Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: Secondary analysis of the NAVIGATE ESUS randomized clinical trial

Jeff S Healey, David J Gladstone, Balakumar Swaminathan, Jens Eckstein, Hardi Mundl, Andrew E Epstein, Karl Georg Haeusler, Robert Mikulik, Scott E Kasner, Danilo Toni, Antonio Arauz, George Ntaios, Kanjana Perera, Graeme J Hankey, Jorge Pagola, Ashfaq Shuaib, Helmi Lutsep, Xiaomeng Yang, Shinichiro Uchiyama, Matthias Endres & 8 others Shelagh B Coutts, Michal Karlinski, Anna Czlonkowska, Carlos A Molina, Gustavo Santo, Scott D Berkowitz, Robert G Hart, Stuart J Connolly

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)764-773
Number of pages10
JournalJAMA Neurology
Volume76
Issue number7
Early online date8 Apr 2019
DOIs
Publication statusPublished - Jul 2019

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Atrial Fibrillation
Aspirin
Randomized Controlled Trials
Stroke
Atrial Premature Complexes
Rivaroxaban
Outcome Assessment (Health Care)
Incidence
Therapeutics

Cite this

Healey, Jeff S ; Gladstone, David J ; Swaminathan, Balakumar ; Eckstein, Jens ; Mundl, Hardi ; Epstein, Andrew E ; Haeusler, Karl Georg ; Mikulik, Robert ; Kasner, Scott E ; Toni, Danilo ; Arauz, Antonio ; Ntaios, George ; Perera, Kanjana ; Hankey, Graeme J ; Pagola, Jorge ; Shuaib, Ashfaq ; Lutsep, Helmi ; Yang, Xiaomeng ; Uchiyama, Shinichiro ; Endres, Matthias ; Coutts, Shelagh B ; Karlinski, Michal ; Czlonkowska, Anna ; Molina, Carlos A ; Santo, Gustavo ; Berkowitz, Scott D ; Hart, Robert G ; Connolly, Stuart J. / Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation : Secondary analysis of the NAVIGATE ESUS randomized clinical trial. In: JAMA Neurology. 2019 ; Vol. 76, No. 7. pp. 764-773.
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title = "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.",
keywords = "ISCHEMIC-STROKE, CRYPTOGENIC STROKE, ORAL ANTICOAGULANTS, UNDETERMINED SOURCE, RISK, METAANALYSIS, RATIONALE, DESIGN, SCORE, SIZE",
author = "Healey, {Jeff S} and Gladstone, {David J} and Balakumar Swaminathan and Jens Eckstein and Hardi Mundl and Epstein, {Andrew E} and Haeusler, {Karl Georg} and Robert Mikulik and Kasner, {Scott E} and Danilo Toni and Antonio Arauz and George Ntaios and Kanjana Perera and Hankey, {Graeme J} and Jorge Pagola and Ashfaq Shuaib and Helmi Lutsep and Xiaomeng Yang and Shinichiro Uchiyama and Matthias Endres and Coutts, {Shelagh B} and Michal Karlinski and Anna Czlonkowska and Molina, {Carlos A} and Gustavo Santo and Berkowitz, {Scott D} and Hart, {Robert G} and Connolly, {Stuart J}",
year = "2019",
month = "7",
doi = "10.1001/jamaneurol.2019.0617",
language = "English",
volume = "76",
pages = "764--773",
journal = "Archives of neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "7",

}

Healey, JS, Gladstone, DJ, Swaminathan, B, Eckstein, J, Mundl, H, Epstein, AE, Haeusler, KG, Mikulik, R, Kasner, SE, Toni, D, Arauz, A, Ntaios, G, Perera, K, Hankey, GJ, Pagola, J, Shuaib, A, Lutsep, H, Yang, X, Uchiyama, S, Endres, M, Coutts, SB, Karlinski, M, Czlonkowska, A, Molina, CA, Santo, G, Berkowitz, SD, Hart, RG & Connolly, SJ 2019, 'Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: Secondary analysis of the NAVIGATE ESUS randomized clinical trial' JAMA Neurology, vol. 76, no. 7, pp. 764-773. https://doi.org/10.1001/jamaneurol.2019.0617

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; Gladstone, David J; Swaminathan, Balakumar; Eckstein, Jens; Mundl, Hardi; Epstein, Andrew E; Haeusler, Karl Georg; Mikulik, Robert; Kasner, Scott E; Toni, Danilo; Arauz, Antonio; Ntaios, George; Perera, Kanjana; Hankey, Graeme J; Pagola, Jorge; Shuaib, Ashfaq; Lutsep, Helmi; Yang, Xiaomeng; Uchiyama, Shinichiro; Endres, Matthias; Coutts, Shelagh B; Karlinski, Michal; Czlonkowska, Anna; Molina, Carlos A; Santo, Gustavo; Berkowitz, Scott D; Hart, Robert G; Connolly, Stuart J.

In: JAMA Neurology, Vol. 76, No. 7, 07.2019, p. 764-773.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation

T2 - Secondary analysis of the NAVIGATE ESUS randomized clinical trial

AU - Healey, Jeff S

AU - Gladstone, David J

AU - Swaminathan, Balakumar

AU - Eckstein, Jens

AU - Mundl, Hardi

AU - Epstein, Andrew E

AU - Haeusler, Karl Georg

AU - Mikulik, Robert

AU - Kasner, Scott E

AU - Toni, Danilo

AU - Arauz, Antonio

AU - Ntaios, George

AU - Perera, Kanjana

AU - Hankey, Graeme J

AU - Pagola, Jorge

AU - Shuaib, Ashfaq

AU - Lutsep, Helmi

AU - Yang, Xiaomeng

AU - Uchiyama, Shinichiro

AU - Endres, Matthias

AU - Coutts, Shelagh B

AU - Karlinski, Michal

AU - Czlonkowska, Anna

AU - Molina, Carlos A

AU - Santo, Gustavo

AU - Berkowitz, Scott D

AU - Hart, Robert G

AU - Connolly, Stuart J

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - ISCHEMIC-STROKE

KW - CRYPTOGENIC STROKE

KW - ORAL ANTICOAGULANTS

KW - UNDETERMINED SOURCE

KW - RISK

KW - METAANALYSIS

KW - RATIONALE

KW - DESIGN

KW - SCORE

KW - SIZE

U2 - 10.1001/jamaneurol.2019.0617

DO - 10.1001/jamaneurol.2019.0617

M3 - Article

VL - 76

SP - 764

EP - 773

JO - Archives of neurology

JF - Archives of neurology

SN - 0003-9942

IS - 7

ER -