1. Three New Trials in Stroke: CADISS, VISSIT, and
ATTEST

2. JAMA. 2015;313(12):1240-1248.

3. Overview
OBJECTIVE To evaluate the efficacy and safety of the balloon-expandable stent plus medical
therapy vs medical therapy alone in patients with symptomatic intracranial stenosis (70%).
DESIGN, SETTING, AND PATIENTS VISSIT (the Vitesse Intracranial Stent Study for Ischemic
Stroke Therapy) trial is an international, multicenter, 1:1 randomized, parallel group trial that
enrolled patients from 27 sites (January 2009-June 2012) with last follow-up in May 2013.
INTERVENTIONS Patients (N = 112) were randomized to receive balloon-expandable stent
plus medical therapy (stent group; n = 59) or medical therapy alone (medical group; n = 53).
JAMA. 2015;313(12):1240-1248.

4. RESULTS
• Enrollmentwas halted by the sponsor after negative results from another trial prompted
an early analysis of outcomes, which suggested futility after 112 patients of a planned
sample size of 250were enrolled.
• The 30-day primary safety end point occurred in more patients in the stent group (14/58;
24.1%[95%CI, 13.9%-37.2%]) vs the medical group (5/53; 9.4%[95%CI, 3.1%-20.7%]) (P =
.05). Intracranial hemorrhage within 30 days occurred in more patients in the stent group
(5/58; 8.6%[95%CI, 2.9%-19.0%]) vs none in the medical group (95%CI, 0%-5.5%) (P = .06).
• The 1-year primary outcome of stroke or hard TIA occurred in more patients in the stent
group (21/58; 36.2%[95%CI, 24.0-49.9]) vs the medical group (8/53; 15.1% [95%CI, 6.7-
27.6]) (P = .02).Worsening of baseline disability score (modified Rankin Scale) occurred in
more patients in the stent group (14/58; 24.1%[95%CI, 13.9%-37.2%]) vs the medical
group (6/53; 11.3%[95%CI, 4.3%-23.0%]) (P = .09).
• The EuroQol-5D showed no difference in any of the 5 dimensions between groups at 12-
month follow-up.
JAMA. 2015;313(12):1240-1248.

5. CONCLUSIONS AND RELEVANCE
• Among patients with symptomatic intracranial arterial stenosis,
the use of a balloon-expandable stent compared with medical
therapy resulted in an increased 12-month risk of added stroke or
TIA in the same territory, and increased 30-day risk of any stroke or
TIA.
• These findings do not support the use of a balloon-expandable
stent for patients with symptomatic intracranial arterial stenosis.
JAMA. 2015;313(12):1240-1248.

6. JAMA. 2015;313(12):1240-1248.

7. 30-Day and 1-Year Primary, Secondary, and Safety End Points
in the Intent-To-Treat Population
JAMA. 2015;313(12):1240-1248.

8. 30-Day and 1-Year Primary, Secondary, and Safety End Points
in the Intent-To-Treat Population
JAMA. 2015;313(12):1240-1248.

9. Conclusion
• Among patients with symptomatic intracranial arterial
stenosis, the use of a balloon-expandable stent compared
with medical therapy resulted in an increased 12-month
risk of added stroke or TIA in the same territory, and
increased 30-day risk of any stroke or TIA.
• These findings do not support the use of a balloon-
expandable stent for patients with intracranial arterial
stenosis.
JAMA. 2015;313(12):1240-1248.

10. Lancet Neurol 2015; 14: 361–67

11. Overview
Background : Extracranial carotid and vertebral artery dissection is an important cause of stroke,
especially in young people. In some observational studies it has been associated with a high risk of
recurrent stroke. Both antiplatelet drugs and anticoagulant drugs are used to reduce risk of stroke but
whether one treatment strategy is more effective than the other is unknown. We compared their efficacy
in the Cervical Artery Dissection in Stroke Study (CADISS), with the additional aim of establishing the true
risk of recurrent stroke.
Methods : We did this randomised trial at hospitals with specialised stroke or neurology services (39 in
the UK and seven in Australia). We included patients with extracranial carotid and vertebral dissection
with onset of symptoms within the past 7 days. Patients were randomly assigned (1:1) by an automated
telephone randomisation service to receive antiplatelet drugs or anticoagulant drugs (specifi c treatment
decided by the local clinician) for 3 months. Patients and clinicians were not masked to allocation, but
investigators assessing endpoints were. The primary endpoint was ipsilateral stroke or death in the
intention-to-treat population.
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12. Findings
• We enrolled 250 participants (118 carotid, 132 vertebral). Mean time to randomisation was 3·65 days (SD 1·91).
• The major presenting symptoms were stroke or transient ischaemic attack (n=224) and local symptoms (headache, neck
pain, or Horner’s syndrome; n=26). 126 participants were assigned to antiplatelet treatment versus 124 to anticoagulant
treatment.
• Overall, four (2%) of 250 patients had stroke recurrence (all ipsilateral).
• Stroke or death occurred in three (2%) of 126 patients versus one (1%) of 124 (odds ratio [OR] 0·335, 95% CI 0·006–4·233;
p=0·63).
• There were no deaths, but one major bleeding (subarachnoid haemorrhage) in the anticoagulant group.
• Central review of imaging failed to confirm dissection in 52 patients.
• Preplanned per-protocol analysis excluding these patients showed stroke or death in three (3%) of 101 patients in the
antiplatelet group versus one (1%) of 96 patients in the anticoagulant group (OR 0·346, 95% CI 0·006–4·390; p=0·66).
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13. Interpretation
We found no diff erence in effi cacy of antiplatelet and anticoagulant
drugs at preventing stroke and death in patients with symptomatic
carotid and vertebral artery dissection but stroke was rare in both
groups, and much rarer than reported in some observational studies.
Diagnosis of dissection was not confirmed after review in many cases,
suggesting that radiographic criteria are not always correctly applied
in routine clinical practice.
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14. Trial profile
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15. Outcomes within 3 months
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16. Adverse events
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17. Lancet Neurol 2015; 14: 368–76

18. Background
In most countries, alteplase given within 4·5 h of onset is the only approved
medical treatment for acute ischaemic stroke. The newer thrombolytic drug
tenecteplase has been investigated in one randomised trial up to 3 h after
stroke and in another trial up to 6 h after stroke in patients selected by
advanced neuroimaging.
In the Alteplase- Tenecteplase Trial Evaluation for Stroke Thrombolysis
(ATTEST), we aimed to assess the efficacy and safety of tenecteplase versus
alteplase within 4·5 h of stroke onset in a population not selected on the
basis of advanced neuroimaging, and to use imaging biomarkers to inform
the design of a defi nitive phase 3 clinical trial.
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19. Methods
In this single-centre, phase 2, prospective, randomised, open-label, blinded end-point evaluation
study, adults with supratentorial ischaemic stroke eligible for intravenous thrombolysis within 4·5 h
of onset were recruited from The Institute of Neurological Sciences, Glasgow, Scotland.
Patients were randomly assigned (1:1) to receive tenecteplase 0·25 mg/kg (maximum 25 mg) or
alteplase 0·9 mg/kg (maximum 90 mg).
Treatment allocation used a mixed randomisation and minimisation algorithm including age and
National Institutes of Health Stroke Scale score, generated by an independent statistician.
Patients were not informed of treatment allocation; treating clinicians were aware of allocation
but those assessing the primary outcome were not. Imaging comprised baseline CT, CT
perfusion, and CT angiography; and CT plus CT angiography at 24–48 h.
The primary endpoint was percentage of penumbra salvaged (CT perfusion-defined penumbra
volume at baseline minus CT infarct volume at 24–48 h).
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20. Findings & Interpretation
Between Jan 1, 2012, and Sept 7, 2013, 355 patients were screened, of whom 157 were eligible for intravenous thrombolysis, and 104
patients were enrolled. 52 were assigned to the alteplase group and 52 to tenecteplase.
Of 71 patients (35 assigned tenecteplase and 36 assigned alteplase) contributing to the primary endpoint, no significant differences were
noted for percentage of penumbral salvaged (68% [SD 28] for the tenecteplase group vs 68% [23] for the alteplase group; mean diff
erence 1·3% [95% CI –9·6 to 12·1]; p=0·81).
Neither incidence of symptomatic intracerebral haemorrhage (by SITS-MOST defi nition, 1/52 [2%] tenecteplase vs 2/51 [4%] alteplase,
p=0·55; by ECASS II defi nition, 3/52 [6%] vs 4/51 [8%], p=0·59) nor total intracerebral haemorrhage events (8/52 [15%] vs 14/51 [29%],
p=0·091) differed significantly.
The incidence of serious adverse events did not diff er between groups (32 in the tenecteplase group, three considered probably or
definitely related to drug treatment; 16 in the alteplase group, five were considered drug-related).
Interpretation Neurological and radiological outcomes did not diff er between the tenecteplase and alteplase
groups. Evaluation of tenecteplase in larger trials of patients with acute stroke seems warranted.
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21. Study outcomes in the per-protocol analysis
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22. Distribution of modified Rankin scale scores at 90 days
The number in each category is the absolute number of participants. Definitions of scores: 0=no symptoms at all;
1=no significant disability despite symptoms, able to carry out all usual duties and activities; 2=slight disability,
unable to carry out all previous activities but able to look after own affairs without assistance; 3=moderate
disability, requiring some help, but able to walk without assistance. 4=moderately severe disability, unable to walk
without assistance, and unable to attend to own bodily needs without assistance; 5=severe disability, bedridden,
incontinent, and requiring constant nursing care and attention; 6=dead.
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23. Serious adverse events
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24. Death or dependance at 3 months (mRS 3–6) in randomised trials
comparing intravenous tenecteplase and intravenous alteplase
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25. Interpretation
• No previous study has compared one dose of tenecteplase against alteplase with patients selected
by criteria currently used in clinical practice to assess eligibility for thrombolysis in a 4.5 h time
window.
• Our results provide information about the limitations of imaging-based endpoints in phase 2 clinical
trials in which imaging has not been used also to select patients.
• Our findings show the potential importance of advanced imaging to ensure biological
characterisation of patients in phase 2 trials, in which clinical features alone could disguise
important prognostic differences.
• Clinical outcomes give more representative data for which to base a phase 3 trial than do imaging
outcomes and these data are more representative of prognosis in the wider population of patients
with acute ischaemic stroke.
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