Ashkan Shoamanesh1, Robert G Hart1, Stuart J Connolly1, Scott E Kasner2, Eric E Smith3, Joan Martí-Fàbregas4, Yan Yun Liu5, Shinichiro Uchiyama6, Robert Mikulik7, Roland Veltkamp8, Martin J O'Donnell1,9, George Ntaios10, Keith W Muir11, Thalia S Field12, Gustavo C Santo13, Veronica Olavarria14, Hardi Mundl15, Helmi Lutsep16, Scott D Berkowitz17, Mukul Sharma1. 1. Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, Ontario, Canada. 2. Department of Neurology, University of Pennsylvania, Philadelphia. 3. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. 4. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 5. Department of Statistics, Population Health Research Institute, Hamilton, Ontario, Canada. 6. Department of Neurology, Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan. 7. International Clinical Research Center and Department of Neurology, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic. 8. Department of Neurology, Imperial College Healthcare NHS Trust, London, United Kingdom. 9. Department of Medicine, National University of Ireland Galway, Galway, Ireland. 10. Department of Internal Medicine, University of Thessaly, Larissa, Greece. 11. Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, Scotland. 12. Division of Neurology, University of British Columbia, Vancouver, Canada. 13. Department of Neurology, Hospitais da Universidade de Coimbra, Coimbra, Portugal. 14. Department of Neurology and Psychiatry, Clínica Alemana de Santiago, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile. 15. Pharmaceuticals Development, TA Cardiovascular, Bayer Pharma AG, Wuppertal, Germany. 16. Department of Neurology, Oregon Health and Science University, Portland. 17. Thrombosis Group, Pharmaceuticals Research and Development, Bayer, Whippany, New Jersey.
Abstract
Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging. Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy. Design, Setting, and Participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial. Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily. Main Outcomes and Measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality. Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97). Conclusions and Relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.
RCT Entities:
Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging. Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy. Design, Setting, and Participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial. Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily. Main Outcomes and Measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality. Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97). Conclusions and Relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.
Authors: Brian Mac Grory; Shadi Yaghi; Charlotte Cordonnier; Luciano A Sposato; Jose G Romano; Seemant Chaturvedi Journal: Circ Res Date: 2022-04-14 Impact factor: 23.213
Authors: Ludwig Schlemm; Tim Bastian Braemswig; Florent Boutitie; Jan Vynckier; Märit Jensen; Ivana Galinovic; Claus Z Simonsen; Bastian Cheng; Tae-Hee Cho; Jens Fiehler; Josep Puig; Vincent Thijs; Jochen Fiebach; Keith Muir; Norbert Nighoghossian; Martin Ebinger; Salvador Pedraza; Götz Thomalla; Christian Gerloff; Matthias Endres; Robin Lemmens; Christian H Nolte Journal: Neurology Date: 2021-11-15 Impact factor: 11.800
Authors: Benjamin Wagner; Lisa Hert; Alexandros A Polymeris; Sabine Schaedelin; Johanna M Lieb; David J Seiffge; Christopher Traenka; Sebastian Thilemann; Joachim Fladt; Valerian L Altersberger; Annaelle Zietz; Tolga D Dittrich; Urs Fisch; Henrik Gensicke; Gian Marco De Marchis; Leo H Bonati; Philippe A Lyrer; Stefan T Engelter; Nils Peters Journal: Front Neurol Date: 2022-09-20 Impact factor: 4.086