Why and When to do

(1)

Why and When to do

Mechanical Thrombectomy

Po-Lin Chen, MD

Stroke Center, Neurological Institute Taichung Veterans General Hospital

(2)

Outline

• Factors associated with outcome of thrombolysis

• Limits of intravenous thrombolysis

• Evidences of intraarterial thrombolysis or thrombectomy

• Selection criteria of potential candidates for thrombectomy

• Setup of a comprehensive stroke center and regional integration

• Conclusions

(3)

Outline

• Conclusions

(4)

Coregistered mismatch: PWI/wDWI volume >1.2, and PWI-wDWI volume ≥10 mL

Stroke. 2011;42:59-64

Malignant: a DWI or PWI_{Tmax >8} lesion> 100 mL;

Small: a DWI lesion < 10 mL and a PWITmax > 6

lesion< 10 mL.

Target Mismatch: a ratio of PWITmax > 6 lesion volume/DWI lesion volume >1.2 and an

absolute difference between PWITmax > 6 lesion volume and DWI lesion volume > 10 mL;

(5)

Stroke. 2011;42:1608-1614.

favorable clinical response

EPITHET + DEFUSE

5.61

(6)

Infarct growth in Target Mismatch patients Reperfusion vs no reperfusion

Infarct growth: baseline MRI and the 3- to 6-hour (DEFUSE) or 3- to 5-day (EPITHET) follow-up MRI

Stroke. 2011;42:1608-1614.

R+ R-

(7)

Modified Rankin Scale (mRS) at 90 days in Target Mismatch patients

Reperfusion vs no reperfusion

Stroke. 2011;42:1608-1614.

P=0.003

64%

29%

Reperfusion: baseline MRI and the 3- to 6-hour (DEFUSE) or 3- to 5-day (EPITHET) follow-up MRI

(8)

Careful selection of candidates

Find mismatch and reperfusion !!

(9)

Collateral flow is critical for Mismatch in patients with major artery occlusion

Right MCA occlusion and leptomeningeal collateral flow

Lancet Neurol 2011; 10: 909–21

(10)

Collaterals Avert HT (Hemorrhagic transformation)

• Data revealed that therapeutic recanalization in the setting of poor collaterals resulted in a high frequency of HT with

worsened clinical neurological status.

• Poor collateral status at baseline may limit effective reperfusion, even when recanalization is successful.

Bang OY. Stroke. 2011;42:2235-2239

(11)

Outline

• Conclusions

(12)

Timing and degree of recanalization in initial MCA occlusion, proximal vs distal

Stroke 2006 Apr; 37 (4): 1000-4

(13)

Recanalization rate by IV rtPA

• Minimal or no recanalization: a worse outcome

• Recanalization depends on the location of the occlusion

• complete recanalization rate

• distal MCA occlusion: 44%

• proximal MCA occlusion: 30%

• tandem cervical ICA and MCA occlusion: 27%

• terminal ICA occlusion: 6%

• basilar artery occlusion: 30%

CLOTBUST Investigators. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke." Stroke, 2007, 38(3): 948-54.

(14)

The importance of size

the thrombus length exceeds 8 mm over M1-MCA occlusions have almost no possibility of recanalization

Stroke 2011 Jun; 42 (6): 1775-7

(15)

(16)

(17)

The brain ages 3.6 years each hour without

treatment during an ischemic stroke

(18)

Meta-analysis of ATLANTIS, ECASS I, II, NINDS

NNT= 3.5 NNT= 7 NNT= 11

OR for a favourable outcome

-1.40 (95% CI 1・05–1・85) between 3 h and 4.5 h -1.15 (0・90–1・47) between at 4.5–6 h

Lancet, 2004; 363(9411): 768-74.

ECASS 3, NNT= 14

(19)

Outline

• Conclusions

(20)

Copen, W. A. et al. Radiology 2009;250:878-886

Figure 2: Volumes of DW image (DWI) lesions (teal bars) and absolute mismatch volumes (red bars) for every patient in study, PAO: proximal arterial occlusion

ischemic penumbra may persist for up to 24 hours in patients with proximal occlusions

(21)

Stroke. 2007;38:967-973

53 studies (trials, case series)

IV IA

< 24 > 24 spontaneous

IV+IA

M

(22)

Recanalization and functional outcome

4.06(2.94, 5.60) Recanalizatio within 6 hours

Recanalizatio within 24 hours

Good outcome : mRS≤ 2 or NIHSS ≤ 4 at 3-month

(23)

Stroke Therapy Timeline

1995 2000 2005 2010

IV tPA ^{PROACT II}_{IA tPA} _MERCI

Penumbra

ACE Solitaire

IV tPA (4.5h) Angioplasty

Stenting

Generation 1 Generation 2 Generation 3

Off-label - Red FDA Approved - Yellow

Bridging IV/IA Trevo

2015

Level I Evidence

MR CLEAN SWIFT PRIME

EXTEND IA ESCAPE REVASCAT

THERAPY

(24)

Intra-arterial thrombolysis

• meta-analysis of 3 trials, IA vs. no thrombolysis

• PROACT 1 & PROACT 2

• Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial [MELT])

• mRS ≤ 1 (31% vs 20%, OR 2.0, 95% CI 1.2 to 3.4, p=0.01)

• mRS ≤ 2 (43% vs 31%, OR 1.9, 95% CI 1.2 to 3.0, p=0.01)

• NIHSS = 0 or 1 at the 90^th day (23% vs 12%, OR 2.4, 95% CI 1.3 to 4.4, p=0.007)

• mortality at 90 days (20% vs 19%, OR 0.84, 95% CI 0.5 to 1.5)

• SICH (11% vs 2%, OR 4.6, 95% CI 1.3 to 16, p=0.02).

J Neurointerv Surg . 2011 ; 3 ( 2 ): 151 - 155 .

(25)

Acute Management: endovascular thrombolysis

• 3 endovascular thrombectomy trials were highlighted at the 2013 International Stroke Conference

• IMS III

• MR RESCUE

• SYNTHESIS Expansion

(26)

Eligibility criteria included:

- receipt of IV t-PA within 3 hours - an NIHSS score ≥10 (large artery

occlusion not required)

- or, a NIHSS score 8-9 with CTA

evidence of an occlusion of M1, ICA, or BA

Merci retriever, Penumbra System, or Solitaire FR, or endovascular delivery of t-PA

Interventional Management of Stroke III

IMS III (2008-2012)

(27)

P = 0.25

P = 0.83

P = 0.06

(28)

• mRS < 2 at 90 days:

– 40.8% in IV/IA and 38.7% in IV groups (p>0.05)

2 hours

(29)

Primary outcome, SYNTHESIS

In the analysis adjusted for age, sex, stroke severity, and presence or absence of atrial fibrillation at baseline, the odds ratio with endovascular treatment was 0.71 (95% confidence interval, 0.44 to 1.14; P = 0.16)

N Engl J Med. 2013 Mar 7. 368(10):904-13.

IV tPA only <3 hrs vs IV + IA tPA and/or Mechanical Device < 6hrs Major artery occlusion not required

Endocvascular Tx: Catheter & wire, Merci and Penumbra, minimal Stent-Retrievers

(30)

Merci Retriever or Penumbra System Infarct core < 90 ml

Penumbra > 30 %

(31)

Penumbral group had better outcome

(32)

(33)

0 10 20 30 40 50 60 70 80 90 100

embolectomy,penum standard care, penum embolectomy, non- penum

standard care, non- penum

reperfusion

revascularization

Reperfusion and revascularization among penumbral

groups by treatments

(34)

Acute Management: endovascular thrombolysis

• All 3 trials failed to show a statistically significant difference between the endovascular therapy group and the best medical management

group (which could include IV-tPA) as measured by an mRS of 2 or less

(35)

IMS III, SYNTHESIS, MR RESCUE Why FAILED ?

• Large vessel occlusion was not required (IMS III, SYNTHESIS,

• No distinction between small and large vessel strokes (IMS III, SYNTHESIS)

• Limited by older endovascular devices (IMS III, SYNTHESIS, MR RESCUE)

• No CTA, No ASPECTS criteria (IMS III, SYNTHESIS)

• Large predicted infarct cores (≤ 90 ml in MR RESCUE)

Stroke. 2014 Dec. 45(12):3606-11.

(36)

• Newer trials, including MR CLEAN, EXTEND-IA, ESCAPE, and

SWIFT PRIME, required imaging that confirmed large vessel

occlusion.

(37)

MR CLEAN: A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke

• Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands

• Published January 1, 2015

• 500 patients with large vessel occlusion(LVO) confirmed by CTA were randomized to intra-arterial treatment (n=233) or medical

management (n=267) within 6 hours of symptom onset

– an occlusion of ICA, MCA (M1 or M2), or ACA (A1 or A2) established by CTA, MRA, or angiography

– NIHSS score ≥ 2

– ASPECT not included in criteria

Berkhemer OA et al. N Engl J Med 2015;372:11-20.

(38)

MR CLEAN

• Those in the endovascular group received either – mechanical thrombectomy,

– an intra-arterial thrombolytic agent, or – both

• The majority of the patients in the intervention group were treated with retrievable stents (81.5%)

• IV tPA:

– endovascular group, 87%

– control group, 91%

• Median ASPECT: 9

(39)

MR CLEAN: A Randomized Trial of IA Treatment for Acute Ischemic Stroke

OR of 1.67 (95% CI1.21-2.30) for favorable outcome

32.6%

19.1%

(40)

ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke

• ESCAPE had planned to randomize 500 participants to standard care or standard care plus endovascular treatment

• stopped due to the release of the results of MR CLEAN.

• AIS ≤ 12 hours after symptom onset

• a small infarct core by CT and CTA:

an ASPECTS sore of 6 - 10

• a proximal artery occlusion in MCA trunk and immediate branches

• good collateral circulation

– defined as the filling of 50% or more of the MCA pial arterial circulation on CTA.

(41)

ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke

• 316 patients with proximal large vessel occlusion (LVO) and good collateral circulation confirmed by CTA were randomized to

endovascular intervention (n=165) or medical management (n=150) within 12 hours of symptoms onset

• IV tPA

– In the intervention arm, 73%

– In the control arm, 79%

– Stroke onset to start of IV alteplase, intervention/control: 110/125 min

Goyal M et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1414905

(42)

ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke

OR 2.6 (95% CI 1.7-3.8); p< 0.001 for favorable outcome

53.0% vs. 29.3%; p< 0.001

(43)

ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke

• Endovascular intervention was associated with reduced mortality (10.4% vs 19.0%; p=0.04)

58%

28%

29%

52%

(44)

EXTEND-IA: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection

• EXTEND-IA had planned to randomize 100 patients to IV tPA plus treatment with the Solitaire FR stent retriever or to IV tPA alone.

• suspended after the enrollment of 70 patients after MR CLEAN reported.

• Inclusion criteria

– AIS with IV tPA within 4.5 hours of onset – IA therapy within 6 hours (groin puncture)

– occlusion of the ICA or MCA M1 or M2 segment by CTA

– RAPID software (Stanford University) showed salvageable brain tissue on CTA

– ischemic core < 70 ml

(45)

EXTEND-IA

No significant difference in mortality or symptomatic ICH 71% versus 40%, p=0.01

72%

39%

(46)

Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke, SWIFT-PRIME

• SWIFT-PRIME randomized patients to IV tPA within 4.5 hours plus

endovascular treatment with the Solitaire FR stent retriever device, or to IV tPA alone within 6 hours of symptom onset

• Patients were 18-80 years of age

• an NIHSS of 8-29

• Large vessel occlusion of the intracranial ICA or M1 by CTA or MRA

• patients with large areas of unsalvageable brain tissue were excluded.

• CT or MRI ASPECT ≥ 7

• RAPID software to assess penumbra

• The study was placed on hold after 196 patients had been enrolled due to the release of the other positive trial results.

N Engl J Med 2015;372:2285-95.

(47)

Primary outcome, SWIFT-PRIME

endovascular group (60.2%) compared to thecontrol group (35.5%), p=

0.0008

60%

36%

(48)

Safety of combined thrombolytic therapy

87% of endovascular group had IV r-tPA, MR CLEAN

0 2 4 6 8 10 12 14 16 18 20

Death in 30 days Parenchymal hematoma, type 2

Other territory new ischemic

stroke

Intervention Control

%

*

5.6 vs 0.4, P< 0.001

(49)

0 2 4 6 8 10 12 14 16 18 20

Death in 30 days Symptomatic ICH Malignant MCA stroke

Intervention Control

Safety of combined thrombolytic therapy

73% of endovascular group had IV r-tPA, ESCAPE

0.5 (0.3-0.8)

1.2 (0.3-4.6)

0.3 (0.1-0.7)

*

(50)

primary outcome (mRS 0–2) of patients treated with endovascular thrombectomy compared with intravenous thrombolysis

International Journal of Stroke 2015, 1168–1178

(51)

(52)

(53)

REVASCAT

(54)

Inclusion criteria, REVASCAT

ASPECT ≥7

(55)

Neuroimaging exclusion criteria, REVASCAT

(56)

43.7 %

28.1%

(57)

REVASCAT

IV tPA failure IV tPA ineligible

44.2%

28.9%

42.5%

26%

(58)

Weber R, et al. J NeuroIntervent Surg 2016;0:1–5.

Retrospective analysis of 283 patients with AIS treated with MT in a center

(59)

Mechanical thrombectomy

with vs without IV thrombolysis

0 10 20 30 40 50 60 70 80

Recanalization SAH sICH any ICH mRS 0-2 Mortality

MT, IVT(+) MT, IVT(-)

%

(60)

Mechanical thrombectomy alone

with vs without IV tPA contraindications

0 10 20 30 40 50 60 70 80

MT /s IV contra MT /c IV contra

*

P= 0.042

%

P= 0.133

(61)

0 50 100 150 200 250 300 350

onset to puncture imaging to puncture onset to end thrombectomy

MT /s IV contra MT /c IV contra

P< 0.001

P= 0.02

*

mins

Mechanical thrombectomy alone

with vs without IV tPA contraindications

(62)

Impact on acute stroke treatment

• All 5 trials showed statistically significant evidence of endovascular treatment in select acute ischemic stroke patients

• Selection of patients should be confirmed by vascular imaging

• IV rt-PA should always be the first line treatment for eligible acute ischemic stroke patients

• On average approximately 5% of stroke patients receive acute stroke treatment

• We need to continue to improve community and physician awareness

(63)

Assess the Penumbra System in the Treatment of Acute Stroke THERAPY, The first aspiration trial

AIS < 4.5 hours of onset with a large vessel occlusion in the anterior circulation a clot length greater than 8 mm

NIHSS≥ 8

IV tPA vs IV tPA plus Penumbra device (41 patients in each group) Mean onset to groin puncture of 226 minutes

(64)

Outline

• Conclusions

(65)

Trial

Imaging Required to Confirm Occlusion Prior to

Randomization?

Device(s) Used in Intervention Arm

TICI 2b/3 Revascularization Rate in the Intervention

Arm

mRS 0-2

Intervention Arm Control Arm

IMS III No

IA Lytic (138), Merci Retriever®

(95), EKOS (22), Penumbra (54), Solitaire FR (5)

38% ICA 44% M1 44% M2 23% multi M2

40.8%

(N=415)

38.7%

(N=214)

MR RESCUE ^No Merci Retriever®, EKOS, IA Lytic, Penumbra

24% pen (n=34) 27% nonp

(n=30)

21% pen (n=34) 17% nonp

(n=30)

26% pen (n=34) 10% nonp

(n=20)

MR CLEAN ^{Head CT} 97% Stent Retrievers, 2% other Mechanical

58.7%

(N=196)

33%

(N=233) 19% (N=267)

ESCAPE CTA Collaterals, ASPECTS 86% Stent Retriever 72.4%

(n=156)

53.0%

(n=164)

29.3%

(n=147)

SWIFT PRIME ^CTP 100% Stent Retriever 88.0%

(n=83)

60.2%

(n=98)

35.5%

(n=93)

EXTEND-IA ^CTP 100% Stent Retriever 86.2%

(n=29)

71%

(n=35)

40%

(n=35)

REVASCAT ^ASPECTS 100% Stent Retriever 66%

(n=102)

44%

(n=102)

28%

(n=103)

THERAPY CTA clot >8mm 100% Penumbra 38%

(n=50)

30%

(n=46)

(66)

Selection criteria

MR CLEAN ESCAPE EXTEND-IA SWIFT-PRIME REVASCAT

Population AIS with occlusion AIS with occlusion AIS with occlusion AIS with occlusion AIS with occlusion

Design Standard vs S+EV Standard vs S+EV IV tPA vs IV tPA + Solitare

IV tPA vs IV tPA + Solitare

Standard vs S + Solitare

NIHSS ² ^8-29 ^{> 6}

ASPECT ^6-10 ^7-10 ^7-10

Ischemic core, ml ^{< 70}

Penumbra V V

Collateral cir. > 50% MCA

Onset to door, hr ⁶ ¹² ^4.5 ^4.5 ⁸

(67)

Outline

• Conclusions

(68)

Conclusion

• Studies have proven the benefit of endovascular treatment in selected patients with large vessel strokes compared to medical therapy alone.

• The development of new device technologies, specifically the

stentriever devices, and systems changes allowing for early treatment and better patient selection likely contributed to this success.

(69)

Conclusion

• endovascular therapy is an opportunity for patients unable to receive IV tPA or IV tPA non-responders:

– those that do not arrive at the hospital early enough – those who are not thrombolytic candidates

– treated with IV tPA with residual vessel occlusion

• Endovascular treatment will now become the standard of care in stroke therapy.

• Early identification of large vessel occlusion will be critical.

• Devices are potentially able to retrieve large clots, and large hemorrhages may occur less frequently with device use.

(70)

Time is Brain Stroke Systems of Care

(71)