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Results of the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) TrialKeith W Muir, Philip White, Alicia Murray, Gary Ford, Andrew
Clifton, Martin Brown, Joanna Wardlaw, Janet Freeman, Ian
Ford
Institute of Neuroscience & Psychology, University of Glasgow
Institute of Neurological Sciences, Queen Elizabeth University Hospital
Disclosures
• Co-Chief Investigator for PISTE– Funded principally from the Stroke Association (start-up
phase 2012-15) and National Institutes of Health Research HTA programme (main phase, 2015-16)
– Unrestricted grants from Codman and Covidien to support start-up phase of PISTE
• Consulted on design of SWIFT-Prime
PISTE Timelines
External PISTE Milestones
Jan 2012 TSA Funding
May, Nov 2012 REC approvals
Feb 2013 IMS-3, MR RESCUE, SYNTHESIS presented First patient
Oct 2014 MR CLEAN presented
Feb 2015 ESCAPE, EXTEND-IA, SWIFT-Prime presented & Published
HTA Funding Agreed
Apr 2015 HTA Funding Start
REVASCAT, THRACE, THERAPY at ESOC iDMC Suspension recommended
July 2015 TSC ends recruitment (n=65), Surveysinvestigators
Aug 2015 LPLV
IAT Strategies in Different Trials: Subtle Variations
Simple ImagingCT brain + LAO on CTA
Wait for IVT responders Proceed ASAP to IAT
MR CLEAN, REVASCAT PISTE
Complex ImagingCTP, multiphase collaterals or MRI
Select favourable profile
ESCAPE (collaterals)EXTEND-IA, SWIFT-Prime (CTP)
THRACE (MRI)THERAPY (clot+CTP)
(REVASCAT) (CTP)
PISTE: Key Inclusion Criteria
Imaging CT + CTA (MRI allowed)
Main clinical inclusioncriteria
• Clinical diagnosis of supratentorial acute ischaemic stroke• Male or nonpregnant female ≥18 years of age• Clinically significant neurological deficit and NIHSS score ≥6.• Eligible for IV rtPA according to standard guidelines and able to be commenced
on IV treatment <4.5h after symptom onset.• Enrolment, randomisation and procedure commencement (groin puncture)
possible within 90 minutes of the start of IV rtPA treatment (groin puncture maximum 5.5h after stroke onset).
• Interventional device delivery (guide catheter placed beyond aortic arch and angio obtained) can be achieved within 6 hours of onset of the stroke.
• Independent prior to stroke (estimated mRS 0-2)• Available for follow-up at 3 months
Main imaging inclusioncriteria
• Occlusion of ICA, M1 or single proximal M2 on CTA (MRA or DSA allowed).
Time constraints • IVT within 4.5 hours; IAT within 6h
Primary outcome analysis • mRS 0-2 at 90 days (mRS 0-2 v 3-6)
Imaging outcome measure • Recanalisation at procedure end (IAT) and 24h CTA (all); ICH
Key Inclusion Criteria: Across Trials
Trial Age Target Vessels NIHSS Advanced Imaging
Selection
IV rtPA Use IAT Time
Window
PISTE ≥18 ICA, M1, M2 ≥6 No + 6h
MR CLEAN ≥18 ICA, M1, M2, A1,
A2
≥2 No +/- 6h
ESCAPE ≥18 ICA, M1 ≥6 Yes (collaterals) +/- 12h
EXTEND-IA ≥18 ICA, M1, M2 0-42 Yes (CTP) + 6h
SWIFT-Prime 18-85 ICA, M1 8-29 Yes (CTP) + 6h
REVASCAT 18-80 ICA, M1 ≥6 No +/- 8h
THRACE 18-80 ICA, M1, BA 10-25 No + 6h
THERAPY 18-85 ICA, M1, M2 ≥8 No +
PISTE: Centres
HSRC n
UCLH + 18
Newcastle Royal Victoria Infirmary + 13
St George's Hospital, London + 12
University Hospital N Staffordshire + 6
Charing Cross Hospital + 5
Salford Royal Hospital + 5
King’s College Hospital + 2
Leeds General Infirmary - 2
Nottingham City Hospital + 1
QE Hospital Birmingham - 1
Demographics
IV rtPA (IVT) IVT+IAT
n 32 33
Age, years mean±SD 64±16 67±17
>80 years 3 (9%) 6 (18%)
Male n(%) 16 (50%) 13 (39%)
Smoker (Current) n(%) 3 (9%) 4 (12%)
MI or IHD n(%) 6 (19%) 4 (12%)
Previous Stroke n(%) 2 (6%) 3 (9%)
Diabetes n(%) 6 (19%) 11 (33%)
Hypertension n(%) 17 (53%) 17 (52%)
Atrial Fibrillation n(%) 8 (25%) 15 (46%)
BP mmHg mean±SD 144/83 (±25/18) 147/77 (±23/15)
NIHSS median, range 14 (6-29) 18 (6-24)
Stroke Characteristics
IVT IVT+IAT
n 32 33
ASPECTS median, range 9 (2-10) 9 (4-10)
0-4 1 1
5-7 9 6
8-10 22 26
CTA Occlusion Site
ICA T/L ±M1 ±M2 6 (19%) 4 (14%)
MCA M1 10 (31%) 14 (48%)
MCA M2 5 (16%) 3 (10%)
Collateral Score
Good 12 18
Moderate 12 10
Poor 6 5
Clot Burden Score median (IQR) 6 (4, 7) 7 (4, 8)
ITT and Per Protocol Populations
Randomised
Best Medical Care incl IVT Additional IAT
N=32 N=33 ITT Population
Per Protocol PopulationN=28 N=30
CTA occlusion ineligible (1)>33% MCA Territory (1)mRS>2 on review (1)Treatment allocation crossover (1)
>33% MCA Territory (2)Treatment allocation crossover (1)
Process Indicators
IVT IVT+IAT
n 32 33
Symptom Onset to IVT Start 120[62, 238]
120[61, 242]
Symptom Onset to Randomisation
150 [88, 268]
150[78, 271]
IVT Start to Groin Puncture 82[28, 140]
Randomisation to Groin Puncture
58[12, 87]
Groin Puncture to Device Removal
49[15, 137]
Total Onset to Procedure End 256
All Times are Minutes median [min, max]
Key Timelines: Comparison with Published Trials
0 30 60 90 120 150 180 210 240 270 300 330 360
MR CLEAN
REVASCAT
PISTE
ESCAPE
EXTEND IA
SWIFT Prime
Onset to Reperfusion
Onset to Groin Puncture
Onset to Randomisation
Onset to IVT
Device & Procedure
Anaesthesia
General 10 (31%)
Sedation or Local only 22 (69%)
Device
Number Used
1 25 (81%)
2-3 6 (19%)
Solitaire or Other Stentriever 23 (68%)
Penumbra or Other aspiration 11 (32%)
IA Thrombolytic Drug 6 (18%)
Technical Success: mTICI at End of Procedure
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
IAT
0
1
2a
2b
3
mTICI 2b-3: n=26/30 (87%)
Technical Success: Recanalisation at 24h CTA
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
IVT IVT+IAT
0
1
2a
2b
3
4
Odds of CTA Occlusion at 24h OR 0.18 (0.05, 0.64), p=0.008 Adjusted for minimisation variables
Day 90 mRS Distribution: ITT Population
5
9
1
5
6
3
7
4
4
4
4
7
3
1
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
IVT
IVT+IAT0
1
2
3
4
5
6
Primary Outcome: mRS 0-2 OR 2.12 (0.65, 6.94), p=0.204
Secondary Outcomes: mRS 0-1 OR 7.63, (1.56, 37.22), p=0.010mRS distribution OR 2.59 (0.93, 7.24), p=0.070
Adjusted for miniimisation variables (Age, NIHSS, OTT)
Day 90 mRS Distribution: Per Protocol Population
0
5
5
9
4
3
7
4
3
3
3
1
4
5
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
IVT
IVT+IAT0
1
2
3
4
5
6
Primary Outcome: mRS 0-2 OR 4.92 (1.23, 19.69), p=0.021
Secondary Outcomes: mRS 0-1 OR 14.6 (2.11, 101.5), p=0.005mRS distribution OR 4.47 (1.45, 13.80), p=0.009
Adjusted for miniimisation variables (Age, NIHSS, OTT)
All Primary and Secondary Clinical Outcomes
ITT PP
Primary Outcome
mRS 0-2 at day 90 OR 2.12 (0.65, 6.94 p=0.204 OR 4.92 (1.23, 19.69) p=0.021
Secondary Outcomes
mRS 0-1 at day 90 OR 7.63 (1.56, 37.22) P=0.010 OR 14.6 (2.11, 101.5) p=0.005
mRS Distribution OR 2.59 (0.93, 7.24) P=0.070 OR 4.47 (1.45, 13.80) p=0.009
Death OR 1.56 (0.29, 8.40) P=0.599 OR 0.69 (0.10, 4.68) P=0.697
Early Major Neurological Improvement (NIHSS 0-1 or improved ≥8)
OR 1.83 (0.54, 6.25) P=0.321 OR 2.98 (0.76, 11.65) P=0.106
Days in Usual Residence day 0-90
68 v 78.5 P=0.782 58 v 79 P=0.411
SICH (SITS MOST) 0 v 0 -
PH1/2 ICH 1 v 3
Systematic Review: Published Trials Including PISTE
mRS 0-1 at day 90
Conclusions
• Planned timelines for rapid IAT were achieved – PISTE fulfilled its place in the ecosystem (rapid IAT initiation without advanced
imaging selection)
• High rate of mTICI 2b-3; 24h CTA shows that some reocclusions occur
• Premature trial termination due to external events
• Primary endpoint (mRS 0-2) non-significant but OR consistent with published data
• Secondary endpoint (mRS 0-1) significant benefit
• All efficacy endpoints consistent with IAT benefit
• Primary and major secondary endpoints significant in per protocol population
• Safety confirmed
Acknowledgements
Trial Coordinator: Alicia MurrayTrial Steering Committee (Stroke Association)Gary Ford (chair), Keith Muir, Phil White, Andy Clifton, Janet Freeman, Ian Ford TSC (HTA Phase)Hugh Markus, Joanna Wardlaw, Independent Data Monitoring Committee (Stroke Association)Kennedy Lees, Andy Molyneux, Steff LewisIDMC (HTA Phase)Tom Robinson, Andy Molyneux, John NorrieInvestigators: Anand Dixit, Geoff Cloud, Fergus Robertson, Naga Kandasamy, Kyriakos Lobotesis, Christine Roffe, Sanjeev Nayak, Tony Goddard, John Bamford, Craig Smith, Amit Herwadkar, Ganesh Subramanian, Rob Lenthall, Edward Littleton, Sal LaminResearch Coordinators: Kelley Storey, Rita Ghatala, Azra Banaras, John Aeron-Thomas, Bath Hazel, Holly Maguire, Emelda Veraque, Louise Harrison, RekhaKeshvara, James Cunningham
PISTE was possible only with the support of the NIHR Stroke Research Network and the Hyperacute Stroke Research Centre infrastructure