Neuro-Interventional Management of Acute Ischemic Stroke

Lotfi Hacein-Bey, MDa,b,*, Jeremy J. Heit, MD, PhDc, Angelos A. Konstas, MDd

KEYWORDS

Acute stroke Ischemia Neuro-interventional management Thrombectomy Endovascular KEY POINTS

Mechanicalthrombectomyisnowstandardofcareinstrokefromlarge-vesselocclusionwithClass IA evidence.

Treatment paradigms will likely evolve from time limits toward personalized physiology-based pa- tient evaluation.

Although a number of effective devices are available, techniques will continue to evolve.

Increasingly better outcomes are obtained, with possible future enhancements through
neuroprotection.

Increasing numbers of patients will be treated, requiring workforce adjustments.

INTRODUCTION

Approximately 795,000 strokes occur each year in the United States alone,1 the vast majority (87%) ischemic (as opposed to hemorrhagic) in nature.2 Many patients survive, left with major limitations of daily life from neurologic prejudice,1 resulting in an estimated annual financial cost to treat stroke survivors currently estimated at approximately $40 billion and rising.3

Currently known stroke risk factors include ag- ing, hypertension, diabetes, obesity (increased waist-to-hip ratio), dyslipidemia, smoking, chronic kidney disease, and chronic cardiac disease.4 Therefore, although prevention may play a signifi- cant role in addressing modifiable risk factors, the prevalence and severity of stroke are such that effective treatment strategies are necessary.

The first important breakthrough was the demon- stration of improved outcomes after intravenous administration of the thrombolytic rt-PA (recombi- nant tissue plasminogen activator) within the appro- priate time window. The process was, however, slow, taking almost 10 years to reach consensus on a 4.5-hour time window to offset the risk of symptomatic intracranial hemorrhage.5–7

During that period, the effectiveness of interven- tional transarterial thrombolytic administration within the clot within 6 hours of stroke onset was also being demonstrated.8 Although never approved by the Food and Drug Administration (FDA), such treatment option soon became commonplace in most major centers.9

Early interventional experience contributed to the realization that clots could be disrupted and

Disclosure Statement: The authors have no disclosures to declare in relation with this article.
a Interventional Neuroradiology and Neuroradiology, Department of Medical Imaging, Sutter Health, Sacra- mento, CA 95815, USA; b Radiology Department, University of California Davis Medical School of Medicine, 4860 Y Street, Sacramento, CA 95817, USA; c Division of Neuroimaging and Neurointervention, Stanford Healthcare, 300 Pasteur Drive, Grant S047, Stanford, CA 94305, USA; d Interventional Neuroradiology and Neuroradiology, Department of Radiology, Huntington Memorial Hospital, 100 West California Boulevard, Pasadena, CA 91105, USA
* Corresponding author. Interventional Neuroradiology and Neuroradiology, Department of Medical Imaging, Sutter Health, Sacramento, CA 95815.
E-mail address: lhaceinbey@yahoo.com

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possibly retrieved by direct mechanical methods, including catheters, guidewires, balloons, and snares, which led to the development of the Me- chanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials.10–12 Following these trials, the FDA approved the MERCI device (initially dubbed the Concentric Retriever), which is made of Nickel-Titanium loops arranged in a corkscrew configuration, which are advanced past the clot and pulled back for retrieval to treat ischemic stroke within a 6-hour time window.

The relatively low performance of the MERCI de- vice was one of the factors resulting in the publica- tion in 2013 of 3 consecutive failed randomized trials comparing medical with endovascular stroke therapy, which was discouraging news for the stroke community at large at the time.13–15

Another suggested cause for these failed trials was inadequate patient selection, leading to the establishment of vascular imaging before triage for endovascular treatment, and a maximum infarct core threshold value measured with diffusion-weighted imaging magnetic resonance imaging (DWI-MRI) of 60 to 70 mL in favor of inter- vention.16 It also became clear that the decision to deliver endovascular therapy had to be carefully made, as successful or not, intervention could be a major source of morbidity and death.16

Major revival of mechanical thrombectomy soon thereafter followed, with the advent of a new class of devices, that is, stent retrievers.

MECHANICAL THROMBECTOMY BECOMES STANDARD OF CARE

The Multicenter Randomized Clinical trial of Endo- vascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) trial,17 published in early 2015, was a landmark study that heralded a major and irreversible turn in stroke therapy. The

study involved 26 centers throughout the Netherlands, in which 500 patients were enrolled prospectively and randomized to either standard, conventional noninterventional treatment that included intravenous (IV) thrombolysis (n 5 267) or IV and intra-arterial treatment (n 5 233). Patients were included who presented within 6 hours of a stroke after confirmation of large-vessel occlusion (LVO): internal carotid artery (ICA), M1, M2, A1 or A2 by either computed tomography angiography (CTA) or magnetic resonance angiography (MRA). The vast majority of patients who received interven- tional care (97%) were treated with Solitaire or Trevo stent retrievers. Recanalization, defined as thrombolysis in cerebral infarction (TICI) 2b-3 reper- fusion scores (Table 1), was obtained in 59% of pa- tients. Positive primary outcomes (modified Rankin score [mRs] at 90 days 0–2) were achieved in 32.6% of the treated group versus 19.1% in the un- treated group; mortality and symptomatic hemor- rhagic transformation were similar in both groups. The MR CLEAN study yielded an absolute 13.5% difference in the rate of functional independence in the treated group (95% confidence interval, 5.9 vs 21.2), the first major advancement in stroke treatment since IV-tPA thrombolysis in 1995. Inter- estingly, although those findings were valid for in- terventions performed within 6 hours of stroke onset, statistical significance was no longer present after 6 hours and 19 minutes of stroke onset.

A number of studies were published in the following months, all but one using stent retrievers, all confirming superiority of mechanical thrombec- tomy over standard management or IV thromboly- sis alone.

The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial involved patients seen up to 12 hours after anterior circulation stroke onset.18 Patients

Table 1
Comparison of reperfusion grade scales used in stroke trials

Grade TIMI Score

. 0 Absence of perfusion

. 1 Contrast penetration without perfusion

. 2 Partial reperfusion

TICI Score

Absence of perfusion

Minimal perfusion

2a. Partial reperfusion to
< two-thirds occluded territory

2b. Complete reperfusion with however slow filling

Modified TICI Score

Absence of perfusion

Minimal perfusion: limited distal artery filling

2a. Reperfusion of
< half occluded territory

2b.Reperfusion > half occluded territory

2c.Reperfusion of > three-fourths occluded territory but not total

Complete reperfusion

3 Complete reperfusion

Complete reperfusion

Abbreviations: TICI, thrombolysis in cerebral infarction; TIMI, thrombolysis in myocardial infarction.

were evaluated by CT techniques, inclusion criteria were small infarct volume, occlusion of the ICA, M1 or at least 2 M2 branches, and CTA evidence of good arterial collaterals (>50% of ipsilateral collat- eral convexity collaterals). Patients were prospec- tively randomized to either IV t-PA within 4.5 hours of ictus (n 5 150) or standard treatment plus me- chanical thrombectomy. In the latter group, adequate reperfusion (TICI 2b-3) was achieved in 72.4%. The group of patients treated within 6 to 12 hours of stroke onset was too small, obviating useful statistical results. Clinical outcomes in pa- tients treated with mechanical thrombectomy were better than in the MR CLEAN trial: mRs scores at 90 days were 53% versus 29.3% for IV t-PA only.

The Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) study, which was prematurely halted on ethical grounds, was published at the same time.19 The SWIFT PRIME trial, sponsored by in- dustry (Covidien/Medtronic Neurovascular Clinical Affairs, Irvine, CA), was therefore primarily designed to evaluate the efficacy of the Solitaire device. Pa- tients (n 5 196) were included if they showed evi- dence by CTA or MRA of ICA or M1 occlusion, a core infarction of 50 mL or less on CT perfusion or diffusion-weighted imaging (DWI), evidence of a target mismatch between the core infarction and perfusion imaging, and were randomized to either IV t-PA within 4.5 hours of stroke onset (n 5 98) or IV t-PA plus mechanical thrombectomy (n 5 98). Reperfusion (TICI 2b-3) was achieved in 88% with the Solitaire device. Favorable outcomes (mRs 0–2 at 3 months) were 60.2% in the throm- bectomy group versus 35.5% in the t-PA group.

The Extending the Time for Thrombolysis in Emergency Neurologic Deficits–Intra-Arterial (EXTEND-IA),20 also industry sponsored, was aimed at assessing the efficacy of the Solitaire de- vice (Covidien/Medtronic Neurovascular Clinical Af- fairs). Patients were evaluated by anatomic and perfusion imaging using either CT or MR modalities, and had to fulfill the following criteria: core infarct size less than 70 mL, LVO of the ICA, M1 or M2 branches, perfusion mismatch greater than 1.2 (ab- solute mismatch >10 mL). A total of 70 patients were randomized to either IV t-PA within 4.5 hours of stroke onset (n 5 35) or IV t-PA plus Solitaire me- chanical thrombectomy (n 5 35). Reperfusion (TICI 2b-3) was achieved in 86% with the Solitaire de- vice. Favorable outcomes (mRs 0–2 at 3 months) were 71% in the thrombectomy group versus 40% in the t-PA group.

The Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circu- lation Large Vessel Occlusion Presenting within

Eight Hours of Symptom Onset (REVASCAT) was published at the same time.21 The REVASCAT study, jointly sponsored by the Spanish government and Covidien/Medtronic, was aimed at evaluating the Solitaire device, and conducted in 4 medical centers in and around Barcelona, Spain. Patients (n 5 206) had to have no evidence of a large infarc- tion, determined as an ASPECTS (Alberta Stroke Program Early CT Score) score greater than 6 on noncontrast CT, CTA, or MRA or angiographic evi- dence of ICA or M1 occlusion, and, again were ran- domized to either IV t-PA within 4.5 hours of stroke onset (n 5 103) or IV t-PA plus Solitaire device me- chanical thrombectomy (n 5 103). Reperfusion (TICI 2b-3) was achieved in 66% with the Solitaire device. Favorable outcomes (mRs 0–2 at 3 months) were 43.7% in the thrombectomy group versus 28.2% in the thrombolysis group. This trial was also prematurely closed for clinical evidence of su- periority of mechanical thrombectomy.

The THERAPY trial was a prospective random- ized study that evaluated the Penumbra aspiration system compared with IV t-PA. The results of the THERAPY trial were published after the 5 studies comparing stent retrievers with medical therapy.22 The major inclusion criterion was the presence of an intracranial arterial clot measuring 8 mm or longer. A total of 102 patients were included before early cessation of the trial due to evidence provided by other mechanical thrombectomy tri- als. Final primary analysis in this study failed to demonstrate a statistical benefit of endovascular therapy, although efficacy of thrombectomy was strongly suggested on secondary analyses.22

The THRACE trial, which was conducted in France, was also halted prematurely after the in- clusion of 404 patients.23

Comparative effectiveness of thrombectomy using either first-line aspiration catheters or first- line stent retrievers was evaluated in the large Contact Aspiration versus Stent Retriever for Suc- cessful Revascularization (ASTER) study of 381 patients treated in 8 large centers in France.24 Similar recanalization rates were found with both techniques: TICI 2b-3 scores of 85.4% for aspira- tion versus 83.1% for stent retrievers; clinical out- comes at 3 months were also similar in both groups. Interestingly, in patients with M2 occlusion (n 5 79), aspiration thrombectomy showed a modest, non–statistically significant advantage (TICI 2b-3 rate of 89.6% vs 83.9%).25

A meta-analysis of 1287 patients enrolled in the 5 major trials concluded to absence of benefit from thrombectomy if performed after 7.3 hours of stroke onset.26

Table 2 summarizes the findings of recent major trials

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Table 2
Summary of recent large randomized stroke trials supporting endovascular treatment

Trial

Inclusion Criteria

Imaging Criteria

Time from Onset

Device

Device Reperfusion Usage, Rate, mTICI % 2b-3, %

Outcome, mRs 0–2 at 90 d, %

Intervention vs IV t-PA (Except ARISE II and DAWN Trials)

MR CLEAN ESCAPE

NIHSS !2 NIHSS !5

LVO on CTA, MRA, DSA, TCD

<6 h <12 h

Trevo/Solitaire Solitaire/Trevo

81.5 59 86 72

32.6 vs 19.0 53.0 vs 29.3

500 (233 vs 267) 315 (165 vs 150)

SWIFT PRIME

NIHSS 8–29

LVO on CT/CTA or MRI/MRA Infarct core 50 mL
Target mismatch

<6h

Solitaire

100 88

60.2 vs 35.5

196 (98 vs 98)

EXTEND-IA

Prestroke mRS 0–1

LVO on CTA/CTP/MRA/MRP Infarct core 70 mL
Target mismatch on

<6h

Solitaire

100 86

71vs40

70 (35 vs 35)

REVASCAT

NIHSS!6 NIHSS 10–25

Perfusion MR
LVO on CTA/MRA/DSA

<8h

Solitaire

100 66

43.7 vs 28.2

206 (103 vs 103)

THRACE THERAPY

ASPECTS score!6 LVO on CT/CTA/MRA

<5h <8h

Solitaire

100
100 70

53.0 vs 42.1 38vs30

404 (200 vs 202) 108 (55 vs 53)

ARISE II DAWN

NIHSS 8–25

LVO on CTA/MRA/DSA

<8h 6–24 h

EmboTrap Trevo

100 79.5 100 84

70
49 vs 13

228 vs literature on Solitaire and Trevo

DEFUSE 3

NIHSS!10
(13 patients NIHSS<10)

DWI-MRI/CTP (RAPID software) infarct core <70 mL (median 35 mL)

6–16 h

Any FDA approved device

98 76

45 vs 17

182 (92 vs 90 standard care)

NIHSS!8

Clot length on CT !8 mm Infarct core 1/3 MCA

Penumbra (Aspiration)

NIHSS!10 (groups A-B)

DWI-MRI/CTP (RAPID software) Small infarct core ( 51 mL)

206 (107 vs 99 standard care)

NIHSS!20 (group C)

LVO on CT/CTA Small infarct core (ASPECTS 6–10)

Good collaterals on multiphase CTA

on Perfusion MR

Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; CTA, computed tomography angiography; CTP, computed tomography perfusion; DSA, digital subtraction angiography; DWI, diffusion-weighted imaging; IV, intravenous; LVO, large-vessel occlusion; MCA, middle cerebral artery; MRA, magnetic resonance angiography; MRP, magnetic resonance perfusion; mRs, modified Rankin score; mTICI, modified treatment in cerebral ischemia; NIHSS, National Institutes of Health Stroke Scale; t-PA, tissue plasminogen activator.

CURRENT DEVICES USED IN MECHANICAL THROMBECTOMY

The Solitaire stent retriever (Fig. 1), initially mar- keted by eV3 Endovascular (Irvine, CA) as the Sol- itaire Flow Restoration (FR) device, was the first of its kind to be granted FDA clearance in 2012. The dedicated study, which evaluated the Solitaire de- vice against the MERCI Retriever (the only FDA- cleared device before that) was the Solitaire FR with the Intention for Thrombectomy (SWIFT) study.27 The study (n 5 113), which time window for intervention was 8 hours, showed TICI 2 to 3 reperfusion rates of 61% for the Solitaire FR versus 24% for the MERCI device, outcomes at 90 days (mRs 0–2) of 58% versus 33%, and reduction in mortality at 3 months from 28% to 17%.

Later the same year, the Trevo stent retriever (Fig. 2), initially marketed as the Trevo ProVue Retriever by Stryker Neurovascular (Kalamazoo, MI), was also evaluated in a study that was designed similarly to the SWIFT trial, and was also found to be superior to the MERCI device. In the 178 study pa- tients, TICI 2 to 3 recanalization rates were 86% (Trevo) versus 60%, good clinical outcomes (mRs 0–2 at 3 months) were 33% versus 24%, and mortal- ity at 3 months was 33% versus 24%.28

The EmboTrap stent retriever (Neuravi-Codman Neuro, Fremont, CA) has an interesting design of 2 channels, the inner allowing immediate flow resto- ration, the outer granting clot trapping (Fig. 3). This device, which was granted CE mark approval (Eu- ropean FDA equivalent) in September 2016, was evaluated in the Analysis of Revascularization in Ischemic Stroke With EmboTrap (ARISE II) Study, which enrolled 228 patients in 19 centers in Europe and the United States. Study results showed a recanalization rate of 79.5% and a high rate of functional independence (mRs 0–2 at 3 months) of 70%. Mortality was 9% and symptomatic hem- orrhage 5%.29

In parallel, newer generation, large-bore aspira- tion catheters led to refinements of the ADAPT (A Direct-Aspiration first-Pass) technique, which al- lows the en bloc extraction of the entire intracranial arterial thrombus.30–33 The Penumbra aspiration de- vice, which is attached to a negative-pressure elec- trical pump (Fig. 4) (Alameda, CA) benefited from several upgrades in luminal size and improvements in navigability, and was evaluated in the THERAPY trial against IV t-PA. Despite recanalization rates of

Fig. 1. The Solitaire device. (Courtesy of Covidien/ Medtronic Neurovascular Clinical Affairs, Irvine, CA; with permission).

70% and good clinical outcomes (mRs 0–2 at 3 months) of 38% versus 30%, it fell short of demon- strating superiority.22

A hybrid interventional technique based on the concomitant use of a stent retriever advanced in the thrombus and a large-bore catheter advanced at the clot base was soon reported, dubbed SOL- UMBRA (the combination of the 2 brand names Solitaire and Penumbra). This technique was re- ported to yield recanalization rates in the 90% to 95% range.34

Another large-bore catheter, the Sofia (Soft tor-

queable catheter Optimized For Intracranial Access;

Microvention, Tustin, CA), with a unique design of

coil and braid reinforcement (Fig. 5) conferring a

high navigability profile, was reported to show high

effectiveness and ultra-short working times with

both the ADAPT and SOLUMBRA techniques.35,36

The Sofia catheter can be safely advanced into the

intracranial circulation without a guidewire or guid-

ing microcatheter owing to a soft tip and a flexible

construct,36 which permits prompt and highly effec-

tive thrombo-aspiration (Fig. 6), and facilitates com-

bined intervention with a stent retriever (Fig. 7) owing

to large inner diameters (0.056-inch and 0.070-inch,

respectively, for the currently available 5-French and

36,37

TIME METRICS AND PRACTICAL ASPECTS OF INTERVENTIONAL CARE

The Brain Attack Coalition, which comprises more than 15 professional societies under the National Institute of Neurologic Disorders and Stroke with the National Institutes of Health (NIH) has gener- ated treatment benchmarks. In 2011, a 2-hour door to endovascular treatment benchmark was recommended.38,39

The Rapid Reperfusion Registry, which was initi- ated based on those guidelines to evaluate the time performance at 7 stroke centers in the United States and Canada demonstrated in 2012 that in no more than 52% of patients was the 2-hour target door-to-puncture time achieved.40

In 2015, the Society of Neurointerventional Sur- gery (SNIS), which is part of the Brain Attack Coa- lition, suggested a number of time metrics to guide the management of patients at institutions that had been granted comprehensive stroke center sta- tus.41 Guidelines recommended by SNIS include the following times: (1) door-to–CTA interpretation less than 20 minutes, (2) door-to–first femoral puncture less than 60 minutes, and (3) door-to– intracranial recanalization less than 90 minutes.

Successful application of such metrics requires several strategies for the optimization of workflow, including parallel processing, team building,

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Fig. 2. The Trevo stent retriever. (Courtesy of Stryker Neurovascular, Fremont, CA; with permission).

training, and standardization of procedures.42 Adequate training of all team members and main- tenance of skills require constant attention and a proactive approach.43

A high level of efficiency is necessary in triaging patients in emergency rooms,44 prioritizing radio- logical studies and interpretation,45 and expediting the process of preparing patients for interven- tion.46 Procedural consent may be a potential cause for delay; this issue was successfully addressed in some clinical trials with a smart- phone application that allows for obtaining an electronic informed consent (e-consent).47

In the United States, current average times from stroke onset to femoral puncture are 6 hours, and recanalization takes an average additional hour.48 Streamlining and parallel processing of tasks involved in patient preparation for procedures have been shown to significantly reduce door-to- puncture times.49 The simultaneous (not sequential) performance of tasks involved in high-level, time- sensitive processes was shown to be key.41,46 Short femoral puncture-to-recanalization times (<30 minutes) may be achieved in most patients.41

SUMMARY OF CURRENT EVIDENCE AND REMAINING QUESTIONS

Despite potential concerns for relationship with industry concerning several of the positive,

industry-sponsored trials published in 2015 and 2016, management of acute ischemic stroke due to LVO using IV t-PA followed by mechanical thrombectomy was granted Class IA clinical practice guideline status in 2016 (the highest recommendation) in Europe and the United States.50 Class I recommendation is a strong indi- cation with demonstrated high effectiveness, high benefit/risk ratio or high comparative effectiveness, whereas level A designates high-level evidence, usually derived from several well-conducted ran- domized, prospective controlled trials.

At this time, although the recommended window for intervention remains 6 hours from ictus, some centers are extending the time window to 8 hours or longer provided infarct size and collateral status are favorable, and there is a strong demand and a clear understanding of risk on the part of the pa- tient’s family.

Beyond 6 Hours

The DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Pre- senting Strokes Undergoing Neurointervention With Trevo) trial has generated significant interest by suggesting that some patients with ischemic stroke could be treated up to 24 hours after the last time they were seen healthy.51 This trial, also industry sponsored (Trevo stent retriever; Stryker

Fig. 3. The EmboTrap stent retriever. (Courtesy of Neuravi-Codman Neuro, Fremont, CA; with permission).

Fig. 4. The Penumbra aspiration device comes with a negative-pressure electrical pump. (Courtesy of Pen- umbra, Alameda, CA; with permission.)

Neurovascular, Fremont, CA) enrolled 206 patients (107 treated with thrombectomy vs 99 with stan- dard therapy). In the DAWN trial, patients were carefully selected, primarily based on small core infarct volume (less than 51 mL in all patients, and <31 mL for most) measured primarily with DWI-MRI (virtually gold standard) or perfusion CT using a validated, FDA-cleared, automated soft- ware (RAPID; iSchemaView, Menlo Park, CA). Pa- tients were offered thrombectomy only if major mismatch between small infarct volume and severity of neurologic deficit was clearly demon- strated. Intervention resulted in recanalization in 84%, and functional independence was 49% for

Fig. 5. The Sofia (soft torqueable catheter optimized for intracranial access). (Courtesy of Microvention, INC, Tustin, CA; with permission.)

thrombectomy versus 13%. Mortality at 3 months was similar in both groups: 19% versus 18% (thrombectomy vs standard therapy, and symp- tomatic hemorrhage 6% in the thrombectomy group vs 3% in the control group, considered beneath statistical significance).

The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE 3) trial enrolled 182 patients (92 in the thrombectomy group vs 90 in the medical treatment group) within 6 to 16 hours of the time last known to be well, and with evidence of significant residual noninfarcted tissue. Again, infarct size had to be <70 mL, measured either with DWI-MRI or perfusion CT us- ing the RAPID software (iSchemaView). Functional independence was 45% for thrombectomy versus 17% for medical treatment. Ninety-day mortality was 14% in the thrombectomy group versus 26% in the medical treatment group, and symp- tomatic hemorrhage 7% in the thrombectomy group versus 4% in the control group, considered not statistically significant.52

At the time of this review, although the recom- mended time window for intervention based on national guidelines in the United States and Europe remains 6 hours, the results of the DAWN and DEFUSE 3 trials have triggered the easing of guidelines past the 6-hour window in properly selected patients. Adequate identification of can- didates (mainly those with small-core infarcts and highly developed collateral networks) for delayed intervention will likely be a major topic of investigation in years to come (Fig. 8).

Beyond First Order Branches (M1)

Retrospective data analysis from 6 trials, including the Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR), SWIFT, and SWIFT PRIME studies, and 3 large multicenter prospective studies identified 50 patients with M2 occlusions, whose outcomes were similar to those with more proximal occlusions.53 A retro- spective review of 288 patients treated at 10 US in- stitutions by mechanical thrombectomy for M2 occlusions also suggested a reasonable safety profile and similar clinical benefit as for more prox- imal occlusions.54

Retrospective review of data from the IMS-III trial showed benefit of mechanical thrombectomy in patients with M2 trunk occlusion, especially when arterial territory harbors highly eloquent function (ie, language). Benefit was not demon- strated for more distal M2 occlusions.55 Risk/ benefit assessment should be made, as arterial branches distal to the anterior cerebral fissure run untethered in the subarachnoid space,

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Fig. 6. A 45-year-old woman with cardiomyopathy 2 hours after acute aphasia and right hemiparesis (NIHSS 21). CT shows dense left MCA (A, arrow). Large MCA territory at risk on perfusion CT (Tmax map) (B, arrow). Angio- gram shows occluded left M1 MCA (C, arrow). Thromboaspiration with the 6-French Sofia catheter (D, arrow) al- lows total revascularization in 9 minutes. Immediate full clinical recovery. Note that retrieved red thrombus maintains shape of MCA bifurcation (E, arrow).

therefore at higher risk for rupture, whereas clinical benefit from distal branch reperfusion may not be significant.

Posterior Circulation

Although posterior circulation strokes account for only approximately 20% of all ischemic strokes, they account for significant morbidity and fatality. Evidence is currently lacking as to effectiveness and risk of endovascular intervention in this patient group, despite anecdotal reports of success stor- ies. Registries and trials are under way that will hopefully result in evidence-based guidelines.

The Basilar Artery International Cooperation Study (BASICS) is an international registry that was initiated in 2013, and aimed at evaluating endovascular therapy (vs medical management including IV t-PA) in acute basilar artery occlusion treated within 6 hours of stroke onset. The primary outcome measure is mRs less than 3.56

The Acute Basilar artery occlusion: Endovascu- lar interventions versus Standard medical Treat- ment (BEST) trial, currently ongoing, aims at enrolling 344 patients in China, treated within 8 hours of acute basilar artery occlusion with me- chanical thrombectomy versus standard medical treatment. The primary outcome measure is mRs less than 3.57

Low National Institutes of Health Stroke Scale

Patients with a low initial NIH Stroke Scale (NIHSS) and LVO are often able to maintain adequate flow thanks to effective arterial collaterals, which may fail secondarily, leading to severe, irreversible ischemia past the time window for intervention.58 In those patients, especially if there is evidence on perfusion imaging of a large territory at risk, acute intervention may be the appropriate option (Fig. 9), although this group remains to be evaluated in a pro- spective, randomized trial. A recent meta-analysis,

however, identified 5 studies that focused on me- chanical thrombectomy in patients with LVO and mild strokes at presentation (NIHSS 5); these pa- tients had better 90-day functional outcomes than those receiving medical therapy alone.59

Occluded Carotid Artery

In patients with anterior circulation strokes and an acutely occluded carotid artery, intracranial access may require intervention on the carotid artery. Although emergent carotid stenting before intracra- nial access was reported to be an acceptable maneuver,60 valid concern is present for significant hemorrhagic risk in relation to necessary dual-antiplatelet therapy.61 Currently, there is no consensus regarding the management of tandem extracranial carotid occlusions due to

atherosclerotic disease. The disparity in practices is reflected in the subgroup analysis of the ESCAPE trial. Of the 30 intervention-arm subjects, 17 (57%) underwent emergency endovascular extracranial stent-assisted revascularization (10 before and 7 on completion of mechanical thrombectomy). Although the use of antiplatelet agents after acute carotid stenting was variable, no symptomatic intracranial hemorrhage was reported in those receiving emergency stenting.62 Until further data are available, when feasible, angioplasty seems a safer strategy to gain emergent intracranial access.

Stroke from Cervicocephalic Arterial Dissection

Dissections account for up to 20% of strokes in adults 45 years old and younger, and more than

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Fig. 7. A 38-year-old 24 hours after transthoracic mitral valve repair, with acute aphasia and right hemiparesis (NIHSS 18). CT (within 1 hours of onset) shows dense left MCA (A, arrow). Angiographic confirmation of left M1 MCA occlusion (B, arrow). After multiple failed passes with stent retriever alone, stent retriever is deployed across left M1-M2 MCA (C, arrowhead), whereas 5-French Sofia catheter is advanced at thrombus base (C, arrow). Fragmented fibrin-rich clot is retrieved (D), resulting in left MCA recanalization (E, arrow); fibrin-rich thrombi respond generally poorly to thrombectomy. Groin to recanalization 5 65 minutes. MRI at 24 hours shows subcor- tical fluid-attenuated inversion recovery changes with no cortical injury (F, arrow). NIHSS 0 at 72 hours.

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Fig. 8. Example of “futile” revascularization. An 83-year-old woman with acute left hemispheric stroke (NIHSS 22). CTA/CTP (within 45 minutes of onset) shows large hypoperfused left MCA area (A, arrow) and large, match- ing penumbra (B, arrow). Angiogram obtained within 90 minutes of stroke onset shows occluded left M1 MCA stem (C, arrow), and large nonperfused area on late capillary phase (D, arrows), consistent with poor collateral status on CTA. Despite left MCA recanalization (E, arrow) within less than 2 hours of stroke onset, progression to total left MCA territory infarction (F, arrow) from poor collaterals and poor cerebrovascular reserve.

2% of strokes in the general population. Patients with steno-occlusive lesions due to arterial dissec- tions and intracranial thrombus should be treated the same way as patients with atherosclerotic le- sions. The assessment of circle of Willis collaterals following thrombectomy is crucial in assisting de- cision making as to the need for carotid revascu- larization. Again, if carotid artery recanalization is necessary for intracranial access, angioplasty is recommended over stenting for fear of increased hemorrhagic risk from antiplatelet therapy.63

Anesthesia: With or Without?

Conflicting data currently exist as to whether gen- eral anesthesia in thrombectomy procedures may lead to worse outcomes compared with thrombec- tomy with or without intravenous sedation. Early studies suggested poorer outcomes in patients receiving general anesthesia,64–66 whereas others suggested no difference in outcomes between pa- tients who received anesthesia and those who did not,67,68 including the Swedish randomized Seda- tion vs Intubation for Endovascular Stroke TreAt- ment Trial (SIESTA) trial, which, however, reported

a higher incidence of pneumonia and other minor anesthesia-related complications.69

More recently, Campbell and colleagues70 per- formed a meta-analysis of 7 trials including 1764 patients, 871 whom were treated by mechanical thrombectomy out of a large European database (HERMES) in which stent retrievers were used in anterior circulation strokes, and found, after adjusting for possible biases, including baseline prognostic variables, worse outcomes in patients who underwent thrombectomy with general anes- thesia compared with those treated with/without sedation. However, patients who received general anesthesia fared better than those treated with IV thrombolysis only, leading to the recommendation to not withhold anesthesia in those for whom it is considered medically necessary.

Mechanisms by which anesthesia may contribute to worsening of ischemia include hypo- tension at the time of anesthesia induction, delay in treatment, a higher risk of aspiration pneumonia, alterations in CO2 reactivity, and arterial steal from “reverse Robin Hood syndrome.”71

A mechanism dubbed cortical spreading depression (CSD) has so far received little

Fig. 9. A 59-year-old man 3 hours within stroke onset with NIHSS fluctuating between 0 and 3. CT shows dense left M2 MCA (A, arrow). CTA shows occluded proximal left M2 MCA superior division (B, arrow). Angiographic evidence of occluded left M2 MCA (C, arrow) and good collaterals (D, arrow) is present. Prompt recanalization is obtained (groin to recanalization 5 16 minutes) (E, arrow), after retrieval of long red thrombus (F, arrow).

attention, although it is likely responsible for signif- icant early worsening of ischemia in patients with stroke in whom brain energy metabolism is compromised. CSD can induce phenomena referred to as “peri-infarct depolarization” and “anoxic depolarization,” both related to transient local increases of neurotransmitters, that is, gluta- mate and extracellular K1.72 Such depolarization further compromises ischemic tissue not only by exhausting energy, but also by causing active par- adoxic vasoconstriction, referred to as “inverse coupling,” which does further compromise tissue integrity. Experimental evidence of gradual in- crease in hypoperfused brain volumes following each peri-infarct depolarization has been demon- strated.72,73 Interestingly, some sedatives used in anesthesia (ie, ketamine) have been shown to reduce the severity of cortical spreading depolar- izations in patients with stroke.74 One important implication of this phenomenon is potential benefit from neuroprotective drugs such as N-methyl-D- aspartate receptor antagonists, nitric oxide do- nors, or other molecules, some of which could be delivered intra-arterially during interventional procedures.75

SUMMARY

Major advances have been made in recent years in the acute medical and interventional management of ischemic stroke. A shift from “time is brain” to more focused individual physiologic assessment toward acute intervention is currently taking place, which is mainly imaging driven. As a result, increasingly larger numbers of patients with intra- cranial LVO, estimated to represent approximately 10% of ischemic strokes76 will become eligible for acute intervention, likely requiring significant worldwide workforce and public health policy adjustments.

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