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

NAVIGATE ESUS Investigators

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: Patent 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. Methods: NAVIGATE 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. Findings: Between 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 interaction =0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; p interaction =0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among 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. Funding: Bayer and Janssen.

Original languageEnglish
Pages (from-to)1053-1060
Number of pages8
JournalThe Lancet Neurology
Volume17
Issue number12
DOIs
Publication statusPublished - 2018 Dec

Fingerprint

Patent Foramen Ovale
Aspirin
Stroke
Transesophageal Echocardiography
Rivaroxaban
Anticoagulants
Echocardiography
Meta-Analysis
Hemorrhage
Therapeutics
Safety
Information Storage and Retrieval
Secondary Prevention
Hemostasis

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

@article{1e9f72598f90473e90a17021bf236f56,
title = "Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial",
abstract = "Background: Patent 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. Methods: NAVIGATE 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. Findings: Between 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 interaction =0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95{\%} CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95{\%} CI 1·69–4·70; p interaction =0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95{\%} CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among 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. Funding: Bayer and Janssen.",
author = "{NAVIGATE ESUS Investigators} and Kasner, {Scott E.} and Balakumar Swaminathan and Pablo Lavados and Mukul Sharma and Keith Muir and Roland Veltkamp and Ameriso, {Sebastian F.} and Matthias Endres and Helmi Lutsep and Mess{\'e}, {Steven R.} and Spence, {J. David} and Krassen Nedeltechev and Kanjana Perera and Gustavo Santo and Veronica Olavarria and Arne Lindgren and Shrikant Bangdiwala and Ashkan Shoamanesh and Berkowitz, {Scott D.} and Hardi Mundl and Connolly, {Stuart J.} and Hart, {Robert G.} and N. Abdelhamid and {Abdul Rahman}, D. and M. Abdul-Saheb and P. Abreu and M. Abroskina and {Abu Ahmad}, F. and S. Accassat and M. Acciaresi and A. Adami and N. Ahmad and F. Ahmed and {Alberto Hawkes}, M. and F. Alemseged and A. Ali and R. Altavilla and L. Alwis and P. Amarenco and S. Amaro and {Amaya Sanchez}, {L. E.} and {Amelia Pinto}, A. and Ameriso, {S. F.} and H. Amin and T. Amino and Amjad, {A. K.} and E. Anagnostou and G. Andersen and C. Anderson and Anderson, {D. C.}",
year = "2018",
month = "12",
doi = "10.1016/S1474-4422(18)30319-3",
language = "English",
volume = "17",
pages = "1053--1060",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "12",

}

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

In: The Lancet Neurology, Vol. 17, No. 12, 12.2018, p. 1053-1060.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source

T2 - a prespecified subgroup analysis from the NAVIGATE ESUS trial

AU - NAVIGATE ESUS Investigators

AU - Kasner, Scott E.

AU - Swaminathan, Balakumar

AU - Lavados, Pablo

AU - Sharma, Mukul

AU - Muir, Keith

AU - Veltkamp, Roland

AU - Ameriso, Sebastian F.

AU - Endres, Matthias

AU - Lutsep, Helmi

AU - Messé, Steven R.

AU - Spence, J. David

AU - Nedeltechev, Krassen

AU - Perera, Kanjana

AU - Santo, Gustavo

AU - Olavarria, Veronica

AU - Lindgren, Arne

AU - Bangdiwala, Shrikant

AU - Shoamanesh, Ashkan

AU - Berkowitz, Scott D.

AU - Mundl, Hardi

AU - Connolly, Stuart J.

AU - Hart, Robert G.

AU - Abdelhamid, N.

AU - Abdul Rahman, D.

AU - Abdul-Saheb, M.

AU - Abreu, P.

AU - Abroskina, M.

AU - Abu Ahmad, F.

AU - Accassat, S.

AU - Acciaresi, M.

AU - Adami, A.

AU - Ahmad, N.

AU - Ahmed, F.

AU - Alberto Hawkes, M.

AU - Alemseged, F.

AU - Ali, A.

AU - Altavilla, R.

AU - Alwis, L.

AU - Amarenco, P.

AU - Amaro, S.

AU - Amaya Sanchez, L. E.

AU - Amelia Pinto, A.

AU - Ameriso, S. F.

AU - Amin, H.

AU - Amino, T.

AU - Amjad, A. K.

AU - Anagnostou, E.

AU - Andersen, G.

AU - Anderson, C.

AU - Anderson, D. C.

PY - 2018/12

Y1 - 2018/12

N2 - Background: Patent 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. Methods: NAVIGATE 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. Findings: Between 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 interaction =0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; p interaction =0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among 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. Funding: Bayer and Janssen.

AB - Background: Patent 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. Methods: NAVIGATE 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. Findings: Between 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 interaction =0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; p interaction =0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among 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. Funding: Bayer and Janssen.

UR - http://www.scopus.com/inward/record.url?scp=85057212822&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057212822&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(18)30319-3

DO - 10.1016/S1474-4422(18)30319-3

M3 - Article

C2 - 30274772

AN - SCOPUS:85057212822

VL - 17

SP - 1053

EP - 1060

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 12

ER -