Association Between Onset-to-Door Time and Clinical

Outcomes After Ischemic Stroke

Ryu Matsuo, MD, PhD*; Yuko Yamaguchi, MPH*; Tomonaga Matsushita, MD, PhD;
Jun Hata, MD, PhD; Fumi Kiyuna, MD; Kenji Fukuda, MD, PhD;
Yoshinobu Wakisaka, MD, PhD; Junya Kuroda, MD, PhD; Tetsuro Ago, MD, PhD;
Takanari Kitazono, MD, PhD; Masahiro Kamouchi, MD, PhD;
on behalf of the Fukuoka Stroke Registry Investigators†

Background and Purpose—The role of early hospital arrival in improving poststroke clinical outcomes in patients without
reperfusion treatment remains unclear. This study aimed to determine whether early hospital arrival was associated with
favorable outcomes in patients without reperfusion treatment or with minor stroke.
Methods—This multicenter, hospital-based study included 6780 consecutive patients (aged, 69.9±12.2 years; 63.9% men)
with ischemic stroke who were prospectively registered in Fukuoka, Japan, between July 2007 and December 2014.
Onset-to-door time was categorized as T0-1, ≤1 hour; T1-2, >1 and ≤2 hours; T2-3, >2 and ≤3 hours; T3-6, >3 and ≤6 hours;
T6-12, >6 and ≤12 hours; T12-24, >12 and ≤24 hours; and T24-, >24 hours. The main outcomes were neurological improvement
(decrease in National Institutes of Health Stroke Scale score of ≥4 during hospitalization or 0 at discharge) and good
functional outcome (3-month modified Rankin Scale score of 0–1). Associations between onset-to-door time and main
outcomes were evaluated after adjusting for potential confounders using logistic regression analysis.
Results—Odds ratios (95% confidence intervals) increased significantly with shorter onset-to-door times within 6 hours,
for both neurological improvement (T0-1, 2.79 [2.28–3.42]; T1-2, 2.49 [2.02–3.07]; T2-3, 1.52 [1.21–1.92]; T3-6, 1.72
[1.44–2.05], with reference to T24-) and good functional outcome (T0-1, 2.68 [2.05–3.49], T1-2 2.10 [1.60–2.77], T2-3 1.53
[1.15–2.03], T3-6 1.31 [1.05–1.64], with reference to T24-), even after adjusting for potential confounding factors including
reperfusion treatment and basal National Institutes of Health Stroke Scale. These associations were maintained in 6216
patients without reperfusion treatment and in 4793 patients with minor stroke (National Institutes of Health Stroke Scale
Downloaded from http://ahajournals.org by on November 26, 2019

≤4 on hospital arrival).
Conclusions—Early hospital arrival within 6 hours after stroke onset is associated with favorable outcomes after
ischemic stroke, regardless of reperfusion treatment or stroke severity.   (Stroke. 2017;48:3049-3056. DOI: 10.1161/
STROKEAHA.117.018132.)
Key Words: emergency medicine ◼ emergency treatment ◼ stroke ◼ treatment outcome

S troke often causes disability and remains one of the lead-

ing causes of death worldwide.1 Reperfusion therapy,
including intravenous recombinant tissue-type plasminogen
activator and endovascular therapy, has become established
as the most effective therapy for improving clinical outcomes
after stroke.2,3 However, the effects of this therapy depend on
the time interval from stroke onset to treatment.4–6 Moreover,
even within the therapeutic time window, the benefits of this
therapy become attenuated with increasing time elapsed from
stroke onset to treatment.4–10 Considerable effort has therefore
been made to reduce delays in hospital admission in patients
with stroke. However, the percentage of patients with stroke
eligible for reperfusion therapy has remained constant during
recent years and most patients are still unable to receive this
therapy.11,12
Previous studies have suggested that early hospital arrival
improves functional outcome and reduces mortality after
stroke.13–16 However, these studies included patients with
stroke who received reperfusion therapy, and the favorable
outcomes were mainly attributed to the beneficial effect of

Received May 21, 2017; final revision received September 1, 2017; accepted September 1, 2017.
From the Department of Medicine and Clinical Science (R.M., T.M., J.H., F.K., K.F., Y.W., J.K., T.A., T.K.), Department of Health Care Administration
and Management (R.M., Y.Y., M.K.), Center for Cohort Study (J.H., Y.W., T.K., M.K.), and Department of Epidemiology and Public Health (J.H.),
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Cerebrovascular Disease, St. Mary’s Hospital, Kurume,
Japan (T.M., K.F.).
*Drs Matsuo and Yamaguchi contributed equally.
†A list of all Fukuoka Stroke Registry study participants is given in the Appendix.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
117.018132/-/DC1.
Correspondence to Masahiro Kamouchi, MD, PhD, Department of Health Care Administration and Management, Graduate School of Medical Sciences,
Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812–8582, Japan. E-mail kamouchi@hcam.med.kyushu-u.ac.jp
© 2017 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.117.018132

3049
 3050  Stroke  November 2017

reperfusion therapy during the hyperacute stage. Whether
a time from symptom onset to arrival of ≤6 hours can also
improve poststroke clinical outcomes in patients without
reperfusion therapy or in those with minor stroke for whom
reperfusion therapy is often deferred, thus remains unclear.
To address this issue, we investigated the time from stroke
onset to hospital arrival in patients with acute ischemic stroke
based on data from a large-scale, multicenter, prospective
stroke registry in Japan. We aimed to determine whether early
hospital arrival was associated with a favorable clinical out-
come in patients with ischemic stroke who did not receive
reperfusion treatment or who had only minor symptoms.
Methods
members. The participating hospitals were stroke centers equipped
with a stroke care unit. Trained stroke neurologists in each hospital
performed emergency evaluations and were able to initiate the opti-
mal stroke treatment as early as possible. Stroke was diagnosed by the
sudden onset of nonconvulsive and focal neurological deficits with
reference to the findings of brain computed tomography, magnetic
resonance imaging, or both on admission.
Participants
A total of 8956 patients with acute ischemic stroke were registered in
the Fukuoka Stroke Registry from July 2007 to December 2014. Of
these patients, we excluded 1765 who were functionally dependent,
corresponding to a modified Rankin Scale score of ≥2, before stroke
onset, and 237 patients whose ictus occurred in hospital. A total of
6954 patients fulfilled the inclusion criteria and were included in the
study (Figure I in the online-only Data Supplement).

Study Design
We analyzed data from a multicenter, hospital-based acute stroke
registry, the Fukuoka Stroke Registry, in Fukuoka, Japan.17,18 The
Fukuoka Stroke Registry enrolled patients with stroke who were hos-
pitalized in participating hospitals within 7 days from stroke onset
(UMIN Clinical Trial Registry: 000000800). The study protocol was
approved by the institutional review board of each hospital. Written
informed consent was obtained from all patients or their family
Study Outcomes
The study outcomes were neurological improvement and good func-
tional outcome at 3 months after stroke onset. Neurological sever-
ity was measured by trained stroke neurologists according to the
National Institutes of Health Stroke Scale (NIHSS) score on admis-
sion and at discharge in all patients. Neurological improvement was
defined as a ≥4-point decrease in NIHSS score between admission

Table 1.  Background Characteristics of All Patients According to Onset-to-Door Time

T0-1 T1-2 T2-3 T3-6 T6-12 T12-24 T24-
n=770 n=578 n=390 n=710 n=766 n=1320 n=2246 Ptrend
Age, y, mean±SD 70±12.9 70±12.5 71.7±12.6 70.1±12.5 70.4±12 70.1±12.1 69.3±11.7 0.001
Men, n (%) 494 (64.2) 390 (67.5) 242 (62.1) 464 (65.4) 495 (64.6) 826 (62.6) 1419 (63.2) 0.17
Downloaded from http://ahajournals.org by on November 26, 2019

Risk factors, n (%)

 Hypertension 574 (74.6) 451 (78) 304 (78) 557 (78.5) 601 (78.5) 1062 (80.5) 1804 (80.3) 0.001
 Dyslipidemia 361 (46.9) 284 (49.1) 194 (49.7) 388 (54.7) 399 (52.1) 720 (54.6) 1345 (59.9) <0.001
 Diabetes mellitus 166 (21.6) 141 (24.4) 107 (27.4) 238 (33.5) 216 (28.2) 438 (33.2) 777 (34.6) <0.001
 Atrial fibrillation 289 (37.5) 170 (29.4) 108 (27.7) 169 (23.8) 160 (20.9) 263 (19.9) 316 (14.1) <0.001
 Smoking 411 (53.4) 348 (60.2) 202 (51.8) 382 (53.8) 425 (55.5) 743 (56.3) 1286 (57.3) 0.18
 Drinking 318 (41.3) 233 (40.3) 158 (40.5) 258 (36.3) 290 (37.9) 538 (40.8) 858 (38.2) 0.25
Previous stroke, n (%) 133 (17.3) 97 (16.8) 80 (20.5) 140 (19.7) 112 (14.6) 219 (16.6) 355 (15.8) 0.09
Ambulance use, n (%) 642 (83.4) 411 (71.1) 274 (70.3) 397 (55.9) 434 (56.7) 567 (43.0) 574 (25.6) <0.001
Arrival on working hour, n (%) 258 (33.5) 234 (40.5) 146 (37.4) 299 (42.1) 269 (35.1) 729 (55.2) 1554 (69.2) <0.001
Cardioembolism, n (%) 287 (37.3) 161 (27.9) 98 (25.1) 157 (22.1) 144 (18.8) 221 (16.7) 230 (10.2) <0.001
Neurological severity
 NIHSS score, median (IQR) 4 (1-11) 3 (1-8) 3 (1-6) 3 (1-5) 3 (1-5) 3 (1-5) 2 (1-4) <0.001
 Minor stroke, n (%) 428 (55.6) 351 (60.7) 263 (67.4) 500 (70.4) 510 (66.6) 982 (74.4) 1871 (83.3) <0.001
Reperfusion treatment, n (%) 270 (35.1) 157 (27.2) 57 (14.6) 35 (4.9) 19 (2.5) 8 (0.6) 18 (0.8) <0.001
 Intravenous rtPA 252 (32.7) 138 (23.9) 49 (12.6) 15 (2.1) 0 (0) 0 (0) 1 (0)
 Endovascular and surgical
6 (0.8) 11 (1.9) 5 (1.3) 16 (2.3) 18 (2.4) 8 (0.6) 17 (0.8)
treatments
 Intravenous rtPA, and
endovascular and surgical 12 (1.6) 8 (1.4) 3 (0.8) 4 (0.6) 1 (0.1) 0 (0) 0 (0)
treatments
The onset-to-door time was categorized as follows: T0-1, ≤1 h; T1-2, >1 and ≤2 h; T2-3, >2 and ≤3 h; T3-6, >3 and ≤6 h; T6-12, >6 and ≤12 h; T12-24, >12 and ≤24 h; and
T24-, >24 h. Neurological severity was evaluated according to NIHSS on admission. Minor stroke was defined as NIHSS score of ≤4 on admission. Reperfusion treatment
included intravenous rtPA, endovascular treatment with thrombectomy, angioplasty, stenting, and intra-arterial thrombolysis with rtPA, and carotid endarterectomy at
postacute stage. IQR indicates interquartile range; NIHSS, National Institutes of Health Stroke Scale; and rtPA, recombinant tissue-type plasminogen activator.
 Matsuo et al   Early Hospital Arrival and Poststroke Outcome    3051

and discharge or a score of 0 at discharge.19–21 Functional outcome
was assessed at 3 months after stroke onset using the modified Rankin
Scale. A good functional outcome was defined as a modified Rankin
Scale score of 0 or 1, considering that most neurological deficits in
the study participants were not severe. The modified Rankin Scale
score at 3 months was evaluated by a trained stroke neurologist or
trained and certified research nurse, either in person or by telephone,
using a standardized structured questionnaire previously validated to
minimize interrater variability.22
Time From Stroke Onset to Hospital Arrival
We calculated the time between stroke onset and hospital arrival
as onset-to-door time. When the exact time of symptom onset was
unknown, we defined the onset time as the last time at which the
patient was known to be neurologically normal. Patients were cat-
egorized into 7 clinically relevant groups according to their onset-
to-door time as follows: T0-1, ≤1 hour; T1-2, >1 and ≤2 hours; T2-3, >2
and ≤3 hours; T3-6, >3 and ≤6 hours; T6-12, >6 and ≤12 hours; T12-24,
>12 and ≤24 hours; and T24-, >24 hours.
Clinical Assessments
The baseline characteristics of the patients were assessed on admis-
sion or during hospitalization. Risk factors for cardiovascular events
included hypertension (systolic blood pressure ≥140 mm Hg or dia-
stolic blood pressure ≥90 mm Hg, or a previous history of hyperten-
sion), dyslipidemia (low-density lipoprotein cholesterol levels ≥3.62
mmol/L, high-density lipoprotein cholesterol levels <1.03 mmol/L,
or triglyceride levels ≥1.69 mmol/L, or a history of antihypercho-
lesterolemic medication), diabetes mellitus (diagnostic criteria of the
Japan Diabetes Society23 or a medical history of diabetes mellitus),
atrial fibrillation (previously diagnosed or identified during hospital-
ization), smoking (previous or current cigarette smoking), drinking
(habitual consumption of alcoholic beverages), and past history of
any stroke. Transportation methods were categorized into ambu-
lance use and others, including other methods of transportation and
walking. Admission time was dichotomized as within working hours
(9:00–17:00 hours) on weekdays and other times (17:00–9:00 hours)
on weekdays or any time on a Saturday, Sunday, or national holiday.
The cause of ischemic stroke was classified into 4 subtypes as
follows: cardioembolism, large-artery atherosclerosis, small-vessel
occlusion, and others.24 Minor stroke was defined as an NIHSS score
of ≤4 on admission. Reperfusion treatment included intravenous
thrombolysis with recombinant tissue-type plasminogen activator,
endovascular treatment with mechanical thrombectomy, angioplasty,
stenting, and intra-arterial thrombolysis with recombinant tissue-type
plasminogen activator, and carotid endarterectomy at postacute stage
(Table I in the online-only Data Supplement).
Statistical Analysis
There were no missing baseline data in this study. Trends according
to onset-to-door time were evaluated using the Jonckheere–Terpstra
test or the Cochran–Armitage test. Differences in clinical characteris-
tics between included and excluded patients were compared by t tests,
Mann–Whitney U tests, or χ2 tests. We evaluated the associations
between onset-to-door time and clinical outcomes by logistic regres-
sion analysis and estimated odds ratios (ORs) and 95% confidence
interval. The multivariate model included age, sex, stroke severity
(NIHSS score) on hospital arrival, previous stroke, stroke subtype,
ambulance use, hypertension, dyslipidemia, diabetes mellitus, atrial

Table 2.  Onset-to-Door Time and Clinical Outcomes in All Patients

Age and Sex Adjusted Multivariate Adjusted
Downloaded from http://ahajournals.org by on November 26, 2019

Events (%) OR (95% CI) P Value OR (95% CI) P Value

Neurological improvement
 
T0-1, n=770 539 (70.0) 2.53 (2.12–3.01) <0.001 2.79 (2.28–3.42) <0.001
 
T1-2, n=578 392 (67.8) 2.28 (1.88–2.77) <0.001 2.49 (2.02–3.07) <0.001
T2-3, n=390
  215 (55.1) 1.35 (1.09–1.67) 0.007 1.52 (1.21–1.92) <0.001
T3-6, n=710
  411 (57.9) 1.49 (1.25–1.76) <0.001 1.72 (1.44–2.05) <0.001
T6-12, n=766
  423 (55.2) 1.34 (1.13–1.58) 0.001 1.52 (1.28–1.81) <0.001
 
T12-24, n=1320 645 (48.9) 1.03 (0.90–1.18) 0.66 1.13 (0.98–1.30) 0.10
 
T24-, n=2246 1085 (48.3) 1.00 (reference) 1.00 (reference)
 
P for trend <0.001 <0.001 <0.001
Good functional outcome
T0-1, n=770
  502 (65.2) 0.79 (0.66–0.94) 0.009 2.68 (2.05–3.49) <0.001
 
T1-2, n=578 388 (67.1) 0.85 (0.70–1.05) 0.13 2.10 (1.60–2.77) <0.001
T2-3, n=390
  246 (63.1) 0.78 (0.61–0.98) 0.03 1.53 (1.15–2.03) 0.004
 
T3-6, n=710 455 (64.1) 0.75 (0.62–0.90) 0.002 1.31 (1.05–1.64) 0.02
 
T6-12, n=766 465 (60.7) 0.65 (0.54–0.77) <0.001 1.17 (0.94–1.45) 0.15
T12-24, n=1320
  858 (65.0) 0.78 (0.67–0.91) 0.001 1.13 (0.95–1.35) 0.16
 
T24-, n=2246 1594 (71.0) 1.00 (reference) 1.00 (reference)
 
P for trend 0.002 0.01 <0.001
The onset-to-door time was categorized as follows: T0-1, ≤1 h; T1-2, >1 and ≤2 h; T2-3, >2 and ≤3 h; T3-6, >3 and ≤6 h; T6-
12
, >6 and ≤12 h; T12-24, >12 and ≤24 h; and T24-, >24 h. ORs and 95% CIs for neurological improvement and good functional
outcome were estimated for each category of onset-to-door time within 24 hours compared with T24-. The multivariate model
included age, sex, stroke severity (National Institutes of Health Stroke Scale score), previous stroke, stroke subtype, ambulance
use, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, working hour hospital arrival, and reperfusion treatment. CI
indicates confidence interval; and OR, odds ratio.
 3052  Stroke  November 2017

fibrillation, working hour hospital arrival, and reperfusion treatment.18
We also conducted subgroup analyses in patients categorized accord-
ing to age (≤80 or >80 years), sex (female or male), stroke severity
(minor or nonminor stroke), and stroke subtype (cardioembolic or
noncardioembolic). The P value for heterogeneity was calculated by
adding the interaction term of onset-to-door time×subgroup variable
in the model. We also conducted sensitivity analyses excluding 564
patients who underwent any reperfusion treatment during hospital-
ization, and 1423 patients with NIHSS scores >4 on admission. All
statistical analyses were performed using JMP Pro 11 and SAS 9.4
(SAS Institute Inc, Cary, NC). All tests were 2 sided, and P<0.05 was
considered to be statistically significant.
Results
Baseline Patient Characteristics
Among the 6954 patients, 174 (2.5%) were excluded because
of a lack of functional outcome data at 3 months and 6780
patients were therefore finally included in the analysis (Figure
I in the online-only Data Supplement). The background char-
acteristics of the included and excluded patients were similar
(Table II in the online-only Data Supplement).
The mean (±SD) age of all the patients was 69.9±12.2 years,
and 63.9% were men (Table 1). Among all the patients, 2448
Downloaded from http://ahajournals.org by on November 26, 2019
(36.1%) arrived at hospital within 6 hours of stroke onset.
Among the 4534 (66.9%) patients who were admitted to hos-
pital within 24 hours after stroke onset, 2725 (60.1%) were
transported by ambulance. The clinical profiles of the patients
differed according to the onset-to-door time. The prevalences
of hypertension, dyslipidemia, diabetes mellitus, and work-
ing hour arrival decreased with shorter onset-to-door time,
whereas the frequencies of ambulance use and cardioembolic
stroke increased with shorter onset-to-door time. Shorter
onset-to-door time was also associated with higher NIHSS
score on admission and less frequent minor strokes (Figure II
in the online-only Data Supplement). Reperfusion treatment
was usually performed within 6 hours of onset, but occasion-
ally later than 6 hours after onset in specific situations.
Association Between Onset-to-Door
Time and Clinical Outcomes
The frequency of neurological improvement tended to
increase as the onset-to-door time became shorter (Table 2).
Even after adjusting for possible confounding factors includ-
ing reperfusion treatment and baseline NIHSS score, the OR
of neurological improvement increased as the onset-to-door

Figure. Association between onset-to-door time and good functional outcome according to baseline characteristics. The onset-to-door
time was categorized as follows: T0-1, ≤1 h; T1-2, >1 and ≤2 h; T2-3, >2 and ≤3 h; T3-6, >3 and ≤6 h; T6-12, >6 and ≤12 h; T12-24, >12 and ≤24
h; and T24-, >24 hours. Odds ratios (ORs) and 95% confidence intervals (CIs) of good functional outcome at 3 months in each category
within 24 hours compared with T24- are shown according to age (≤80 or >80 y, A), sex (female or male, B), stroke severity (minor or nonmi-
nor stroke, C), and stroke subtype (noncardioembolism or cardioembolism, D). Minor stroke was defined as National Institutes of Health
Stroke Scale score of ≤4. The multivariate model included age, sex, stroke severity, previous stroke, stroke subtype, ambulance use,
hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, working hour hospital arrival, and reperfusion treatment. Pt and Ph indicate
P for trend and P for heterogeneity, respectively.
 Matsuo et al   Early Hospital Arrival and Poststroke Outcome    3053

time became shorter. About functional outcome, the frequency
of good functional outcome or age- and sex-adjusted ORs
tended to be low in patients who arrived at hospital within 24
hours of stroke onset compared with those who arrived >24
hours after onset (Table 2). However, after adjusting for mul-
tiple confounding factors including reperfusion treatment and
baseline NIHSS score, the multivariate-adjusted OR of good
functional outcome at 3 months after stroke onset was sig-
nificantly higher in patients who arrived at hospital within 6
hours of symptom onset than in those who arrived >24 hours
after onset.
Subgroup Analysis
We also investigated the association between onset-to-door
time and good functional outcome at 3 months in relation to
age, sex, stroke severity, and stroke subtype, but there was
no heterogeneity between the 2 groups in relation to any of
the above factors (Figure). A similar association was found
in patients with large-artery atherosclerosis or small-vessel
occlusion (Table III in the online-only Data Supplement).
Sensitivity Analysis
Intravenous recombinant tissue-type plasminogen activator
and endovascular treatment were clearly associated with neu-
rological improvement and good functional outcome (Table IV
in the online-only Data Supplement). We therefore conducted
sensitivity analysis by further excluding 564 patients who
underwent reperfusion treatment. Among the 6216 patients
without reperfusion treatment, modified Rankin Scale score at
3 months tended to be lower as the onset-to-door time became
shorter (Table V in the online-only Data Supplement). After
adjustment for multiple confounding factors, we found similar
associations between onset-to-door time and clinical outcomes
among patients who did not receive reperfusion treatment
(Table 3; Figure III in the online-only Data Supplement).
Furthermore, the trends were also maintained among 4793
patients with minor stroke, defined as NIHSS score ≤4 (Table
V in the online-only Data Supplement; Table 4).
Discussion
This study demonstrated that early hospital arrival within
6 hours of stroke onset was associated with neurological
improvement during hospitalization and good functional out-
come after 3 months in patients with acute ischemic stroke.
These associations existed even in patients without reperfu-
sion treatment and in those with minor stroke and were inde-
pendent of age, sex, stroke severity, and stroke subtype.
Previous studies showed that clinical outcomes were better
in patients with ischemic stroke who arrived in hospital within
3 hours of stroke onset compared with those who arrived

Table 3.  Onset-to-Door Time and Clinical Outcomes in Patients Without Reperfusion Treatment
Age and Sex Adjusted Multivariate Adjusted
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Events (%) OR (95% CI) P Value OR (95% CI) P Value

Neurological improvement
 
T0-1, n=500 346 (69.2) 2.42 (1.96–2.97) <0.001 2.82 (2.25–3.53) <0.001
 
T1-2, n=421 276 (65.6) 2.04 (1.64–2.54) <0.001 2.36 (1.88–2.96) <0.001
T2-3, n=333
  183 (55.0) 1.34 (1.06–1.68) 0.01 1.58 (1.24–2.01) <0.001
T3-6, n=675
  391 (57.9) 1.49 (1.26–1.78) <0.001 1.74 (1.45–2.09) <0.001
T6-12, n=747
  411 (55.0) 1.33 (1.12–1.57) 0.001 1.53 (1.28–1.83) <0.001
 
T12-24, n=1312 641 (48.9) 1.03 (0.90–1.18) 0.64 1.13 (0.98–1.31) 0.08
 
T24-, n=2228 1075 (48.3) 1.00 (reference) 1.00 (reference)
 
P for trend <0.001 <0.001 <0.001
Good functional outcome
T0-1, n=500
  385 (77.0) 1.38 (1.09–1.74) 0.008 2.72 (2.00–3.70) <0.001
 
T1-2, n=421 312 (74.1) 1.14 (0.89–1.46) 0.29 2.10 (1.54–2.87) <0.001
T2-3, n=333
  217 (65.2) 0.83 (0.64–1.07) 0.15 1.51 (1.11–2.06) 0.009
 
T3-6, n=675 440 (65.2) 0.78 (0.65–0.95) 0.01 1.32 (1.05–1.67) 0.02
 
T6-12, n=747 454 (60.8) 0.64 (0.53–0.77) <0.001 1.16 (0.93–1.45) 0.19
T12-24, n=1312
  852 (64.9) 0.77 (0.66–0.90) 0.001 1.14 (0.96–1.37) 0.14
 
T24-, n=2228 1585 (71.1) 1.00 (reference) 1.00 (reference)
 
P for trend 0.09 0.07 <0.001
The onset-to-door time was categorized as follows: T0-1, ≤1 h; T1-2, >1 and ≤2 h; T2-3, >2 and ≤3 h; T3-6, >3 and ≤6 h; T6-12,
>6 and ≤12 h; T12-24, >12 and ≤24 h; and T24-, >24 h. Odds ratios and 95% confidence intervals for neurological improvement
and good functional outcome were estimated for each category of onset-to-door time within 24 hours compared with T24-. The
multivariate model included age, sex, stroke severity (National Institutes of Health Stroke Scale score), previous stroke, stroke
subtype, ambulance use, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and working hour hospital arrival. CI
indicates confidence interval; and OR, odds ratio.
 3054  Stroke  November 2017

Table 4.  Onset-to-Door Time and Clinical Outcomes in Patients With Minor Stroke
Age and Sex Adjusted Multivariate Adjusted
Events (%) OR (95% CI) P Value OR (95% CI) P Value
Neurological improvement
 
T0-1, n=390 274 (70.3) 2.32 (1.84–2.94) <0.001 3.07 (2.38–3.96) <0.001
T1-2, n=323
  217 (67.2) 2.02 (1.58–2.60) <0.001 2.50 (1.93–3.25) <0.001
T2-3, n=247
  137 (55.5) 1.24 (0.95–1.63) 0.11 1.53 (1.16–2.03) 0.003
T3-6, n=491
  289 (58.9) 1.42 (1.16–1.74) 0.001 1.68 (1.36–2.07) <0.001
T6-12, n=505
  278 (55.1) 1.21 (0.99–1.48) 0.06 1.36 (1.11–1.67) 0.004
 
T12-24, n=977 479 (49.0) 0.95 (0.81–1.11) 0.52 1.04 (0.88–1.21) 0.66
 
T24-, n=1860 937 (50.4) 1.00 (reference) 1.00 (reference)
 
P for trend <0.001 <0.001 <0.001
Good functional outcome
T0-1, n=390
  338 (86.7) 1.64 (1.19–2.25) 0.003 2.63 (1.87–3.71) <0.001
T1-2, n=323
  275 (85.1) 1.45 (1.04–2.03) 0.03 2.15 (1.51–3.04) <0.001
T2-3, n=247
  195 (79.0) 1.07 (0.76–1.49) 0.71 1.57 (1.10–2.22) 0.01
T3-6, n=491
  387 (78.8) 0.99 (0.77–1.27) 0.92 1.27 (0.98–1.65) 0.07
 
T6-12, n=505 389 (77.0) 0.86 (0.67–1.10) 0.22 1.08 (0.84–1.40) 0.56
T12-24, n=977
  763 (78.1) 0.92 (0.76–1.12) 0.41 1.09 (0.89–1.34) 0.38
T24-, n=1860
  1481 (79.6) 1.00 (reference) 1.00 (reference)
 
P for trend 0.002 0.001 <0.001
The onset-to-door time was categorized as follows: T0-1, ≤1 h; T1-2, >1 and ≤2 h; T2-3, >2 and ≤3 h; T3-6, >3 and ≤6 h; T6-12,
>6 and ≤12 h; T12-24, >12 and ≤24 h; and T24-, >24 h. Neurological improvement was defined as National Institutes of Health
Downloaded from http://ahajournals.org by on November 26, 2019

Stroke Scale 0 at discharge, given that the baseline National Institutes of Health Stroke Scale for minor stroke was ≤4. ORs
and 95% CIs for neurological improvement and good functional outcome were estimated for each category of onset-to-door
time within 24 hours compared with T24-. The multivariate model included age, sex, previous stroke, stroke subtype, ambulance
use, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and working hour hospital arrival. CI indicates confidence
interval; and OR, odds ratio.

later.13,15 However, these studies concluded that this favorable
effect was probably attributable to thrombolytic therapy. Denti
et al16 investigated a cohort of Italian patients with stroke but
without reperfusion therapy and found a significant asso-
ciation between early arrival at hospital and a reduced risk
of 1-month mortality, but no association with disability. In
contrast, our present study indicated that the ORs of favor-
able clinical outcomes, including neurological improvement
and good functional outcome, increased with faster hospital
arrival after stroke onset, regardless of the administration of
reperfusion treatment or of stroke severity.
The benefits of early treatment with thrombolytic therapy
are clear, and guidelines therefore recommend minimizing the
prehospital delay in patients with acute ischemic stroke.25,26
Considerable efforts have thus been made to avoid unneces-
sary prehospital delays.27 However, fibrinolytic therapy is
often withheld because of the narrow therapeutic window
or contraindications to the therapy. Our findings indicate
that early presentation is associated with better outcomes in
patients who do not receive thrombolysis or thrombectomy.
Moreover, we found no heterogeneity in this relationship
between onset-to-door time and clinical outcomes in relation
to age, sex, stroke severity, and stroke subtype, suggesting that
delays in arrival at hospital are associated with unfavorable
clinical outcomes in all patients with stroke, regardless of their
background characteristics.
There are some possible explanations for the beneficial
effects of a short onset-to-door time on clinical outcomes.
In the case of reperfusion treatment, a fibrinolytic agent
or thrombectomy using endovascular devices reopens the
occluded arteries and salvages the ischemic penumbra in a
time-dependent manner. The benefits of other stroke treat-
ments, such as anticoagulants, antiplatelet agents, blood pres-
sure control, and neuroprotective statins,26 may also increase
with shorter times from stroke onset to treatment. Given that
the association between onset-to-door time and clinical out-
comes was still found in patients with strokes caused by large-
artery atherosclerosis or small-vessel occlusion, mechanisms
other than reopening of the occluded artery, such as improved
collateral flow or microcirculation and early protection of neu-
rons from ischemic insult, may also contribute to the benefit
of early arrival in terms of poststroke outcome. Additionally,
a shorter onset-to-door time may allow the earlier initiation
of general supportive care or treatment for acute complica-
tions,26 which may contribute to decreased morbidity and mor-
tality after acute ischemic stroke. Further studies are needed to
determine the time sensitivities of stroke treatments other than
reperfusion treatment.
 Matsuo et al   Early Hospital Arrival and Poststroke Outcome    3055
This study had some strengths, including a relatively large
sample size, with no missing baseline data, and the provi-
sion of stroke care by experts using standardized methods.
However, the study also had some limitations. The onset-to-
door time may have been overestimated in a proportion of
patients, such as those with wake-up stroke, because the exact
time of the stroke was unknown, and stroke onset was thus
defined as the last time at which the patient was known to
be neurologically normal. Furthermore, the study participants
were homogenous in terms of ethnicity and healthcare system,
and the generalizability of the results needs to be validated in
other cohorts, especially in other countries.
Conclusions
Early hospital arrival is associated with favorable clinical
outcomes after acute ischemic stroke, regardless of the poten-
tial indication for reperfusion treatment or the severity of the
stroke.
Appendix
Participating Hospitals in the Fukuoka Stroke Registry: Kyushu
University Hospital, National Hospital Organization Kyushu
Medical Center, National Hospital Organization Fukuoka Higashi
Medical Center, Fukuoka Red Cross Hospital, St. Mary’s Hospital,
Nippon Steel Yawata Memorial Hospital, and Japan Labour
Health and Welfare Organization Kyushu Rosai Hospital. Steering
Committee and Research Working Group in the Fukuoka Stroke
Registry: The steering committee of the Fukuoka Stroke Registry
included Takao Ishitsuka (Fukuoka Mirai Hospital), Setsuro Ibayashi
(Seiai Rehabilitation Hospital), Kenji Kusuda (Seiai Rehabilitation
Hospital), Kenichiro Fujii (Japan Seafarers Relief Association Moji
Downloaded from http://ahajournals.org by on November 26, 2019
Ekisaikai Hospital), Tetsuhiko Nagao (Midorino Clinic), Yasushi
Okada (National Hospital Organization Kyushu Medical Center),
Masahiro Yasaka (National Hospital Organization Kyushu Medical
Center), Hiroaki Ooboshi (Fukuoka Dental Collage Medical and
Dental Hospital), Takanari Kitazono (Kyushu University), Katsumi
Irie (Hakujyuji Hospital), Tsuyoshi Omae (Imazu Red Cross
Hospital), Kazunori Toyoda (National Cerebral and Cardiovascular
Center), Hiroshi Nakane (National Hospital Organization Fukuoka-
Higashi Medical Center), Masahiro Kamouchi (Kyushu University),
Hiroshi Sugimori (Saga-Ken Medical Centre Koseikan), Shuji
Arakawa (Steel Memorial Yawata Hospital), Kenji Fukuda (St.
Mary’s Hospital), Ago Tetsuro (Kyushu University Hospital), Jiro
Kitayama (Fukuoka Red Cross Hospital), Shigeru Fujimoto (Jichi
Medical University), Shoji Arihiro (Japan Labor Health and Welfare
Organization Kyushu Rosai Hospital), Junya Kuroda (Kyushu
University Hospital), Yoshinobu Wakisaka (Kyushu University
Hospital), Yoshihisa Fukushima (St. Mary’s Hospital), and Ryu
Matsuo (Kyushu University).
Acknowledgments
We thank all study participants, Fukuoka Stroke Registry inves-
tigators for collecting data, and all clinical research coordinators
(Hisayama Research Institute for Lifestyle Diseases) for their help in
obtaining informed consent and collecting clinical data.
Sources of Funding
This study was supported by the Japan Society for the Promotion
of Science, Grant-in-Aid for Scientific Research, grant numbers
26293158, 15K08849, and 17H04143 from the Japanese Ministry of
Education, Culture, Sports, Science and Technology.
Disclosures
None.
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