Non-cardioembolic risk factors in atrial fibrillation-associated ischemic stroke

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Abstract

Introduction

Cardioembolic (CE) risks is usually considered as the main mechanism of ischemic stroke in non-valvular atrial fibrillation (NVAF) patients. However, a substantial number of ischemic strokes in NVAF patients are related to non-CE mechanisms. The aim of this study was to investigate the non-CE risk factors in ischemic stroke patients had NVAF.

Methods

We included 401 patients (65.6% male, 68.6 ± 9.6 years old) who had been hospitalized due to ischemic stroke and had a known or newly diagnosed NVAF. The CE (intracardiac thrombus, dense spontaneous echo contrast, or low left atrial appendage flow velocity) and non-CE (complex aortic plaque, significant carotid stenosis, or intracranial arterial stenosis) risk factors were investigated at the time of the index stroke.

Results

The number of CE and non-CE risk factors increased with increasing CHA ₂DS ₂-VASc scores (p for trends < 0.001). The presence of CE risk factors was independently associated with persistent atrial fibrillation (p < 0.001), body mass index (p = 0.003), heart failure (p = 0.003), and left atrial volume index (p < 0.001). In contrast, the presence of non-CE risk factors was independently associated with age (p < 0.001), hypertension (p = 0.049), diabetes (p = 0.030), and coronary artery calcium score (CACS; p < 0.001). CACS had the added value in predicting non-CE risk factors of ischemic stroke regardless of the CHA ₂DS ₂-VASc risk category (p < 0.001).

Conclusion

Non-CE risk factors in ischemic stroke patients with NVAF are associated with high CHA ₂DS ₂-VASc score and CACS. Atherosclerotic non-CE risk factors should be considered as potential mechanisms of stroke even in patients with AF-associated ischemic stroke.

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Most cited references 24

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Rivaroxaban in patients with a recent acute coronary syndrome.

Jessica Mega, Eugene Braunwald, Stephen Wiviott … (2012)

Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

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Left atrial size and the risk of stroke and death. The Framingham Heart Study.

Emelia Benjamin, Ralph B. D’Agostino, Albert Belanger … (1995)

The medical literature contains conflicting reports on the association of left atrial (LA) enlargement with risk of stroke. The relation of LA size to risk of stroke and death in the general population remains largely unexplored. Subjects 50 years of age and older from the Framingham Heart Study were studied to assess the relations between echocardiographic LA size and risk of stroke and death. During 8 years of follow-up, 64 of 1371 (4.7%) men and 73 of 1728 (4.2%) women sustained a stroke, and 296 (21.6%) men and 271 (15.7%) women died. Sex-specific Cox proportional-hazards models were adjusted for age, hypertension, diabetes, atrial fibrillation, smoking, ECG left ventricular (LV) hypertrophy, and congestive heart failure or myocardial infarction. After multivariable adjustment, for every 10-mm increase in LA size, the relative risk of stroke was 2.4 in men (95% CI, 1.6 to 3.7) and 1.4 in women (95% CI, 0.9 to 2.1); the relative risk of death was 1.3 in men (95% CI, 1.0 to 1.5) and 1.4 in women (95% CI, 1.1 to 1.7). Adjusting for ECG LV mass/height attenuated the relation of LA size to stroke and death. After multivariable adjustment, LA enlargement remained a significant predictor of stroke in men and death in both sexes. The relation of LA enlargement to stroke and death appears to be partially mediated by LV mass.

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Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial.

Swarnalatha Y Reddy, Horst Sievert, S. Rosendahl Huber … (2013)

The multicenter PROTECT AF study (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) was conducted to determine whether percutaneous left atrial appendage closure with a filter device (Watchman) was noninferior to warfarin for stroke prevention in atrial fibrillation. Patients (n=707) with nonvalvular atrial fibrillation and at least 1 risk factor (age >75 years, hypertension, heart failure, diabetes, or prior stroke/transient ischemic attack) were randomized to either the Watchman device (n=463) or continued warfarin (n=244) in a 2:1 ratio. After device implantation, warfarin was continued for ≈45 days, followed by clopidogrel for 4.5 months and lifelong aspirin. Study discontinuation rates were 15.3% (71/463) and 22.5% (55/244) for the Watchman and warfarin groups, respectively. The time in therapeutic range for the warfarin group was 66%. The composite primary efficacy end point included stroke, systemic embolism, and cardiovascular death, and the primary analysis was by intention to treat. After 1588 patient-years of follow-up (mean 2.3±1.1 years), the primary efficacy event rates were 3.0% and 4.3% (percent per 100 patient-years) in the Watchman and warfarin groups, respectively (relative risk, 0.71; 95% confidence interval, 0.44%-1.30% per year), which met the criteria for noninferiority (probability of noninferiority >0.999). There were more primary safety events in the Watchman group (5.5% per year; 95% confidence interval, 4.2%-7.1% per year) than in the control group (3.6% per year; 95% confidence interval, 2.2%-5.3% per year; relative risk, 1.53; 95% confidence interval, 0.95-2.70). The "local" strategy of left atrial appendage closure is noninferior to "systemic" anticoagulation with warfarin. PROTECT AF has, for the first time, implicated the left atrial appendage in the pathogenesis of stroke in atrial fibrillation. : URL: http://www.clinicaltrials.gov. Unique identifier: NCT00129545.

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Author and article information

Contributors

Pil-Sung Yang: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – original draft

Hui-Nam Pak:

ORCID: http://orcid.org/0000-0002-3256-3620

Role: ConceptualizationRole: Data curationRole: SupervisionRole: Writing – review & editing

Dong-Hyuk Park: Role: Data curationRole: Formal analysis

Joonsang Yoo: Role: Data curation

Tae-Hoon Kim: Role: Data curation

Jae-Sun Uhm: Role: Data curation

Young Dae Kim: Role: Data curation

Hyo Suk Nam: Role: Data curation

Boyoung Joung: Role: Data curation

Moon-Hyoung Lee: Role: Data curation

Ji Hoe Heo: Role: Data curationRole: Writing – review & editing

Giuseppina Novo: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 20 July 2018

Publication date Collection: 2018

Volume: 13

Issue: 7

Electronic Location Identifier: e0201062

Affiliations

[1 ] Division of Cardiology, Department of Internal Medicine, Yonsei University Health System, Seoul, Republic of Korea

[2 ] Department of Neurology, Yonsei University Health System, Seoul, Republic of Korea

University of Palermo, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: hnpak@ 123456yuhs.ac (HNP); jhheo@ 123456yuhs.ac (JHH)

Author information

Hui-Nam Pak http://orcid.org/0000-0002-3256-3620

Article

Publisher ID: PONE-D-18-00614

DOI: 10.1371/journal.pone.0201062

PMC ID: 6054400

PubMed ID: 30028885

SO-VID: fc680459-246a-489d-8128-f3476682794b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 7 January 2018

Date accepted : 6 July 2018

Page count

Figures: 3, Tables: 3, Pages: 11

Funding

Funded by: funder-id http://dx.doi.org/10.13039/501100003625, Ministry of Health and Welfare;

Award ID: A085136

Award Recipient :

ORCID: http://orcid.org/0000-0002-3256-3620

Hui-Nam Pak

This work was supported by the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea ( https://www.htdream.kr/) [A085136 to HNP]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Non-cardioembolic risk factors in atrial fibrillation-associated ischemic stroke

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Abstract

Introduction

Methods

Results

Conclusion

Related collections

PLOS Climate

Most cited references 24

Rivaroxaban in patients with a recent acute coronary syndrome.

Left atrial size and the risk of stroke and death. The Framingham Heart Study.

Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial.

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Cited by 9

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