1. 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

2. DISCLOSURES Consultant: Air Liquide- modest
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

3. 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
Background.
AAN, 2015 Washington DC

4. 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.

5. 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

6. 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

7. 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

8. Central blinded evaluation
METHODS
Evaluation of mRS scores at 90 days
Local evaluation
Central blinded evaluation
First trial half: one certified nurse by structured phone interview to the patient/relative.
Face-to-face interview
Certified local neurologist
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
Central evaluation: two different methods along the study
Each site will designate one or more individual(s) to perform
the follow-up evaluation. Data entry would not reveal the study arm assignment and
patients will be instructed to minimize the chance of disclosing
their treatment group to the evaluator.
Regarding the primary end-point, first, a local independent
neurologist, not involved in the trial patient management, will
record the mRS score in a face to face clinical visit; and second, an
experienced and mRS-certified nurse will centrally evaluate mRS
score by telephone call, recording the interview in an audio-tape.
In case of disagreement between the two assessors, a centralized
neurologist will rate mRS by using the audio-tape recording and
his mark will be the primary end-point value in this case. All of
them will directly introduce mRS score in the database without
access to any further information
Video recordings were transferred via FTP to the external assessor in a blinded fashion

9. 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
The sequential design, is illustrated in the next figure where statistics Z* and V* are plotted. The vertical axis represents Z*, a cumulative measure of the evidence that Solitaire is more efficacious than the other medical therapy. Thus Z* > 0 if the evidence favors therapy Solitaire, Z* = 0 if there is no difference at all in success rates of the two therapies, and Z* < 0 if Solitaire is inferior. The statistic Z* is the number of successes on Solitaire minus the number that would be expected if there were no therapy difference, allowing for the prognostic factors being adjusted for. The statistic Z without adjusting for minimization variables is calculated using the next formula:
Whitehead J, Group sequential trials revisited: Simple implementation using SAS; 2011, Statistical Methods in Medical Research –656.
Whitehead J, Branson M. and Todd S., A combined score test for binary and ordinal endpoints from clinical trials; 2010, Statistics in Medicine vol
The horizontal axis represents V*, a measure of the information about the advantage of therapy Solitaire contained in the data that is related to sample size. The V* statistic is a scaled version of the total information measures associated with each separate scale. The statistic V without adjusting for minimization factors is calculated using the next formula:
Molina C et al. Int J Stroke 2014

10. 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 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.
AAN, 2015 Washington DC

11. Allocated to control arm (n=103)
Consort flow diagram
Randomized (n=207)
Removed due to withdraw informed consent (n=1)
Intervention
Control
Received tPA
(n=70)
Did not receive
tPA (n=33)
(n=80)
tPA (n=23)
Allocated to intervention arm (n=103)
-Did not undergo thrombectomy (n=5)*
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)
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)
Jovin TG et al. NEJM 2015
AAN, 2015 Washington DC

12. Baseline characteristics
Variable
Thrombectomy
(n=103)
Control
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)
Location of intracranial arterial occlusion¶
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)
Ipsilateral cervical carotid occlusion
19 (18.4)
13 (12.6)
Comentar el ASPECT del investigador
* 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
AAN, 2015 Washington DC

13. Workflow Times Thrombectomy (n=103) Control
Time from onset to IV t-PA infusion, min – median [IQR]
N=70
117.5 (90.0, 150.0)
N=80
105.0 (86.0, 137.5)
Time from onset to imaging, min – median [IQR]
192 (129, 272)
183 (132, 263)
Time from onset to randomization, min – median [IQR]
223 (170, 312)
226 (168, 308)
Time from hospital arrival to groin puncture, min – median [IQR]
109 [85, 163] NA
Time from onset to reperfusion, min – median [IQR]
355 (269, 430)
Jovin TG et al., NEJM 2015
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14. SAFETY RESULTS
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15. Variable Thrombectomy (n=103) Control Difference (95%CI) Ratio
Adjusted Ratio
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)
1.1 (0.8, 1.4)
Symptomatic intracranial hemorrhage (SITS-MOST) – no. (%)*
2 (1.9%)
0.0 (-3.8, 3.8)
1.0 (0.1, 7.0)
Symptomatic intracranial hemorrhage (ECASS II) – no. (%)
5 (4.9%)
-2.9 (-7.8, 2.0)
2.5 ( )
* 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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16. EFFICACY RESULTS
(ITT Population)
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17. Primary Outcome variable: modified Rankin Scale
Common Odds Ratio, 1.71; 95%CI, *
(N=103)
(N=103)
Patients (%)
* Adjusted for minimization factors and IV tPA therapy
Jovin TG et al., NEJM 2015
AAN, 2015 Washington DC

18. SENSITIVITY ANALYSES Final analysis Sensitivity analysis I
OR (95%CI)
Final analysis
(video/local)
1.71 (95%CI, )
Sensitivity analysis I
(central: phone/video)
1.83 (95%CI, )
Sensitivity analysis II
(local investigators)
1.93 (95%CI, ) 1 2 3
Favors endovascular treatment
Lopez Cancio E et al., ESOC 2015
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19. Secondary outcomes Outcome Thrombectomy (n=103) Control Effect
variable
Unadjusted Value
(95% CI)
Adjusted value
Modified Rankin scale score 0-2 at 90 days - no (%)
45 (43.7)
29 (28.2)
Odds ratio
2.0 (1.1, 3.5)
2.12 (1.1, 4.0)
Dramatic neurologic improvement at 24h – no. (%)*
59 (57.8)
20 (20.0)
5.5 (2.9, 10.3)
5.8 (3.0, 11.1)
NIHSS score at 90 days – Median [IQR]
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)
Barthel index of at 90 days – no. (%)
47 (57.3)
23 (26.4)
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]
0.13 (0.03, 0.23)
0.11 (0.02, 0.21)
Modified TICI – no. (%)
2b-3
Pre
3 (3.0)
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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20. 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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21. Subgroup analysis
Jovin TG et al., NEJM 2015
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22. REVASCAT
A clinical trial embeded within, SONIIA a population based reperfusion registry
ESOC 2015 Glasgow
Abilleira S. et al., Stroke 2014
2/12 21

23. Near-consecutive enrolment
88%
5/12

24. 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

25. 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 Reperfusion
Symptom CT
CT Reperfusion

26. “end of procedure” time
Methods
43.7%
Symptom Reperfusion
Symp CT
CT Reperfusion
* If final TICI < 2b
we used
“end of procedure” time

27. Time from symptoms to revascularization
Probability of mRS 0-2
-5% every 30’
Symptoms CT
Reperfusion

28. Probability of mRS 0-2
-1% every 30’
Probability of mRS 0-2
-17% every 30’
Symptoms CT
Reperfusion

29. CT
ASPECTS ≥ 8
Symptoms
Reperfusion

30. ASPECTS < 8 CT Symptoms Reperfusion
Figure 1. Time from symptoms to revascularization (minutes) (unadjusted) – Aspects < 8 CT
ASPECTS < 8
Symptoms
Reperfusion

31. Which workflow metric is correlated with highest treatment effect?
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

32. Thank you!
ESOC 2015 Glasgow
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12/12

33. Investigators 12/12 SONIIA Registry Other Comprehensive Stroke Centers
Miquel Gallofré
Sonia Abilleira
Other Comprehensive Stroke Centers
Hospital del Mar
Hospital Parc Taulí
12/12