New developments in endovascular therapy or sfoktr...

New developments in endovascular therapy

for stroke

Dr Bruce Campbell Consultant Neurologist and Head of Hyperacute Stroke Royal Melbourne Hospital, University of Melbourne

1

Acute Stroke interventions: evidence base Interven�on Outcome RRR ARR NNT

All stroke types and severi�es

Stroke Unit care Cochrane 2007

Death/Dependency 17 3.6 28

Ischemic Stroke

tPA <4.5hr Emberson et al, 2014

mRS 0-‐1 20 6.8 15

thombectomy <6hr MR-‐CLEAN ,EXTEND-‐IA,

ESCAPE, SWIFT-‐PRIME, 2015

Death/Dependency 70 30 3

Aspirin IST, CAST 1997

Recurrent stroke/Death 10 0.9 111

Hemicraniectomy Vahedi K et al, 2007

Death 69 49 2

Intracerebral hemorrhage

BP lowering in ICH Anderson et al, 2013

Death/Dependency 6.5 3.6 28 2

Number Needed to Treat 4.5 9 14.1

tPA -‐ Time is BRAIN!

Our aim: shi� pa�ents up the curve!

Emberson Lancet 2014

Excellent outcome (mRS 0-‐1) n=6756

3

USA – “TARGET-‐STROKE”

Fonarow JAMA 2014

15min reduction in DTN from 74min to 59min based on prenotification and direct to CT associated with:

5

Generalized benefit of tPA

Emberson Lancet 2014 6

Do we need be�er than tPA?

7

Saver et al UCLA Stroke Center

WHY??

Non-‐contrast CT “selec�on” includes: -‐ already reperfused -‐ no penumbra remaining  more advanced imaging selec�on?

tPA doesn’t always open the artery  be�er reperfusion strategies

Effect of IV tPA on outcome 0-‐3hr post onset

8

Site of occlusion Success at 2 hours

Caro�d terminus 5%

MCA M1 30%

MCA M2 42%

Basilar 11%

Overall 30%

Early Recanaliza�on a�er IV tPA

9

Distribution of reperfusion Distribution of change in NIHSS

Selection = visually assessed CT perfusion mismatch + arterial occlusion tPA 0.1mg/kg TNK 0.25mg/kg tPA 0.1mg/kg TNK 0.25mg/kg

10

Desmoteplase?

11

Endovascular Therapy

12

SYNTHESIS

  Italian trial n=362 –  compared IV tPA with “direct to endovascular” –  ~1hr delay between when tPA was started and when IA was started

–  no requirement for proven vessel occlusion and loose clinical criteria

–  mostly intra-‐arterial tPA and a few of the older devices –  no data released on reperfusion rates

14

SYNTHESIS

Ciccone NEJM 2013

  Italian n=362 IV vs IA (no bridging)   Selec�on based on tPA criteria only   No requirement for vessel occlusion

  6% sICH both groups

15

MR-‐RESCUE

  USA trial n=118 –  compared endovascular to standard care (which included tPA in

%) –  MRI or CT perfusion imaging prior but not used for selec�on –  Different defini�on of “penumbra” to the EPITHET-‐DEFUSE

groups, allowed core volume up to 90mL as “penumbral” (we limit to 70mL)

–  older devices – 27% TICI 2b/3 (>50% reperfusion) –  only 6 “penumbral” pa�ents using EPITHET-‐DEFUSE criteria had

reperfusion –  suspected selec�on bias due to lack of equipoise in inves�gators

(glacial recruitment – 22 sites, 7 years)

16

MR-‐RESCUE

Kidwell NEJM 2013 17

IMS-‐3

  large NIH funded trial stopped for fu�lity a�er n=656 –  compared IV tPA versus IV tPA (mostly 2/3 of standard dose) + endovascular

–  no requirement to prove arterial occlusion

–  older devices – 40% TICI 2b/3 rate (ie >50% reperfusion) –  suspected selec�on bias due to lack of equipoise in inves�gators

18

OVERALL

IV-‐IA

IV only

NIHSS 8-‐19

IV-‐IA

IV only

NIHSS ≥20

IV-‐IA

IV only

IMS-‐3

Broderick NEJM 2013

p=0.25 for shi�

p=0.83 for shi�

p=0.06 for shi�

19

IMS-‐3   IA success at end of procedure:

TICI 2-‐3 TICI2b-‐3

Overall 74% 40%

Extracranial ICA 83% 33%

Intracranial ICA 65% 38%

ie subop�mal IA strategy (1st genera�on devices & IA tPA)

0

20

40

60

80

100

0 1 2a 2b 3

Good outcome (mRS 0-‐2)

20

IMS-‐3

Time?

  mean �me to recanaliza�on = 5hr25min (range 3-‐7hr)

~3.5hr delay to consent, randomise, transport and do IA Rx

 every 30min delay a/w 14% RRR in independent outcome (mRS 0-‐2)

21

so how do we do be�er?

  be faster   increase recanaliza�on success – new devices (and raise the bar for defining success – TICI 2b/3)   stop “an�-‐selec�ng” ie trea�ng the best candidates open label!

  Exclude pa�ents likely to be fu�le/risky (large core)

22

Excellent outcome (mRS 0-‐1) n=6756

IV tPA meta-‐analysis

Emberson Lancet 2014

IV tPA -‐ Time is BRAIN!

23

IA therapy – �me is s�ll brain (in unselected pa�ents)

Khatri Neurology 2009

IMS-‐3 median onset-‐recan

24

Collaterals ma�er imaging selec�on

Ribo Stroke 2011

Good Collaterals

25

More effec�ve devices

26

SWIFT & TREVO-‐2

TICI 2b/3 68% vs 44% 27

STAR Solitaire registry Pa�ent characteris�cs (n=188)

combined IV-‐IA 59%

Age 72 (18-‐85) NIHSS 17 (8-‐30)

ICA 18% M1 67% M2 14%

0-‐3hr 26% 3-‐4.5hr 38% >4.5hr 36%

Procedural characteris�cs Mean ± SD

number of passes 1.5 ± 0.7

onset to groin 251 ± 99min

Median groin to comple�on 44min

Symptoma�c hemorrhage 1.5%

Success (TICI 2b/3) = 79% core lab adjudicated (85% a�er “rescue”) mRS 0-‐2 58%

Pereira ISC 2013

28

Selec�on beyond occlusion? ASPECTS NCCT

CTP mismatch

DWI –MRA or diff-‐perf mismatch Collateral score (mul�phasic CTA)

Clot length

29

MR-‐CLEAN

  n=500 Dutch trial – 19 centres, universal enrolment due to government funding restricted to trial pa�ents

– “endovascular <6hr vs standard care” but 90% were tPA vs tPA + IA

– vessel occlusion documented on non-‐invasive imaging, no penumbral selec�on

31

MR-‐CLEAN

  Age (~65) and NIHSS (~17) well matched   ~60% M1, 25% ICA + a few M2s   Although protocol was IA vs best medical therapy ~90% had tPA as “medical therapy”   Although protocol was liberal ~97% of pa�ents were treated with “stentrievers” – the newer more effec�ve devices   TICI 2b/3 (>50% reperfusion) was 58% (versus 40% IMS3 and 27% MR-‐RESCUE)

32

MR-‐CLEAN

Timing:   onset to tPA ~90min

  onset to randomiza�on ~200min

  onset to procedure ~260min ie tPA to groin ~2hr50min

33

MR-‐CLEAN

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mRS IA vs medical (unadj p-‐value)

0-‐1 (back to all ac�vi�es) 11.6 vs 6% p=0.037

0-‐2 (Independent) 32.6% vs 19.1% p=0.001 NNT 7

0-‐3 (Ambula�ng independently, some assistance with domes�c ADLs)

51.1 vs 35.6% p=0.001

6 (death) 21.0% vs 22.0% p=0.77

ORDINAL SHIFT OR 1.67 (95% CI 1.21-‐2.30) 34

MR-‐CLEAN

Secondary endpoints   NIHSS reduc�on at 24hr and 7 days significant   recanaliza�on at 24hr -‐ 33% medical vs 75% IA   symptoma�c hemorrhage 11% IA vs 10% medical (PH2 – large parenchymal haematoma 6% vs 5%)

  subgroups – no heterogeneity in treatment effect across age (>/<80) or NIHSS strata

35

MR-‐CLEAN

  well conducted RCT   no penumbral selec�on in protocol (but many had CTP, only a small number had ASPECTS 0-‐4 non-‐contrast CT scans)   clear posi�ve result for func�onal outcome and consistent with secondary outcomes of recanaliza�on and early NIHSS response.

36

IMS-‐3 + MR-‐CLEAN

  The two “bridging” IV vs IV-‐IA trials

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mRS 0-1 – p=0.001 mRS 0-2 – p<0.001 mRS 0-3 – p<0.001 Death – p=0.45 Shift analysis p<0.001

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37

MR-‐CLEAN

ISC 2015 38

MR-‐CLEAN: �me to reperfusion

ISC 2015 39

Extending the �me for Thrombolysis in Emergency Neurological Deficits – Intra-‐Arterial

A randomized controlled trial of endovascular thrombectomy a�er standard dose intravenous t-‐PA within 4.5 hours of stroke onset

u�lizing dual target imaging selec�on

Acknowledging support from: Solitaire FR™ device supplied free of charge by

Bruce Campbell Peter Mitchell Co-‐PI and Medical Coordinator Co-‐PI and Head of Neurointerven�on

Stephen Davis and Geoffrey Donnan Co-‐chairs

ClinicalTrials.gov NCT01492725

40

Ra�onale

  In 2011 (before IMS-‐3, SYNTHESIS, MR-‐RESCUE neutral) –  Fu�le recanaliza�on noted in single arm studies (need be�er selec�on)

–  Major improvement in procedural success observed in pa�ents ineligible for IMS-‐3 treated with stentrievers versus our pa�ents eligible for IMS-‐3

  Aimed to select pa�ents with best chance of response to reperfusion -‐ “dual target” –  proven major vessel occlusion and

–  salvageable �ssue downstream with ischemic core <70mL (CT perfusion)

  Treat as fast as possible (no wai�ng to assess “tPA failure”)

  Use the most effec�ve device (stentriever)

42

CT perfusion

  Clinically useful to improve diagnos�c certainty1

  With appropriate thresholding provides similar informa�on on the presence of penumbra to MRI2,3

  Fast acquisi�on and processing ~6min (and need IV access and contrast for CT angiogram anyway)4

1Campbell et al JNNP 2013;84:613 2,3Campbell et al Stroke 2011;42:3435, 2012;43:2648 4Campbell et al Int J Stroke 2015;10:51-54

43

CT perfusion MRI

RAPID for CT and MRI Fast, standardized, fully automated, quan�ta�ve, thresholded mismatch

CT relCBF / Diffusion MRI

RAPID ischemic core segmenta�on CT relCBF<30%

Tmax

RAPID Tmax>6sec segmenta�on

Ischemic core: 6mL Perfusion lesion: 58mL Mismatch ra�o = 9.7 Absolute mismatch = 52mL

Randomize pa�ent

Ischemic core: 7mL Perfusion lesion: 55mL Mismatch ra�o = 7.6 Absolute mismatch = 48mL

Randomize pa�ent

Straka et al JMRI 2010 44

Example – mismatch

Ischemic core volume: 24mL Perfusion (Tmax>6s) lesion: 119mL

45

70mL ischemic core

Ischemic core volume: 73mL Perfusion (Tmax>6s) lesion: 88mL

46

Example – large ischemic core

Ischemic core volume: 146mL Perfusion (Tmax>6s) lesion: 215mL 47

Inclusion criteria:

  Age ≥18 years (no upper limit), No NIHSS restric�ons

  Anterior circula�on ischemic stroke eligible for intravenous tPA within 4.5 hours of stroke onset

  Imaging “dual target”

–  Major vessel occlusion – ICA, M1, M2 amenable to clot retrieval

–  RAPID “Mismatch” CT or MRI Mismatch ra�o > 1.2 AND Absolute mismatch >10mL AND Ischemic core <70mL

  Able to commence intra-‐arterial therapy within 6 hours of onset

  Informed consent obtained from pa�ent or person responsible

Exclusion criteria:

  Premorbid disability (mRS≥2)

  Inability to access the cerebral vasculature in the opinion of the neurointerven�onal team

  Contra-‐indica�on to imaging with contrast agents

  Major neurological recovery (to NIHSS 0-‐1 or inves�gator’s discre�on) prior to randomiza�on.

  ie BEFORE RANDOMIZATION neurologists had to check that the neurointerven�onist was available and had assessed proximal access

* Campbell et al Stroke 2011 Bivard et al Cerebrovasc Dis 2011 Kamalian et al Stroke 2011

48

10.15am Solitaire FR device 10:35am

Eligible Pa�ents

TRIAL DESIGN -‐ PROBE design, planned 100 pa�ents

24hr MRI reperfusion* (recan/growth/ICH) 24hr NIHSS

3 day NIHSS*

90 day NIHSS & mRS *co-‐primary outcome

Blinded outcomes

IV tPA only

Randomise 50:50 (web-‐based)

0.9mg/kg IV tPA + Solitaire FR clot retrieval -‐ start asap (<6hr)

49

2 4 7 9 11 13

16 17 17 19

25 27 29 30

35 38 40

43 45 47 49

55 60

63 66 68

70

0

20

40

60

80

100

120

No. Par�cipants

EXTEND-‐IA Recruitment

No. Par�cipants Randomised -‐ Expected

No. Par�cipants Randomised -‐ Actual

14 centres in Australia and New Zealand

MR-‐CLEAN results DSMB halted EXTEND-‐IA recruitment (Haybi�le-‐Peto boundary for efficacy)

Planned n=100

IMS3/SYNTHESIS/MR-‐RESCUE NEJM

50

Generalizability

Acute Ischemic stroke patients

n= 7798

Patients treated with alteplase n= 1044 (13%)

EXTEND-IA n= 70

Listed reason for exclusion:

No major vessel occlusion (n=495, 47%)

Out of operating hours (n=225, 22%)

Poor pre-morbid function (n=171, 16%)

Large ischemic core (n=42, 4%)

Cervical arterial dissection or poor vascular access (n=18, 1.7%)

Inability to obtain multimodal CT imaging (n=16, 1.5%)

Inability to obtain consent (n=7, 0.7%)

85%

51

Generalizability -‐ RMH

  In largest center 21 randomized + 7 with occlusion and clinical eligibility excluded for large core ie ~25% (95%CI 11-45%) excluded by CTP

  Endovascular appropriate for ~37-40% of tPA patients + tPA ineligible

Acute Ischemic stroke patients

N=954

Patients treated with alteplase N=178 (19%)

EXTEND-IA n= 21

(12% of tPA)

Hierarchical reason for exclusion:

No major vessel occlusion (n=106, 60%)

Poor pre-morbid function (n=28, 16%)

Out of operating hours (n=13, 7%)

Large ischemic core (n=7, 4% BUT 25% of otherwise eligible)

Cervical arterial dissection or poor vascular access (n=1, 0.5%)

Inability to obtain multimodal CT imaging (n=0, 0%)

Inability to obtain consent (n=2, 1%)

83%

52

CONSORT trial profile

Randomized (n=70)

Alteplase + Endovascular (n=35) Alteplase only (n=35)

Did not receive Angiogram (n=2)

Received tPA only (n=35)

Received angiogram (n=33)

1 – major improvement (temporary) 1 – major deterioration (unrecognized 2nd embolism)

4 – already recanalized by tPA 1 – ICA stent sufficient to restore flow 1 – wire perforation pre-deployment

Solitaire device not deployed (n=6)

Solitaire device deployed (n=27)

All analyses = intention to treat 53

Demographics Characteristic IV tPA only IV tPA +

endovascular Number 35 35

Age – yr: Mean (SD) 70.2 (11.8) 68.6 (12.3)

Male sex – no. (%) 17 (48.6%) 17 (48.6%)

NIHSS score: Median (IQR) 13 (9-19) 17 (13-20)

Onset to tPA – min Median (IQR) 145 (105-180) 127 (93-162)

Door-to-needle – min Median (IQR) 46 (35-70) 43 (19-61)

tPA to randomization – min Median (IQR) 36 (18-55) 29 (23-46)

54

Ini�al imaging Characteristic IV tPA only IV tPA +

endovascular Site of vessel occlusion ICA MCA-M1 MCA-M2

11 (31%) 18 (51%) 6 (17%)

11 (31%) 20 (57%) 4 (11%)

Baseline Ischemic core – mL Mean, Median (IQR)

19.6, 18 (4-29)

18.9, 12.3 (4-32)

Baseline Perfusion lesion – mL Mean, Median (IQR)

116, 115 (72-158)

105, 106 (76-137)

55

Procedural Characteris�cs

ie s�ll room for improvement as becomes standard care

Characteristic median, (IQR) IV tPA + endovascular

ONSET to groin puncture – min 210 (166-251)

CT to groin puncture – min 93 (71-138)

Groin puncture to TICI 2b/3 or completion 43 (24-53)

ONSET to mTICI 2b/3 or completion 248 (204-277)

* MR-CLEAN onset to groin = 260min = 50 min slower * IMS-3 onset to groin = 208min - similar * IMS-3 onset to recanalization = 325min = 77min slower

56

Procedural Characteris�cs Characteristic median, (IQR) IV tPA + endovascular

Final mTICI (core lab adjudicated) mTICI 2b/3 25/29 (86%)

mTICI 3 14/29 (48%)

mTICI 2b/3 ICA

M1

M2

10/11 (91%)

14/15 (93%)

1/3 (33%)

57

Co-‐primary outcome

58

Reperfusion at 24hr (Inten�on to treat)

median 37% vs 100% p<0.0001

tPA only tPA + endovascular Treatment Group

% Reperfusion at 24 hours

59

>90% Reperfusion at 24hr without SICH

Pa�e

nts (%

)

p<0.001

60

Reperfusion and mRS:

7

30

4

28

19

14

7

19

19

5

11

2

33

2

0% 20% 40% 60% 80% 100%

Reperfusion <90%

Reperfusion>90%

0 1 2 3 4 5 6

70% chance of death/dependence

Patients (%)

Modified Rankin Scale Score No symptoms Death

61

Early neurological recovery Reduc�on of ≥8 NIHSS points or reaching 0-‐1 by day 3

Pa�e

nts (%

)

p=0.002

62

NIHSS recovery

P=0.001 P=0.007 P=0.03

63

17

26

11

26

11

20

11

17

17

3

11 20

9

0% 20% 40% 60% 80% 100%

0 1 2 3 4 5 6

Combined Intravenous t-PA and Endovascular Therapy

Intravenous t-PA alone

Patients (%)

Ordinal p=0.006 (unadj), p=0.02 (adj) NNT 3 for ≥1 point better on mRS

mRS 0-2 p=0.01 71% vs 40% - NNT 3.2 for independence

mRS 0-1 p=0.09

Day 90 mRS

64

Recanaliza�on at 24hr

Characteristic

median, (IQR)

IV tPA only IV tPA +

endovascular

TIMI 2-3 (overall) 15/35 (47%) 33/35 (94%)

p<0.001

ICA M1 M2

2/11 (18%) 9/18 (50%) 4/6 (67%)

10/11 (91%) 19/20 (95%) 4/4 (100%)

65

Infarct volume & growth

Characteristic

median, (IQR)

IV tPA only IV tPA +

endovascular

Baseline Ischemic core 18 (4-29) 12.3 (4-32)

24hr Ischemic core 49 (17-82) 18 (12-52)

Infarct Growth 35 (6-73) 11 (0-24)

p=0.007 (adj)

66

Adverse events

Adverse Event IV tPA only IV tPA + endovascular p value

Deaths 7/35 (20%) 3/35 (9%) 0.18

SICH* 2/35 (6%) 0/35 (0%) 0.49

PH§ 3/35 (9%) 4/35 (11%) 0.99

Wire perforation - 1/35 (2.9%) -

Emboli - 2/35 (5.7%) -

* pre-specified SITS definition = PH2 + ≥4 point increase NIHSS § PH = parenchymal hematoma

67

Outcome of mTICI 2b vs 3

  10/11 (91%) of mTICI 2b had 100% reperfusion by 24h perfusion imaging

  10/11 (91%) had major early neurological recovery versus 13/14 (93%) TICI 3 pa�ents   8/11 (73%) had mRS 0-‐2 at 90 days versus 10/14 (71%) TICI 3 pa�ents

(and the 4 extra cases that were 2b at ini�al angiogram (due to tPA) also proceeded to 100% reperfusion by 24h)

68

Limita�ons

  Sample size 70 -‐ unable to interrogate subgroups (planned individual pa�ent meta-‐analysis)   Cannot exclude some benefit of endovascular therapy in pa�ents excluded from this trial on the basis of large ischemic core/no mismatch.

  Purely volume-‐based criteria do not account for the loca�on of the ischemic core, which is also relevant to clinical outcome.   Early termina�on of the trial does create poten�al for overes�ma�on of the effect size.

69

Conclusions

  early mechanical stent-‐thrombectomy a�er tPA using Solitaire FR led to: – Faster and more complete reperfusion

  In this popula�on selected for vessel occlusion and salvageable �ssue this translated to: –  Improved early neurological recovery –  Improved func�onal outcome at 3 months – No safety concerns

70

Implica�ons

  tPA + mechanical stent-‐thrombectomy should be the new standard of care

  Systems re-‐organiza�on and transfer protocols

  Details of selec�on paradigm remain a key discussion – EXTEND-‐IA indicates a popula�on with high probability of major clinical response but others may derive some benefit – requires further study

71

Acknowledgements

  Recrui�ng Sites Royal Melbourne Hospital (21) B.C.V. Campbell, P.J. Mitchell, S.M. Davis, B. Yan, R.J. Dowling,

N. Yassi, T.J. Oxley, T.Y. Wu, G. Silver, A. McDonald, R. McCoy; Royal Adelaide Hospital (12) T.J. Kleinig, R. Scroop; Aus�n Hospital (10) H.M. Dewey, M. Simpson, M. Brooks, B. Coulton; Royal North Shore Hospital (6) M. Krause, T.J. Harrington, B. Steinfort, K. Faulder, M. Priglinger, S. Day; Monash Medical Centre (4) T. Phan, W. Chong, M. Holt, R.V. Chandra, H. Ma, D. Young; Western Hospital (4) T. Wijeratne, H. Tu, E. Mackay; Box Hill Hospital (3) C.F. Bladin, P.S. Loh, A. Gilligan, Z. Ross, S. Coote, T Frost; John Hunter Hospital (3) M.W. Parsons, F. Miteff, C.R. Levi, T. Ang, N. Spra�; Gold Coast University Hospital (3) M. Badve, H. Rice, L. de Villiers. New Zealand: Auckland City Hospital (4) P.A. Barber, B. McGuinness, A. Hope, M. Moriarty.

  Neuroscience Trials Australia – E Cowley, R McCoy

  CSIRO (eCRF) – S McBride, K Harrap, C Stanbridge

  Stanford Stroke Centre (RAPID) – G Albers, R Bammer

  Pa�ents and families

72

Methods

  22 centres in Canada (11), US (6), Korea (3), UK (1), Ireland (1)   Acute ischemic stroke pa�ents within a 12-‐hour window from onset, good func�onal status, with no age limit

  tPA given when pa�ent eligible (no wai�ng for tPA response)   Imaging must have shown: small core, proximal intracranial artery occlusion, moderate-‐good collaterals using CT, mCTA (use of MRI discouraged)

  Intensive quality improvement program with personalized site visits

74

Inclusion and exclusion criteria

  > 5 NIHSS   < 12 hours from symptom onset   Adult; No age limit   Good pre-‐morbid status

  CT head: ASPECTS > 5 (exclude large core)   CTA: ICA + M1 or M1 or func�onal M1 (all M2s)   CTA (preferably mul�phase): moderate to good collaterals

75

Workflow and Interven�on

  Randomiza�on: standard of care vs. standard of care + endovascular treatment

  Focus on speed – �me targets: -‐ CT head to groin puncture: 60 min* -‐ CT head to first recanaliza�on: 90 min*

  Use of retrievable stents recommended

  Use of balloon guide catheter recommended *Time from first slice NCCT Head chosen to encourage fast imaging acquisition and interpretation

76

Trial designed for speed

  Deferral of consent where applicable   Internet based, rapid randomiza�on process using randomized minimiza�on (MSB algorithm)   Site signed agreements – document speed; commit to serial randomiza�on

  Communica�on and feedback network to promote enrolment   Quality improvement and follow-‐up program

77

Target Recruitment was 500 prior to the study being halted

316

Just below pace for 1.5 subjects/site/month

78

  At 11 of 22 sites this was an approved mechanism of consent

  17.8% of pa�ents were enrolled using this approach

  The qualita�ve assessment from inves�gators was that this very much facilitated enrolment at those 11 sites and the lack of available surrogate decision maker was a major factor in slower enrolment at sites where this was not available.

Deferral of Consent

79

Quality Improvement

We reviewed each sites performance on treatment times and on imaging selection internally and then with each site by teleconference (times) and webinar (imaging) to promote achievement of time targets and to promote appropriate patient selection by imaging.

80

Low % Imaging Protocol Devia�ons

Sites interpreta�on: all appropriate Core Lab:

ASPECTS CTA occlusion Collaterals 3.6% 4.5% 6.5%

ASPECTS 5 n=5 M2-‐MCA n=9 Poor collaterals (<50% of the MCA territory)

ASPECTS 4 n=3

ASPECTS 3 n=2 ICA, no MCA

n=5

ASPECTS 3 n=1

81

Comparing Interval Times

ESCAPE MR CLEAN IMS III SYNTHESIS

Onset Randomiza�on

171 min (IQR 118-‐285)

204 min (IQR 152-‐251)

~135 min ~146 min

Onset IV tPA 114 min (IQR 82-‐160)

85 min (IQR 67-‐110)

~111 min 165 min (IQR 140-‐200)

Onset Groin Puncture

200 min (IQR 144-‐315)

260 min (IQR 210-‐313)

~196 min ~225 (?200) min**

Onset Reperfusion

241 min (IQR 176-‐359)

-‐-‐-‐ ~321 min -‐-‐-‐

NEJM. 2015; 372(1): 11-20.; NEJM 2013: 368(25): 2433-34; Circulation. 2014;130:265-272

**Onset-to-treatment (eg. infusion of intra-arterial tPA)

82

Comparing Interval Times

ESCAPE IMS III CT Groin Puncture “Picture to puncture”

51 min ~107 min.

CT Reperfusion “picture to perfusion”

84 min ~232 min

Circulation. 2014;130:265-272

  Picture = first slice non-contrast CT   ESCAPE patients were first encountered at similar times to prior trials but were

effectively treated much faster

83

Reperfusion

Interven�on Control

IV tPA No IV tPA IV tPA No IV tPA

TICI 2b/3 70.5% 77.3% -‐-‐-‐ -‐-‐-‐

mAOL 2-‐3 -‐-‐-‐ -‐-‐-‐ 37.3% 7.1%

mAOL assessed on CTA done at 2-8h post randomization

84

Comparing Reperfusion

ESCAPE MR CLEAN IMS-‐III

TICI 2b/3 72.6% 58.7% 45.2%

  Higher rates of reperfusion with current technique and devices

  Early assessment of the control group (2-8h in ESCAPE) shows only modest rates of reperfusion in the control group; 24h assessment time is too late

85

Results

  A�er MR CLEAN results were presented at the WSC, the trial steering commi�ee suspended recruitment in the trial   The planned interim analysis was conducted several weeks early

  The trial was then halted at the recommenda�on of the DSMB because the efficacy boundary had been crossed

86

Baseline Characteris�cs Demographics Intervention (N=165) Control (N=150)

Age yr – median (IQR) 71 (60-81) 70 (60-81)

Female sex 52.1% 52.7%

Caucasian 87.3% 87.3%

Baseline NIHSS – median

(IQR)

16 (13-20) 17 (12-20)

Hypertension 63.4% 72.0%

Diabetes Mellitus 20.0% 26.0%

Atrial fibrillation 37.0% 40.0%

88

Baseline Imaging

Imaging characteristics – (%)

Intervention (N=165)

Control (N=150)

CT ASPECTS median (IQR) 9 (8-10) 9 (8-10)

CTA occlusion location –(%)

ICA ‘T’ or ‘L’ 27.6% 26.5%

M1-MCA or both/all M2-MCA 68.1% 71.4%

M2-MCA 3.7% 2.0%

Ipsilateral cervical carotid

occlusion

12.7% 12.7%

89

Process times min – median (IQR)

Intervention [N=165]

Control [N=150]

Symptom onset to

randomization (N=315)

169 (117-285) 172.5 (119-284)

Onset to IV alteplase (N=237) 110 (80-142) 125 (89-183)

CT to groin puncture 51 (39-68) ---

CT to first reperfusion 84 (65-115) ---

Onset to first reperfusion 241 (176-359) ---

Treatment with IV alteplase 72.7% 78.6%

Treatment Time Intervals

90

Safety Outcomes

Intervention [n=165]

Control [n=150]

RR (CI95) Adjusted§

RR (CI95)

Death [N=311] 10.4% 19.0% 0.5 (0.3-0.95)

0.5 (0.3-0.8)

Large MCA/malignant MCA

stroke

4.9% 10.7% 0.5 (0.2-1.0) 0.3 (0.1-0.7)

sICH (clinically determined at

site)

3.6% 2.7% 1.4 (0.4-4.7) 1.2 (0.3-4.6)

Access site hematoma 1.8% 0% --- ---

MCA perforation 0.6% 0% --- ---

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Angiographic Outcomes

Intervention Control

Final Reperfusion TICI 2b/3 [Angio Core lab determined]

72.4% ---

mAOL 2-3 (at 2-8h CTA) [CT Core lab determined]

--- 31.2%

Retrievable Stent Use 86.1%

92

Outcomes (NNT = 4)

Clinical Intervention [n=165]

Control [n=150]

RR or cOR (CI95)

Adj RR or cOR (CI95)

mRS primary

outcome (“shift

analysis”) [n=311]

--- --- 2.6 (1.7-3.8) 3.1 (2.0-4.7)

mRS 0-2 at 90d

[n=311] 53.0% 29.3% 1.8 (1.4-2.4) 1.7 (1.3-2.2)

EQ-VAS at 90d

(median, iqr) 80 (30) 65 (30) P<0.001 (rank sum

test) 93

14.6 20.7 17.7 16.5 13.4 6.7 10.4

7.5 10.2 11.6 15.0 24.5 12.2 19.0

0 29.3 53 100percent

intervention (N=165)

control (N=150)

cOR adj = 3.1 (95%CI 2.0-4.7)Shift on 90-d mRS

Overall ESCAPE trial results

mRS 0 mRS 1 mRS 2 mRS 3mRS 4 mRS 5 Death

94

12.6 21.0 17.6 17.6 17.6 6.7 6.7

7.8 12.1 9.5 16.4 20.7 12.9 20.7

0 20 40 60 80 100percent

intervention (N=119)

control (N=116)

Shift on 90-d mRS

N=238, 3 lost to follow-up. P for interaction = 0.889

IV tPA group [N=235]


95

20.0 20.0 17.8 13.3 2.2 6.7 20.0

6.5 3.2 19.4 9.7 38.7 9.7 12.9

0 20 40 60 80 100percent

intervention (N=45)

control (N=31)

Shift on 90-d mRS

N=77, 1 lost to follow-up. P for interaction = 0.889

Non-IV tPA group [N=76]


96

0.0

00.2

50.5

00.7

51.0

0M

ort

alit

y

0 30 60 90Days from Stroke Onset

90-day K-M Curve

Kaplan Meier Curve of Mortality

97

10.9 15.2 10.9 15.2 17.4 10.9 19.6

2.6 10.3 5.1 10.3 12.8 15.4 43.6

16.1 22.9 20.3 16.9 11.9 5.1 6.8

9.3 10.2 13.9 16.7 28.7 11.1 10.2

0 20 40 60 80 100percent

> 80 yrs

<= 80 yrs

Intervention (n=46)

Control (n=39)

Intervention (n=118)

Control (n=108)

Shift on 90 day mRS


99

15.3 16.5 16.5 16.5 18.8 7.1 9.4

3.8 9.0 14.1 17.9 23.1 12.8 19.2

13.9 25.3 19.0 16.5 7.6 6.3 11.4

11.6 11.6 8.7 11.6 26.1 11.6 18.8

0 20 40 60 80 100percent

Female

Male

Intervention (n=85)

Control (n=78)

Intervention (n=79)

Control (n=69)

Shift on 90 day mRS


100

15.3 24.6 18.6 15.3 14.4 5.1 6.8

9.4 11.3 14.2 12.3 26.4 12.3 14.2

14.0 11.6 16.3 16.3 11.6 11.6 18.6

2.5 7.5 5.0 22.5 20.0 12.5 30.0

0 20 40 60 80 100percent

NIHSS<20

NIHSS>=20


Control (n=106)

Intervention (n=43)

Control (n=40)

Shift on 90 day mRS


101

Imaging-‐Defined Sub-‐groups All Benefit

102

16.4 22.7 16.4 15.6 14.1 6.2 8.6

9.0 10.7 11.5 14.8 24.6 13.1 16.4

10.3 13.8 17.2 20.7 13.8 10.3 13.8

0.0 8.0 12.0 16.0 24.0 8.0 32.0

0 20 40 60 80 100percent

ASPECTS>7

ASPECTS<=7


Control (n=122)

Intervention (n=25)

Control (n=29)

Shift on 90 day mRS


Supplementary Figure 7b: Figure shows benefit in the intervention group when compared to the control group across the 90-day mRS distribution in subjects with baseline non-contrast CT ASPECTS ≤ 7 vs. > 7. Nine subjects had CT ASPECTS 0-5 (protocol violators) and are included in the ASPECTS < 7 group for this analysis. Threshold for ASPECTS was pre-defined. There is no evidence of heterogeneity of treatment effect between these subgroups. (pinteraction=0.914, Wald test).

103

19.0 23.8 19.0 23.8 0.00.0 14.3

0.0 10.5 5.3 10.5 21.1 31.6 21.1

14.0 20.3 17.5 15.4 15.4 7.7 9.8

8.6 10.2 12.5 15.6 25.0 9.4 18.8

0 20 40 60 80 100percent

Yes

No

Intervention (n=21)

Control (n=19)


Control (n=128)

Shift on 90 day mRS


15.8%

61.8%

104

14.5 21.8 20.9 15.5 13.6 6.4 7.3

7.8 9.7 12.6 17.5 26.2 11.7 14.6

13.3 15.6 8.9 22.2 13.3 8.9 17.8

2.6 10.5 10.5 7.9 21.1 15.8 31.6

0 20 40 60 80 100percent

MCA

ICA


Control (n=103)

Intervention (n=45)

Control (n=38)

Shift on 90 day mRS


31.5%

60%

105

Effect size for Interven�on

common OR* (“shi�”) 3.1 (2.0-‐4.7)

mRS 0-‐2 29.3% 53.0% NNT = 4

Death HR* 19.0% 10.4% 0.4 (0.2-‐0.8)

*Adjusted for age, sex, baseline NIHSS score, baseline ASPECTS score, IV alteplase use, baseline occlusion loca�on

106

Conclusion

  Endovascular thrombectomy is a safe, highly effec�ve procedure that saves lives and drama�cally reduces disability WHEN: – Pa�ents are carefully selected by imaging to iden�fy proximal occlusions, and exclude large core and exclude pa�ents with absent collaterals

– Treatment is extremely fast with target first slice   imaging to groin puncture < 60 min and

  imaging to reperfusion < 90 min

– Safe effec�ve technology (retrievable stents) is used 107

ESCAPE: Key Messages

  Select pa�ents with imaging – measure the physiology -‐ www.aspectsinstroke.com – Good scan (exclude the large core pa�ents), proximal artery occlusion, moderate-‐good collaterals on mCTA

  Act very fast on that informa�on – Picture-‐to-‐puncture (First slice CTgroin puncture) < 60 minutes

– Picture-‐to-‐perfusion (First slice CTreperfusion) < 90 minutes

  Achieve reperfusion – TICI 2b/3   Work as a team! 108

Key Inclusion Criteria

  Age 18 – 80

  Pre-‐stroke Modified Rankin Score ≤ 1

  NIHSS 8 – 29 at randomiza�on

  Received IV t-‐PA within 4.5 hours of stroke onset

  CTA or MRA confirma�on of large vessel occlusion (intracranial ICA, M1 or caro�d terminus)

  Groin puncture within 6 hours of stroke onset and within 90 minutes* of qualifying imaging

*op�mal target: within 70 mins

110

Key Exclusion Criteria  CT/MRI evidence of hemorrhage

 CT hypodensity or MRI hyperintensity > 1/3 of the MCA territory (or in other territories, >100 cc of �ssue)

 Caro�d dissec�on or complete cervical caro�d occlusion requiring sten�ng at the �me of the mechanical thrombectomy procedure  ASPECTS < 6*

Protocol Rev F “Small to moderate core”

Protocol B-D “Target mismatch”

a)  MRI- or CT-assessed core infarct lesion greater than 50 cc

b)  Severe hypoperfusion lesion (10 sec or more Tmax lesion larger than 100 cc)

c)  Ischemic penumbra < 15 cc and mismatch ratio ≤1.8

a)  ASPECTS < 6

*Implemented after 1st 71 patients were enrolled

Imaging entry criteria revised to accommodate sites with limited perfusion imaging capability and ensure accelerated treatment delivery

111

Final Assessment Available (n=93) ¨ Attended 90d follow-up (n=78) ¨ Died prior to 90d (n=12) ¨ LOCF from 7-10d or 30d follow-up (n=3)

Final Assessment Unavailable (n=5) ¨ Investigator withdrew after entry criteria deviation (n=2) ¨ Subject withdrew consent after randomization(n=1) ¨ Subject withdrew consent after 27h visit (n=1) ¨ Subject withdrew consent after 7-10d & requested deletion of all data (n=1)

Allocated to Solitaire + IV t-PA (n=98)

Received Solitaire (n=87)

Randomiza�on & Follow-‐up

Intention to Treat (n=98) Intention to Treat with data (n=98) Modified Intention to Treat (n=98)

Final Assessment Available (n=98)

¨ Attended 90d visit (n=88) ¨ Died prior to 90d (n=9) ¨ LOCF from 7-10d or 30d follow-up (n=1)

Allocated to IV tPA only (n=98)

Intention to Treat (n=98) Intention to Treat with data (n=97) Modified Intention to Treat (n=93)

Randomized (n=196)

112

Solitaire + IV t-PA IV t-PA P

value Age – yr – mean (SD) N=98 65.0 (±12.5) N=95 66.3 (±11.3) 0.44

Male N=98 54 (55.1%) N=96 45 (46.9%) 0.31

Race N=90 N=92 0.94

White 79 (88.8%) 83 (90.2%)

Black 10 (11.2%) 8 (8.7%)

Asian 0 (0%) 1 (1.1%)

Other 1 (1.1%) 0 (0%)

Ethnicity, Hispanic N=90 8 (8.9%) N=92 7 (7.6%) 0.79

Prestroke mRS – median (IQR)

N=98 0 (0-0) N=94 0 (0-0) 0.76

NIHSS Score – median (IQR)

N=98 17.0 (13-20) N=94 17.0 (13-19) 0.76

Baseline Characteris�cs: Demographics and Severity

113

Solitaire + IV t-PA IV t-PA P value

Medical History N= 98 N= 97

Hypertension 66 (67.4%) 56 (57.7%) 0.18 Diabetes Mellitus 12 (12.2%) 15 (15.5%) 0.54 Hyperlipidemia 24 (24.5%) 22 (22.7%) 0.87 Current or Ex-Smoker 15 (15.3%) 14 (14.4%) 1.00 Atrial Fibrillation 35 (35.7%) 38 (39.2%) 0.66 Myocardial Infarction 8 (8.2%) 11 (11.3%) 0.48 Peripheral Arterial Disease 7 (7.1%) 5 (5.2%) 0.77 Neurological History N= 98 N= 97

Prior Ischemic Stroke 3 (3.1%) 1 (1.0%) 0.62 Hemorrhagic Stroke 0 (0%) 0 (0%) 1.00 Transient Ischemic Attack 3 (3.1%) 5 (5.2%) 0.50

Baseline Characteris�cs: Medical History

114

Solitaire + IV t-PA IV t-PA P

Systolic blood pressure (mmHg) – median (IQR)

N=98 150.0 (135 - 166) N=94 148.5 (135 -

165) 0.32

Serum glucose (mmol / liter) - mean (SD)

N=97 7.3 (±2.5) N=94 7.3 (±2.6) 0.93

ASPECTS – median (IQR) N=97 9.0 (7-10) N=96 9.0 (8-10) 0.68

Site of occlusion* N=93 N=94 0.57

Intracranial ICA 4 (4.3%) 4 (4.3%) Carotid terminus 13 (14.0%) 11 (11.7%) M1 MCA 63 (67.7%) 73 (77.7%) M2 MCA 13 (14.0%) 6 (6.4%)

Side of occlusion – Left N=96 39 (41.9%) N=97 48 (51.1%) 0.24

Penumbral Imaging performed N=98 85 (86.7%) N=97 76 (78.4%) 0.13

Target mismatch profile** 69 (70.4%) 64 (66.0%) 0.54 Malignant profile*** 13 (13.3%) 7 (7.2%) Time from onset to IV t-PA (mins) – median (IQR)

N=98 110.5 (85 - 156) N=94 117 (80 - 155)

Site of IV t-PA – outside hospital N=98 31 (31.6%) N=97 35 (37.2%) 0.45

Baseline Characteris�cs: Physiologic and Imaging

*Site of occlusion was assessed by the core lab **Target mismatch profile: MRI- or CT-assessed core infarct lesion ≤50 cc, Tmax>10s lesion ≤100cc, mismatch volume ≥15cc and mismatch ratio >1.8 ***Malignant profile: MRI or CT-assessed core infarct >50cc and Tmax>10s lesion more than 100cc

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Core Lab Assessed Reperfusion Outcomes

TICI 2B/3 rate is 88.0% N=83 pts Based on all patients with final TICI data

1Reperfusion measured by reperfusion ratio assessed by core lab: reperfusion volume at 27hrs ÷ hypoperfusion lesion volume (Tmax >6s) at baseline

Solitaire + IV t-PA IV t-PA Odds Ratio P value Successful reperfusion1 (≥90% reperfusion) at 27hrs 53 (82.8%) 21 (40.4%) 7.11 [3.03,

16.70] <.0001

Modified TICI scale

TICI 2B: Perfusion of half or greater of the vascular distribution of the occluded artery

TICI 3: Full perfusion with filling of all distal branches

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8.6

17.3

10.8

25.5

16.1

17.3

17.2

12.2

21.5

15.3

25.8

12.2

0 1 2 3 4 5 & 6

Primary Endpoint

IV t-PA

(n=93)

Solitaire + IV t-PA

(N=98)

Modified Rankin Scale Score p = 0.0002 (Cochran-Mantel-Haenszel p value)

Subjects (%)

117

Conclusions

  We have a new standard of care   tPA is s�ll the star�ng point for all eligible pa�ents <4.5hr

  Stent-‐thrombectomy works <6hr if large vessel occlusion regardless of age or severity   CT angiography needs to be standard (minimum – ideally also CT perfusion)

  Need to work out how to implement imaging and transfer outside metropolitan regions

118

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