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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.

A quarter occurs in patients

with stenosis in the vertebral and/or basilar arteries.

Information about optimal management is

lacking compared with symptomatic carotid stenosis, for which large international trials dem-

onstrated a benefit from endarterectomy

and that stenting may be appropriate in selected

patients.

*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.

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.

Vertebral

artery (VA) stenosis can be treated with angio-

plasty and/or stenting.

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%.

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

; however, there were few patients with

VA stenosis.

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.

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.

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.

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).

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

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

5 88)

Stent group

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)

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

V2 or V3

Intracranial (V4)

14 (16)

17 (19)

0.62

Modified Rankin Scale score, median (IQR)

1 (1

–2)

2 (1

–2)

0.74

Abbreviation: IQR

5 interquartile range.

Missing data for 1 patient.

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

5 88)

Stent

group

5 91)

Medical

group

5 82)

Stent

group

5 88)

Medical

group

5 83)

Stent

group

5 85)

Medical

group

5 79)

Stent

group

5 84)

Medical

group

5 62)

Stent

group

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 (%)

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)

140.0 (2.2)

139.1 (2.3)

141.8 (2.6)

DBP, mean (SD), mm Hg

79.5 (1.3)

77.0 (1.3)

77.4 (1.2)

77.7 (1.2)

78.3 (1.4)

79.1 (1.3)

Diabetes mellitus therapy,

n (%)

19 (22)

20 (22)

20 (24)

21 (24)

19 (24)

19 (23)

Current smoker, n (%)

25 (29)

18 (20)

20 (24)

11 (12)

16 (20)

13 (16)

Abbreviations: DBP

5 diastolic blood pressure; NA 5 not available; SBP 5 systolic blood pressure.

The number in parenthesis is the number of patients evaluated at each time point during follow-up.

Combination of aspirin and clopidogrel.

Data available for 78 patients.

Data available for 86 patients.

Data available for 70 patients.

Data available for 74 patients.

Data available for 89 patients.

Data available for 78 patients.

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.

This is a pattern similar to that

seen in symptomatic carotid stenosis.

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.

SAMMPRIS randomized

patients with a variety of intracranial stenoses to stent-

ing or BMT.

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.

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.

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.

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.

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

Endpoints

Intention-to-treat analysis

Per-protocol analysis

Events, n/person-y

HR (95% CI)

p Value

Events, n/person-y

HR (95% CI)

p Value

Medical

group

5 88)

Stent

group

5 91)

Medical

group

5 88)

Stent

group

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

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

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.

Complete follow-up (

$1 y) if not otherwise indicated.

Stent group vs medical group.

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.

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.

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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