Dabigatran for prevention of stroke after embolic stroke of undetermined source

Hans-Christoph Diener; Ralph L. Sacco; J. Donald Easton; Christopher B. Granger; Richard A. Bernstein; Shinichiro Uchiyama; Jörg Kreuzer; Lisa Cronin; Daniel Cotton; Claudia Grauer; Martina Brueckmann; Marina Chernyatina; Geoffrey Donnan; Jose M. Ferro; Martin Grond; Bernd Kallmünzer; Jerzy Krupinski; Byung-Chul Lee; Robin Lemmens; Jaime Masjuan; Miroslav Odinak; Jeffrey L. Saver; Peter D. Schellinger; Danilo Toni; Kazunori Toyoda; RE-SPECT ESUS Steering Committee and Investigators; Candice Delcourt

doi:10.1056/NEJMoa1813959

Dabigatran for prevention of stroke after embolic stroke of undetermined source

Hans-Christoph Diener, Ralph L. Sacco, J. Donald Easton, Christopher B. Granger, Richard A. Bernstein, Shinichiro Uchiyama, Jörg Kreuzer, Lisa Cronin, Daniel Cotton, Claudia Grauer, Martina Brueckmann, Marina Chernyatina, Geoffrey Donnan, Jose M. Ferro, Martin Grond, Bernd Kallmünzer, Jerzy Krupinski, Byung-Chul Lee, Robin Lemmens, Jaime MasjuanMiroslav Odinak, Jeffrey L. Saver, Peter D. Schellinger, Danilo Toni, Kazunori Toyoda, RE-SPECT ESUS Steering Committee and Investigators, Candice Delcourt

Research output: Contribution to journal › Article › peer-review

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Abstract

Background Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. Methods We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. Results A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. Conclusions In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

Original language	English
Pages (from-to)	1906-1917
Number of pages	12
Journal	New England Journal of Medicine
Volume	380
Issue number	20
DOIs	https://doi.org/10.1056/NEJMoa1813959
Publication status	Published - 16 May 2019
Externally published	Yes

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10.1056/NEJMoa1813959

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Diener, H.-C., Sacco, R. L., Easton, J. D., Granger, C. B., Bernstein, R. A., Uchiyama, S., Kreuzer, J., Cronin, L., Cotton, D., Grauer, C., Brueckmann, M., Chernyatina, M., Donnan, G., Ferro, J. M., Grond, M., Kallmünzer, B., Krupinski, J., Lee, B.-C., Lemmens, R., ... Delcourt, C. (2019). Dabigatran for prevention of stroke after embolic stroke of undetermined source. New England Journal of Medicine, 380(20), 1906-1917. https://doi.org/10.1056/NEJMoa1813959

@article{900522aa4ad44c93afb0d5b075aee867,

title = "Dabigatran for prevention of stroke after embolic stroke of undetermined source",

abstract = "Background Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. Methods We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. Results A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. Conclusions In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).",

author = "Hans-Christoph Diener and Sacco, {Ralph L.} and Easton, {J. Donald} and Granger, {Christopher B.} and Bernstein, {Richard A.} and Shinichiro Uchiyama and J{\"o}rg Kreuzer and Lisa Cronin and Daniel Cotton and Claudia Grauer and Martina Brueckmann and Marina Chernyatina and Geoffrey Donnan and Ferro, {Jose M.} and Martin Grond and Bernd Kallm{\"u}nzer and Jerzy Krupinski and Byung-Chul Lee and Robin Lemmens and Jaime Masjuan and Miroslav Odinak and Saver, {Jeffrey L.} and Schellinger, {Peter D.} and Danilo Toni and Kazunori Toyoda and {RE-SPECT ESUS Steering Committee and Investigators} and Conrado Estol and Cecilia Bahit and Geoff Donnan and Michael Brainin and Robin Lemmens and Sheila Martins and Frank Silver and Sergio Illanes and Yongjun Wang and Mario Munoz and Zdravka Poljakovic and Daniel Sanak and Janika Korv and Didier Leys and Martin Grond and Tsivgoulis, {Georgios K.} and Wong, {Lawrence Ka Sing} and Laszlo Csiba and Srivastava, {M. V. Padma} and Natan Bornstein and Danilo Toni and Kazunori Toyoda and Byung-Chul Lee and Basri, {Hamidon Bin} and Jorge Villareal-Careaga and {Barrientos Iman}, {Danny Moises} and Argomedo, {Segundo Carlos Abanto} and Adam Stepien and Jose Ferro and Miroslav Odinak and Ljiljana Beslac-Bumbasirevic and Chang, {Hui Meng} and Zuzana Gdovinova and Bojana Zvan and Christo Coetzee and Jamie Masjuan and Christina Sjostrand and Philippe Lyrer and Chia-Wei Liou and Suwanwela, {Nijasri Charnnarong} and Nevzat Uzuner and Tamara Mishchenko and Jeffrey Saver and Robert Makuch and Kennedy Lees and Paulus Kirchhof and {Von Kummer}, Ruediger and Tijssen, {Jan G. P.} and Frank Schuetz and Heinrich Mattle and Tai, {Waimei Amy} and Valeria Caso and Louis Caplan and James Januzzi and Kenneth Mahaffey and Alan Miller and Renato Lopes and Zurru, {Maria Cristina} and Francisco Klein and Alberto Caccavo and Alberto Lorenzatti and Pablo Ioli and Chris Bladin and Martin Krause and Tim Kleinig and Rohan Grimley and Neil Spratt and Stephen Davis and Andrew Lee and Candice Delcourt",

year = "2019",

month = may,

day = "16",

doi = "10.1056/NEJMoa1813959",

language = "English",

volume = "380",

pages = "1906--1917",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "20",

}

Diener, H-C, Sacco, RL, Easton, JD, Granger, CB, Bernstein, RA, Uchiyama, S, Kreuzer, J, Cronin, L, Cotton, D, Grauer, C, Brueckmann, M, Chernyatina, M, Donnan, G, Ferro, JM, Grond, M, Kallmünzer, B, Krupinski, J, Lee, B-C, Lemmens, R, Masjuan, J, Odinak, M, Saver, JL, Schellinger, PD, Toni, D, Toyoda, K, RE-SPECT ESUS Steering Committee and Investigators & Delcourt, C 2019, 'Dabigatran for prevention of stroke after embolic stroke of undetermined source', New England Journal of Medicine, vol. 380, no. 20, pp. 1906-1917. https://doi.org/10.1056/NEJMoa1813959

TY - JOUR

T1 - Dabigatran for prevention of stroke after embolic stroke of undetermined source

AU - Diener, Hans-Christoph

AU - Sacco, Ralph L.

AU - Easton, J. Donald

AU - Granger, Christopher B.

AU - Bernstein, Richard A.

AU - Uchiyama, Shinichiro

AU - Kreuzer, Jörg

AU - Cronin, Lisa

AU - Cotton, Daniel

AU - Grauer, Claudia

AU - Brueckmann, Martina

AU - Chernyatina, Marina

AU - Donnan, Geoffrey

AU - Ferro, Jose M.

AU - Grond, Martin

AU - Kallmünzer, Bernd

AU - Krupinski, Jerzy

AU - Lee, Byung-Chul

AU - Lemmens, Robin

AU - Masjuan, Jaime

AU - Odinak, Miroslav

AU - Saver, Jeffrey L.

AU - Schellinger, Peter D.

AU - Toni, Danilo

AU - Toyoda, Kazunori

AU - RE-SPECT ESUS Steering Committee and Investigators

AU - Estol, Conrado

AU - Bahit, Cecilia

AU - Donnan, Geoff

AU - Brainin, Michael

AU - Lemmens, Robin

AU - Martins, Sheila

AU - Silver, Frank

AU - Illanes, Sergio

AU - Wang, Yongjun

AU - Munoz, Mario

AU - Poljakovic, Zdravka

AU - Sanak, Daniel

AU - Korv, Janika

AU - Leys, Didier

AU - Grond, Martin

AU - Tsivgoulis, Georgios K.

AU - Wong, Lawrence Ka Sing

AU - Csiba, Laszlo

AU - Srivastava, M. V. Padma

AU - Bornstein, Natan

AU - Toni, Danilo

AU - Toyoda, Kazunori

AU - Lee, Byung-Chul

AU - Basri, Hamidon Bin

AU - Villareal-Careaga, Jorge

AU - Barrientos Iman, Danny Moises

AU - Argomedo, Segundo Carlos Abanto

AU - Stepien, Adam

AU - Ferro, Jose

AU - Odinak, Miroslav

AU - Beslac-Bumbasirevic, Ljiljana

AU - Chang, Hui Meng

AU - Gdovinova, Zuzana

AU - Zvan, Bojana

AU - Coetzee, Christo

AU - Masjuan, Jamie

AU - Sjostrand, Christina

AU - Lyrer, Philippe

AU - Liou, Chia-Wei

AU - Suwanwela, Nijasri Charnnarong

AU - Uzuner, Nevzat

AU - Mishchenko, Tamara

AU - Saver, Jeffrey

AU - Makuch, Robert

AU - Lees, Kennedy

AU - Kirchhof, Paulus

AU - Von Kummer, Ruediger

AU - Tijssen, Jan G. P.

AU - Schuetz, Frank

AU - Mattle, Heinrich

AU - Tai, Waimei Amy

AU - Caso, Valeria

AU - Caplan, Louis

AU - Januzzi, James

AU - Mahaffey, Kenneth

AU - Miller, Alan

AU - Lopes, Renato

AU - Zurru, Maria Cristina

AU - Klein, Francisco

AU - Caccavo, Alberto

AU - Lorenzatti, Alberto

AU - Ioli, Pablo

AU - Bladin, Chris

AU - Krause, Martin

AU - Kleinig, Tim

AU - Grimley, Rohan

AU - Spratt, Neil

AU - Davis, Stephen

AU - Lee, Andrew

AU - Delcourt, Candice

PY - 2019/5/16

Y1 - 2019/5/16

N2 - Background Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. Methods We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. Results A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. Conclusions In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

AB - Background Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. Methods We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. Results A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. Conclusions In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

UR - http://www.scopus.com/inward/record.url?scp=85065845198&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1813959

DO - 10.1056/NEJMoa1813959

M3 - Article

C2 - 31091372

SN - 0028-4793

VL - 380

SP - 1906

EP - 1917

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 20

ER -

Dabigatran for prevention of stroke after embolic stroke of undetermined source

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