Supplementary Appendix

Supplement to: Yoshimura S, Sakai N, Yamagami H, et al. Endovascular therapy for acute stroke with a large
ischemic region. N Engl J Med 2022;386:1303-13. DOI: 10.1056/NEJMoa2118191

This appendix has been provided by the authors to give readers additional information about the work.

(PDF updated February 18, 2022)

 Supplementary Appendix

Table of contents

2 Figure S1. Number of enrollment at each participating hospital.

3 Figure S2. Distribution of modified Rankin scale scores at 90 days in per-protocol
population.
4 Figure S3. Subgroup analyses of a modified Rankin scale score of 0 to 3 at 90 days
(primary outcome) in per-protocol population.
5 Table S1. Participating hospitals and site investigators.
7 Table S2. Study organization.
9 Table S3. Additional demographic and clinical characteristics of the patients at
baseline in full analysis population.
10 Table S4. Representativeness of study participants.
11 Table S5. Details in endovascular therapy.
12 Table S6. Adverse events.
13 Table S7. Utility-weighted modified Rankin scale scores at 90 days in full analysis
population.
14 Table S8. Patients removed from per-protocol population after adjudication of
committees.
15 Table S9. Demographic and clinical characteristics of the patients at baseline in per-
protocol population.
17 Table S10. Trial outcomes in per-protocol population.

List of investigators

Shinichi Yoshimura, MD, PhD, Nobuyuki Sakai, MD, PhD, Hiroshi Yamagami, MD, PhD,
Kazutaka Uchida, MD, PhD, Mikiya Beppu MD, PhD, Kazunori Toyoda, MD, PhD, Yuji
Matsumaru, MD, PhD, Yasushi Matsumoto, MD, Kazumi Kimura, MD, PhD, Masataka
Takeuchi, MD, PhD, Yukako Yazawa, MD, PhD, Naoto Kimura, MD, PhD, Keigo Shigeta,
MD, PhD, Hirotoshi Imamura, MD, PhD, Ichiro Suzuki, MD, PhD, Yukiko Enomoto, MD,
PhD, So Tokunaga, MD, Kenichi Morita, MD, PhD, Fumihiro Sakakibara, MD, Norito
Kinjo, MD, Takuya Saito, MD, Reiichi Ishikura, MD, PhD, Manabu Inoue, MD, PhD,
Takeshi Morimoto, MD, PhD, MPH

1
Figure S1. Number of enrollment at each participating hospital.

2
Figure S2. Distribution of modified Rankin scale scores at 90 days in per-protocol population.

3
Figure S3. Subgroup analyses of a modified Rankin scale score of 0 to 3 at 90 days (primary
outcome) in per-protocol population.

CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; rt-PA, recombinant tissue
plasminogen activator.
* Post hoc subgroup

4
Table S1. Participating hospitals and site investigators.

Participating hospitals Site investigators

Seisho Hospital Masataka Takeuchi
Hyogo College of Medicine Shinichi Yoshimura
Kohnan Hospital Yasushi Matsumoto
Iwate Prefectural Central Hospital Naoto Kimura
National Hospital Organization Disaster Medical Center Keigo Shigeta
Japanese Red Cross Kumamoto Hospital Seigo Shindo
Kobe City Medical Center General Hospital Hirotoshi Imamura
Hachinohe City Hospital Ichiro Suzuki
Gifu University Hospital Yukiko Enomoto
National Hospital Organization Kyusyu Medical Center So Tokunaga
Niigata City General Hospital Kenichi Morita
National Cerebral and Cardiovascular Center Hospital Kanta Tanaka
Nagareyama Central Hospital Ryuzaburo Kanazawa
National Hospital Organization Nagoya Medical Center Takumi Asai
Hirosaki University Graduate School of Medicine Norihito Shimamura
Yamaguchi University Hospital Hideyuki Ishihara
Yokohama Shintoshi Neurosurgical Hospital Masafumi Morimoto
Ohnishi Neurological Center Hiroyuki Ohnishi
Tenri Yorozu Hospital Yoshinori Akiyama
Kochi Red Cross Hospital Nobuhisa Matsushita
University of Tsukuba Yuji Matsumaru
Tokushima University Hospital Nobuaki Yamamoto
Hakodate Shintoshi Hospital Koichi Haraguchi
Araki Neurosurgical Hospital Hayato Araki
Graduate School of Medicine, Nippon Medical School Kazumi Kimura
Saga University Hospital Atsushi Ogata
Showa University Hospital Hirotaka Okumura
Nakamura Memorial Hospital Tatsuya Ogino
Nishinomiya Kyoritsu Neurosurgical Hospital Yoshitaka Yamada
Tokyo Metropolitan Tama Medical Center Takahiro Ota
Kawasaki Saiwai Hospital Yoshifumi Tsuboi

5
 Japanese Red Cross Society Kyoto Daini Hospital Takehiro Yamada
Hyogo Prefectural Amagasaki General Medical Center Manabu Nagata
Osaka University Hospital Kenichi Todo
Shimizu Hospital Fuminori Shimizu
Shinko Hospital Yasushi ueno
Tsuchiura Kyodo General Hospital Masataka Yoshimura
Toranomon Hospital Wataro Tsuruta
National Hospital Organization Nagasaki Medical Center Yoichi Morofuji
Mie University Hospital Naoki Toma
Omagari Kousei Medical Center Tomoya Omae
Tottori University Makoto Sakamoto
National Hospital Organization Osaka National Hospital Hiroshi Yamagami
St. Marianna University School of Medicine, Toyoko
Toshihiro Ueda
Hospital
Saitama Medical University International Medical Center Shinya Koyama

6
 Table S2. Study organization.

Committee and
Member Responsible roles
study role
Shinichi Yoshimura Study concept and
(Department of Neurosurgery, Hyogo College of Medicine) study design
Nobuyuki Sakai
Study concept and
(Department of Neurosurgery, Kobe City Medical Center General
study design
Hospital)
Hiroshi Yamagami
Study concept and
(Division of Stroke Medicine, National Hospital Organization
study design
Osaka National Hospital)
Takeshi Morimoto
Study design and
(Department of Clinical Epidemiology, Hyogo College of
writing manuscript
Steering Committee Medicine)
Kazunori Toyoda
Study design and
(Department of Cerebrovascular Medicine, National Cerebral and
deciding to publish
Cardiovascular Center)
Yuji Matsumaru
Study design and
(Division of Stroke Prevention and Treatment, Department of
deciding to publish
Neurosurgery, University of Tsukuba)
Yasushi Matsumoto Study design and
(Department of Endovascular Neurosurgery, Kohnan Hospital) deciding to publish
Kazumi Kimura Study design and
(Department of Neurology, Nippon Medical School) deciding to publish
Naoya Kuwayama
(Department of Endovascular Medicine, Toyama University Data monitoring
Hospital)
Independent
Kuniaki Ogasawara
Monitoring Committee Data monitoring
(Department of Neurosurgery, Iwate Medical University)
Teruyuki Hirano
Data monitoring
(Department of Stroke Medicine, Kyorin University)
Reiichi Ishikura
Vouching imaging
(Department of Radiology, Hyogo College of Medicine)
Imaging-Evaluation
Manabu Inoue
Committee
(Department of Cerebrovascular Medicine, National Cerebral and Vouching imaging
Cardiovascular Center)

7
 Fumihiro Sakakibara Vouching clinical
(Department of Neurosurgery, Aijinkai Chibune General Hospital) course and outcomes
Event-Adjudication Norito Kinjo Vouching clinical
Committee (Department of Neurosurgery, Matsumoto Hospital) course and outcomes
Takuya Saito Vouching clinical
(Department of Stroke Neurology, Kohnan Hospital) course and outcomes
Takeshi Morimoto
Chief Study
(Department of Clinical Epidemiology, Hyogo College of Statistical analysis
Statistician
Medicine)
Kazutaka Uchida
Gathering data
(Department of Neurosurgery, Hyogo College of Medicine)
Study Secretariat
Mikiya Beppu
Gathering data
(Department of Neurosurgery, Hyogo College of Medicine)
Masataka Takeuchi
Gathering data
(Department of Neurosurgery, Seisho Hospital)
Yukako Yazawa
Gathering data
(Department of Stroke Neurology, Kohnan Hospital)
Naoto Kimura
Gathering data
(Department of Neurosurgery, Iwate Prefectural Central Hospital)
Keigo Shigeta
(Department of Neurosurgery, National Hospital Organization Gathering data
Disaster Medical Center)
Hirotoshi Imamura
(Department of Neurosurgery, Kobe City Medical Center General Gathering data
Site Investigator Hospital)
Ichiro Suzuki
(Department of Neuroendovascular Therapy, Hachinohe City Gathering data
Hospital)
Yukiko Enomoto
Gathering data
(Department of Neurosurgery, Gifu University Hospital)
So Tokunaga
(Department of Neuroendovascular Therapy, National Hospital Gathering data
Organization Kyusyu Medical Center)
Kenichi Morita
(Department of Cerebrovascular Medicine, Niigata City General Gathering data
Hospital)
Akito Uchio
Data Center Data management
(Nexis)
8
 Table S3. Additional demographic and clinical characteristics of the patients at baseline in full
analysis population.

Endovascular-Therapy Medical-Care
Variable Group (N=101) Group (N=102)
Medical history
Hypertension — no. (%) 71 (70.3) 70 (68.6)
Diabetes mellitus — no. (%) 23 (22.8) 20 (19.6)
Hyperlipidemia — no. (%) 25 (24.8) 24 (23.5)
Atrial fibrillation — no. (%) 60 (59.4) 60 (58.8)
Ischemic heart disease — no. (%) 14 (13.9) 8 (7.8)
Ischemic stroke — no. (%) 25 (24.8) 26 (25.5)
Current smoker — no. (%) 18 (17.8) 21 (20.6)
Systolic blood pressure (SD) — mmHg* 156 (28.2) 163 (29.1)
Diastolic blood pressure (SD) — mmHg* 85.5 (18.5) 90.6 (20.7)
Laboratories at baseline
LDL cholesterol (SD) — mg/dl* 108 (29.8) 110 (35.1)
HDL cholesterol (SD) — mg/dl* 55.6 (15.9) 57.2 (17.5)
Median blood glucose (IQR) — mg/dl* 128 (116–156) 133 (116–156)
Median creatinine (IQR) — mg/dl 0.76 (0.67–1.06) 0.86 (0.70–1.05)
Median CRP (IQR) — mg/dl 0.19 (0.09–0.76) 0.17 (0.07–0.72)
Stroke classification*
Cardioembolic — no. (%) 83 (82.2) 76 (74.5)
Atherothrombotic — no. (%) 4 (4.0) 8 (7.8)
Cryptogenic — no. (%) 12 (11.9) 13 (12.7)
Others — no. (%) 1 (1.0) 5 (4.9)

CRP, C-reactive protein; HDL, high density lipoprotein; IQR, interquartile range; LDL, low density
lipoprotein; SD, standard deviation.
* Missing data (n): Systolic blood pressure (2), Diastolic blood pressure (2), LDL cholesterol (33),
HDL cholesterol (34), Blood glucose (2), Stroke classification (1).

9
 Table S4. Representativeness of study participants.

Category Representativeness
Disease, problem, or Acute ischemic stroke due to large-vessel occlusion with large ischemic
condition under investigation region.
Special considerations
related to
Large-vessel occlusion affects men and women equally or is slightly
Sex and gender
dominant in men than women (53% vs. 47% in a meta-analysis*).
Prevalence of large-vessel occlusion increases steeply with age but large-
Age
vessel occlusion occurs at any age.
Risk of stroke is nearly twice as high for blacks as for whites in the United
Race or ethnic group
States.
Ischemic stroke occurs in any countries but the incidence and cause vary
Geography
among countries.
The Alberta Stroke Program Early CT Score (ASPECTS) value was
Other considerations generally evaluated with computed tomography (CT) in North America
and Western Europe.
The participants in the present trial demonstrated the similar ratio of men
to women. Biologic sex was reported by the charts. Gender identity was
not asked in the present trial. Population age is generally elder in Japan;
thus, the age distribution in the study population was elder than North
Overall representativeness of America and Western Europe. Because all study participants were East
this trial Asian, other ethnic groups were not represented. The 86% of participants
were evaluated with diffusion-weighted magnetic resonance imaging
(MRI) to determine the ASPECTS value. Because diffusion-weighted MRI
is more sensitive than CT to evaluate the ASPECTS value, the potentially
severer participants were not enrolled.

* Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel
ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet
2016;387:1723-31.

10
Table S5. Details in endovascular therapy.

Endovascular-Therapy
Variable Group (N=100)
Endovascular therapy details — no.
Thrombectomy 98
Stent retriever only 9
Aspiration catheter only 11
Combined techniques 78
Intra-arterial thrombolysis 2
Intracranial angioplasty 2
Carotid-artery angioplasty and/or stenting 5
TICI grade — no.
0 or 1 5
2a 9
2b 43
3 43

TICI, thrombolysis in the cerebral infarction.

11
Table S6. Adverse events.

Endovascular-Therapy Medical-Care
Group (N=101) Group (N=102)
Patients Patients
AEs AEs
Adverse events with AEs with AEs
Procedural complications 9 9 (8.9%) - -
Vessel perforation 5 5 (5.0%) - -
Vessel dissection 2 2 (2.0%) - -
Thrombus formation 1 1 (1.0%) - -
Groin pseudoaneurysm 1 1 (1.0%) - -
Other serious adverse events 44 34 (33.7%) 24 19 (18.6%)
Cardiovascular events 10 10 (9.9%) 3 3 (2.9%)
Renal failure 5 5 (5.0%) 1 1 (1.0%)
Liver injury 10 10 (9.9%) 6 6 (5.9%)
Anemia 5 5 (5.0%) 1 1 (1.0%)
Pneumonia 14 14 (13.9%) 12 12 (11.8%)
Gastrointestinal bleeding 0 0 1 1 (1.0%)

AE, adverse event.

12
 Table S7. Utility-weighted modified Rankin scale scores at 90 days in full analysis population.

Endovascular-Therapy Medical-Care
Post hoc outcomes Group (N=100) Group (N=102)
Median utility-weighted modified Rankin scale score
0.33 (0–0.65) 0 (0–0.33)
in DAWN study (IQR)
Median utility-weighted modified Rankin scale score
0.19 (0.03–0.65) 0.03 (0.03–0.19)
in BEST-MSU study (IQR)

IQR, interquartile range.

13
Table S8. Patients removed from per-protocol population after adjudication of committees.

Reasons Evaluation at registration Evaluation by committee

Endovascular-Therapy Group
Modified Rankin scale score other Modified Rankin scale score
than 0 or 1 before stroke of 1
An ASPECTS value of 3
An ASPECTS value of 3
An ASPECTS value other than 3 to 5 An ASPECTS value of 3
An ASPECTS value of 3
An ASPECTS value of 3
Medical-Care Group
Randomized at 730 min and
Randomized after 6 hr without MRI
planned MRI
Modified Rankin scale score other Modified Rankin scale score
than 0 or 1 before stroke of 1
Occlusion of ICA
No ICA or M1 segment occlusion Occlusion of M1
Occlusion of M1
An ASPECTS value of 3
An ASPECTS value other than 3 to 5 An ASPECTS value of 3
An ASPECTS value of 3
Modified Rankin scale score
of 2
An ASPECTS value of 1
An ASPECTS value of 1
An ASPECTS value of 2
An ASPECTS value of 2
An ASPECTS value of 2
MRI was not conducted
Modified Rankin scale score
of 3
Occlusion of M2
Occlusion of M2
Occlusion of M2
An ASPECTS value of 0
An ASPECTS value of 2
An ASPECTS value of 2

ASPECTS, Alberta Stroke Program Early CT Score; ICA, internal carotid artery; M1, M1 segment
of the middle cerebral artery; M2, M2 segment of the middle cerebral artery; MRI, magnetic
resonance imaging.

14
 Table S9. Demographic and clinical characteristics of the patients at baseline in per-protocol
population.

Endovascular- Medical-Care
Therapy Group Group
Variable (N=94) (N=94)
Age (SD) — yr 76.7 (10.1) 75.3 (10.4)
Male sex — no. (%) 52 (55.3) 54 (57.5)
Median modified Rankin scale score before stroke (IQR) 0 (0–1) 0 (0–1)
Median NIHSS score at baseline (IQR) 22 (18–26) 21 (17–26)
Medical history
Hypertension — no. (%) 69 (73.4) 62 (66.0)
Diabetes mellitus — no. (%) 22 (23.4) 20 (21.3)
Hyperlipidemia — no. (%) 25 (26.6) 21 (22.3)
Atrial fibrillation — no. (%) 55 (58.5) 57 (60.6)
Ischemic heart disease — no. (%) 13 (13.8) 7 (7.5)
Ischemic stroke — no. (%) 25 (26.6) 23 (24.5)
Current smoker — no. (%) 18 (19.2) 20 (21.3)
Systolic blood pressure (SD) — mmHg* 155 (28.4) 163 (28.6)
Diastolic blood pressure (SD) — mmHg* 85.1 (18.2) 90.9 (21.0)
Laboratories at baseline
LDL cholesterol (SD) — mg/dl* 108 (30.2) 110 (34.7)
HDL cholesterol (SD) — mg/dl* 55.8 (15.8) 57.8 (17.5)
Median blood glucose (IQR) — mg/dl* 128 (115–158) 132 (117–158)
Median creatinine (IQR) — mg/dl 0.79 (0.67–1.07) 0.85 (0.70–1.03)
Median CRP (IQR) — mg/dl 0.20 (0.09–0.84) 0.16 (0.07–0.59)
Occlusion site — no. (%)
Internal carotid artery 42 (44.7) 45 (47.9)
M1 segment of the middle cerebral artery 70 (74.5) 68 (72.3)
Tandem lesion of internal carotid artery and
18 (19.2) 19 (20.2)
M1 segment of the middle cerebral artery
Patients with an ASPECTS value based on MRI — no. 81 83
Patients with an ASPECTS value based on CT — no. 13 11
ASPECTS
Median value (IQR) 3 (3–4) 4 (3–4)
3 — no. (%) 51 (54.3) 44 (46.8)
4 — no. (%) 24 (25.5) 30 (31.9)
5 — no. (%) 19 (20.2) 20 (21.3)
15
Median infarction volume (IQR) — ml* 94 (65–143) 110 (73–139)
Intravenous rt-PA use — no. (%) 25 (26.6) 28 (29.8)
Median interval between time of stroke onset and hospital
185 (84–380) 170 (83–335)
arrival (IQR) — min
Patients with an interval of <120 min between time
34 (36.2) 33 (35.1)
of stroke onset and hospital arrival — no. (%)
Median interval between time of stroke onset and time of
175 (98–402) 178 (105–350)
imaging (IQR) — min
Interval between time of stroke onset and time of
randomization
Median (IQR) — min 227 (144–453) 214 (142–378)
< 4.5 hr — no. (%) 53 (56.4) 61 (64.9)
4.5 to <6.0 hr — no. (%) 13 (13.8) 7 (7.5)
6.0 to <12.0 hr — no. (%) 17 (18.1) 13 (13.8)
12.0 to 24.0 hr — no. (%) 11 (11.7) 13 (13.8)
Median interval between time of stroke onset and
251 (165–466) NA
puncture time (IQR) — min
Median interval between time of stroke onset and
306 (211–501) NA
time of reperfusion (IQR) — min
TICI grade ≥2b reperfusion — no. (%) 80 (85.1) NA
Stroke classification
Cardioembolic — no. (%) 78 (83.0) 70 (74.5)
Atherothrombotic — no. (%) 4 (4.3) 7 (7.5)
Cryptogenic — no. (%) 11 (11.7) 13 (13.8)
Others — no. (%) 1 (1.1) 4 (4.3)

ASPECTS, Alberta Stroke Program Early CT Score; CRP, C-reactive protein; CT, computed
tomography; HDL, high density lipoprotein; IQR, interquartile range; LDL, low density lipoprotein;
MRI, magnetic resonance imaging; NA, not applicable; NIHSS, National Institutes of Health Stroke
Scale; rt-PA, recombinant tissue plasminogen activator; SD, standard deviation; TICI, thrombolysis
in the cerebral infarction.
* Missing data (n): Systolic blood pressure (2), Diastolic blood pressure (2), LDL cholesterol (31),
HDL cholesterol (30), Blood glucose (2), Infarction volume (17).

16
 Table S10. Trial outcomes in per-protocol population.

Endovascular-Therapy Medical-Care Treatment Effect

Outcome Group (N=94) Group (N=94) (95% CI)*
Primary outcome
Modified Rankin scale score of 0 to 3 at 90 days — no. (%) 30 (31.9) 12 (12.8) 2.50 (1.36–4.58)
Secondary outcomes
Modified Rankin scale score of 0 to 2 at 90 days — no. (%) 14 (14.9) 7 (7.4) 2.00 (0.85–4.73)
Modified Rankin scale score of 0 or 1 at 90 days — no. (%) 5 (5.3) 3 (3.2) 1.67 (0.41–6.78)
Ordinal shift across the range of modified Rankin scale scores
NA NA 2.57 (1.51–4.35)
toward a better outcome — no. (%)
Improvement of ≥8 points on the NIHSS at 48 hr — no. (%) 31 (33.0) 9 (9.6) 3.44 (1.74–6.83)
Safety outcomes
Symptomatic intracranial hemorrhage within 48 hr — no. (%) 8 (8.5) 4 (4.3) 2.00 (0.62–6.42)
Any intracranial hemorrhage within 48 hr — no. (%) 55 (58.5) 30 (31.9) 1.83 (1.30–2.58)
Death within 90 days — no. (%) 17 (18.1) 20 (21.3) 0.85 (0.48–1.52)
Recurrence of cerebral infarction within 90 days — no. (%) 4 (4.3) 7 (7.5) 0.57 (0.17–1.89)
Decompressive craniectomy within 7 days — no. (%) 7 (7.5) 12 (12.8) 0.58 (0.24–1.42)
Post hoc outcomes
Median utility-weighted modified Rankin scale score
0.33 (0–0.65) 0 (0–0.33) NA
in DAWN study (IQR)
Median utility-weighted modified Rankin scale score
0.19 (0.03–0.65) 0.03 (0.03–0.19) NA
in BEST-MSU study (IQR)

* Treatment effects are reported as relative risks with 95% confidence interval for all outcomes, except for the ordinal shift across the range of modified Rankin scale
scores toward a better outcome, for which the treatment effect is reported as a common odds ratio with the 95% confidence interval. CI, confidence interval; IQR,
interquartile range; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale.
17