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