Revascularization for Acute Ischemic Stroke

Chapter 34

Revascularization for Acute Ischemic Stroke: Contemporary Perspectives on the Role and Yield of Thrombolytic Therapy and Endovascular Intervention Ayman Al-Salaimeh and Larry B. Goldstein University of Kentucky, Lexington, KY, United States

INTRODUCTION Following heart disease, stroke is the second most common cause of death worldwide [1]. In the United States, 87% of strokes are ischemic, with 13% due to subarachnoid or parenchymal intracerebral hemorrhage (ICH) [2]. In 2010, the incidence of ischemic stroke in the United States was 143 per 100,000, the mortality rate was 19 per 100,000, and there were 295.76 per 100,000 disability-adjusted life years (DALYs) lost [3]. There were reductions in stroke incidence, mortality, and DALYs lost between 1990 and 2010 [3]. The lower stroke incidence and mortality are largely related to improved medical management of cardiovascular risk factors, including the use of antithrombotic medications and statins in addition to better blood pressure management [4]. This, combined with improvements in medical care, contributes to the reduction in stroke-related mortality [4]. Ischemic stroke is caused by an interruption of blood flow to the brain resulting in reduced tissue perfusion, reduced oxygen delivery, and metabolic derangements, with consequent parenchymal necrosis. This may be caused by a wide variety of conditions, including large-artery atherosclerosis, small-vessel disease, cardiogenic embolism, and arterial dissection, among others. Prognosis and treatment depend on stroke subtype and etiology. Large-artery atherosclerotic, cardioembolic, and dissection-related ischemic stroke can result in massive tissue injury that can be lethal or disabling. Large-artery atherosclerotic, cardioembolic, and small vessel-type stroke may be related to an occlusive thrombus. In the following chapter, we discuss the evolution of thrombolytic and endovascular therapies for patients with acute ischemic stroke and their impact on improving poststroke functional outcomes.

EVOLUTION OF THROMBOLYSIS IN STROKE MANAGEMENT With thrombolysis being a well-established treatment for patients with ST-segment elevation myocardial infarction, it was reasonable to test the approach in patients with acute ischemic stroke. The first relevant trial, published in 1963, included 40 patients who were randomized to receive intravenous plasmin or placebo within 72 h of ischemic stroke [5]. Participants who improved following intravenous plasmin infusion had lower levels of plasmin and antiplasmin. Angiographic recanalization was demonstrated in one case.

Streptokinase Streptokinase was the next clinically evaluated thrombolytic drug. The Multicenter Acute Stroke TrialeEurope (MAST-E) was a controlled trial performed in the United Kingdom that enrolled patients with moderate-to-severe stroke [6].

Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00034-X Copyright © 2018 Elsevier Inc. All rights reserved.

493

494 Cardiovascular Thrombus

Participants were randomized to receive either streptokinase or placebo within 6 h of stroke onset, taken as the last time they were known to be symptom free (“last well known”). The trial was stopped because of poor outcomes in the streptokinase group, which had higher rates of symptomatic hemorrhagic conversion, higher 10-day mortality, and no difference in the overall rate of disability or death after 6 months. The second clinical trial of streptokinase for acute ischemic stroke was the Australian Streptokinase (ASK) trial [7]. In the ASK trial, 340 patients with acute ischemic stroke were randomized to receive either streptokinase or placebo. Those who received streptokinase were more likely to develop brain hemorrhages and had poorer outcomes compared with those who received placebo. Participants who were treated with streptokinase within 3 h of symptom onset fared better compared with those treated after 3 h. The use of streptokinase as an approach for thrombolysis in patients with acute ischemic stroke was not pursued based on the results of the MAST-E and the ASK trials.

Recombinant Tissue Plasminogen Activator The European Cooperative Acute Stroke Study (ECASS) was a multicenter randomized controlled trial that compared intravenous alteplase (1.1 mg/kg) with placebo in patients presenting with ischemic stroke within 6 h of the last time they were symptom free. Outcomes included functional recovery, speed of recovery, and 90-day mortality. There were no significant differences between the groups for the primary outcome measures, although the per-protocol population appeared to have benefited from treatment [8]. The National Institute of Neurological Diseases and Stroke (NINDS) recombinant tissue plasminogen activator (rtPA) trial was a randomized controlled trial comparing intravenous alteplase (0.9 mg/kg) with placebo in patients enrolled within 3 h of known symptom onset [9]. Those allocated to alteplase had better outcomes after 3 months compared with those who received placebo, with a 12% absolute difference between the groups. ICH occurred more frequently in the rtPA group, with about 50% of the hemorrhages being fatal [9]. The overall benefit of treatment, however, included these adverse outcomes. The NINDS trial heralded a revolution in the management of patients with acute ischemic stroke, although routine management requires adherence to a strict protocol [9]. ECASS-II followed the NINDS trial. It, too, was a multicenter trial that randomized patients to receive either intravenous rtPA (0.9 mg/kg) or placebo [10]. Randomization was stratified in two time ranges (0e3 and 3e6 h). There was no difference in outcome based on the trial’s primary end point (modified Rankin Score [mRS] 0e1). There was a benefit of treatment with alteplase in a post hoc analysis using an mRS of 0e2 as indicative of a favorable outcome (54.3% of those treated with rtPA had an mRS of 0e2 compared with 46% of patients treated with placebo). Mortality was similar in the two groups by 30 days. There was a higher rate of ICHs among participants treated with intravenous rtPA (8.8% vs. 3.4%). Few participants were treated within 3 h of symptom onset (<100 in each group), and almost half were large strokes that had involvement of up to 33% of middle cerebral artery (MCA) territory [10]. The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study evaluated the efficacy of intravenous rtPA for the management of patients with ischemic stroke up to 6 h from the time of symptom onset. Patients received either intravenous rtPA 0.9 mg/kg or placebo [11]. There was no difference in the frequency of excellent outcomes (defined as an mRS of 0e1) between the two groups after 90 days and no difference in secondary outcomes. Participants randomized to intravenous rtPA had a greater likelihood of developing symptomatic and fatal ICH. The results of ECASS-II and ATLANTIS did not support the use of intravenous rtPA beyond 3 h. A subgroup analysis of patients enrolled within 3 h of symptom onset was consistent with the results of the NINDS trial [12]. The design of ECASS-III was based on an analysis of the previous thrombolysis trials, and it found that intravenous rtPA given between 3 and 4.5 h led to favorable outcomes [13]. The trial excluded patients with severe stroke (i.e., NIH Stroke Scale [NIH-SS] score
25), those over age 80 years, those receiving an anticoagulant regardless of international normalized ratio, and those with a history of both diabetes and previous ischemic stroke. ECASS-III enrolled 812 patients, with the primary outcome being an mRS of 0e1 at 90 days. Secondary outcomes included a Barthel index
95, a Glasgow outcome scale score of 1, an NIH-SS score of 0e1, or a more than 8-point improvement in the NIH-SS. There was benefit of treatment based on the primary and secondary outcomes in both the intention to treat and per protocol analyses. The rate of symptomatic ICH was higher in the rtPA group. Based on the results of ECASS-III, the recommended time window for rtPA administration was increased to 3e4.5 h with exclusion criteria similar to those used in the trial [14]. Table 34.1 summarizes the major intravenous alteplase trials.

Revascularization for Acute Ischemic Stroke: Contemporary Perspectives Chapter | 34

495

TABLE 34.1 Outcomes of Trials of Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke Number of Subjects

MRSb 90 days a

Symptomatic ICHc

Barthel Index a

Mortality a

IVT (%)

Control (%)

IVT (%)

Control (%)

IVT (%)

Control (%)

IVTa (%)

Study

Control

IVT

Control (%)

ECASS-II

143

165

46.1

54.3

45.8

49.9

0.8

8.1

10.3

10.5

NINDS (part 1 þ part 2)

312

309

27.2

17

24.3

33.3

0.64

6.4

21

17

ATLANTIS (all patients)

306

307

38.9

42.3

34.5

37.9

1.1

7

4.4

7

ATLANTIS (0e3 h)

38

23

45.5

61.1

57.9

65.2

0

3

2

4

ECASS-III

403

418

45.4

54.9

59.4

66.1

0.2

2.4

8.4

7.7

a

ATLANTIS, Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; ECASS, European Cooperative Acute Stroke Study; NINDS, National Institute of Neurological Diseases and Stroke. a Intravenous thrombolysis. b Modified Rankin Scale. c Intracerebral hemorrhage.

Cost Effectiveness of Intravenous rtPA The NINDS trial was a landmark study that resulted in US Food and Drug Administration (FDA) approval of intravenous alteplase for the treatment of patients with ischemic stroke within 3 h of symptom onset. The study found that more treated patients were discharged home, had less disability, and had fewer admissions to nursing facilities. This translated to lower costs of care for patients receiving intravenous rtPA related to the initial hospital stay, rehabilitation needs, and need for nursing home admission, and lower total acute and long-term health costs [15]. Other studies also reported lower total cost of care per patient and improved quality-adjusted life years [16,17]. Thrombolytic treatment not only improves clinical outcomes of individual patients, but also reduces the societal economic burden of ischemic stroke.

Efficacy of Intravenous rtPA in the Setting of Large-Vessel Occlusion One study evaluated the recanalization rate following intravenous rtPA in patients who presented with a documented internal carotid artery (ICA) or MCA occlusion or an isolated MCA occlusion [18]. Those who had an isolated MCA occlusion more frequently had recanalization and better clinical outcomes compared with those with ICA occlusions. A subgroup analysis of data from the Interventional Management of Stroke-III (IMS-III) trial evaluated the utility of endovascular treatment compared with intravenous rtPA alone using pre- and posttreatment CT or MR angiography on follow-up imaging after 24 h [19]. Endovascular treatment was associated with higher recanalization rates compared with intravenous rtPA alone. Participants with larger thrombus burden, including those with an ICA occlusion, L occlusion, or T occlusion, had lower recanalization rates compared with those with proximal or distal M1- or M2-segment occlusions. A meta-analysis that evaluated imaging markers of recanalization following intravenous rtPA found that patients with isolated ICA occlusions or tandem ICA/MCA occlusions had worse functional outcome compared with those with an MCA occlusion alone [20]. These studies suggest poorer recanalization rates and poorer outcomes with intravenous rtPA in patients with larger amounts of thrombus associated with more proximal occlusions.

ENDOVASCULAR MANAGEMENT OF ACUTE ISCHEMIC STROKE (TABLE 34.2) Intraarterial Thrombolysis Intraarterial administration of thrombolytic drugs allows lower systemic and higher local levels of the drug at the site of a thrombus. An initial case series reported on intraarterial administration of urokinase in five patients with an angiographically confirmed arterial occlusion [21]. There was complete or partial recanalization on follow-up angiography.

496 Cardiovascular Thrombus

TABLE 34.2 Outcomes of Trials of Endovascular Therapy for Acute Ischemic Stroke Number of Patients

TICIb (2b/3)

Symptomatic ICHd

MRSc (0e2) a

a

Mortality a

EVT (%)

Control (%)

EVT (%)

Control (%)

EVT (%)

Control (%)

EVTa (%)

Trial

Control

EVT

Control (%)

MR CLEAN

233

267

N/A

59

19.1

32.6

6.4

7.7

22

21

ESCAPE

150

165

31.2

72.4

29.3

53

2.7

3.6

19

10.4

EXTENDIA

35

35

34

89

40

71

0

6

20

9

SWIFT-PRIME

98

98

40

83

35

60

3

0

12

9

REVASCAT

103

103

N/A

65.7

28.2

43

1.9

1.9

16

19

THRACE

192

185

N/A

N/A

42

53

2

2

13

12

28

30

N/A

87

35

57

0

0

14.2

16.6

PISTE

a

ESCAPE, Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; SWIFT-PRIME, SOLITAIRE With the Intention for Thrombectomy as Primary Endovascular Treatment; EXTEND-IA, Extending the Time for Thrombolysis in Emergency Neurological DeficitsdIntra-Arterial: PISTE, the Pragmatic Ischaemic Stroke Thrombectomy Evaluation; THRACE, Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke; REVASCAT, the Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset: the Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset. a Endovascular therapy. b Thrombolysis in cerebral infarction. c Modified Rankin Scale. d Intracerebral hemorrhage.

The Prolyse in Acute Cerebral Thromboembolism (PROACT) trial was a phase II study evaluating the safety of intraarterial recombinant pro-urokinase (rpro-UK) in the management of patients with acute ischemic stroke. Participants with documented M1- or M2-segment occlusions received either intraarterial rpro-UK plus intravenous heparin or placebo plus intravenous heparin. The primary outcome was achieving recanalization within 120 min of the infusion, with the development of symptomatic hemorrhagic transformation being the primary safety outcome. Patients who received rpro-UK had a greater chance of achieving partial or complete recanalization at 2 h compared with placebo (57.7% vs. 14.3%, P ¼ .017). There was a higher incidence of hemorrhagic infarctions and parenchymal hemorrhages with rpro-UK. By 90 days after randomization, there was a trend toward better functional outcomes and lower mortality with intraarterial therapy [22]. PROACT was followed by Prolyse in Acute Cerebral Thromboembolism II (PROACT-II). This randomized controlled trial included patients with angiographically confirmed MCA occlusions. The patients were again randomized to receive either intraarterial rpro-UK plus heparin or heparin alone [23]. The primary outcome was clinical efficacy based on the NIH-SS, Barthel index, and mRS. After 90 days, 40% of patients treated with rpro-UK had an mRS  2 compared with 25% of the control group (P ¼ .04). This corresponded to an absolute difference of 15% with a number needed to treat of 7. The frequency of achieving a Barthel index
90 assessed at 5 and 7 days following treatment was higher in the rpro-UK group compared with the control group (22% vs. 10%, P ¼ .04), but there was no difference after 90 days. Symptomatic hemorrhages were more frequent in the rpro-UK group and occurred in patients with NIH-SS scores
11. Those treated with rpro-UK had higher recanalization rates (partial or complete) compared with controls. The rates of hemorrhagic transformation were higher in the PROACT-II trial compared with the NINDS rtPA, ATLANTIS, and ECASS trials. This was attributed to the higher proportion of severe strokes in the PROACT-II trial; however, the trials also differed in the thrombolytic drug (rpro-UK vs. rtPA), route of administration, and concomitant treatment with heparin.

Combined Intravenous/Intraarterial Thrombolysis The Emergency Management of Stroke Study (EMS) was a randomized trial designed to evaluate the efficacy of combined treatment with intravenous and intraarterial rtPA compared with intraarterial rtPA alone. All patients were evaluated with angiography following the intravenous infusion; intraarterial rtPA was administered if a thrombus was visualized. The median treatment time was 5.5 h after symptom onset. There was a higher recanalization rate with combination therapy,

Revascularization for Acute Ischemic Stroke: Contemporary Perspectives Chapter | 34

497

with complete recanalization in 54% of treated participants compared with 10% in the intraarterial-only group. A higher NIH-SS score on presentation predicted a greater chance of a thrombus demonstrated on angiography. There was no difference in clinical outcomes or the rate of hemorrhagic complications between the two groups. The mortality rate tended to be higher in the combined group compared with intraarterial rtPA alone (29% vs. 5.5%, P ¼ .06) [24]. The IMS-I trial evaluated earlier administration of intraarterial rtPA compared with the EMS trial (within 3 h of symptom onset); 80 patients received intravenous rtPA, of whom 62 were also treated with intraarterial rtPA [25]. Combined treatment resulted in a higher rate of recanalization compared with the NINDS intravenous rtPA trial placebo arm, with efficacy and safety comparable to those of intravenous rtPA treatment. Participants who received combined treatment had a higher rate of asymptomatic hemorrhagic infarction after 36 h compared with the NINDS trial placebo and rtPA groups. The frequencies of asymptomatic hemorrhage (43% vs. 5.7% vs. 6%, P < .0001) and symptomatic ICH (6.3% vs. 1%, P ¼ .018) were higher compared with the NINDS placebo group, but the rates of adverse outcomes were similar, with intravenous rtPA and combined treatment (6.7 vs. 6.3%, P ¼ .91). Mortality rates after 3 month were similar. The IMS-II study evaluated a new microcatheter delivery system [26]. Similar to IMS-I, intravenous rtPA alone was administered to 26 participants, and 55 received combined intravenous and intraarterial treatment. Those in the combination group were further randomized to a standard microcatheter and the new system. The mortality rate at 3 months, symptomatic and asymptomatic ICH, and serious bleeding were higher in the combination groups in both IMS-I and IMS-II compared with the NINDS rtPA and placebo groups. Outcomes were better in the combination group in comparison with the NINDS placebo group (including mRS, NIH-SS, and Barthel index). As in the IMS-I trial, there was no difference in efficacy compared with the NINDS intravenous rtPA group. Recanalization rates were higher with the new system compared with the standard microcatheter used in the IMS-I trial. Combined data from IMS-I and IMS-II were consistent with the previous results of revascularization success and favorable outcomes [27].

Rationale for Thrombectomy and Thrombectomy Devices Following PROACT-II, another modality of recanalization was needed. Intraarterial thrombolysis in PROACT-II required a continuous infusion of intraarterial rpro-UK over 2 h, delaying recanalization. Several devices were subsequently introduced with the goal of more rapidly achieving recanalization. The following discussion will describe these different devices and their modes of action (Fig. 34.1).

Clot Retrieval Devices The first of the clot retrieval devices studied after PROACT-II was the MERCI device. This consists of a spiral coil attached to the end of a microcatheter. The helical structure integrates with the clot and then the clot can be removed. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial was a safety study that enrolled 30 patients who presented more than 3 h after last well known or had a contraindication for treatment with intravenous rtPA within the 3 h window. Successful recanalization was achieved in 43% with the use of the MERCI retriever alone and increased to 64% when used in conjunction with intraarterial rtPA. The mortality rate approached 36% and was attributed to the disease state rather than the device [28]. Following the results of MERCI-I, the US FDA approved the use of the MERCI retriever as a tool for removal of a clot from a brain blood vessel, but not as a treatment for stroke. The Multinational Controlled Registry to Evaluate the Concentric MERCI Retriever System (Multi-MERCI) trial followed the MERCI safety study. Multi-MERCI used a modified retriever device. Patients were enrolled within 8 h of onset of symptoms and were treated with intravenous recombinant tissue plasminogen activator (rTPA) if eligible, and all had conventional angiography. The recanalization was successful in 55% of cases, with the newer device achieving higher recanalization rates compared with the older one. Participants with persistent occlusion could receive intraarterial rtPA, which achieved up to a 68% rate of recanalization. Device-related side effects occurred in 2.4% [29]. An mRS of 0e2 at 90 days was achieved in 36% of participants and 24-h NIH-SS scores improved in 36% (improvement by 8 or more points or a score of 0) [29]. The trial showed the importance of successful recanalization, with 49% who achieved revascularization having an mRS 0e2 at 90 days compared with 9.4% of those with a persistent occlusion [29].

Stent Retrievers The SOLITAIRE stent retriever was first evaluated in six patients with acute ischemic stroke due to large-vessel occlusion (LVO), all of whom achieved recanalization within 60 min [30]. A second report on 26 patients demonstrated a high rate of

498 Cardiovascular Thrombus

FIGURE 34.1 Evolution of endovascular techniques for acute ischemic stroke and clinical trials. IMS, Interventional Management of Stroke; MERCI, Mechanical Embolus Removal in Cerebral Ischemia; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; PROACT, Prolyse in Acute Cerebral Thromboembolism; SWIFT, SOLITAIRE With the Intention for Thrombectomy; TREVO, Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke. Modified from Pierot L, Soize S, Benaissa A, Wakhloo AK. Techniques for endovascular treatment of acute ischemic stroke; from intra-arterial fibrinolytics to stent-retrievers. Stroke 2015;46:909e14.

recanalization and good clinical outcomes [31]. A retrospective multicenter study of patients with ischemic stroke and LVO treated with the SOLITAIRE device had similar positive results [32]. The SOLITAIRE FR With the Intention for Thrombectomy (SWIFT) trial was performed following these positive reports and compared the SOLITAIRE device with the MERCI retrieval system. The SOLITAIRE stent retriever achieved higher recanalization rates, better outcomes, and lower mortality rates compared with the MERCI device [33]. Following the SWIFT trial, the US FDA approved the use of the SOLITAIRE stent retriever for endovascular therapy of ischemic stroke. The TREVO device is another stent retrieval system. It was first evaluated in a study that included 60 subjects with severe ischemic stroke associated with LVO, all of whom were treated with TREVO device [34]. Based on promising results, a randomized trial was then conducted comparing the TREVO and MERCI devices, which demonstrated higher recanalization rates, more patients having good clinical outcomes, and comparable safety with the use of the TREVO versus the MERCI device [35]. The results suggested that the utility of the TREVO device for the management of patients with severe ischemic stroke was similar to that of the SOLITAIRE device. Following the report of the Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO-II) trial, the TREVO device gained US FDA approval.

Aspiration Thrombectomy The PENUMBRA system is an aspiration thrombectomy device that was first studied in 20 subjects with severe ischemic stroke due to an LVO [36]. All treated patients had complete recanalization, with good clinical outcomes achieved in 45%. Mortality was 45% after 30 days, a rate lower than expected based on the severity of the strokes. A European study evaluated the safety and efficacy of the PENUMBRA system [37]. The initial Post Market Experience of the Penumbra System (POST trial) was a postmarketing study that supported the safety and efficacy of the PENUMBRA system (Fig. 34.2) [38].

Revascularization for Acute Ischemic Stroke: Contemporary Perspectives Chapter | 34

(A)

(B)

(C)

499

(D)

FIGURE 34.2 Combined Stentriever plus aspiration thrombectomy. (A) Baseline angiogram, anteroposterior view, left ICA injection, MCA occlusion (white arrow). (B) Combined left ICA and microcatheter injection shows the extent of the thrombus within the left MCA (dotted black lines). Black arrow, tip of the microcatheter within an M2 branch of the MCA. (C) SOLITAIRE FR stent retriever is deployed within the M1 MCA segment. Black arrow, distal tip of the reperfusion catheter. (D) Final angiogram after successful thrombectomy shows robust filling of the left MCA branches except for some distal superior trunk vessels (final recanalization grade is TICI 2b). ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; TICI, thrombolysis in cerebral infarction. Modified from Mokin M, Setlur Nagesh SV, Ionita CN, Levy EI, Siddiqui AH. Comparison of modern stroke thrombectomy approaches using an in vitro cerebrovascular occlusion model. AJNR 2015;36:547e51.

REPERFUSION SCALES Recanalization and reperfusion are sometimes incorrectly used interchangeably. Achieved reperfusion is better correlated with clinical and tissue outcomes [39]. Reperfusion is defined as anterograde flow with establishment of a capillary blush [39]. Several methods are commonly used to assess postthrombectomy reperfusion. The thrombolysis in myocardial infarction (TIMI) scale was adopted from the scale used to assess the efficacy of reperfusion therapies in patients with myocardial infarction. TIMI describes flow through the MCA-supplied territories, but does not assess tissue reperfusion [39]. There are four grades: 0, absent antegrade flow; 1, any faint antegrade flow beyond target occlusion with incomplete distal filling; 2, sluggish or delayed flow with filling of the distal M2 branches; and 3, normal flow filling the M3 and M4 branches. The thrombolysis in cerebral infarction (TICI) scale is among the most commonly described stroke recanalization scoring systems. The scale demonstrated better interrater reliability compared with the TIMI scoring system [39]. The original TICI scale was later modified and was easier to use and correlated better with clinical outcomes. The modified TICI score has five categories: 0, no recanalization; 1, minimal reperfusion with failure to opacify the arterial bed beyond the occlusion site for the angiographic run; 2a, partial perfusion of vascular territory is visualized (with up to 2/3 of the arterial territory in TICI and <50% in modified TICI); 2b, partial perfusion of the vascular territory is visualized, complete with slow flow and clearance of the contrast material or >50% of the arterial territory is visualized; and 3, complete perfusion. Recanalization scales include the arterial occlusive lesion (AOL) score. This was first described in the IMS-I pilot study and was reported in the IMS-III trial. It focuses on the original occlusion site. Analysis of the IMS trial revealed a modest association between the TIMI score and the AOL score. The AOL score categories are 0, no recanalization of the arterial occlusion; 1, complete or partial recanalization with no distal flow; 2, incomplete or partial recanalization of the AOL with any distal flow; and 3, complete recanalization with any distal flow. Both the AOL and the modified TICI scores predicted clinical outcome (61% for AOL 2e3 and 71% for modified TICI 2a  3, P ¼ .9). Several limitations of the AOL scale have been discussed [39]. Recanalization of a proximal occlusion does not assess the more distal circulation. An occlusion that has extensive involvement of distant branches such as a T occlusion involving up to M2 branches is difficult to evaluate with this scale. Partial recanalization categorized with the AOL scale does not differentiate between partial recanalization and underlying stenosis or vasospasm.

500 Cardiovascular Thrombus

MECHANICAL THROMBECTOMY EFFICACY TRIALS The IMS-III was a randomized controlled trial comparing standard-dose intravenous rtPA with intravenous rtPA followed by endovascular treatment. The endovascular therapy was based on interventionalist preference and included the EKOS microcatheter system and the MERCI, SOLITAIRE FR, and PENUMBRA devices [40]. Endovascular treatment needed to be performed within 5.5 h and completed by 7 h after symptom onset. The trial enrolled 656 patients, with no difference in efficacy based on the NIH-SS score or achieving an mRS 0e2 after 3 month. Computed tomographic (CT) angiography was performed in almost 25% of patients 24 h postintervention and showed higher recanalization rates in the endovascular compared with the intravenous rtPA-alone group, regardless of the occluded vessel (ICA, M1, or M2 occlusion). The timing of revascularization and achieving higher revascularization rates predicted better outcomes. An Alberta Stroke Program Early CT Score (ASPECTS) of 8e10 predicted both higher recanalization rates, regardless of treatment modality, and better clinical outcomes after 90 days [41]. Higher pretreatment collateral circulation predicted better ASPECTS, better clinical outcome, and a higher likelihood of recanalization compared with patients with poor collaterals [42]. Patients with T occlusions and tandem ICA/MCA occlusions had higher recanalization rates and better clinical outcomes with endovascular therapy [19]. In the Intra-arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) Expansion trial, patients were randomized to receive either intravenous rtPA or endovascular treatment [43]. Endovascular treatment was based on interventionalist preference and could include pharmacological and/or mechanical thrombolysis. Although there was a higher recanalization rate with endovascular therapy, it was not superior to intravenous rtPA alone. Evidence of occlusion was not required prior to randomization. Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) was a phase IIb multicenter randomized controlled open-label trial with blinded outcome assessments in which patients were randomized to receive either intravenous rtPA alone or endovascular therapy with or without intravenous rtPA [44]. Endovascular treatment was performed with the MERCI device or the PENUMBRA system. All participants were evaluated with multimodal CT scan or MRI of the brain to define the penumbral area. There was no difference between the embolectomy and the standard treatment groups in clinical outcome, regardless of the penumbral pattern. There was a difference in final infarct volumes between the penumbral and the nonpenumbral groups, with smaller final infarct volumes in the penumbral group. Participants who had successful recanalization were more likely to have a better clinical outcome after 90 days. None of these showed a benefit of endovascular treatment compared with standard care. Several critical issues regarding these three trials were raised, including the enrollment of patients with mild deficits, a lack of angiographic confirmation of occlusion prior to enrollment in the IMS-III and SYNTHESIS Expansion trials, and, in MR RESCUE, a long delay to endovascular treatment. Newer stent retrievers were used infrequently [45]. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a phase III randomized controlled trial evaluating the utility of mechanical thrombectomy and intraarterial treatment in the management of patients with an LVO [46]. Participants were randomized to receive either intravenous rtPA alone or combination intravenous rtPA with endovascular treatment. The interventionalist could choose the type of intraarterial treatment and could include mechanical and pharmacological treatment. Enrolled participants had to have a definite arterial occlusion detected with CT angiography, MR angiography, or catheter angiography. The occlusions had to involve the anterior circulation. Some patients were also evaluated with CT perfusion. Participants in the interventional arm had better functional outcome, with a higher percentage of patients achieving independency (mRS 0e1, 11.6% vs. 6%; 0e2, 32.6% vs. 19.1%; and 0e3, 51.1% vs. 35.6%), lower NIH-SS score on discharge, and higher recanalization rates (75.4% vs. 34%). Subgroup analyses showed that patients older than age 80 years responded well with interventional treatment. Those with an ASPECTS
8 had better results than those with a lower ASPECTS. Those treated without general anesthesia had better clinical outcomes (odds ratio 2.1, 95% CI 1.02e4.31), although this was not significant after adjusting for risk factors (odds ratio 1.9, 95% CI 0.89e4.24) [47]. Benefits were greater in patients with smaller ischemic core on CT perfusion [48] and in those with good collaterals on CT angiography [49]. Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) was a randomized controlled trial of endovascular treatment with standard care compared with standard care alone [50]. Participants were functionally independent prior to the stroke, had a small infarct core defined as ASPECTS 6e10, and moderate-to-good collaterals on CT angiography. Participants treated with endovascular therapy more frequently achieved an mRS 0e2 at 90 days (53% compared with 29.3% in the control group, P < .0001). The intervention group had higher recanalization rates (72.4% vs. 31.2%), better Barthel index scores (95e100; 57.2% vs. 33.6%), and lower NIH-SS scores after 90 days.

Revascularization for Acute Ischemic Stroke: Contemporary Perspectives Chapter | 34

501

SOLITAIRE With the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT-PRIME) was a multicenter randomized trial comparing intravenous rtPA with intravenous rtPA with endovascular therapy using the SOLITAIRE stent retriever [51]. Participants were selected to receive intravenous rtPA within 4.5 h of symptoms onset and endovascular therapy within 6 h from symptom onset. They had to have an LVO detected by CT or MR angiography and needed to have a small infarct core as measured with CT perfusion. After 71 subjects were enrolled, CT perfusion criteria were modified to identify those with a small-to-moderate core volume. The study demonstrated the superiority of interventional treatment in achieving better functional outcomes after 90 days (60% vs. 35%, P < .001), lower NIH-SS scores after 24 h, and higher successful reperfusion rates (83% vs. 40%, P < .001). An analysis of three studies of patients with isolated M2 occlusions, including SWIFT-PRIME, did not find better outcomes compared with intravenous rtPA alone [52]. Analysis of the cost effectiveness of the thrombectomy cases in SWIFT-PRIME found improved quality-adjusted life years in the intervention group (6.79 vs. 5.05 QUALYs). There was an initially higher cost of care with endovascular therapy but the cost of care between discharge and 90 days was lower in the intervention group ($4909 total savings per patient) [53]. Extending the Time for Thrombolysis in Emergency Neurological DeficitseIntra-arterial (EXTEND-IA) was a multicenter randomized, open-label, blinded end-point evaluation trial in which participants were randomized to receive either intravenous rtPA alone within 4.5 h of symptom onset or intravenous rtPA with endovascular therapy using the SOLITAIRE flow restoration device within 8 h of symptoms onset [54]. All patients had CT perfusion to identify those with potentially salvageable tissue. There were no baseline differences in clinical features, CT perfusion deficits, or occluded vessels on angiography between the groups, although those treated with intravenous rtPA alone tended to have lower NIH-SS scores. Participants enrolled in the endovascular arm had higher revascularization rates (89% vs. 34%, P < .001) and a higher proportion achieved functional independence at 90 days (71% vs. 40%, P ¼ .01). EXTEND-IA suggested that perfusion imaging might be helpful for selecting patients for endovascular treatment, although there was no comparison with patients selected based on other clinical or imaging criteria without CT perfusion. Randomized Trial of Revascularization with SOLITAIRE FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) was a randomized controlled open-label trial with blinded end-point evaluation. It included patients with an LVO within the anterior circulation using CT angiography who had an ASPECTS
6 [55]. Participants were randomized to receive standard care or standard care plus endovascular therapy using the SOLITAIRE flow restoration stent retriever. A total of 206 patients were randomized, with no difference in baseline clinical characteristics, patterns of intracranial and extracranial occlusions, or ASPECTS. Intravenous rtPA was administered to 68% of those in the endovascular group compared with 77% in the control group. Participants treated with endovascular therapy more frequently had higher functional independence after 90 days as reflected in an mRS score 0e2 (43.7% vs. 28.2) and Barthel index of 95e100 (57.3% vs. 26.4). There was a lower final infarct volume in the endovascular group (median interquartile range [IQR] 16.3 mL) compared with the control group (median IQR 38.6 mL, P ¼ .02). Of patients treated with endovascular therapy, 65.7% achieved a reperfusion score of TICI 2b or TICI 3. The safety of endovascular treatment was comparable to medical treatment alone with no difference in symptomatic ICH, neurological complications, or mortality. Procedure-related complications occurred in up to 10.7% of endovascular patients (groin hematoma, arterial dissection, vasospasm requiring treatment, and arterial perforation occurred in 3.9%e4.9% of patients). During the same study period, 540 patients were treated with endovascular therapy, with 103 of these enrolled in the REVASCAT trial (97 were apparently eligible for REVASCAT but were not enrolled because of age or pattern of arterial occlusion exclusions). There was no difference in functional outcome at 3 months between patients treated in compared with outside REVASCAT. Of patients who were treated beyond 8 h, 50% had an mRS of 0e2 after 90 days. The results of this analysis suggested that endovascular therapy might be useful in patients with LVO and evidence of salvageable tissue even if not meeting the criteria of enrollment in the clinical trials [56]. Guidelines for ischemic stroke care changed based on the results of these trials. A pooled analysis of five trials supported an increase in the rate of functional independence after 3 months with shorter intervals from symptom onset to time of reperfusion. For those in whom reperfusion occurred within 180 min, 64% achieved functional independence; if time to reperfusion increased to 480 min, the rate of function independence dropped to 46%. Each hour of delay led to a reduction in functional independence [57]. Another pooled analysis of these five trials found an overall improvement in qualityadjusted life years along with lower costs of care with endovascular therapy [58,59], although cost effectiveness in patients with a baseline ASPECTS 5 and in those who had an M2 occlusion on CT angiography remained unclear [59]. Table 34.2 summarizes the clinical outcomes of endovascular treatment trials.

502 Cardiovascular Thrombus

TIME-BASED VERSUS TISSUE-BASED APPROACHES FOR PATIENT SELECTION Recommendations for intravenous rtPA administration as of this writing limit treatment to 4.5 h from the time the patient was last known to be normal. Several studies evaluated the utility of imaging to select patients who might benefit from treatment when the time of onset is unknown. These include the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) [60] and a Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients (MR WITNESS) (ClinicalTrials.gov: NCT01282242). The latter study was presented at the International Stroke Conference 2016 and found that intravenous rtPA may be safe in patients who awaken with stroke symptoms based on MRI criteria. An ongoing study in Europe titled Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) is designed to evaluate the safety and efficacy of intravenous rtPA in patients with unknown time of stroke onset based on MRI criteria (ClinicalTrials.gov: NCT01525290). At this writing, guidelines recommend endovascular therapy up to 6 h from last well known, although accumulating data suggest patients may be selected using MRI criteria. The Diffusion Weighted Imaging Evaluation for Understanding Stroke Evolution Study (DEFUSE-2) evaluated the use of MRI to identify diffusioneperfusion mismatch in patients with ischemic stroke and LVO within 12 h from the last well known [61]. There was a favorable outcome in treated patients with a target mismatch. A retrospective study suggested the safety of endovascular therapy in patients treated beyond 8 h selected using CT perfusion and MRI of the brain [62]. The pooled analysis of the five trials mentioned earlier suggested clinical benefits with treatment up to 7.3 h from last well known [62]. Several trials are in progress as of this writing evaluating the benefit of treating patients with endovascular therapy beyond 6 h. Of these, Diffusion Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention (DAWN) and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE-3) aim to identify patients with potentially salvageable tissue at risk using computed tomography, CT angiography, and CT perfusion or MRI-based studies. Enrollment is between 6 and 34 h from last known well in the DAWN trial and between 6 and 16 h in the DEFUSE-3 trial. The DAWN trial was presented as an abstract at the European Stroke Conference. Patients treated with thrombectomy between 6 and 24 h from stroke onset achieved higher functional independence after 90 days, with a 35% increase in the proportion of patients achieving mRS 0e2 (corresponds to a number needed to treat of 2.8). The clinical benefit was maintained for up to 24 h from onset of symptoms. At the time of writing this chapter, the DEFUSE-3 trial was stopped. Imaging may prove useful in patient selection for those without known time of stroke.

GUIDELINES FOR THROMBOLYSIS AND ENDOVASCULAR THERAPY As of this writing, the guidelines for management of acute ischemic stroke had been last updated in 2015. There was no change in alteplase administration compared with the previous guidelines, but there were revisions to reflect data on endovascular therapy. Criteria for endovascular management include patients with LVO, 18 years of age or older with a prestroke mRS of 0e1, NIH-SS of 6 or more, and ASPECTS of 6 or more [63]. The guidelines for endovascular therapy are strict and can exclude many patients who might benefit from this treatment. Few patients enrolled in the studies were of age
80 years. A study evaluated the recanalization rate and clinical outcomes in elderly patients, including patients more than 80 years of age. The study found no difference in recanalization rates and good outcomes between patients
80 and <80 years of age [64]. Current guidelines recommend the use of stent retrievers for LVO. The Contact Aspiration Versus Stent Retriever for Successful Revascularization (CASTER) trial evaluated the use of contact aspiration as a model of mechanical thrombectomy and found no difference in recanalization rates [65].

FUTURE PERSPECTIVES There remain several issues to be addressed in the use of thrombolysis and endovascular therapy in patients with largevessel-type ischemic stroke. The best approach for patients with mild neurological deficits and LVO is not clear. Whether patients with presumed LVO should bypass local primary stroke center hospitals and be transported directly to a comprehensive strokes center has not been determined. The use of glycoprotein IIb/IIIa inhibitors as adjunctive therapy for recanalization has not been evaluated. Although thrombectomy is used for the management of basilar occlusion, supportive data from randomized trials are lacking. Previous trials that evaluated the safety and efficacy of endovascular treatment enrolled patients with anterior circulation ischemic strokes, with few having basilar occlusions. Despite all that has been done to evaluate treatment strategies for patients with LVO-related stroke, much work remains.

Revascularization for Acute Ischemic Stroke: Contemporary Perspectives Chapter | 34

503

REFERENCES [1] Lozano R. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet December 15, 2012;380(9859):2095e128. [2] Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statisticsd2017 update: a report from the American Heart Association. Circulation 2017;135:e146e603. [3] Krishnamurthi RV. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990e2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health November 2013;1(5):e259e81. [4] Lackland DT, Roccella EJ, Deutsch AF, et al. Factors influencing the decline in stroke mortality: a statement from the American Heart Association/ American Stroke Association. Stroke 2014;45:315e53. [5] Meyer JS. Therapeutic thrombolysis in cerebral thromboembolism. Double-blind evaluation of intravenous plasmin therapy in carotid and middle cerebral artery occlusion. Neurology November 1963;13:927e37. [6] Multicenter Acute Stroke Trial-Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. New Engl J Med July 18, 1996;335(3):145e50. [7] Donnan GA. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. J Am Med Assoc September 25, 1996;276(12):961e6. [8] Hacke W. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). J Am Med Assoc October 4, 1995;274(13):1017e25. [9] The National Institute of Neurological Disorders, Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New Engl J Med 1995;333:1581e8. [10] Hacke W. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet October 17, 1998;352(9136):1245e51. [11] Clark WM. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. J Am Med Assoc December 1, 1999;282(21):2019e26. [12] Albers GW. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. Stroke February 2002;33(2):493e5. [13] Hacke W. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. New Engl J Med September 25, 2008;359(13):1317e29. [14] del Zoppo GJ, Saver JL, Jauch EC, Adams HP. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. Stroke 2009;40:2945e8. [15] Fagan SC. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology April 1998;50(4):883e90. [16] Sinclair SE. Cost-utility analysis of tissue plasminogen activator therapy for acute ischaemic stroke: a Canadian healthcare perspective. Pharmacoeconomics 2001;19(9):927e36. [17] Sandercock P. Cost-effectiveness of thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke assessed by a model based on UK NHS costs. Stroke June 2004;35(6):1490e7. [18] Linfante I. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke August 2002;33(8):2066e71. [19] Demchuk AM. Recanalization and clinical outcome of occlusion sites at baseline CT angiography in the interventional management of stroke III trial. Radiology October 2014;273(1):202e10. [20] Nogueira RC. Meta-analysis of vascular imaging features to predict outcome following intravenous rtPA for acute ischemic stroke. Front Neurol May 18, 2016;7:77. [21] Casto L. Local intraarterial thrombolysis for acute stroke in the carotid artery territories. Acta Neurol Scand September 1992;86(3):308e11. [22] del Zoppo GJ. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke January 1998;29(1):4e11. [23] Furlan A. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. J Am Med Assoc December 1, 1999;282(21):2003e11. [24] Lewandowski CA. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) bridging trial. Stroke December 1999;30(12):2598e605. [25] IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the interventional management of stroke study. Stroke April 2004;35(4):904e11. [26] IMS II Trial Investigators. The interventional management of stroke (IMS) II Study. Stroke July 2007;38(7):2127e35. [27] Tomsick T. Revascularization results in the interventional management of stroke II trial. Am J Neuroradiol March 2008;29(3):582e7. [28] Gobin YP. MERCI 1: a phase 1 study of mechanical embolus removal in cerebral ischemia. Stroke December 2004;35(12):2848e54. [29] Smith WS. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke April 2008;39(4):1205e12. [30] Cohen JE. Preliminary experience with the use of self-expanding stent as a thrombectomy device in ischemic stroke. Neurol Res March 2011;33(2):214e9. [31] Miteff F. Mechanical thrombectomy with a self-expanding retrievable intracranial stent (Solitaire AB): experience in 26 patients with acute cerebral artery occlusion. Am J Neuroradiol JuneeJuly 2011;32(6):1078e81. [32] Dávalos A. Retrospective multicenter study of Solitaire FR for revascularization in the treatment of acute ischemic stroke. Stroke October 2012;43(10):2699e705.

504 Cardiovascular Thrombus

[33] Saver JL. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet October 6, 2012;380(9849):1241e9. [34] San Román L. Single-center experience of cerebral artery thrombectomy using the TREVO device in 60 patients with acute ischemic stroke. Stroke June 2012;43(6):1657e9. [35] Nogueira RG. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet October 6, 2012;380(9849):1231e40. [36] Bose A. The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. Am J Neuroradiol August 2008;29(7):1409e13. [37] Grunwald IQ. Revascularization in acute ischaemic stroke using the penumbra system: the first single center experience. Eur J Neurol November 2009;16(11):1210e6. [38] Tarr R. The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe. J Neurointerv Surg December 2010;2(4):341e4. [39] Zaidat OO. Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement. Stroke September 2013;44(9):2650e63. [40] Broderick JP. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. New Engl J Med March 7, 2013;368(10):893e903. [41] Hill MD. Alberta Stroke Program early computed tomography score to select patients for endovascular treatment: interventional management of stroke (IMS)-III trial. Stroke February 2014;45(2):444e9. [42] Liebeskind DS. Collaterals at angiography and outcomes in the interventional management of stroke (IMS) III trial. Stroke March 2014;45(3):759e64. [43] Ciccone A. Endovascular treatment for acute ischemic stroke. New Engl J Med 2013;368:904e13. [44] Kidwell CS. A trial of imaging selection and endovascular treatment for ischemic stroke. New Engl J Med March 7, 2013;368(10):914e23. [45] Qureshi AI. Endovascular treatment for acute ischemic stroke patients: implications and interpretation of IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials: a report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol May 2014;7(1):56e75. [46] Berkhemer OA. A randomized trial of intraarterial treatment for acute ischemic stroke. New Engl J Med January 1, 2015;372(1):11e20. [47] van den Berg LA, Koelman DL, Berkhemer OA, et al. Type of anesthesia and differences in clinical outcome after intra-arterial treatment for ischemic stroke. Stroke May 2015;46(5):1257e62. [48] Borst J. Value of computed tomographic perfusion-based patient selection for intra-arterial acute ischemic stroke treatment. Stroke December 2015;46(12):3375e82. [49] Berkhemer OA, Jansen IG, Beumer D, et al. Collateral status on baseline computed tomographic angiography and intra-arterial treatment effect in patients with proximal anterior circulation stroke. Stroke March 2016;47(3):768e76. [50] Goyal M. Randomized assessment of rapid endovascular treatment of ischemic stroke. New Engl J Med March 12, 2015;372(11):1019e30. [51] Saver JL. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. New Engl J Med June 11, 2015;372(24):2285e95. [52] Coutinho JM. Mechanical thrombectomy for isolated M2 occlusions: a post hoc analysis of the STAR, SWIFT, and SWIFT PRIME studies. Am J Neuroradiol April 2016;37(4):667e72. [53] Shireman TI, Wang K, Saver JL, Goyal M, et al. Cost-effectiveness of Solitaire stent retriever thrombectomy for acute ischemic stroke: results from the SWIFT-PRIME trial (Solitaire with the intention for thrombectomy as primary endovascular treatment for acute ischemic stroke). Stroke February 2017;48(2):379e87. [54] Campbell BC. Endovascular therapy for ischemic stroke with perfusion-imaging selection. New Engl J Med March 12, 2015;372(11):1009e18. [55] Jovin TG. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med June 11, 2015;372(24):2296e306. [56] Urra X. Mechanical thrombectomy in and outside the REVASCAT trial: insights from a concurrent population-based stroke registry. Stroke December 2015;46(12):3437e42. [57] Saver JL. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. J Am Med Assoc September 27, 2016;316(12):1279e88. [58] Aronsson M. Cost-effectiveness of endovascular thrombectomy in patients with acute ischemic stroke. Neurology March 15, 2016;86(11):1053e9. [59] Kunz WG. Cost-effectiveness of endovascular stroke therapy: a patient subgroup analysis from a US healthcare perspective. Stroke November 2016;47(11):2797e804. [60] Albers GW. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol November 2006;60(5):508e17. [61] Lansberg MG. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol October 2012;11(10):860e7. [62] Jovin TG. Imaging-based endovascular therapy for acute ischemic stroke due to proximal intracranial anterior circulation occlusion treated beyond 8 hours from time last seen well: retrospective multicenter analysis of 237 consecutive patients. Stroke August 2011;42(8):2206e11. [63] Powers WJ, Derdeyn CP, Biller J, et al. 2015 AHA/ASA focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment. Stroke 2015;46:3024e39. [64] Sallustio F. Efficacy and safety of mechanical thrombectomy in older adults with acute ischemic stoke. J Am Geriatr Soc August 2017;65(8):1816e20. [65] Lapergue B, Consoli A, et al. Effect of endovascular contact aspiration vs stent retriever on revascularization in patients with acute ischemic stroke and large vessel occlusion: the ASTER randomized clinical trial. J Am Med Assoc August 1, 2017;318(5):443e52.