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Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

ABSTRACT: Importance:The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF). Objective:To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. Design, Setting, and Participants:Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. Intervention:Rivaroxaban treatment vs aspirin. Main Outcomes and Measures:Risk of ischemic stroke. Results:Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6?(1.8), the mean (SD) left atrial diameter was 3.8?(1.4) cm (n?=?4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction?=?.67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio,?0.26; 95% CI, 0.07-0.94; P for interaction?=?.02). Conclusions and Relevance:The HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

SUBMITTER: Healey JS

PROVIDER: S-EPMC6583060 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Healey Jeff S JS Gladstone David J DJ Swaminathan Balakumar B Eckstein Jens J Mundl Hardi H Epstein Andrew E AE Haeusler Karl Georg KG Mikulik Robert R Kasner Scott E SE Toni Danilo D Arauz Antonio A Ntaios George G Hankey Graeme J GJ Perera Kanjana K Pagola Jorge J Shuaib Ashfaq A Lutsep Helmi H Yang Xiaomeng X Uchiyama Shinichiro S Endres Matthias M Coutts Shelagh B SB Karlinski Michal M Czlonkowska Anna A Molina Carlos A CA Santo Gustavo G Berkowitz Scott D SD Hart Robert G RG Connolly Stuart J SJ

JAMA neurology 20190701 7

<h4>Importance</h4>The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF).<h4>Objective</h4>To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF.<h4>Design, setting, and participants</h4>P ...[more]

PMID: 30958508

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Project description: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; pinteraction=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; pinteraction=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.

Project description:ImportanceIt is uncertain whether anticoagulation is superior to aspirin at reducing recurrent stroke in patients with recent embolic strokes of undetermined source (ESUS) and left ventricular (LV) dysfunction.ObjectiveTo determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction.Design, setting, and participantsPost hoc exploratory analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, a randomized, phase 3 clinical trial with enrollment from December 2014 to September 2017. The study setting included 459 stroke recruitment centers in 31 countries. Patients 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of the 7213 NAVIGATE ESUS participants, 7107 (98.5%) had a documented assessment of LV function at study entry and were included in the present analysis. Data were analyzed in January 2021.InterventionsParticipants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily.Main outcomes and measuresThe study examined whether rivaroxaban was superior to aspirin at reducing the risk of (1) the trial primary outcome of recurrent stroke or systemic embolism and (2) the trial secondary outcome of recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. LV dysfunction was identified locally through echocardiography and defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios for those randomized to rivaroxaban vs aspirin by LV dysfunction status.ResultsLV dysfunction was present in 502 participants (7.1%). Of participants with LV dysfunction, the mean (SD) age was 67 (10) years, and 130 (26%) were women. Among participants with LV dysfunction, annualized primary event rates were 2.4% (95% CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95% CI, 4.0-11.0) in those assigned aspirin. Among the 6605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95% CI, 4.5-6.2) vs aspirin (4.5%; 95% CI, 3.8-5.3). Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of the primary outcome (hazard ratio, 0.36; 95% CI, 0.14-0.93), unlike those without LV dysfunction (hazard ratio, 1.16; 95% CI, 0.93-1.46) (P for treatment interaction = .03). Results were similar for the secondary outcome.Conclusions and relevanceIn this post hoc exploratory analysis, rivaroxaban was superior to aspirin in reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction.Trial registrationClinicalTrials.gov Identifier: NCT02313909.

Dataset Information

Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Publications

Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

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