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.

Department of Clinical Neurosciences University of Calgary Calgary Alberta Canada

Department of Internal Medicine University of Thessaly Larissa Greece

Department of Medicine National University of Ireland Galway Galway Ireland

Department of Neurology and Psychiatry Clínica Alemana de Santiago Facultad de Medicina Clínica Alemana Universidad del Desarrollo Santiago Chile

Department of Neurology Clinical Research Center for Medicine International University of Health and Welfare Tokyo Japan

Department of Neurology Hospitais da Universidade de Coimbra Coimbra Portugal

Department of Neurology Imperial College Healthcare NHS Trust London United Kingdom

Department of Neurology Oregon Health and Science University Portland

Department of Neurology University of Pennsylvania Philadelphia

Department of Statistics Population Health Research Institute Hamilton Ontario Canada

Division of Neurology McMaster University Population Health Research Institute Hamilton Ontario Canada

Division of Neurology University of British Columbia Vancouver Canada

Hospital de la Santa Creu i Sant Pau Barcelona Spain

Institute of Neuroscience and Psychology University of Glasgow Glasgow Scotland

International Clinical Research Center and Department of Neurology St Anne's University Hospital and Masaryk University Brno Czech Republic

Pharmaceuticals Development TA Cardiovascular Bayer Pharma AG Wuppertal Germany

Thrombosis Group Pharmaceuticals Research and Development Bayer Whippany New Jersey

JAMA Neurol. 2021 Jan 1;78(1):9-10. doi: 10.1001/jamaneurol.2020.3847. PubMed

JAMA Neurol. 2021 Jan 1;78(1):120. doi: 10.1001/jamaneurol.2020.4698. PubMed

Zobrazit více v PubMed

Charidimou A, Shams S, Romero JR, et al. ; International META-MICROBLEEDS Initiative. Clinical significance of cerebral microbleeds on MRI: a comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1). Int J Stroke . 2018;. 13(5):454-468. doi:10.1177/1747493017751931 PubMed DOI PMC

Romero JR, Preis SR, Beiser A, et al. . Cerebral microbleeds as predictors of mortality: the Framingham Heart Study. Stroke. 2017;48(3):781-783. doi:10.1161/STROKEAHA.116.015354 PubMed DOI PMC

Wilson D, Ambler G, Lee KJ, et al; Microbleeds International Collaborative Network. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol . 2019;. 18(7):653-665. doi:10.1016/S1474-4422(19)30197-8 PubMed DOI PMC

Wilson D, Ambler G, Shakeshaft C, et al. ; CROMIS-2 Collaborators . Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study. Lancet Neurol. 2018;17(6):539-547. doi:10.1016/S1474-4422(18)30145-5 PubMed DOI PMC

Shoamanesh A, Charidimou A, Sharma M, Hart RG. Should patients with ischemic stroke or transient ischemic attack with atrial fibrillation and microbleeds be anticoagulated? Stroke. 2017;48(12):3408-3412. doi:10.1161/STROKEAHA.117.018467 PubMed DOI

Hart RGSM, 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:10.1177/2396987316663049 PubMed DOI PMC

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/NEJMoa1802686 PubMed DOI

Kasner SE, Lavados P, Sharma M, et al. ; NAVIGATE ESUS Steering Committee and Investigators . Characterization of patients with embolic strokes of undetermined source in the NAVIGATE ESUS randomized trial. J Stroke Cerebrovasc Dis. 2018;27(6):1673-1682. doi:10.1016/j.jstrokecerebrovasdis.2018.01.027 PubMed DOI PMC

Shoamanesh A, Pearce LA, Bazan C, et al. ; SPS3 Trial Investigators . Microbleeds in the Secondary Prevention Of Small Subcortical Strokes trial: stroke, mortality, and treatment interactions. Ann Neurol. 2017;82(2):196-207. doi:10.1002/ana.24988 PubMed DOI PMC

Shoamanesh A, Morotti A, Romero JM, et al; Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) and the Neurological Emergencies Treatment Trials (NETT) Network Investigators. Cerebral microbleeds and the effect of intensive blood pressure reduction on hematoma expansion and functional outcomes: a secondary analysis of the ATACH-2 randomized clinical trial. JAMA Neurol. 2018;75(7):850-859. doi:10.1001/jamaneurol.2018.0454 PubMed DOI PMC

Kidwell CS, Rosand J, Norato G, et al. Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage. Neurology. 2017;88(8)782-788. doi:10.1212/WNL.0000000000003630 PubMed DOI PMC

Oliveira-Filho J, Ay H, Shoamanesh A, et al. Incidence and etiology of microinfarcts in patients with ischemic stroke. J Neuroimaging . 2018;28(4):406-411. doi:10.1111/jon.12512 PubMed DOI

Wilson D, Charidimou A, Ambler G, et al. . Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: a meta-analysis. Neurology. 2016;87(14):1501-1510. doi:10.1212/WNL.0000000000003183 PubMed DOI PMC

Al-Shahi Salman R, Minks DP, Mitra D, et al. ; RESTART Collaboration . Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial. Lancet Neurol. 2019;18(7):643-652. doi:10.1016/S1474-4422(19)30184-X PubMed DOI PMC

Haji S, Planchard R, Zubair A, et al. . The clinical relevance of cerebral microbleeds in patients with cerebral ischemia and atrial fibrillation. J Neurol. 2016;263(2):238-244. doi:10.1007/s00415-015-7966-2 PubMed DOI

Charidimou A, Inamura S, Nomura T, Kanno A, Kim SN, Imaizumi T. Cerebral microbleeds and white matter hyperintensities in cardioembolic stroke patients due to atrial fibrillation: single-centre longitudinal study. J Neurol Sci. 2016;369:263-267. doi:10.1016/j.jns.2016.08.050 PubMed DOI

Song TJ, Kim J, Song D, et al. . Association of cerebral microbleeds with mortality in stroke patients having atrial fibrillation. Neurology. 2014;83(15):1308-1315. doi:10.1212/WNL.0000000000000862 PubMed DOI

Eikelboom JW, Wallentin L, Connolly SJ, et al. . Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123(21):2363-2372. doi:10.1161/CIRCULATIONAHA.110.004747 PubMed DOI

Ruff CT, Giugliano RP, Braunwald E, et al. . Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. doi:10.1016/S0140-6736(13)62343-0 PubMed DOI

Connolly SJ, Ezekowitz MD, Yusuf S, et al. ; RE-LY Steering Committee and Investigators . Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561 PubMed DOI

Granger CB, Alexander JH, McMurray JJ, et al. ; ARISTOTLE Committees and Investigators . Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039 PubMed DOI

Patel MR, Mahaffey KW, Garg J, et al. ; ROCKET AF Investigators . Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638 PubMed DOI

Giugliano RP, Ruff CT, Braunwald E, et al. ; ENGAGE AF-TIMI 48 Investigators . Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907 PubMed DOI

Hori M, Matsumoto M, Tanahashi N, et al; J-ROCKET AF Study Investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation - the J-ROCKET AF study. Circ J . 2012;76(9):2104-2111. doi:10.1253/circj.cj-12-0454 PubMed DOI

O’Donnell MJ, Eikelboom JW, Yusuf S, et al. . Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study. Am Heart J. 2016;178:145-150. doi:10.1016/j.ahj.2016.03.019 PubMed DOI

Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867. doi:10.7326/0003-4819-146-12-200706190-00007 PubMed DOI

Connolly SJ, Eikelboom J, Joyner C, et al. ; AVERROES Steering Committee and Investigators . Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817. doi:10.1056/NEJMoa1007432 PubMed DOI

Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37(5):360-363. PubMed

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02313909