UDATE ON REVASCAT:
(Randomized Trial Of Revascularization With
Solitaire FR® Device Versus Best Medical Therapy In
The Treatment Of Acute Stroke Due To Anterior
Circulation Large Vessel Occlusion Presenting Within
8 Hours Of Symptom Onset)
Tudor G. Jovin, M.D.
Associate Professor of Neurology and Neurosurgery
Director, UPMC Stroke Institute
Director, UPMC Center for Neuroendovascular Therapy
University of Pittsburgh Medical Center
DISCLOSURES
Consultant/Advisory Board: Ownership Interest: Silk Road Medical – modest
Consultant: Air Liquide- modest
Consultant/Advisory Board: Covidien/Medtronic: unpaid
Consultant: Stryker Neurovascular unpaid
PI: REVASCAT (Fundacio Ictus Malaltia Vascular), unpaid
PI: DAWN (Stryker Neurovascular), unpaid
Disclosures
• Study funded with an unrestricted grant by Covidien
• Sponsor: Fundació ICTUS (Non-profit foundation)
• Covidien was not involved in the study design, conduct, writing or review
of the protocol or manuscript
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Study objective
To determine efficacy and safety of neurovascular thrombectomy with Solitaire in
conjunction with medical therapy versus medical therapy alone, among eligible
acute ischemic stroke patients treatable within 8 hours of symptom onset;
To assess the proportion of REVASCAT eligible patients treated outside the study.
Study design
• Sequential, randomized and open trial with external blinded-endpoint evaluation
• Clinical sites: four designated Comprehensive Stroke Centers in Catalonia, Spain
• Randomization 1:1 ratio of thrombectomy with the stentriever Solitaire FR® plus
medical therapy (including IV tPA when eligible) versus medical therapy alone
• Randomization was done under a minimization process using :
Age (≤70 or >70 years)
Baseline NIHSS (6-16, or 17 or more)
Randomization window (≤4.5 or >4.5 hours)
Vessel occlusion site (Intracranial ICA or M1)
Investigational center
Molina C et al. Int J Stroke 2014
Elegibility criteria
•
•
•
•
•
•
•
•
Acute ischemic stroke ineligible for IV thrombolysis or where patient had
received IV thrombolytic therapy without recanalization after 30 min from tPA
proven by CTA or MRA
No pre-stroke functional disability (mRS ≤ 1)
Baseline NIHSS ≥ 6 points
Age ≥18 and  80*
Intracranial internal carotid (distal ICA or T occlusions) proximal MCA (M1)
occlusion or tandem occlusions (proximal ICA + M1) as evidenced by CTA or
MRA
Patient treatable (groin puncture) within 8 hours of symptom onset and < 90
min from imaging
Small ischemic core: Brain CT ASPECTS ≥ 7 or MR DWI ASPECTS ≥ 6
Informed consent
* Age was amended up to 85 year in mid 2014 when ASPECTS 9 or 10
Molina C et al. Int J Stroke 2014
Primary efficacy endpoint
Distribution of the modified Rankin Scale scores at 90 days as evaluated by two
separate certified assessors who were masked to treatment:
• Primary analysis carried out
based on central video adjudication
or in case this was missing on local
blinded neurologist adjudication
(31%)
Molina C et al. Int J Stroke 2014
METHODS
Evaluation of mRS scores at 90 days
Local evaluation
-
Face-to-face interview
Certified local neurologist
Central blinded evaluation
• First trial half: one certified nurse by
structured phone interview to the
patient/relative.
Blinded to treatment assignment
Structured interview
• Second trial half (after protocol
amendment): one expert neurologist
looking at video recording of the local
face-to-face interview
Video recordings were transferred via
FTP to the external assessor in a
blinded fashion
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Statistical design
• Outcome:
Intention to treat analysis of modified Rankin Scale (shift
analysis), merging 5 and 6 categories, evaluated at 90 days
• Effect measure: Common OR of mRS improvement
• Analysis: Ordinal Logistic Regression
• Strategy: 3 interim looks once 174, 346 and 518 patients completed 90
days follow-up
• Maximum sample size: 690 patients
• Power: 90% for an effect size OR=1.615 (10% improvement)
• Adjustments: sequential design, minimization factors and IV tPA therapy
Molina C et al. Int J Stroke 2014
Trial termination
On December 12, 2014, following the first interim analysis (n=174), the
steering committee decided to accept the DSMB’s recommendation to
stop the trial due to loss of equipoise in the trial population. Consequently,
adjustment for sequential design was not necessary.
REVASCAT enrolled 206 patients from November 2012 through December
2014 at 2.1 patients per center per month.
90 day follow-up ended in March 10th 2015, and main primary and
secondary outcomes were available in March 20th.
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Consort flow diagram
Randomized (n=207)
Removed due to withdraw informed consent (n=1)
Intervention
Received tPA
(n=70)
Control
Did not receive
tPA (n=33)
Allocated to intervention arm (n=103)
-Did not undergo thrombectomy (n=5)*
Received tPA
(n=80)
Did not receive
tPA (n=23)
Allocated to control arm (n=103)
Cross over from control to endovascular (n=0)
Received endovascular treatment (n=98)*
Lost to follow-up (n=0)
Lost to follow-up (n=0)
103 Evaluable subjects†
103 Evaluable subjects†
* TICI 3 or TICI 2b on conventional angiography;
† 1 an 4 patients evaluated by phone interview due to poor conditions (Rankin 4 or 5)
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Jovin TG et al. NEJM 2015
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Baseline characteristics
Thrombectomy
(n=103)
Control
(n=103)
Age, mean (SD)
65.7 (11.3)
67.2 (9.5)
Gender, male – no. (%)
55 ( 53.4)
54 ( 52.4)
Atrial fibrillation – no. (%)
35 ( 34.0)
37 ( 35.9)
Diabetes mellitus – no. (%)
22 ( 21.4)
19 ( 18.4)
History of hypertension – no. (%)
62 ( 60.2)
72 ( 69.9)
History of ischemic stroke or TIA – no. (%)
12 ( 11.7)
18 ( 17.5)
NIHSS score, median [IQR]
17.0 (14.0, 20.0)
17.0 (12.0, 19.0)
ASPECTS – median [IQR] *
7.0 (6.0, 9.0)
8.0 (6.0, 9.0)
Terminus ICA with involvement of M1
26 (25.5)
28 (26.7)†
M1 middle cerebral artery segment
66 (64.3)
65 (64.4)
Single M2 middle cerebral artery segment
10 (9.8)
8 (7.9)
19 (18.4)
13 (12.6)
Variable
Location of intracranial arterial occlusion¶
Ipsilateral cervical carotid occlusion
* Evaluated by the independent CT/MR Corelab
¶ Location site was not available in 1 patient in the intervention group and 2 patients in the control group;
† 1 patient had terminus ICA “I” occlusion
Jovin TG et al., NEJM 2015
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Workflow
Times
Thrombectomy
(n=103)
Control
(n=103)
Time from onset to IV t-PA infusion, min – median
[IQR]
Time from onset to imaging, min – median [IQR]
N=70
117.5 (90.0, 150.0)
N=80
105.0 (86.0, 137.5)
192 (129, 272)
183 (132, 263)
223 (170, 312)
226 (168, 308)
109 [85, 163]
NA
355 (269, 430)
NA
Time from onset to randomization, min – median
[IQR]
Time from hospital arrival to groin puncture, min –
median [IQR]
Time from onset to reperfusion, min – median
[IQR]
Jovin TG et al., NEJM 2015
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SAFETY RESULTS
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Variable
Thrombectomy Control
(n=103)
(n=103)
Difference
(95%CI)
Ratio
(95%CI)
Adjusted
Ratio
(95%CI)
1.1 (0.8, 1.4)
Safety variables
Death at 90 days – no.(%)
19 (18.4%)
16 (15.5%)
-2.9 (-13.2 , 7.3)
1.2 (0.6, 2.2)
Symptomatic intracranial
hemorrhage (SITS-MOST) – no.
(%)*
2 (1.9%)
2 (1.9%)
0.0 (-3.8, 3.8)
1.0 (0.1, 7.0)
Symptomatic intracranial
hemorrhage (ECASS II) – no. (%)
5 (4.9%)
2 (1.9%)
-2.9 (-7.8, 2.0)
2.5 (0.5 -12.6)
* Symptomatic (neurologic worsening ≥ 4 point in the National Institutes of Health Stroke Scale) ICH adjudicated by
the Critical Events Committee plus PH2 or rPH2 classified according to the neuroimaging Corelab
Jovin TG et al., NEJM 2015
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EFFICACY RESULTS
(ITT Population)
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Primary Outcome variable: modified Rankin Scale
Common Odds Ratio, 1.71; 95%CI, 1.05-2.81*
(N=103)
(N=103)
Patients (%)
* Adjusted for minimization factors and IV tPA therapy
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Jovin TG et al., NEJM 2015
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SENSITIVITY ANALYSES
OR (95%CI)
1.71 (95%CI, 1.05-2.81)
Final analysis
(video/local)
Sensitivity analysis I
1.83 (95%CI, 1.12-3.00)
(central: phone/video)
Sensitivity analysis II
1.93 (95%CI, 1.18-3.17)
(local investigators)
0
1
2
3
Favors endovascular treatment
Lopez Cancio E et al., ESOC 2015
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Secondary outcomes
Thrombectomy
(n=103)
Control
(n=103)
Effect
variable
Unadjusted
Value
(95% CI)
Adjusted value
(95% CI)
45 (43.7)
29 (28.2)
Odds
ratio
2.0 (1.1, 3.5)
2.12 (1.1, 4.0)
59 (57.8)
20 (20.0)
Odds
ratio
5.5 (2.9, 10.3)
5.8 (3.0, 11.1)
2.0 (0.0, 8.0)
6.0 (2.0, 11.0)
Beta
-2.7 (-4.4,-0.9)
-2.4 (-4.1,-0.8)
47 (57.3)
23 (26.4)
Odds
ratio
3.7 (2.0, 7.1)
4.2 (2.1, 8.4)
EQ-5D score at 90 days
– Median [IQR]
0.65 [0.21, 0.79]
0.32 [0.13, 0.70]
Beta
0.13 (0.03, 0.23)
0.11 (0.02, 0.21)
Modified TICI – no. (%)
2b-3
Pre
3 (3.0)
Outcome
Modified Rankin scale
score 0-2 at 90 days no (%)
Dramatic neurologic
improvement at 24h –
no. (%)*
NIHSS score at 90 days
– Median [IQR]
Barthel index of 95-100
at 90 days – no. (%)
Post
67 (65.7)
* Dramatic neurological improvement as determined by a NIHSS drop of ≥8 or NIHSS 0-2 at 24 hours
† Adjudicated by the independent agio Corelab
Jovin TG et al., NEJM 2015
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Infarct volume at 24h by CT (n=189) or DWI (n=15)
Median [IQR], mL
38.6 [12, 87]
17.2 [9, 58]
† Wilcoxon-Mann Whitney, p=0.030
Jovin TG et al., NEJM 2015
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Subgroup analysis
Jovin TG et al., NEJM 2015
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REVASCAT
A clinical trial embeded within, SONIIA a population based reperfusion registry
ESOC 2015 Glasgow
Abilleira S. et al., Stroke 2014
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2/12
Near-consecutive enrolment
88%
22
5/12
REVASCAT Conclusions
• Solitaire thrombectomy caused a shift towards better outcomes along meaningful
disability cutpoints.
• Thrombectomy improved by 15.5% functional independence (mRS 0-2), from
28.2% to 43.7%, corresponding to a NNT of 6.
• Results of other secondary clinical endpoints and infarct volume were also in
favour of the interventional group
• Due to near consecutive enrolment results apply to all eligible patients
• REVASCAT provided evidence that in patients with anterior circulation stroke
treatable within 8 hours of symptoms onset, stent retriever thrombectomy with
Solitaire reduces post-stroke disability
Jovin TG et al., NEJM 2015
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We aimed to determine which workflow metric is
correlated with highest treatment effect in a
prospective randomized trial of mechanical
embolectomy for acute stroke.
Symptom
Symptom
Reperfusion
CT
CT
Reperfusion
Methods
43.7%
Symptom
Symp.
Reperfusion
CT
CT
Reperfusion
* If final TICI < 2b
we used
“end of procedure” time
Time from symptoms to revascularization
Probability of mRS 0-2
-5% every 30’
Symptoms
CT
Reperfusion
Probability of mRS 0-2
-1% every 30’
Symptoms
Probability of mRS 0-2
-17% every 30’
CT
Reperfusion
ASPECTS ≥ 8
CT
Symptoms
Reperfusion
Figure 1. Time from symptoms to revascularization (minutes) (unadjusted) – Aspects < 8
ASPECTS < 8
CT
Symptoms
Reperfusion
Conclusions
The benefitial effect of reperfusion declines over time
Which workflow metric is correlated with highest
treatment effect?
Time from symptom to imaging
does not have a determinant impact on the outcome of the treated patients,
However it defines the number of elegible patients for thrombectomy
Time from imaging to reperfusion
is a strong determinant of the treatment effect
and the outcome of treated patients
Our result may suggest that in cases with unknown time from onset
a compatible favorable CT-scan may be sufficient to select patients for
thrombectomy
Thank you!
AAN, 2015
Washington
DC
ESOC
2015
Glasgow
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Investigators
SONIIA Registry
Miquel Gallofré
Sonia Abilleira
Other Comprehensive Stroke Centers
Hospital del Mar
Hospital Parc Taulí
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