stetler [read-only]€¦ · ninds: 0 to 3 hours n engl j med 1995; 333:1581‐1588. 8/29/2017 4 iv...

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Endovascular Treatment of Acute Ischemic Stroke

William R. Stetler, Jr, MD

Assistant Professor

UAB, Dept of Neurosurgery

Disclosures

• No financial disclosures

IA Stroke Therapy

• 28 y/o F w/ h/o HTN, DM, Obesity, prior “clots” in legs w/ resulting toe amputations

• Acute onset R hemiplegia and aphasia at 14:30

• Went to OSH

• CT scan – no hemorrhage, hyperdense MCA

• IV tPA administered at 16:30

• Transferred to UAB

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Stroke Incidence

An estimated 795,000 Americans will suffer a new or recurrent stroke this year…

…that’s one every 40 seconds

American Heart Association. Heart Disease and Stroke Statistics 2012 Update At-a-Glance.

Two Types of Stroke

87% of strokes are ischemic; only 1% of these patients get intervention.

13% of strokes are hemorrhagic:

• 10% intracerebral• 3% subarachnoid

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Physiological Impact of Stroke

Saver, Jeffrey, Time is Brain – Quantified. Stroke 2006; 37: 263-266.

Time Neurons Lost Synapses LostMyelinatedFibers Lost

AcceleratedAging

1 second 32,000 230 million 218 yards 8.7 hours

1 minute 1.9 million 14 billion 7.5 miles 3.1 weeks

1 hour 120 million 830 billion 447 miles 3.6 years

Avg. stroke 1.2 billion 8.3 trillion 4470 miles 36 years

Estimated Pace of Neural Circuitry Lost in a Typical Large Vessel Acute Ischemic Stroke

IV t‐PA (alteplase)

• Currently the only FDA‐approved medical treatment for acute ischemic stroke

• ≤ 3 hours since symptom onset

• Approved in Europe for ≤ 4.5 hours since symptom onset

NINDS: 0 to 3 hours

N Engl J Med 1995; 333:1581‐1588

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IV t‐PA Exclusion criteriaSignificant head trauma or prior stroke in previous 3 months

Symptoms suggest subarachnoid hemorrhage

Arterial puncture at noncompressible site in previous 7 days

History of previous intracranial hemorrhage

Intracranial neoplasm, arteriovenous malformation, or aneurysm

Recent intracranial or intraspinal surgery

Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg)

Active internal bleeding

Acute bleeding diathesis, including but not limited to

Platelet count <100 000/mm3

Heparin received within 48 hours, resulting in abnormally elevated aPTT

greater than the upper limit of normal

Current use of anticoagulant with INR >1.7 or PT >15 seconds

Current use of direct thrombin inhibitors or direct factor Xa inhibitors with

elevated sensitive laboratory tests (such as aPTT, INR, platelet count, and

ECT; TT; or appropriate factor Xa activity assays)

Blood glucose concentration <50 mg/dL (2.7 mmol/L)

CT demonstrates multilobar infarction (hypodensity >1/3 cerebral hemisphere)

Meta‐analysis Shows a Strong Correlation Between Revascularization and Good Patient Outcomes

*Differences in sICH were not statistically significant between the revascularized and non-revascularized groups

Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007 Mar;38(3):967-73.

58.1%

14.4% 13.7%

24.8%

41.6%

12.5%

0%

10%

20%

30%

40%

50%

60%

70%

Good Outcome

(mRS 0‐2)

90‐Day Mortality SICH

% of Patients

Revascularized Non‐revascularized

*

Impact of Clot Burden on Success Rate of IV tPA

~40% recanalization

Successful Recanalization

Persistent Occlusion

Christian H. Riedel et. al. The Importance of Size: Successful Recanalization by Intravenous Thrombolysis in Acute Anterior Stroke Depends on Thrombus Length. Stroke, 2011;42:1775-

1777

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35‐40% of Ischemic Strokes are Considered “Large Vessel”

• This subset of ischemic stroke comprises blockages in the:

• Internal Carotid Artery (ICA)

• Middle Cerebral Artery (MCA)

• Vertebral / Basilar Artery

• If left untreated, patient prognosis with these types of stroke is poor

1. Jansen O, et al.2. Furlan A et al. PROACT II Trial

3. Brückmann H et al.

Vessel Mortality Rate

ICA 53%1

MCA 27%2

Basilar Artery 89‐90%3

Endovascular Horizon

PROACT IIFurlan et al 1999

• 180 patients, < 6 hrs• IA Urokinase vs IA heparin• Primary outcome = mRS 2 or less

• Slight better outcome with IA lytic• Symptomatic ICH slightly higher IA lytic

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MERCI -2005• Phase I study, 161 ptnts, < 8 hrs• Recanalization ~ 50%• Symptomatic ICH in 8%• Good outcome more likely w/

recanalization

Penumbra-2008

• Phase I study• < 8 hrs, NIHSS > 8• Primary outcome = recanalization achieved in 100%

• Good outcome in 45%

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Stroke 2013 Negative Trials• IMS III

• IV tpa vs IV tpa + IA (MERCI)• Stopped early secondary to futility

• MR Rescue• IV tpa vs IA- stratified based off penumbral imaging

patterns• No statistical significantly

• Synthesis• IV tpa vs IA tpa• Equivalent outcomes

DOES ENDOVASCULAR THERAPY WORK?

Cushing operating at Brigham and Women’s, circa 1913

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'Whoever wishes to foresee the future must consult the past; for human events ever resemble those of preceding times..' ‐Machiavelli

• First document case of intracoronary administration of fibrinolysis in acute MI in 1976 (article in Russian)

• Then described again in 1982 via Meyer et al (article in German)

• Then multiple small series and abstracts that did not show significant benefit.

• Then…..

Lessons Learned from Cardiology

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Question is answered, right?

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Failures of Previous Trials

• Past trials of endovascular stroke treatment failed to show benefit in the intervention arm

• IMS 3, MR RESCUE, SYNTHESIS‐Expansion

• Key learnings to improve IA Stroke trial results:

• Imaging to confirm large vessel occlusion

• Imaging to exclude patients with a large infarct core

• Improve time to treatment

• Use newest devices to improve recanalization rates

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*Non FDA‐Approved Therapies

Turning PointThe Era of Stent‐Retrievers

Technological advances

• Stent-retriever technology for safe, reliable performance

• Significant improvement in revascularization and patient outcomes vs older technology, proven in randomized clinical trials*

Image courtesy of Stryker Neurovascular.

* Raul G Nogueira, et. al. Trevo versus Merci retrievers for thrombectomy revascularisationof large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial.

Lancet, 2012; 380: 1231-40 and Jefferey L Saver et. al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised,

parallel-group, non-inferiority trial. Int J Stroke; 2012, 1747-4949

Stent Retrievers• Two Devices:

• Solitaire – eV3, 2012 FDA• TREVO – Stryker 2012 FDA

Stent-Retriever Studies• SWIFT – Saver et al 2012

• Solataire vs MERCI• mRS 2 or less twice as likely with Solitaire• Symptomatic ICH less in Solitaire

• TREVO-2 – Nogueira et al 2012• Trevo vs MERCI• Better recanalization Trevo• mRS 2 or less twice as likely Trevo

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• Multicenter (16 Centers in Netherlands), prospective, RCT:

• Blinded assessment of functional outcome at 90 days

• Blinded assessment of neuro‐imaging at baseline and follow‐up

• Masked, web‐based, 1:1 random treatment allocation

• Intraarterial treatment + BMT vs BMT alone

• Inclusion Criteria

• Acute ischemic stroke, Age ≥18, NIHSS ≥2

• Intracranial anterior circulation occlusion (confirmed by CTA)

• Initiation of IA treatment within 6 hours from onset

Design

O.A. Berkhemer et. al. A Randomized Trial for Intraarterial Treatment for Acute Ischemic Stroke. N Eng J Med December 2014.

Patients were randomized 1:1

Baseline CT, CTA N=502

InterventionN=233

ControlN=267

Standard txN=266

mRS Assessment N=267

20 DSA Only

*IAT N=196

mRS Assessment N=233

2 pts withdrew consent

1 pt received IAT

IAT never initiated in 17 pts

Received Therapy

End of Follow Up

Randomized

*Actual IA Therapy was performed in 196 of 233 pts


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Baseline Patient Characteristics

CharacteristicIntervention (N=233)

Control (N=267)

Age in years (median) 65.8 65.7

Male sex 135 (57.9%) 157 (58.8%)

NIHSS score (median) 17 18

Treatment with IV alteplase

203 (87.1%) 242 (90.6%)

Extracranial ICA occlusion 32.2% 26.3%

ASPECTS (median) 9 9


0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

ICAterminus*

M1 M2 A1/A2

Control (N=266) Intervention (N=233)

Distribution of Occlusion Location at Baseline

* ICA with involvement of the M1


97%

2%0%

20%

40%

60%

80%

100%

Retrievable stent (190/196) Other mechanical (4/196)

Stent Retrievers were 97% of IAT Treatment in the Intervention Arm

Of the 233 patients randomized to the intervention arm, 37 did not receive IA treatment; in 17/37 patients IAT was never started and no DSAs performed and in the other 20/37 the procedure was prematurely aborted. Other mechanical included: Merci Retriever® in 2 patients, wire manipulation in 1 patient and thromboaspiration through the guiding catheter in 1 patient. IA lytic in 1 patient.


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19.4%21.9%

34.7%

24.0%

0.0%

10.0%

20.0%

30.0%

40.0%

TICI 0‐1 TICI 2a TICI 2b TICI 3

Post‐intervention TICI Scores In Treated Patients (N=196)


7x More Likely to Recanalize with Intra‐Arterial Treatment*

33%

75%

0%

20%

40%

60%

80%

100%

Control (68/207) Intervention (141/187)

Recanalization on CTA after 24 Hours

*Adjusted value odds ratio (95% CI) for "no intracranial occlusion on follow up CT angiography" in the intervention group versus the control group was 6.88 (4.34 to 10.94). Values were adjusted for age, NIHSS at baseline, time from onset to randomization, status with respect to previous stroke, atrial fibrillation, diabetes mellitus and occlusion of the ICAT. Data for follow up CT angiography were not available for 106 patients.


Effect Of Intervention On Primary Outcome

Common adjusted odds ratio: 1.67 (95% CI: 1.21 to 2.30)


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Serious Adverse EventsIntervention (N=233)

Control (N=267)

Any serious adverse event 110 (47.2%) 113 (42.3%)

Parenchymal hematoma type 2 14 (6.0%) 14 (5.2%)

New ischemic stroke in different vascular territory*

13 (5.6%) 1 (0.4%)

Pneumonia 25 (10.7%) 41 (15.4%)

Hemicraniectomy 14 (6.0%) 13 (4.9%)

Death

Within 7 days 27 (11.6%) 33 (12.4%)

Within 30 days 44 (18.9%) 49 (18.4%)

No Significant Between‐Group Difference in the Occurrence of Serious Adverse Events @ 90 days (P=0.31)

*P<0.001


• Endovascular thrombectomy in acute ischemic stroke secondary to large vessel

occlusion in anterior circulation was safe and effective within 6 hours after onset

• This treatment leads to a clinically significant increase in the functional

independence in daily life by 3 months, without an increase in mortality

• Primary outcome measure: mRSS at 90 days

• mRSS 0‐2:

• IA group: 32.6%

• Control group: 19.1%

MR CLEAN Study Conclusion


2015: Important Clinical Trials

• MR CLEAN

• SYNTHESIS

• SWIFT PRIME

• EXTEND‐IA

• REVASCAT

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Stent Retriever Trials

JAMA Neurol 2015; 72:1101‐1103

Thrombectomy Trials

Albers GW, Halpern JL. J Am Col Cardiol 2015;66(22):2506‐9

IA Trials: Recanalization Rates

27%41%

59%72%

86% 88%

66%

0%

20%

40%

60%

80%

100%

TICI 2b‐3

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Stent Retriever Trials

JAMA Neurol 2015; 72:1101‐1103

2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke

• “Patients SHOULD receive endovascular therapy with a stent retriever if they meet all of the following criteria:

• Prestroke mRS score 0 to 1

• Acute ischemic stroke receiving intravenous t‐tPA with 4.5 hour of onset

• Causative occlusion of the internal carotid artery

• Age ≥ 18 years

• ASPECTS of ≥ 6 and

• Treatment can be initiated within 6 hours of symptom onset

• Etc etc…”

Stroke 2015; 46:000‐000

Risks and benefits of IA thrombectomy summarized

• Chance of reopening the blocked artery: 60‐80%

• Risk of a major complication (symptomatic hemorrhage): 5‐15%

• Chance of providing some neurological benefit: 20‐60%

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Intra‐arterial thrombectomy: Patient selection

• Intra‐arterial treatment of acute ischemic stroke

• Patients with acute ischemic stroke who cannot be treated with IV t‐PA

• Non‐responders to t‐PA

• Large clot burden (large vessel occlusion or >8 mm in length)

• May treat out to 6 hours after symptom onset

• Favorable imaging ‐ ? Perfusion

Perfusion Imaging

Stroke 2016; 47:1153‐1158

Stroke 2016; 47:1153‐1158

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DEFUSE and DAWN Trials

• Both – randomized trials to select patients for IA therapy beyond 6hrs since last known normal

• Select patients with favorable perfusion imaging and randomize to IA therapy and best medical management

• UAB is a DEFUSE site, but currently on hold since DAWN trial has finished.

DAWN• DAWN = DWI or CTP Assessment with Clinical Mismatch

in the Triage of Wake‐Up and Late Presenting Strokes Undergoing Neurointervention

• RCT of ischemic stroke from LVO treated 6‐24 hours after onset using perfusion imaging (CT or MRI)

• Inclusion:

• Baseline NIHSS score ≥10

• ICA or MCA‐M1 occlusion

• Primary endpoint: 90 day mRS

DAWN

• Planned enrollment of 500 patients• Recently stopped early after 204 patients given significant benefit

• Primary endpoint met in 48.6% IA vs 13.1% BMT

• Relative reduction in disability of 73%

• NNT = 2.8

• Industry sponsored; paper is pending

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Back to our original case…...

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Back to our original case…...

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• Patient left hospital several days later, antigravity in RUE, speech intact

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QUESTIONS?

stetler [read-only]€¦ · ninds: 0 to 3 hours n engl j med 1995; 333:1581‐1588. 8/29/2017 4 iv...

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