udate on revascat: (randomized trial of revascularization with solitaire fr® device versus best...

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 NeurosurgeryDirector, UPMC Stroke Institute

Director, UPMC Center for Neuroendovascular TherapyUniversity of Pittsburgh Medical Center

DISCLOSURES

Consultant/Advisory Board: Ownership Interest: Silk Road Medical – modestConsultant: Air Liquide- modestConsultant/Advisory Board: Covidien/Medtronic: unpaidConsultant: Stryker Neurovascular unpaidPI: 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

3AAN, 2015 Washington DC

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 objective

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

• 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

Elegibility criteria


Primary efficacy endpointDistribution 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%)

• First trial half: one certified nurse by structured phone interview to the patient/relative.

Evaluation of mRS scores at 90 days

- Face-to-face interview

- Certified local neurologist

- Blinded to treatment assignment

- Structured interview

Central blinded evaluation

METHODS

• 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

Local evaluation

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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


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.

AAN, 2015 Washington DC 10

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Randomized (n=207)

Removed due to withdraw informed consent (n=1)

Intervention Control

Received tPA(n=70)

Did not receivetPA (n=33)

Received tPA

(n=80)

Did not receivetPA (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†

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)

Consort flow diagram

AAN, 2015 Washington DC

Jovin TG et al. NEJM 2015

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Baseline characteristics

VariableThrombectomy

(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)

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)

* 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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Times Thrombectomy(n=103)

Control(n=103)

Time from onset to IV t-PA infusion, min – median [IQR]

N=70117.5 (90.0, 150.0)

N=80105.0 (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) NA

Workflow



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SAFETY RESULTS


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* 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



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EFFICACY RESULTS(ITT Population)


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Patients (%)

(N=103)

(N=103)

Primary Outcome variable: modified Rankin Scale

Common Odds Ratio, 1.71; 95%CI, 1.05-2.81*

* Adjusted for minimization factors and IV tPA therapy



SENSITIVITY ANALYSES

10 2 3

1.71 (95%CI, 1.05-2.81)

1.83 (95%CI, 1.12-3.00)

1.93 (95%CI, 1.18-3.17)

Final analysis(video/local)

Sensitivity analysis I(central: phone/video)

Sensitivity analysis II(local investigators)

Favors endovascular treatment

OR (95%CI)

17AAN, 2015 Washington DC

Lopez Cancio E et al., ESOC 2015

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OutcomeThrombectomy

(n=103)Control(n=103)

Effect variable

Unadjusted Value

(95% CI)

Adjusted value(95% CI)

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) Odds ratio

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 95-100 at 90 days – no. (%) 47 (57.3) 23 (26.4) Odds

ratio3.7 (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

Pre3 (3.0)

Post67 (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

Secondary outcomes



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† Wilcoxon-Mann Whitney, p=0.030

17.2 [9, 58]

38.6 [12, 87]

Infarct volume at 24h by CT (n=189) or DWI (n=15)

Median [IQR], mL



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Subgroup analysisSubgroup analysis



REVASCAT

2/12

A clinical trial embeded within, SONIIA a population based reperfusion registry

ESOC 2015 Glasgow

21Abilleira S. et al., Stroke 2014

5/12

Near-consecutive enrolment

88%

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REVASCAT Conclusions 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


We aimed to determine which workflow metric is correlated with highest treatment effect in a prospective randomized trial of mechanical

embolectomy for acute stroke.

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

Symptom Reperfusion

Symp. CT

CT Reperfusion

* If final TICI < 2b we used

“end of procedure” time

MethodsMethods

43.7%

Time from symptoms to revascularization

Probability of mRS 0-2 -5% every 30’

Symptoms CT Reperfusion

Symptoms CT Reperfusion



Symptoms Reperfusion

CT

ASPECTS ≥ 8

Symptoms Reperfusion

Figure 1. Time from symptoms to revascularization (minutes) (unadjusted) – Aspects < 8

CT

ASPECTS < 8

The benefitial effect of reperfusion declines over time

Conclusions

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 reperfusionis a strong determinant of the treatment effectand the outcome of treated patients

Our result may suggest that in cases with unknown time from onseta compatible favorable CT-scan may be sufficient to select patients for thrombectomy

Our result may suggest that in cases with unknown time from onseta compatible favorable CT-scan may be sufficient to select patients for thrombectomy

Which workflow metric is correlated with highest treatment effect?

Which workflow metric is correlated with highest treatment effect?

Thank you!ESOC 2015 Glasgow

12/1225AAN, 2015 Washington DC

Investigators

12/12

SONIIA RegistryMiquel GallofréSonia Abilleira

Other Comprehensive Stroke CentersHospital del MarHospital Parc Taulí

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udate on revascat: (randomized trial of revascularization with solitaire fr® device versus best...

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