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

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74 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

Bibliographical note

Funding Information:
SFA and SB report grants from Bayer and Janssen during the conduct of the study. SDB was employed by Bayer during the conduct of the study. SJC reports grants from Bayer and Janssen during the conduct of the study; grants and personal fees from Boehringer Ingelheim, Sanofi Aventis, and Bayer; personal fees from Portola; grants from Boston Scientific, outside of the submitted work; and an institutional research grant from Bayer. ME reports grants and non-financial support from Bayer during the conduct of the study; grants and fees paid to his institution for lectures and advisory board participation from Bayer; and fees paid to his institution for lectures and advisory board participation from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Amgen, Sanofi, Covidien, GlaxoSmithKline, Ever, and Novartis, outside of the submitted work. RGH a research contract from Bayer, during the conduct of the study, and a research contract from Bayer, outside of the submitted work. SEK reports grants from Bayer, grants and personal fees from Janssen, during the conduct of the study; personal fees from Bristol-Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Medtronic, personal fees from AbbVie, and grants from WL Gore, outside of the submitted work. PL reports grants and personal fees from Bayer and grants from PHRI, during the conduct of the study; grants and personal fees from The George Institute for Global Health; grants from FONIS CONICYT, non-financial support from Boehringer Ingelheim; non-financial support from Bayer, and grants and non-financial support from Clinica Alemana, outside of the submitted work. AL reports grants from Bayer and Janssen during the conduct of the study; and personal fees from Bayer, Bristol-Myers Squibb/Pfizer, AstraZeneca, Boehringer Ingelheim, and Reneuron, outside of the submitted work. HL reports grants from Bayer and Janssen during the conduct of the study. SRM reports grants from Bayer and Janssen during the conduct of the study; and grants from WL Gore & Associates outside of the submitted work. HM was employed by Bayer during the conduct of the study. KM reports grants from Bayer and Janssen, and personal fees from Bayer during the conduct of the study; and personal fees from Daiichi-Sankyo and non-financial support from Boehringer Ingelheim outside of the submitted work. KN reports personal fees from advisory boards for Bayer (Schweiz) AG, outside of the submitted work. VO reports grants from Bayer and Janssen during the conduct of the study. KP reports grants and personal fees from Bayer and grants from Janssen during the conduct of the study. GS reports grants from Bayer and Janssen during the conduct of the study. MS reports grants and personal fees from Bayer and Janssen during the conduct of the study; personal fees from Bristol-Myers Squibb, Boehringer Ingelheim, Portola, and Daiichi Sankyo outside of the submitted work. AS reports grants from Bayer, Janssen, and Bayer Canada, and personal fees from Bayer Canada, during the conduct of the study. JDS reports grants from Bayer and Janssen during the conduct of the study. RV reports grants from Bayer and Janssen during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, outside of the submitted work. BS declares no competing interests.

Publisher Copyright:
© 2018 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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