

AU - Lavados, Pablo

AU - Wang, Yongjun

AU - Wang, Yilong

AU - Davalos, Antonio

AU - Shamalov, Nikolay

AU - Mikulik, Robert

AU - Cunha, Luis

AU - Lindgren, Arne

AU - Arauz, Antonio

AU - Lang, Wilfried

AU - Czlonkowska, Anna

AU - Eckstein, Jens

AU - Gagliardi, Rubens J

AU - Amarenco, Pierre

AU - Ameriso, Sebastian F

AU - Tatlisumak, Turgut

AU - Veltkamp, Roland

AU - Hankey, Graeme J

AU - Toni, Danilo

AU - Bereczki, Daniel

AU - Uchiyama, Shinichiro

AU - Ntaios, George

AU - Yoon, Byung-Woo

AU - Brouns, Raf

AU - Endres, Matthias

AU - Muir, Keith W

AU - Bornstein, Natan

AU - Ozturk, Serefnur

AU - O'Donnell, Martin J

AU - De Vries Basson, Matthys M

AU - Pare, Guillaume

AU - Pater, Calin

AU - Kirsch, Bodo

AU - Sheridan, Patrick

AU - Peters, Gary

AU - Weitz, Jeffrey I

AU - Peacock, W Frank

AU - Shoamanesh, Ashkan

AU - Benavente, Oscar R

AU - Joyner, Campbell

AU - Themeles, Ellison

AU - Connolly, Stuart J

AU - Oberndorfer, Stefan

N1 - Funding Information: The trial was conducted and reported in accordance with the protocol (available with the full text of this article at NEJM.org) and the statistical analysis plan. The trial was initiated by the two principal investigators, who designed the trial with input from a steering committee (which included representatives of the trial sponsors, Bayer and Janssen Research and Development). The Population Health Research Institute at McMaster University selected the trial sites, collected and managed the data, and performed the data analysis, with financial support from the sponsors. The trial sponsors provided trial medications, contracted with and paid the members of the steering committee and the trial sites, and provided site monitoring. Publisher Copyright: © 2018 Massachussetts Medical Society. All rights reserved.

PY - 2018/6/7

Y1 - 2018/6/7

N2 - BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

AB - BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

KW - Aged

KW - Aspirin/adverse effects

KW - Brain Ischemia/prevention & control

KW - Factor Xa Inhibitors/adverse effects

KW - Female

KW - Hemorrhage/chemically induced

KW - Humans

KW - Intracranial Embolism/drug therapy

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Platelet Aggregation Inhibitors/adverse effects

KW - Rivaroxaban/adverse effects

KW - Secondary Prevention/methods

KW - Stroke/etiology

UR - http://www.scopus.com/inward/record.url?scp=85047954755&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1802686

DO - 10.1056/NEJMoa1802686

M3 - Journal article

C2 - 29766772

SN - 0028-4793

VL - 378

SP - 2191

EP - 2201

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 23

ER -

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source

Abstract

Keywords

ASJC Scopus subject areas

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