LV Dysfunction Among Patients With Embolic Stroke of Undetermined Source and the Effect of Rivaroxaban vs Aspirin | Cardiology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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

Educational Objective
To investigate whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with recurrent embolic stroke of undetermined source and left ventricular dysfunction.
1 Credit CME
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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: August 30, 2021.

Published Online: October 25, 2021. doi:10.1001/jamaneurol.2021.3828

Corresponding Author: Alexander E. Merkler, MD, MS, Department of Neurology, Weill Cornell Medical College, 525 E 68th St, Room F610, New York, NY 10065 (alm9097@med.cornell.edu).

Author Contributions: Drs Kamel and Sharma had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Merkler, Shoamanesh, Birnbaum, Sheth.

Acquisition, analysis, or interpretation of data: Pearce, Kasner, Shoamanesh, Kamel, Sharma.

Drafting of the manuscript: Merkler, Sharma.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Pearce.

Administrative, technical, or material support: Birnbaum.

Supervision: Sheth, Sharma.

Conflict of Interest Disclosures: Dr Merkler reports grants from the American Heart Association during the conduct of the study and has served as an expert witness regarding neurological disorders outside the submitted work. Dr Kasner reports grant support from Bayer during the conduct of the study and grant support from W.L. Gore & Associates, Medtronic, Genentech, and Bristol-Myers Squibb; consulting fees from Medtronic, Bristol-Myers Squibb, and Abbott; and royalties from UpToDate outside the submitted work. Dr Shoamanesh reports grant support from Bayer during the conduct of the study and grant support from Bayer, Daiichi Sankyo Company, Bristol-Myers Squibb, Servier Canada, Portola Pharmaceuticals, and Octapharma and consulting fees from Bayer, Daiichi Sankyo Company, and Servier Canada outside the submitted work. Dr Kamel serves as co–principal investigator for the National Institutes of Health–funded ARCADIA trial, which receives in-kind study drugs from the Bristol-Myers Squibb–Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; serves as Deputy Editor for JAMA Neurology; as a steering committee member of Medtronic’s Stroke AF trial (uncompensated); serves on an end point adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim; and has served on an advisory board for Roivant Sciences related to Factor XI inhibition outside the submitted work. Dr Sheth reports grants from Hyperfine Research Inc, Bard, Biogen, and Novartis; personal fees from Zoll for service as chair of the data and safety monitoring board; personal fees from Ceribell and NControl; and other support from Alva outside the submitted work. No other disclosures were reported.

Funding/Support: Dr Merkler is supported by American Heart Association grant 18CDA34110419. Dr Kamel is supported by National Institutes of Health grants K23NS082367, R01NS097443, and U01NS095869, as well as the Michael Goldberg Research Fund. Dr Sheth is supported by National Institutes of Health grants U24NS107136, U24NS107215, R01NR018335, R01NS107215, U01NS106513, and R03NS112859 and American Heart Association grants 18TPA34170180 and 17CSA33550004.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Kelsey Lansdale, BS, and Natalie LeMoss, BS, for their administrative assistance.

References
1.
Krishnamurthi  RV , Feigin  VL , Forouzanfar  MH ,  et al; Global Burden of Diseases, Injuries, Risk Factors Study 2010 (GBD 2010); GBD Stroke Experts Group.  Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.   Lancet Glob Health. 2013;1(5):e259-e281. doi:10.1016/S2214-109X(13)70089-5PubMedGoogle ScholarCrossref
2.
Hart  RG , Catanese  L , Perera  KS , Ntaios  G , Connolly  SJ .  Embolic stroke of undetermined source: a systematic review and clinical update.   Stroke. 2017;48(4):867-872. doi:10.1161/STROKEAHA.116.016414PubMedGoogle ScholarCrossref
3.
Hart  RG , Diener  HC , Coutts  SB ,  et al; Cryptogenic Stroke/ESUS International Working Group.  Embolic strokes of undetermined source: the case for a new clinical construct.   Lancet Neurol. 2014;13(4):429-438. doi:10.1016/S1474-4422(13)70310-7PubMedGoogle ScholarCrossref
4.
Hart  RG , Sharma  M , Mundl  H ,  et al; NAVIGATE ESUS Investigators.  Rivaroxaban for stroke prevention after embolic stroke of undetermined source.   N Engl J Med. 2018;378(23):2191-2201. doi:10.1056/NEJMoa1802686PubMedGoogle ScholarCrossref
5.
Diener  HC , Sacco  RL , Easton  JD ,  et al; RE-SPECT ESUS Steering Committee and Investigators.  Dabigatran for prevention of stroke after embolic stroke of undetermined source.   N Engl J Med. 2019;380(20):1906-1917. doi:10.1056/NEJMoa1813959PubMedGoogle ScholarCrossref
6.
Ntaios  G , Pearce  LA , Veltkamp  R ,  et al; NAVIGATE ESUS Investigators.  Potential embolic sources and outcomes in embolic stroke of undetermined source in the NAVIGATE-ESUS trial.   Stroke. 2020;51(6):1797-1804. doi:10.1161/STROKEAHA.119.028669PubMedGoogle ScholarCrossref
7.
Kamel  H , Merkler  AE , Iadecola  C , Gupta  A , Navi  BB .  Tailoring the approach to embolic stroke of undetermined source: a review.   JAMA Neurol. 2019;76(7):855-861. doi:10.1001/jamaneurol.2019.0591PubMedGoogle ScholarCrossref
8.
Adams  HP  Jr , Bendixen  BH , Kappelle  LJ ,  et al.  Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial: TOAST trial of org 10172 in acute stroke treatment.   Stroke. 1993;24(1):35-41. doi:10.1161/01.STR.24.1.35PubMedGoogle ScholarCrossref
9.
Choi  JY , Cha  J , Jung  JM ,  et al.  Left ventricular wall motion abnormalities are associated with stroke recurrence.   Neurology. 2017;88(6):586-594. doi:10.1212/WNL.0000000000003588PubMedGoogle ScholarCrossref
10.
Takasugi  J , Yamagami  H , Noguchi  T ,  et al.  Detection of left ventricular thrombus by cardiac magnetic resonance in embolic stroke of undetermined source.   Stroke. 2017;48(9):2434-2440. doi:10.1161/STROKEAHA.117.018263PubMedGoogle ScholarCrossref
11.
Hart  RG , Sharma  M , Mundl  H ,  et al.  Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial.   Eur Stroke J. 2016;1(3):146-154. doi:10.1177/2396987316663049PubMedGoogle ScholarCrossref
12.
Jain  P , Hayward  CS .  Left ventricular ejection fraction under continuous-flow mechanical support.   Circ Heart Fail. 2020;13(9):e007427. doi:10.1161/CIRCHEARTFAILURE.120.007427PubMedGoogle Scholar
13.
Monge García  MI , Jian  Z , Settels  JJ ,  et al.  Determinants of left ventricular ejection fraction and a novel method to improve its assessment of myocardial contractility.   Ann Intensive Care. 2019;9(1):48. doi:10.1186/s13613-019-0526-7PubMedGoogle ScholarCrossref
14.
Schulman  S , Kearon  C ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.  Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.   J Thromb Haemost. 2005;3(4):692-694. doi:10.1111/j.1538-7836.2005.01204.xPubMedGoogle ScholarCrossref
15.
Andreotti  F , Testa  L , Biondi-Zoccai  GG , Crea  F .  Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients.   Eur Heart J. 2006;27(5):519-526. doi:10.1093/eurheartj/ehi485PubMedGoogle ScholarCrossref
16.
Rothberg  MB , Celestin  C , Fiore  LD , Lawler  E , Cook  JR .  Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit.   Ann Intern Med. 2005;143(4):241-250. doi:10.7326/0003-4819-143-4-200508160-00005PubMedGoogle ScholarCrossref
17.
Ramasamy  S , Yaghi  S , Salehi Omran  S ,  et al.  Association between left ventricular ejection fraction, wall motion abnormality, and embolic stroke of undetermined source.   J Am Heart Assoc. 2019;8(9):e011593. doi:10.1161/JAHA.118.011593PubMedGoogle Scholar
18.
Hays  AG , Sacco  RL , Rundek  T ,  et al.  Left ventricular systolic dysfunction and the risk of ischemic stroke in a multiethnic population.   Stroke. 2006;37(7):1715-1719. doi:10.1161/01.STR.0000227121.34717.40PubMedGoogle ScholarCrossref
19.
Kleindorfer  DO , Towfighi  A , Chaturvedi  S ,  et al.  2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association.   Stroke. 2021;52(7):e364-e467. doi:10.1161/STR.0000000000000375PubMedGoogle ScholarCrossref
20.
Wein  T , Lindsay  MP , Cote  R ,  et al.  Canadian stroke best practice recommendations: secondary prevention of stroke, sixth edition practice guidelines, update 2017.   Int J Stroke. 2018;13(4):420-443. doi:10.1177/1747493017743062PubMedGoogle ScholarCrossref
21.
Homma  S , Thompson  JL , Pullicino  PM ,  et al; WARCEF Investigators.  Warfarin and aspirin in patients with heart failure and sinus rhythm.   N Engl J Med. 2012;366(20):1859-1869. doi:10.1056/NEJMoa1202299PubMedGoogle ScholarCrossref
22.
Beggs  SAS , Rørth  R , Gardner  RS , McMurray  JJV .  Anticoagulation therapy in heart failure and sinus rhythm: a systematic review and meta-analysis.   Heart. 2019;105(17):1325-1334. doi:10.1136/heartjnl-2018-314381PubMedGoogle ScholarCrossref
23.
Vinogradova  Y , Coupland  C , Hill  T , Hippisley-Cox  J .  Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care.   BMJ. 2018;363:k4413. doi:10.1136/bmj.k2505PubMedGoogle Scholar
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close