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Original Investigation
October 25, 2021

Left Ventricular Dysfunction Among Patients With Embolic Stroke of Undetermined Source and the Effect of Rivaroxaban vs Aspirin: A Subgroup Analysis of the NAVIGATE ESUS Randomized Clinical Trial

Author Affiliations
  • 1Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute, New York, New York
  • 2Department of Neurology, Weill Cornell Medical College, New York, New York
  • 3Biostatistics Consultant, St Catharines, Ontario, Canada
  • 4Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia
  • 5Department of Medicine (Neurology), McMaster University, Population Health Research Institute, Hamilton, Canada
  • 6Department of Neurosurgery, University of Texas Health Sciences Center, San Antonio
  • 7Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
JAMA Neurol. Published online October 25, 2021. doi:10.1001/jamaneurol.2021.3828
Visual Abstract. Left Ventricular Dysfunction Among Patients With Embolic Stroke of Undetermined Source and the Effect of Rivaroxaban vs Aspirin
Left Ventricular Dysfunction Among Patients With Embolic Stroke of Undetermined Source and the Effect of Rivaroxaban vs Aspirin
Key Points

Question  Is anticoagulation superior to aspirin in reducing recurrent stroke in patients with recent embolic stroke of undetermined source (ESUS) and left ventricular (LV) dysfunction?

Findings  Among 7213 participants of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, 502 (7.1%) had evidence of LV dysfunction. Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of recurrent stroke or systemic embolism compared with those without LV dysfunction.

Meaning  Rivaroxaban was superior to aspirin at reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction in this post hoc exploratory analysis.

Abstract

Importance  It 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.

Objective  To determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction.

Design, Setting, and Participants  Post 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.

Interventions  Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily.

Main Outcomes and Measures  The 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.

Results  LV 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 Relevance  In 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 Registration  ClinicalTrials.gov Identifier: NCT02313909

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    1 Comment for this article
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    Misclassification of large artery disease as ESUS accounts for failure to show benefit of anticoagulation
    J David Spence, M.D. | Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Canada
    In 2019 I discussed the rationale for anticoagulating patients in whom a cardiac source is strongly suspected.[1]

    This is the second subgroup analysis of an ESUS study to show superiority of anticoagulation in some patients with ESUS. The first was an analysis of ESUS patients with patent foramen ovale (PFO),[2] in which a meta-analysis showed superiority of anticoagulation over aspirin in patients with PFO. Another meta-analysis reported that anticoagulant was superior to aspirin and equivalent to PFO closure.[3]

    It is likely that the reason the ESUS trials failed to show superiority of anticoagulation over aspirin in ESUS
    was misclassification of large artery atherosclerosis (LAA) as unknown or ESUS. In patients whose stroke was due to large artery disease, aspirin would probably be more efficacious. The problem is that the ESUS studies used the TOAST subtype classification, which defines LAA by the presence of stenosis. However, because of compensatory enlargement, [4]many patients with a very high carotid plaque burden do not have stenosis. Among 1535 patients with a carotid Total Plaque Area > 1.19 cm2, a plaque burden that predicts a 19.5% 5-year risk of stroke/MI/vascular death, only 21% had stenosis > 50%.[5] Thus, defining LAA by percent stenosis misses 79% of LAA.

    Both the SPARKLE[5] and CISS [6] stroke subtype classifications incorporate a high carotid plaque burden into LAA; they both detect more LAA and have a lower percentage of Undetermined causes of stroke than TOAST.[6]

    1. Spence JD. Anticoagulation in patients with Embolic Stroke of Unknown Source. Int J Stroke. 2019;14(4):334-6.
    2. Kasner SE, Swaminathan B, Lavados P, Sharma M, Muir K, Veltkamp R, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol. 2018;17(12):1053-60.
    3. Saber H, Palla M, Kazemlou S, Azarpazhooh MR, Seraji-Bozorgzad N, Behrouz R. Network meta-analysis of patent foramen ovale management strategies in cryptogenic stroke. Neurology. 2018;91(1):e1-e7.
    4. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. New England Journal of Medicine. 1987;316:1371-5.
    5. Bogiatzi C, Wannarong T, McLeod AI, Heisel M, Hackam D, Spence JD. SPARKLE (Subtypes of Ischaemic Stroke Classification System), incorporating measurement of carotid plaque burden: a new validated tool for the classification of ischemic stroke subtypes. Neuroepidemiology. 2014;42(4):243-51.
    6. Zhang H, Li Z, Dai Y, Guo E, Zhang C, Wang Y. Ischaemic stroke etiological classification system: the agreement analysis of CISS, SPARKLE and TOAST. Stroke Vasc Neurol. 2019;4(3):123-8.

    CONFLICT OF INTEREST: None Reported
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