Age- and sex-specific analysis of patients with embolic stroke of undetermined source

doi:10.1212/WNL.0000000000004199

. 2017 Aug 8;89(6):532-539.

doi: 10.1212/WNL.0000000000004199. Epub 2017 Jul 7.

Age- and sex-specific analysis of patients with embolic stroke of undetermined source

George Ntaios¹, Gregory Y H Lip², Konstantinos Vemmos², Eleni Koroboki², Efstathios Manios², Anastasia Vemmou², Ana Rodríguez-Campello², Elisa Cuadrado-Godia², Jaume Roquer², Valentina Arnao², Valeria Caso², Maurizio Paciaroni², Exuperio Diez-Tejedor², Blanca Fuentes², Josefa Pérez Lucas², Antonio Arauz², Sebastian F Ameriso², Lucía Pertierra², Maia Gómez-Schneider², Maximiliano A Hawkes², Fabio Bandini², Beatriz Chavarria Cano², Ana Maria Iglesias Mohedano², Andrés García Pastor², Antonio Gil-Núñez², Jukka Putaala², Turgut Tatlisumak², Miguel A Barboza², George Athanasakis², Fotios Gioulekas², Konstantinos Makaritsis², Vasileios Papavasileiou²

Affiliations

¹ From the Department of Medicine (G.N., G.A., K.M., V.P.), Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece; University of Birmingham Institute of Cardiovascular Sciences (G.Y.H.L.), City Hospital, UK; Department of Clinical Therapeutics (K.V., E.K., E.M., A.V.), Medical School of Athens, Alexandra Hospital, Greece; Stroke Unit (A.R.-C., E.C.-G., J.R.), Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona, Spain; Stroke Unit (V.A., V.C., M.P.), University of Perugia, Italy; Department of Neurology and Stroke Center (E.D.-T., B.F., J.P.L.), La Paz University Hospital-Autónoma University of Madrid, IdiPAZ Health Research Institute, Spain; Stroke Clinic (A.A.), Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico; Department of Neurology (S.F.A., L.P., M.G.-S.), Institute for Neurological Research, FLENI, Buenos Aires, Argentina; Department of Neurology (M.A.H.), Division of Critical Care Neurology, Mayo Clinic, Rochester, MN; Department of Neurology (F.B.), S. Paolo Hospital, Savona, Italy; Vascular Neurology Section (B.C.C., A.M.I.M., A.G.P., A.G.-N.), Stroke Center, Hospital General Universitario Gregorio Marañón, IiSGM Health Research Institute, Universidad Complutense de Madrid, Spain; Department of Neurology (J.P., T.T.), Helsinki University Central Hospital and University of Helsinki, Finland; Department of Clinical Neurosciences (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Neurosciences Department (M.A.B.), Hospital Dr. Rafael A. Calderón Guardia, CCSS, University of Costa Rica; Subdirectorate of Informatics (F.G.), Larissa General University Hospital, Greece; and Stroke Service (V.P.), Department of Neurosciences, Leeds Teaching Hospitals NHS Trust and Medical School, University of Leeds, UK. gntaios@med.uth.gr.
² From the Department of Medicine (G.N., G.A., K.M., V.P.), Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece; University of Birmingham Institute of Cardiovascular Sciences (G.Y.H.L.), City Hospital, UK; Department of Clinical Therapeutics (K.V., E.K., E.M., A.V.), Medical School of Athens, Alexandra Hospital, Greece; Stroke Unit (A.R.-C., E.C.-G., J.R.), Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona, Spain; Stroke Unit (V.A., V.C., M.P.), University of Perugia, Italy; Department of Neurology and Stroke Center (E.D.-T., B.F., J.P.L.), La Paz University Hospital-Autónoma University of Madrid, IdiPAZ Health Research Institute, Spain; Stroke Clinic (A.A.), Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico; Department of Neurology (S.F.A., L.P., M.G.-S.), Institute for Neurological Research, FLENI, Buenos Aires, Argentina; Department of Neurology (M.A.H.), Division of Critical Care Neurology, Mayo Clinic, Rochester, MN; Department of Neurology (F.B.), S. Paolo Hospital, Savona, Italy; Vascular Neurology Section (B.C.C., A.M.I.M., A.G.P., A.G.-N.), Stroke Center, Hospital General Universitario Gregorio Marañón, IiSGM Health Research Institute, Universidad Complutense de Madrid, Spain; Department of Neurology (J.P., T.T.), Helsinki University Central Hospital and University of Helsinki, Finland; Department of Clinical Neurosciences (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Neurosciences Department (M.A.B.), Hospital Dr. Rafael A. Calderón Guardia, CCSS, University of Costa Rica; Subdirectorate of Informatics (F.G.), Larissa General University Hospital, Greece; and Stroke Service (V.P.), Department of Neurosciences, Leeds Teaching Hospitals NHS Trust and Medical School, University of Leeds, UK.

PMID: 28687720
PMCID: PMC5562957
DOI: 10.1212/WNL.0000000000004199

Free PMC article

Age- and sex-specific analysis of patients with embolic stroke of undetermined source

George Ntaios et al. Neurology. 2017.

Free PMC article

. 2017 Aug 8;89(6):532-539.

doi: 10.1212/WNL.0000000000004199. Epub 2017 Jul 7.

Authors

Affiliations

¹ From the Department of Medicine (G.N., G.A., K.M., V.P.), Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece; University of Birmingham Institute of Cardiovascular Sciences (G.Y.H.L.), City Hospital, UK; Department of Clinical Therapeutics (K.V., E.K., E.M., A.V.), Medical School of Athens, Alexandra Hospital, Greece; Stroke Unit (A.R.-C., E.C.-G., J.R.), Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona, Spain; Stroke Unit (V.A., V.C., M.P.), University of Perugia, Italy; Department of Neurology and Stroke Center (E.D.-T., B.F., J.P.L.), La Paz University Hospital-Autónoma University of Madrid, IdiPAZ Health Research Institute, Spain; Stroke Clinic (A.A.), Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico; Department of Neurology (S.F.A., L.P., M.G.-S.), Institute for Neurological Research, FLENI, Buenos Aires, Argentina; Department of Neurology (M.A.H.), Division of Critical Care Neurology, Mayo Clinic, Rochester, MN; Department of Neurology (F.B.), S. Paolo Hospital, Savona, Italy; Vascular Neurology Section (B.C.C., A.M.I.M., A.G.P., A.G.-N.), Stroke Center, Hospital General Universitario Gregorio Marañón, IiSGM Health Research Institute, Universidad Complutense de Madrid, Spain; Department of Neurology (J.P., T.T.), Helsinki University Central Hospital and University of Helsinki, Finland; Department of Clinical Neurosciences (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Neurosciences Department (M.A.B.), Hospital Dr. Rafael A. Calderón Guardia, CCSS, University of Costa Rica; Subdirectorate of Informatics (F.G.), Larissa General University Hospital, Greece; and Stroke Service (V.P.), Department of Neurosciences, Leeds Teaching Hospitals NHS Trust and Medical School, University of Leeds, UK. gntaios@med.uth.gr.
² From the Department of Medicine (G.N., G.A., K.M., V.P.), Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece; University of Birmingham Institute of Cardiovascular Sciences (G.Y.H.L.), City Hospital, UK; Department of Clinical Therapeutics (K.V., E.K., E.M., A.V.), Medical School of Athens, Alexandra Hospital, Greece; Stroke Unit (A.R.-C., E.C.-G., J.R.), Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona, Spain; Stroke Unit (V.A., V.C., M.P.), University of Perugia, Italy; Department of Neurology and Stroke Center (E.D.-T., B.F., J.P.L.), La Paz University Hospital-Autónoma University of Madrid, IdiPAZ Health Research Institute, Spain; Stroke Clinic (A.A.), Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico; Department of Neurology (S.F.A., L.P., M.G.-S.), Institute for Neurological Research, FLENI, Buenos Aires, Argentina; Department of Neurology (M.A.H.), Division of Critical Care Neurology, Mayo Clinic, Rochester, MN; Department of Neurology (F.B.), S. Paolo Hospital, Savona, Italy; Vascular Neurology Section (B.C.C., A.M.I.M., A.G.P., A.G.-N.), Stroke Center, Hospital General Universitario Gregorio Marañón, IiSGM Health Research Institute, Universidad Complutense de Madrid, Spain; Department of Neurology (J.P., T.T.), Helsinki University Central Hospital and University of Helsinki, Finland; Department of Clinical Neurosciences (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden; Neurosciences Department (M.A.B.), Hospital Dr. Rafael A. Calderón Guardia, CCSS, University of Costa Rica; Subdirectorate of Informatics (F.G.), Larissa General University Hospital, Greece; and Stroke Service (V.P.), Department of Neurosciences, Leeds Teaching Hospitals NHS Trust and Medical School, University of Leeds, UK.

PMID: 28687720
PMCID: PMC5562957
DOI: 10.1212/WNL.0000000000004199

Abstract

Objective: To investigate whether the correlation of age and sex with the risk of recurrence and death seen in patients with previous ischemic stroke is also evident in patients with embolic stroke of undetermined source (ESUS).

Methods: We pooled datasets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. We performed Cox regression and Kaplan-Meier product limit analyses to investigate whether age (<60, 60-80, >80 years) and sex were independently associated with the risk for ischemic stroke/TIA recurrence or death.

Results: Ischemic stroke/TIA recurrences and deaths per 100 patient-years were 2.46 and 1.01 in patients <60 years old, 5.76 and 5.23 in patients 60 to 80 years old, 7.88 and 11.58 in those >80 years old, 3.53 and 3.48 in women, and 4.49 and 3.98 in men, respectively. Female sex was not associated with increased risk for recurrent ischemic stroke/TIA (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.84-1.58) or death (HR 1.35, 95% CI 0.97-1.86). Compared with the group <60 years old, the 60- to 80- and >80-year groups had higher 10-year cumulative probability of recurrent ischemic stroke/TIA (14.0%, 47.9%, and 37.0%, respectively, p < 0.001) and death (6.4%, 40.6%, and 100%, respectively, p < 0.001) and higher risk for recurrent ischemic stroke/TIA (HR 1.90, 95% CI 1.21-2.98 and HR 2.71, 95% CI 1.57-4.70, respectively) and death (HR 4.43, 95% CI 2.32-8.44 and HR 8.01, 95% CI 3.98-16.10, respectively).

Conclusions: Age, but not sex, is a strong predictor of stroke recurrence and death in ESUS. The risk is ≈3- and 8-fold higher in patients >80 years compared with those <60 years of age, respectively. The age distribution in the ongoing ESUS trials may potentially influence their power to detect a significant treatment association.

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Figures

**Figure 1. Age- and sex-specific frequency distribution and annualized event rates for ischemic stroke/TIA recurrence and mortality**
(A) Female patients; (B) male patients.

**Figure 2. Age- and sex-specific comorbidities in patients with ESUS**
(A) Female patients; (B) male patients. ESUS = embolic stroke of undetermined source.

**Figure 3. Cox regression analyses of the association between age, sex, and ischemic stroke/TIA recurrence**
(A) Adjusted for age, coronary artery disease, arterial hypertension, dyslipidemia and previous stroke/TIA/thromboembolism, and mortality. (B) Adjusted for age, sex, NIHSS score, diabetes mellitus, arterial hypertension, smoking heart failure, peripheral artery disease, acute treatment, and coronary artery disease. Associations are presented as HRs and 95% CIs. The full models are presented in table e-2. CI = confidence interval; HR = hazard ratio; NIHSS = NIH Stroke Scale.

**Figure 4. Age- and sex-specific cumulative probability of recurrent ischemic stroke/TIA and mortality in patients with ESUS**
(A) Female ischemic stroke/TIA recurrence, (B) female mortality, (C) male ischemic stroke/TIA recurrence, and (D) male mortality. ESUS = embolic stroke of undetermined source.

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Comment in

Age and the fuzzy edges of embolic stroke of undetermined source: Implications for trials.
Charidimou A. Charidimou A. Neurology. 2017 Aug 8;89(6):526-527. doi: 10.1212/WNL.0000000000004220. Epub 2017 Jul 7. Neurology. 2017. PMID: 28687717 No abstract available.

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References

1. Brown RD, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996;27:373–380. - PubMed
1. Wolf PA, D'Agostino RB, O'Neal MA, et al. . Secular trends in stroke incidence and mortality: the Framingham study. Stroke 1992;23:1551–1555. - PubMed
1. Marinigh R, Lip GY, Fiotti N, Giansante C, Lane DA. Age as a risk factor for stroke in atrial fibrillation patients: implications for thromboprophylaxis. J Am Coll Cardiol 2010;56:827–837. - PubMed
1. Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham study. Lancet Neurol 2007;6:1106–1114. - PubMed
1. Mikkelsen AP, Lindhardsen J, Lip GY, Gislason GH, Torp-Pedersen C, Olesen JB. Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study. J Thromb Haemost 2012;10:1745–1751. - PubMed

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[1] Brown RD, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996;27:373–380. - PubMed

[2] Brown RD, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996;27:373–380. - PubMed

[3] Wolf PA, D'Agostino RB, O'Neal MA, et al. . Secular trends in stroke incidence and mortality: the Framingham study. Stroke 1992;23:1551–1555. - PubMed

[4] Wolf PA, D'Agostino RB, O'Neal MA, et al. . Secular trends in stroke incidence and mortality: the Framingham study. Stroke 1992;23:1551–1555. - PubMed

[5] Marinigh R, Lip GY, Fiotti N, Giansante C, Lane DA. Age as a risk factor for stroke in atrial fibrillation patients: implications for thromboprophylaxis. J Am Coll Cardiol 2010;56:827–837. - PubMed

[6] Marinigh R, Lip GY, Fiotti N, Giansante C, Lane DA. Age as a risk factor for stroke in atrial fibrillation patients: implications for thromboprophylaxis. J Am Coll Cardiol 2010;56:827–837. - PubMed

[7] Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham study. Lancet Neurol 2007;6:1106–1114. - PubMed

[8] Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham study. Lancet Neurol 2007;6:1106–1114. - PubMed

[9] Mikkelsen AP, Lindhardsen J, Lip GY, Gislason GH, Torp-Pedersen C, Olesen JB. Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study. J Thromb Haemost 2012;10:1745–1751. - PubMed

[10] Mikkelsen AP, Lindhardsen J, Lip GY, Gislason GH, Torp-Pedersen C, Olesen JB. Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study. J Thromb Haemost 2012;10:1745–1751. - PubMed

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Age- and sex-specific analysis of patients with embolic stroke of undetermined source

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Age- and sex-specific analysis of patients with embolic stroke of undetermined source

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