Hugh S. Markus, DM
Susanna C. Larsson, PhD
Wilhelm Kuker, FRCR
Ursula G. Schulz, DPhil
Ian Ford, PhD
Peter M. Rothwell,
FMedSci
*
Andrew Clifton, FRCR
*
For the VIST
Investigators
Correspondence to
Dr. Markus:
hsm32@medschl.cam.ac.uk
Editorial, page 1204
Supplemental data
at Neurology.org
Stenting for symptomatic vertebral artery
stenosis
The Vertebral Artery Ischaemia Stenting Trial
ABSTRACT
Objective:
To compare in the Vertebral Artery Ischaemia Stenting Trial (VIST) the risks and bene-
fits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for symptom-
atic vertebral artery stenosis.
Methods:
VIST was a prospective, randomized, open-blinded endpoint clinical trial performed in
14 hospitals in the United Kingdom. Participants with symptomatic vertebral stenosis
$50%
were randomly assigned (1:1) to vertebral angioplasty/stenting plus BMT or to BMT alone with
randomization stratified by site of stenosis (extracranial vs intracranial). Because of slow recruit-
ment and cessation of funding, recruitment was stopped after 182 participants. Follow-up was
a minimum of
$1 year for each participant.
Results:
Three patients did not contribute any follow-up data and were excluded, leaving 91 pa-
tients in the stent group and 88 in the medical group. Mean follow-up was 3.5 (interquartile range
2.1
–4.7) years. Of 61 patients who were stented, stenosis was extracranial in 48 (78.7%) and
intracranial in 13 (21.3%). No periprocedural complications occurred with extracranial stenting;
2 strokes occurred during intracranial stenting. The primary endpoint of fatal or nonfatal stroke
occurred in 5 patients in the stent group vs 12 in the medical group (hazard ratio 0.40, 95%
confidence interval 0.14
–1.13, p 5 0.08), with an absolute risk reduction of 25 strokes per
1,000 person-years. The hazard ratio for stroke or TIA was 0.50 (
p 5 0.05).
Conclusions:
Stenting in extracranial stenosis appears safe with low complication rates. Large
phase 3 trials are required to determine whether stenting reduces stroke risk.
ISRCTN.com identifier:
ISRCTN95212240.
Classification of evidence:
This study provides Class I evidence that for patients with symptomatic
vertebral stenosis, angioplasty with stenting does not reduce the risk of stroke. However, the
study lacked the precision to exclude a benefit from stenting.
Neurology
®
2017;89:1229
–1236
GLOSSARY
BMT
5 best medical therapy; CAVATAS 5 Carotid and Vertebral Artery Transluminal Angioplasty Study; CI 5 confidence
interval; DSA
5 digital subtraction angiography; HR 5 hazard ratio; MR 5 magnetic resonance; NASCET 5 North American
Symptomatic Carotid Endarterectomy Trial; SAMMPRIS
5 Stenting and Aggressive Medical Management for Preventing
Recurrent Stroke in Intracranial Stenosis; VA
5 vertebral artery; VAST 5 Vertebral Artery Stenting Trial; VISSIT 5 Vitesse
Intracranial Stent Study for Ischemic Therapy; VIST
5 Vertebral Artery Ischaemia Stenting Trial; WASID 5 Warfarin Aspirin
Symptomatic Intracranial Disease.
Posterior circulation stroke accounts for 20% of ischemic stroke.
1
A quarter occurs in patients
with stenosis in the vertebral and/or basilar arteries.
1
Information about optimal management is
lacking compared with symptomatic carotid stenosis, for which large international trials dem-
onstrated a benefit from endarterectomy
2
and that stenting may be appropriate in selected
patients.
3
*These authors contributed equally to this work.
From the Stroke Research Group (H.S.M., S.C.L.), Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical
Campus; Nuffield Department of Clinical Neurosciences (W.K., U.G.S., P.M.R.), John Radcliffe Hospital, University of Oxford; Robertson Centre
for Biostatistics (I.F.), University of Glasgow; and Department of Neuroradiology (A.C.), St. George
’s Hospital, London, UK.
VIST Coinvestigators are listed at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
The Article Processing Charge was funded by NIHR.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
1229
Patients with recently symptomatic verte-
brobasilar stenosis have a high risk of recurrent
stroke similar to carotid stenosis, with the
highest risk in the first month.
4
Vertebral
artery (VA) stenosis can be treated with angio-
plasty and/or stenting.
1
Case series have sug-
gested that stenting may be an effective
treatment option, but nonrandomized studies
are subject to publication bias.
5,6
Very low
complication rates (1%
–1.5%) have been re-
ported with stenting for extracranial VA ste-
nosis,
6
but higher complication rates have
been noted for intracranial stenosis at 7% to
10%.
5
However, recent data from randomized
trials have dampened enthusiasm. The Stent-
ing and Aggressive Medical Management for
Preventing Recurrent Stroke in Intracranial
Stenosis (SAMMPRIS) trial reported worse
outcome for stenting compared with best
medical therapy (BMT) in patients with ste-
nosis in a variety of intracranial cerebral ar-
teries
7
; however, there were few patients with
VA stenosis.
8
The Vertebral Artery Stenting
Trial (VAST) included patients with intracra-
nial and extracranial VA stenosis and found no
significant difference between stenting and
BMT, but it was underpowered to detect
a difference.
9
The Vertebral Artery Ischaemia Stenting
Trial (VIST) compared risks and benefits of
angioplasty and stenting plus BMT for
recently symptomatic VA stenosis with BMT
alone. A meta-analysis combining results from
VIST and previous trials was conducted.
METHODS
Study design and participants.
VIST was
a prospective, randomized open-blinded endpoint clinical trial
performed at 14 hospitals with specialized stroke and interven-
tional radiology services in the United Kingdom. VIST sites and
recruitment rate are shown in table e-1 at Neurology.org. The
plan was to extend the study to other countries, but as a result of
cessation of funding because of slower-than-anticipated recruit-
ment, 182 of 540 patients, from the United Kingdom alone, were
recruited.
Patients presenting with posterior circulation TIA or nondis-
abling stroke and VA stenosis resulting from presumed atheroma-
tous disease with stenosis
$50% were included. Other eligibility
criteria were ability to consent and willingness to be randomized
to either treatment; if randomized to stenting, it could be per-
formed within 2 weeks. During recruitment of the first 100
patients, patients had to have had symptoms within the last 6
months, but this was changed to 3 months in view of data show-
ing that stroke risk was highest in the first 3 months.
Exclusion criteria were VA stenosis caused by dissection, ver-
tebral stenting felt to be technically impracticable (e.g., access
problems), previous stenting in randomized artery, and preg-
nancy and lactation in women.
Before randomization, the likely presence of a VA stenosis
had to be demonstrated on imaging and confirmed by 2 experi-
enced neuroradiologists. The following imaging modalities were
acceptable: magnetic resonance (MR) angiography (preferably
contrast enhanced), contrast-enhanced CT angiography, and
intra-arterial digital subtraction angiography (DSA). It was rec-
ommended that an additional imaging modality be used if there
was any doubt about the result of a noninvasive screening test.
The patient would be randomized only if the 2 methods provided
concordant and appropriate results. The degree of VA stenosis
was calculated by a method based on North American Symptom-
atic Carotid Endarterectomy Trial (NASCET) in which the resid-
ual luminal diameter (R) was divided by vessel diameter (D) at
a point distal to the stenosis where normal vessel caliber was
restored and applying the following formula: ([1
– R]/D) 3
100
5 degree of stenosis.
2
When normal distal vessel was not
available, e.g., for distal stenosis, the proximal normal artery
diameter was used as the denominator, a method based on the
Warfarin Aspirin Symptomatic Intracranial Disease (WASID)
measurement of intracranial stenosis.
10
Standard protocol approvals, registrations, and patient
consents.
The study was approved by Multicentre Ethics Com-
mittee in England (REC 08/H0711/2). All patients gave written
informed consent.
Randomization and masking.
Patients were randomly as-
signed (1:1) to vertebral angioplasty/stenting plus BMT or
BMT alone by an online randomization service provided by
Kings College London. To account for the differing recurrent
stroke risk associated with site of VA stenosis, randomization
was stratified by site of VA stenosis (V1 vs V2/V3 vs V4).
1
Both
patients and clinicians were aware of treatment allocation, but an
independent adjudication committee masked to treatment allo-
cation assessed all primary and secondary endpoints.
Procedures.
All patients were expected to receive BMT, includ-
ing antiplatelets or anticoagulation (when appropriate) and con-
trol of medical risk factors. Use of antiplatelet agents was
recorded. Specific drugs to be used were not mandated.
The recommended antiplatelet therapy during the procedure
was clopidogrel and aspirin with loading with clopidogrel at least
12 hours before the procedure (300
–600 mg) if the patient was
not already taking clopidogrel. It was recommended that clopi-
dogrel and aspirin be continued for at least 1 month after the
procedure, after which standard antiplatelet therapy for stroke
prevention was used.
It was recommended that stenting, rather than angioplasty, be
preferred for proximal vertebral stenosis, but for distal stenosis,
the choice was at the discretion of the radiologist. Stent choice
was at the discretion of the radiologist, but stents were CE
marked for treatment of arterial stenosis. To be eligible to partic-
ipate, a center had to have a consultant neurologist/stroke physi-
cian and a consultant interventional radiologist with experience in
cerebral angioplasty/stenting. Interventionists were expected to
have performed a minimum of 50 stenting procedures, of which
at least 10 were on cerebral vessels.
Follow-up.
Both entry and follow-up data were collected via an
online electronic case report form. Participants allocated to
stenting were seen at the time of the procedure and at 1 month
and 1 year after randomization. In addition, telephone follow-up
was performed at 6 months and 2 years and then yearly by the
coordinating center by a designated stroke physician or
1230
Neurology 89 September 19, 2017
neurologist using a standard form. If patients had outcome events
during follow-up, an endpoint form was completed, results of
imaging were obtained, and data were reviewed by the adjudi-
cation committee. Repeat imaging with either MR angiography
or CT angiography at 1 year to check for vessel patency was
encouraged but not mandated.
Angiographic imaging at baseline and at 12 months was as-
sessed by central reading by an experienced neuroradiologist
(A.C.). Restenosis was defined as any residual or recurrent steno-
sis of at least 50% or occlusion of the VA on CT or MR angiog-
raphy during follow-up.
Outcomes.
The primary endpoint was fatal or nonfatal stroke in
any arterial territory (including periprocedural stroke) during
follow-up. Stroke was defined as a focal neurologic deficit of
presumed vascular cause, lasting
.24 hours, of any severity.
Secondary endpoints included stroke and TIA during follow-up,
posterior circulation stroke (including periprocedural stroke)
during follow-up, fatal or nonfatal stroke in any arterial territory
within 90 days of randomization, and death resulting from any
cause during follow-up. Periprocedural stroke was defined as
stroke within 30 days of intervention.
Sample size.
For sample size estimates, the following numbers
were used: stroke risk in the medically treated arm of 24% over
a 3-year period, and a risk reduction in the stented arm of 45%.
The number of patients needed was estimated to be 245 per group,
assuming
p 5 0.05 and 80% power. Calculations were performed
with a
x
2
test comparing 2 proportions with nQuery Advisor soft-
ware version 6.02. Sample size was increased by 10% to account for
crossovers or loss to follow-up to give a sample size of 540. Because of
slow recruitment, support for continued recruitment by the funder
was withdrawn after 182 patients were recruited; at that point, an
analysis was planned after every patient had
$1 years of follow-up.
Statistical analysis.
The main analyses performed were on an
intention-to-treat basis. We also conducted per-protocol analy-
ses including patients who received the assigned treatment and
had at least 50% VA stenosis confirmed at angiogram. Differ-
ences in baseline characteristics between treatment groups were
compared by use of the
t test for continuous variables and x
2
or
Fisher exact tests for categorical variables.
Hazard ratios (HRs) with 95% confidence intervals (CIs) were
estimated with Cox proportional hazards regression models. Each
patient accrued follow-up time from the date of randomization until
the time of first event of each type, death, or March 1, 2016, by
which follow-up of at least 1 year was available for all patients. Abso-
lute event rates were calculated by dividing the number of events by
the number of person-years. The proportional hazards assumption
was tested with scaled Schoenfeld residuals. Kaplan-Meier survival
analysis was used to construct time-to-event curves, and the log-
rank test was used to compare the cumulative events between groups.
Figure 1
Trial profile
*Intention-to-treat population.
Neurology 89 September 19, 2017
1231
Meta-analysis.
A random-effects meta-analysis was performed to
combine the results from VIST and previous trials. The search strategy
for identifying previous trials is reported in the supplemental data.
All statistical tests were 2 sided. Statistical analyses were per-
formed with Stata version 14.1 (StataCorp, College Station, TX).
RESULTS
Trial profile and baseline characteristics.
The trial profile is shown in figure 1. Between October
23, 2008, and February 4, 2015, 182 patients were
enrolled. Three patients (2 withdrew after randomiza-
tion and 1 did not attend after the initial randomiza-
tion visit) did not contribute any follow-up data and
were excluded. None of these patients had outcome
events. Of the 179 remaining, 88 were assigned to
BMT alone (medical group) and 91 to stenting/
angioplasty plus BMT (stent group). Follow-up data
until March 2016 were available for all 179 patients.
Characteristics of patients at baseline were well
matched (table 1), but time from last symptoms to
randomization was shorter in the stenting arm by
a mean of 12.8 days (
p 5 0.04). The percentage of
patients randomized within 14 days of last symptoms
was 47% in the stented and 30% in the medical arm
(
p 5 0.02). The location of the VA target stenosis was
extracranial in 83% and intracranial in 17%; most
extracranial stenoses affected the V1 segment.
Median follow-up was 3.5 years (interquartile range
2.1
–4.7 years). Medical treatment and risk factor con-
trol at baseline and follow-up were well balanced
between the 2 groups, except for slightly higher antipla-
telet use in the stented arm in the first month (table 2).
Details of intervention.
Of 91 patients randomized to
stenting, the procedure was not performed in 30
(33.0%) (figure 1). The major reason, in 23 (76.7%)
participants, was the finding of stenosis
,50% on DSA
performed at the time of planned stenting. Of the 61
patients stented, the stenosis was extracranial in 48
(78.7%) and intracranial in 13 (21.3%). Fifty-eight
(63.7%) patients had a stent (56 balloon-expandable
Table 1
Baseline characteristics of study participants
Characteristic
Medical group
(n
5 88)
Stent group
(n
5 91)
p Value
Age, mean (SD) [range], y
66.6 (10.2) [45
–86]
68.3 (9.2) [44
–89]
0.25
Male, n (%)
75 (85)
73 (80)
0.38
Treated hypertension, n (%)
60 (68)
66 (73)
0.52
Treated hyperlipidemia, n (%)
77 (88)
77 (85)
a
0.70
Treated diabetes mellitus, n (%)
19 (22)
20 (22)
0.95
Systolic blood pressure, mean (SD), mm Hg
139.3 (2.3)
138.4 (2.0)
0.77
Diastolic blood pressure, mean (SD), mm Hg
79.5 (1.3)
77.0 (1.3)
0.17
Total cholesterol, mean (SD), mmol/L
4.5 (0.14)
4.4 (0.13)
0.65
Current smoker, n (%)
25 (29)
18 (20)
0.12
Ischemic heart disease, n (%)
9 (10)
19 (21)
0.05
Peripheral arterial disease, n (%)
4 (4.6)
9 (9.9)
0.25
Atrial fibrillation, n (%)
8 (9.1)
10 (11)
0.67
Qualifying event, n (%)
Ischemic stroke
58 (66)
63 (69)
0.64
TIA
30 (34)
28 (31)
0.64
Time between last vertebrobasilar event and randomization,
median, d
24.5
14.0
0.04
£14 d since last vertebrobasilar event, n (%)
30 (34)
47 (52)
0.02
Time from randomization to stenting, mean (SD), d
—
16.1 (1.9)
—
Location of vertebral artery target stenosis, n (%)
Extracranial (V1
–V3)
74 (84)
74 (81)
0.62
V1
70
71
V2 or V3
4
3
Intracranial (V4)
14 (16)
17 (19)
0.62
Modified Rankin Scale score, median (IQR)
b
1 (1
–2)
2 (1
–2)
a
0.74
Abbreviation: IQR
5 interquartile range.
a
Missing data for 1 patient.
b
The disability rating can be caused by medical conditions other than stroke.
1232
Neurology 89 September 19, 2017
and 2 self-expanding stents) placed, and 3 patients had
angioplasty alone; no distal protection devices were
used. Mean stenosis in the treated VA of stented pa-
tients was 78.7% (SD 1.6%) before stenting and 9.6%
(SD 1.8%) after stenting.
There were 2 major complications during the
stenting procedure, both in patients with intracranial
stenosis. One died of subarachnoid hemorrhage dur-
ing stenting caused by vessel rupture. A second had
a nonfatal periprocedural brainstem stroke. In pa-
tients with extracranial stenosis, 1 stented patient
had a nonfatal stroke within 30 days of intervention.
Primary outcome.
The primary endpoint of fatal or
nonfatal stroke occurred in 5 patients (including 1 fatal
stroke) in the stent group and in 12 patients (including
2 fatal strokes) in the medical group, with an HR of
0.40 (95% CI 0.14
–1.13, p 5 0.08) (table 3 and
figure 2A). For the primary endpoint, there were 41
strokes per 1,000 person-years in the medical group
compared with 16 strokes per 1,000 person-years in
the stent group. Therefore, the absolute risk benefit
was 25 strokes per 1,000 person-years.
During follow-up, 1 stroke occurred among the 8
patients with atrial fibrillation in the medical group.
No strokes occurred among the 10 patients with atrial
fibrillation in the stent group.
As a result of the imbalance in time from symptoms
to randomization between groups, an exploratory post
hoc analysis was performed with adjustment for days
from last symptoms (i.e., last vertebrobasilar TIA or
stroke) to randomization. The corresponding HR for
the primary endpoint was 0.34 (95% CI 0.12
–0.98,
p 5 0.046). In addition, a second post hoc analysis in
patients randomized within 2 weeks after the last
symptom was performed; the HR of the primary end-
point was 0.30 (95% CI 0.09
–0.99, p 5 0.048; med-
ical group 8 of 30, stent group 4 of 47).
Key secondary outcomes.
For the composite secondary
endpoint of fatal or nonfatal stroke or TIA, the HR
was 0.50 (95% CI 0.25
–1.01, p 5 0.05) (table 3 and
figure 2B). The HR in patients with extracranial and
intracranial VA stenosis was 0.37 (95% CI 0.10
–1.36)
and 0.47 (95% CI 0.08
–2.60), respectively (table 3).
Other secondary endpoints, fatal or nonfatal stroke
within 90 days and death resulting from any cause (figure
2C), did not differ between the 2 groups (table 3). The
per-protocol analyses yielded similar results (table 3).
Adverse events.
Adverse events are listed in table e-2.
There was no difference between the 2 treatment groups.
Follow-up angiographic imaging.
Follow-up angio-
graphic imaging with CT or MR angiography was
Table 2
Medical treatment, blood pressure, and smoking status at baseline and at each follow-up visit
Medical treatment, blood
pressure, and smoking
status
Baseline
At 1 mo
At 6 mo
At 1 y
At 2 y
Medical
group
(n
5 88)
a
Stent
group
(n
5 91)
Medical
group
(n
5 82)
Stent
group
(n
5 88)
Medical
group
(n
5 83)
Stent
group
(n
5 85)
Medical
group
(n
5 79)
Stent
group
(n
5 84)
Medical
group
(n
5 62)
Stent
group
(n
5 70)
Aspirin, n (%)
51 (58)
60 (66)
42 (51)
60 (68)
27 (33)
43 (51)
24 (30)
45 (54)
17 (27)
21 (30)
Clopidogrel, n (%)
62 (70)
63 (69)
62 (76)
75 (85)
59 (71)
69 (81)
55 (70)
62 (74)
45 (73)
49 (70)
Dual antiplatelet therapy,
n (%)
b
30 (34)
38 (42)
27 (33)
50 (57)
14 (17)
32 (38)
12 (15)
29 (35)
9 (15)
10 (14)
Dipyridamole, n (%)
10 (11)
9 (10)
7 (9)
4 (5)
5 (6)
6 (7)
4 (5)
5 (6)
2 (3)
4 (6)
Oral anticoagulants, n (%)
4 (4.6)
3 (3.3)
8 (10)
4 (5)
11 (13)
5 (6)
12 (15)
6 (7)
9 (15)
13 (19)
Statin therapy, n (%)
82 (93)
84 (92)
80 (98)
83 (94)
79 (95)
82 (96)
74 (94)
78 (93)
56 (90)
63 (90)
Antihypertensive medication,
n (%)
65 (74)
70 (77)
66 (80)
69 (78)
64 (77)
69 (82)
60 (76)
71 (85)
49 (79)
59 (84)
SBP, mean (SD), mm Hg
139.3 (2.3)
138.4 (2.0)
138.4 (2.0)
c
140.0 (2.2)
d
NA
NA
139.1 (2.3)
e
141.8 (2.6)
f
NA
NA
DBP, mean (SD), mm Hg
79.5 (1.3)
77.0 (1.3)
77.4 (1.2)
c
77.7 (1.2)
d
NA
NA
78.3 (1.4)
e
79.1 (1.3)
f
NA
NA
Diabetes mellitus therapy,
n (%)
19 (22)
20 (22)
20 (24)
21 (24)
g
NA
NA
19 (24)
h
19 (23)
i
NA
NA
Current smoker, n (%)
25 (29)
18 (20)
20 (24)
11 (12)
g
NA
NA
16 (20)
h
13 (16)
i
NA
NA
Abbreviations: DBP
5 diastolic blood pressure; NA 5 not available; SBP 5 systolic blood pressure.
a
The number in parenthesis is the number of patients evaluated at each time point during follow-up.
b
Combination of aspirin and clopidogrel.
c
Data available for 78 patients.
d
Data available for 86 patients.
e
Data available for 70 patients.
f
Data available for 74 patients.
g
Data available for 89 patients.
h
Data available for 78 patients.
i
Data available for 82 patients.
Neurology 89 September 19, 2017
1233
performed in 47 of 61 participants undergoing stent-
ing. This showed 3 stent occlusions, 2 in V1 and 1 in
V2; 2 patients were asymptomatic, and 1 participant
had a TIA.
DISCUSSION
VIST is the largest RCT comparing
stenting plus BMT with BMT alone in patients with
symptomatic VA stenosis. Stenting, particularly for
extracranial stenosis, appeared safe. No significant dif-
ference was found in risk of stroke between the 2
treatment arms. Over a median follow-up of 3.5
years, the stented group had a nonsignificant 60%
lower risk for the primary endpoint of fatal and
nonfatal stroke compared with the BMT group. A
similar magnitude of risk reduction was seen for
posterior circulation stroke alone and for the com-
bined endpoint of stroke and TIA.
Natural history data have shown that the risk of
recurrent stroke after TIA or minor stroke due to ver-
tebral stenosis is much greater in the first days and few
weeks after the event.
4
This is a pattern similar to that
seen in symptomatic carotid stenosis.
2
Therefore, any
intervention is likely to have greater benefit if admin-
istered early. Consistent with this, an analysis of pa-
tients randomized within 2 weeks of last symptoms
showed a significant treatment benefit.
Four previous RCTs have compared stenting and/
or angioplasty with medical therapy in patients with
VA stenosis. The Carotid and Vertebral Artery Trans-
luminal Angioplasty Study (CAVATAS) randomized
16 patients with extracranial VA stenosis to angio-
plasty or medical therapy; no stroke endpoints
occurred in either group.
11
SAMMPRIS randomized
patients with a variety of intracranial stenoses to stent-
ing or BMT.
7
Only 60 (13%) patients had intracra-
nial VA stenosis, and among them, the 2-year primary
event rate was 9.5% in the medical group and 21.1%
in the stenting group.
8
The Vitesse Intracranial Stent
Study for Ischemic Therapy (VISSIT) randomized
112 patients with symptomatic intracranial stenosis
in a variety of intracerebral arteries to stenting or
BMT and reported a risk similar to that in SAMMP-
RIS, but the number with VA stenosis was not docu-
mented.
12
VAST randomized 115 patients (83% with
extracranial stenosis) and showed a nonsignificantly
higher risk of early outcomes at 30 days in the stented
group but similar risk of any stroke in both groups
after a median follow-up of 3 years.
9
A meta-analysis
of SAMMPRIS, VAST, and VIST showed no advan-
tage for stenting/angioplasty vs BMT alone in extra-
cranial and intracranial VA stenosis combined or in
extracranial or intracranial VA stenosis (figure e-1).
Previous observational studies have shown that the
risk of stenting is low with extracranial VA stenosis,
on the order of 1%, compared with 7% to 10% for
intracranial stenosis.
5,6
However, natural history data
have shown that the risk of early recurrent stroke is
higher for intracranial stenosis.
4
For this reason, it is
possible that the treatment benefits vary in the 2
locations. Therefore, randomization was stratified
Table 3
HRs of primary and secondary endpoint events during follow-up
a
Endpoints
Intention-to-treat analysis
Per-protocol analysis
Events, n/person-y
HR (95% CI)
b
p Value
Events, n/person-y
HR (95% CI)
b
p Value
Medical
group
(n
5 88)
Stent
group
(n
5 91)
Medical
group
(n
5 88)
Stent
group
(n
5 61)
Primary endpoint
Fatal or nonfatal stroke in any arterial
territory
12/291
5/308
0.40 (0.14
–1.13)
0.08
12/291
4/208
0.47 (0.15
–1.46)
0.19
Extracranial VA target stenosis
c
8/246
3/258
0.37 (0.10
–1.38)
0.14
8/245
2/173
0.37 (0.08
–1.73)
0.21
Intracranial VA target stenosis
d
4/45
2/50
0.47 (0.08
–2.60)
0.39
4/45
2/35
0.60 (0.11
–3.33)
0.56
Secondary endpoints
Fatal or nonfatal stroke or TIA
22/255
12/291
0.50 (0.25
–1.01)
0.05
22/255
9/192
0.57 (0.26
–1.24)
0.16
Posterior circulation stroke
8/291
4/308
0.47 (0.14
–1.58)
0.39
8/291
3/208
0.53 (0.14
–1.99)
0.35
Fatal or nonfatal stroke within 90 d
4/21
3/22
0.71 (0.16
–3.18)
0.66
4/21
3/15
1.07 (0.24
–4.76)
0.93
Death resulting from any cause
9/316
8/323
0.86 (0.33
–2.22)
0.76
9/316
7/218
1.12 (0.41
–3.01)
0.82
Abbreviations: CI
5 confidence interval; HR 5 hazard ratio; VA 5 vertebral artery.
a
Complete follow-up (
$1 y) if not otherwise indicated.
b
Stent group vs medical group.
c
The number of patients with extracranial VA stenosis in the medical and stent groups was 74 and 74 in the intention-to treat analysis and 74 and 70 in
the per-protocol analysis, respectively.
d
The number of patients with intracranial VA stenosis in the medical and stent groups was 14 and 17 in the intention-to treat analysis and 14 and 13 in the
per-protocol analysis, respectively.
1234
Neurology 89 September 19, 2017
according to location of stenosis. Because the majority
of patients in VIST had extracranial stenosis, drawing
firm conclusions on benefit in intracranial stenosis is
difficult, although the risk of periprocedural stroke
appeared higher for intracranial stenosis and the re-
sults are in line with those from SAMMPRIS showing
higher risk in stented than in medically treated
patients.
Strengths of VIST include the randomized design,
that it is the largest study of stenting for VA stenosis,
and that no patients were lost to follow-up. A criticism
is that recruitment was stopped because of funding is-
sues before the planned number of patients had been
recruited. A further consideration is the intensity of
medical treatment in the 2 arms. There was no differ-
ence in the use of statins or antihypertensive agents
between the 2 arms. There was a slightly increased
use of antiplatelet agents at the first-month follow-up
in the stented arm, but it was small, reflecting the advice
given that both groups should be given intensive med-
ical therapy. An additional consideration is the high
proportion of patients in the stenting arm who were
found not to have stenosis
.50% on DSA at the time
of stenting. As a result of the small size of the vertebral
arteries, noninvasive imaging with CT or MR angiog-
raphy is more challenging.
1
However, previous studies
comparing these 2 noninvasive modalities with intra-
arterial DSA have shown high sensitivity and specific-
ity.
13
Central review of entry imaging failed to confirm
stenosis in approximately half of the cases in which
stenosis was not confirmed, while in others, entry imag-
ing was adjudged to be of insufficient quality to confirm
stenosis. This suggests that misdiagnosis was in some
cases due to radiologic interpretation, and the misdiag-
nosis rate appeared higher in certain centers. This find-
ing emphasizes the need for very careful ongoing quality
control with rapid review of imaging throughout the
trial. A further consideration is the experience of neuro-
interventionists who had to perform only 10 previous
procedures to enter the study.
Recruitment into the trial was slower than ex-
pected, and rates varied widely between centers. This
partly reflects the fact that in the United Kingdom
not all patients with posterior circulation stroke receive
CT or MR angiography. This would be likely to
change if further data show that stenting is associated
with improved outcome. The intention was to extend
the trial to overseas centers, but this was delayed
because of regulatory and contract issues and sites were
not opened before the funder withdrew funding.
Stenting of extracranial symptomatic vertebral steno-
sis was performed in this multicenter study with a low
periprocedural risk and appears safe compared with
BMT alone. There was a nonsignificant reduction in
recurrent stroke risk in the stented compared with the
BMT arm. As a result of early termination of
Figure 2
Kaplan-Meier curves
Kaplan-Meier cures for the cumulative probability of (A) fatal or nonfatal stroke in any arterial
territory (primary endpoint), (B) fatal or nonfatal stroke in any arterial territory or TIA, and (C)
death resulting from any cause during follow-up, according to treatment group (intention-to-
treat population). Log-rank test was used to test the hypothesis that stroke incidence, stroke
or TIA incidence, or mortality rate between groups was the same.
Neurology 89 September 19, 2017
1235
recruitment, the projected sample size was not reached,
and larger trials are now required to confirm this
finding.
AUTHOR CONTRIBUTIONS
Hugh S. Markus contributed to study design, obtaining funding, study
organization, patient recruitment, data interpretation, and writing the
first draft of paper. Susanna C. Larsson contributed to developing the sta-
tistical analysis, data analysis, and writing the first draft of the paper.
Wilhelm Kuker contributed to obtaining funding, study design, and
neuroradiologic oversight. Ursula G. Schulz contributed to obtaining
funding, patient recruitment and follow-up, and revising the manuscript.
Ian Ford contributed to study design, advised on the statistical analysis,
and critically reviewed the paper. Peter M. Rothwell contributed to study
design, obtaining funding, patient recruitment, and revising the manu-
script. Andrew Clifton contributed to study design, obtaining funding,
neuroradiologic analysis and oversight, and revising the manuscript.
ACKNOWLEDGMENT
VIST centers and number of patients recruited: St. Georges University
Hospitals NHS Foundation Trust (Barry Moynihan, Hugh Markus, Andrew
Clifton, Jeremy Madigan) 77; Oxford University Hospitals NHS Trust (Peter
Rothwell, Ursula Schulz, Wilhelm Kuker) 38; University Hospitals of North
Midlands NHS Trust (Christine Roffe, Sanjeev Nayak) 14; Sheffield Teach-
ing Hospitals NHS Foundation Trust (Ralf-Bjoern Lindert, Peter Gaines) 11;
The Walton Centre NHS Foundation Trust, Liverpool (Alakendu Sekhar,
Hans Nahser) 8; King
’s College Hospital NHS Trust (Dr. Bartlomiej
Piechowski-Jozwiak, Timothy Hampton) 8; Newcastle Upon Tyne Hospitals
NHS Foundation Trust (Anand Dixit, Anil Gholkhar) 7; University College
Hospitals NHS Foundation Trust, London (David Werring, Stefan Brew) 6;
Imperial College Healthcare NHS Trust, London (Pankaj Sharma, Maneesh
Patel) 4; Cambridge University Hospitals NHS Foundation Trust (Hugh
Markus, Nick Higgins) 2; Leeds Teaching Hospital NHS Trust (Ahamad
Hassan, Anthony Goddard) 2; North Bristol NHS Trust (Neil Baldwin,
Marcus Bradley) 2; Nottingham University Hospital NHS Trust (Senthil
Raghunathan, Robert Crossley) 2; Royal Preston Hospital (Hedley Emsley,
Siddhartha Wuppalapati) 1.
STUDY FUNDING
The run-in phase with recruitment of the first 100 patients was supported
by a grant from the Stroke Association. Recruitment after patient 100 was
supported by a grant from the National Institute for Health Research
(NIHR) Health Technology Assessment. Recruitment was supported
by the NIHR Clinical Research Network. Hugh S. Markus is supported
by an NIHR Senior Investigator award, and his work is supported by the
Cambridge University Hospitals Trust NIHR Comprehensive Biomedi-
cal Research Centre. Peter M. Rothwell is supported by Wellcome Trust
and NIHR Senior Investigator awards, and his work is supported by the
NIHR Biomedical Research Centre, Oxford.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received January 17, 2017. Accepted in final form June 5, 2017.
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Neurology 89 September 19, 2017
DOI 10.1212/WNL.0000000000004385
2017;89;1229-1236 Published Online before print August 23, 2017
Neurology
Hugh S. Markus, Susanna C. Larsson, Wilhelm Kuker, et al.
Stenting Trial
Stenting for symptomatic vertebral artery stenosis: The Vertebral Artery Ischaemia
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