Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study
Wi-Sun Ryu, Keun-Sik Hong, Sang-Wuk Jeong, Jung E. Park, Beom Joon Kim, Joon-Tae Kim, Kyung Bok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Hong-Kyun Park, Dong-Eog Kim
Abstract
Background
Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke.
Introduction
Despite a well-known morning increase in adverse cardiovascular events such as stroke [1,2] and myocardial infarction [3], there are only a few relatively small studies on the relationship between stroke onset time and short-term/long-term outcomes, with results being inconsistent [4–6]. In addition, these studies often did not account for subtypes of ischemic stroke, a heterogenous disease caused by different pathophysiological mechanisms, and often did not focus solely upon witnessed strokes with confirmed onset timing [7].
A recent preclinical study suggested that circadian rhythms may modulate the extent of brain ischemia and effects of treatment in acute stroke. Neuroprotective treatments reduced infarct growth in day-onset (inactive phase) rodent models of stroke (which corresponds to night-onset stroke in humans), but not in night-onset (active phase) rodent models of stroke (which corresponds to day-onset stroke in humans) [8].
Methods
Study Population
This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist). This study was conducted using a prospective multicenter stroke registry: Clinical Research Collaboration for Stroke-Korea (CRCS-K) [11–16]. Using a standardized protocol [17], data were collected from all patients with acute ischemic stroke or TIA who were admitted to 11 academic hospitals within 7 days of symptom onset between May 2011 and July 2020. Inclusion criteria for this study were as follows: (1) witnessed stroke onset; (2) hospital arrival within 6 hours of onset; and (3) agreement to be monitored for the CRCS-K registry-related poststroke outcomes.
Results
A total of 60,364 patients with acute ischemic stroke or TIA were admitted within 7 days of symptom onset between May 2011 and July 2020 at the 11 participating centers. After excluding 42,903 patients based on the exclusion crteria, 17,461 patients were finally included in this study. A total of 1,893 (12.8%) patients were lost to follow-up and were excluded from the 3-month outcome analysis.
Discussion
In this nationwide multicenter study on 17,461 witnessed acute ischemic stroke or TIA with the onset-to-arrival time being less than 6 hours, night-onset stroke patients had a higher admission NIHSS score, a higher likelihood of experiencing END, and a lower likelihood of favorable 3-month outcome than day-onset stroke patients. Circadian variation patterns differed among ischemic stroke subtypes, with LAA patients particularly showing more frequent END and worse 3-month functional outcome with night-onset, CE patients showing more severe presenting deficits and worse 3-month functional outcome with night-onset, and SVO patients not evidencing night compared with day differences. To the best of our knowledge, this is the first large-scale study demonstrating circadian effects on END as well as ischemic stroke severity and 3-month functional outcome.
Citation: Ryu W-S, Hong K-S, Jeong S-W, Park JE, Kim BJ, Kim J-T, et al. (2022) Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study. PLoS Med 19(2): e1003910. https://doi.org/10.1371/journal.pmed.1003910
Academic Editor: Joshua Z. Willey, Columbia University, UNITED STATES
Received: September 22, 2021; Accepted: January 11, 2022; Published: February 4, 2022
Copyright: © 2022 Ryu et al. 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.
Data Availability: The informed consent obtained from the study participants does not allow the data to be made freely available through any third party maintained public repository. However, data used for this submission can be made available upon reasonable request (stroke@stroke.or.kr) and the approval of the ‘Comprehensive Registry Collaboration for Stroke in Korea’ steering committee.
Funding: D-E.K is supported by the the National Priority Research Center Program Grant (NRF-2021R1A6A1A03038865), the Basic Science Research Program Grant (NRF-2020R1A2C3008295), and the Multi-ministry Grant for Medical Device Development (KMDF_PR_20200901_0098) of National Research Foundation, funded by the Korean government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: For the following roles, Dr. JS receives contracted hourly payments: Abbott / St. Jude Medical Clinical Trial Steering Committee Medtronic Clinical Trial Steering Committee BrainsGate Clinical Trial Steering Committee Stryker Clinical Trial Steering Committee Boehringer-Ingelheim (Prevention Only) Clinical Trial Steering Committee Cerenovus / Neuravi) Clinical Trial Steering Committee Phagenesis Clinical Trial Steering Committee For the following role, Dr. JS receives contracted stock options: Rapid Medical Clinical Trial Steering Committee.
Abbreviations: CE, cardioembolism; CRCS-K, Clinical Research Collaboration for Stroke-Korea; END, early neurological deterioration; INTERACT, Intensive Blood Pressure Reduction in an Acute Cerebral Hemorrhage Trial; LAA, large artery atherosclerosis; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study; STEMI, ST-elevation myocardial infarction; SVO, small vessel occlusion; TIA, transient ischemic attack; TOAST, Trial of Org 10172 in Acute Stroke Treatment.
