Intraarterial therapy background

Intraarterial therapy for acute ischemic stroke can be broadly divided into chemical clot dissolution with locally delivered fibrinolytic agents (ie, intraarterial fibrinolysis) and mechanical thrombectomy with various devices. Intraarterial fibrinolysis with streptokinase for large vessel occlusion was initially described in the 1980s prior to the FDA approval of intravenous rtPA (52). The first trial to evaluate the efficacy of intraarterial fibrinolysis was the Prolyse in Acute Cerebral Thromboembolism II trial (PROACT II), published in 1999, which demonstrated better outcomes with intraarterial r-pro-urokinase versus intravenous heparin alone (17). Although the PROACT II results showed clinical benefit of intraarterial thrombolysis, the results may not be currently applicable, as the control group did not receive intravenous fibrinolysis, which has become the standard of care for many acute ischemic stroke patients.

Although initial intraarterial fibrinolysis results were promising, the excitement was dampened by multiple follow-up trials, which failed to demonstrate clinical benefit of intraarterial therapy compared with intravenous fibrinolysis alone. Starting in the mid-1990s, NINDS funded a series of studies examining the efficacy and safety of intraarterial therapy (both chemical clot dissolution and eventually mechanical thrombectomy) for the treatment of severe acute ischemic strokes. These were known as the Emergency Management of Stroke (EMS) (30) and International Management of Stroke trials (IMS, IMS II, and IMS III) (23; 22; 11). Two additional randomized, controlled trials published in 2013, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) (28) and SYNTHESIS (14), also failed to demonstrate a statistically significant clinical benefit of intraarterial therapy compared with standard medical management of acute ischemic stroke. The failure of these trials to demonstrate efficacy of intraarterial therapy was largely attributed to methodologic shortcomings, including long intervals between symptom onset and intraarterial therapy, and lack of pretreatment noninvasive vascular imaging to confirm the presence of a large vessel occlusion.

Nevertheless, comparison trials such as TREVO2 (35) and SWIFT (47) showed that mechanical thrombectomy with stent retrievers was more effective than first-generation thrombectomy devices like the concentric Merci device (Stryker Inc, Fremont, CA) (35; 47). These wire-mounted, self-expanding stents proved to be faster and easier to deploy than first-generation thrombectomy devices and had higher recanalization rates (38). This led to a subsequent revolution in 2015, with the publication of multiple randomized control trials proving the benefit of timely stent retriever thrombectomy for acute ischemic stroke (37). These trials, dubbed “the Fab Five,” are the basis of ischemic stroke care that is practiced today and the jumping off point for subsequent research involving thrombectomy alone (without intravenous fibrinolytics), thrombectomy of middle and even distal artery occlusions, direct-to-angiography (one-stop) protocols, and inclusion of patients with large core infarct at presentation.

Stroke imaging

Noninvasive cross-sectional imaging plays a crucial role in the workup of acute ischemic stroke. The widespread availability of computed tomography (CT) scanners at most medical centers in developed countries has made CT the modality of choice for initial diagnostic evaluation. All acute ischemic stroke patients should undergo noncontrast CT (NCCT) of the head to exclude intracranial hemorrhage, evaluate for early signs of infarction, and exclude other potential causes of neurologic deficits. Excluding intracranial hemorrhage on NCCT is the crucial first step, as the presence of hemorrhage is an absolute contraindication to IV-rtPA (40). Furthermore, infarction of greater than one third of the middle cerebral artery territory puts the acute ischemic stroke patient at increased risk of hemorrhagic conversion if IV-rtPA is administered or mechanical thrombectomy is performed (40). The Alberta Stroke Program Early CT Score (ASPECTS) (06) is a commonly used 10-point quantitative topographic score used to assess for early ischemic changes on NCCT. ASPECTS is calculated by evaluating standardized regions of the middle cerebral artery territory for early ischemic changes (ie, hypodensity of the parenchyma). A point is subtracted for each region that demonstrates ischemic changes. A normal NCCT will have an ASPECTS score of 10, whereas lower scores indicate more extensive ischemic involvement. Higher ASPECTS scores (8 to 10) are associated with greater benefit from IV-rtPA and better functional outcomes, whereas lower ASPECTS scores (≤ 7) are associated with worse functional outcome and increased rates of symptomatic intracranial hemorrhage. The ASPECTS score can be rapidly calculated in the acute setting and provides a reasonable estimation of core infarct size. ASPECTS limitations include high inter- and intra-observer variability, use limited to the middle cerebral artery territory emphasis, watershed infarcts, and patients with extensive white matter changes or chronic infarcts. Additionally, it should be noted that a normal appearing NCCT (ASPECTS score of 10) does not exclude the presence of a large infarct core, as NCCT is much less sensitive than DWI-MRI (the gold standard for measurement of ischemic core infarct size) in the acute setting (06; 39; 03; 43). Patients with severe neurologic deficits based on the National Institute of Health Stroke Scale (NIHSS) score should also undergo a CT angiogram (CTA) of the head and neck (including aortic arch to head vertex) to evaluate for an intracranial large vessel occlusion, which is usually defined as occlusion of the intracranial internal carotid artery, M1 or proximal M2 segments of the middle cerebral artery, or the basilar artery. In some circumstances, patients may undergo initial imaging evaluation with magnetic resonance imaging (MRI) of the head as well as magnetic resonance angiography (MRA) of the head and neck (48).

More advanced noninvasive imaging techniques, such as CT perfusion, multiphase CTA (12), and MR perfusion (49), are utilized during the work-up of acute ischemic stroke patients. These imaging tools can measure potentially salvageable ischemic brain tissue (ie, penumbra) and grade collateral circulation in the ischemic arterial territory.

Mechanical thrombectomy for large vessel occlusion

The shortcomings of previous intraarterial therapy trials were addressed in five landmark prospective randomized open-label blind-endpoint trials published in 2015 that demonstrated the superiority of mechanical thrombectomy to best medical therapy in carefully identified patients with large vessel occlusions. Although all five study designs differed in certain details, they shared several common core principles: (1) each randomized acute ischemic stroke patients to standard medical therapy (mostly IV-rtPA) or standard medical therapy plus intraarterial thrombectomy; (2) each used noninvasive neuroimaging protocols to carefully select patients with a large vessel occlusion of the anterior circulation, a small core infarction, and the presence of salvageable brain tissue; (3) each required strict time parameters and implemented more efficient workflows to improve reperfusion; and (4) each used newer generation stent retrievers almost exclusively. Listed in chronological order of publication, they are: Multicenter Randomized Clinical Trial of Endovascular Treatment (MR CLEAN) (09), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) (18), Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) (13), 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) (24), and Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) (46). A summary of the individual trials, with their clinical applicability and results, are shown in Tables 1 through 3 below.

Table 1. Study Demographics

Study	Control/intervention	Media age (years)	Median baseline NIHSS	Large vessel occlusion distribution (%)	Median ASPECTS	Stent retriever usage (%) – intervention group only	Median time from stroke onset to groin puncture (min) – intervention group only
MR CLEAN	267/233	66/66	18/17	ICA 1.1/0.4 ICA + M1 28.2/25.3 M1 62.0/66.1 M2 7.9/7.7 A1-A2 0.8/0.4	9/9	81.5	260
ESCAPE	150/165	70/71	17/16	ICA + M1 26.5/27.6 M1/all M2 71.4/68.1 M2 2.0/3.7	9/9	86.1	185
EXTEND-IA	35/35	70/69	13/17	ICA 31/31 M1 51/57 M2 17/11	Not recorded	100	210
REVASCAT	103/103	67/66	17/17	ICA 1/0 ICA + M1 27/26 M1 64/65 M2 8/10	8/7	100	269
SWIFT PRIME	98/98	66/65	17/17	ICA 16.0/18.3 M1 77/68 M12 6/14	9/9	100	224
HERMES	653/634	68/68	17/17	ICA 22/21 M1 69/69 M2 7/8 Other 2/2	9/9	89.6	285 (Median stroke onset to reperfusion)

Table 2. Select Inclusion Criteria

Study	Age inclusion criteria (years)	Select imaging inclusion criteria (all studies required large vessel occlusion)	Initial NIHSS	Baseline mRS (pre-stroke)	Stroke onset to groin puncture (hours)
MR CLEAN	≥18 (no upper age limit)	ASPECTS documented, but not used as inclusion criteria	≥2	Not part of inclusion criteria	≤6
ESCAPE	≥18 (no upper age limit)	-CT ASPECTS ≥6 AND -Moderate-good collaterals	≥6	Barthel Index >90 (similar to mRS ≤1)	≤12
EXTEND-IA	≥18 (no upper age limit)	-CT Perfusion target mismatch profile	Documented, but not part of inclusion criteria	≤2	≤6
REVASCAT	18-80 (eventually up to 85)	-CT ASPECTS ≥7, revised to ≥9 OR -MRI ASPECTS ≥6	≥6	≤1	≤8
SWIFT PRIME	18-80	-CT Perfusion target mismatch profile OR -CT/MRI ASPECTS ≥7 OR -Infarct <1/3 of MCA territory on CT or MRI	8-29	≤2	≤6

Table 3. Select Study Outcomes

Study	Median mRS at 90 days (control or intervention)	mRS 0-2 at 90 days (%)	mRS score reduction at 90 days (shift analysis), OR (95% CI)	Death at 90 days (%)	Symptomatic ICH (%)	TICI 2b/3 (%)-Intervention group only
MR CLEAN	4/3	19.1/32.6	1.67 (1.21-2.30)	22/21	6.4/7.7 (at 90 days)	59
ESCAPE	4/2	29.3/53	3.1 (2.0-4.7)	19/10.4	2.7/3.6 (at 90 days)	72.4
EXTEND-IA	3/1	40/71	2 (1.2-3.8)	20/9	6/0 (at 36 hours)	86
REVASCAT	Not recorded	43.7/28.2	1.7 (1.05-2.8)	16/18	2/2 (at 90 days)	66
SWIFT PRIME	3/2	35/60	1.7 (1.23-2.33)	12/9	3/0 (at 27 hours)	88
HERMES	Not recorded	26.5/46	2.49 (1.76-3.53)	18.9/15.3	4.3/4.4	71

Each study demonstrated that mechanical thrombectomy significantly reduced disability rates in carefully selected patients with acute ischemic stroke caused by large vessel occlusion in the proximal anterior circulation. The patients who benefited most had a combination of large vessel occlusion, small core infarction, and large salvageable brain tissue as identified on noninvasive neuroimaging (CTA/MRA) prior to intervention. After publication of these studies, the investigators pooled their patient-level data together to create the HERMES collaboration, a meta-analysis of over 1200 patients and 600 thrombectomy cases (19). Overall, the HERMES data demonstrated that mechanical thrombectomy more than doubled the odds for a better outcome (mRS 0-2) compared to standard medical therapy alone (common OR 2.49, 95% CI 1.76-3.53). The number needed to treat with endovascular thrombectomy to reduce disability was 2.6. TICI 2b/3 (nearly complete) reperfusion was achieved in 71% of patients randomized to endovascular thrombectomy in the 2015 trials compared to 25% and 41% achieved in the MR RESCUE and IMS III trials, respectively. Baseline NIHSS was 17 in both groups; the NIHSS at 24 hours was significantly lower in the intervention group (median NIHSS 8 in the intervention group, median NIHSS 15 in the control group), and improvement from baseline at 24 hours was significantly greater in the treatment group (median change in NIHSS -6.4 in the intervention group, median change in NIHSS -2.6 in the control group). The authors concluded that for every 100 patients treated with mechanical thrombectomy, 38 will have less disability at 90 days compared with standard medical management, and an additional 20 more patients will be functionally independent at 90 days (mRS 0-2). There was not a significant difference in serious adverse events (mortality and symptomatic intracranial hemorrhage) between the groups.

The HERMES meta-analysis favored mechanical thrombectomy across multiple subgroups including age, sex, NIHSS, tPA administration, ASPECTS, and time from onset. There was clinical benefit across all age groups, including patients 80 years old or older (80-year-old and older subgroup common OR 3.68, 95% CI 1.95-6.92). Mechanical thrombectomy was favored in both the male and female subgroups analyzed in the HERMES meta-analysis (males common OR 2.54, 95% CI 1.92-3.36 and females common OR 2.38, 95% CI 1.46-3.88). Most of the eligible patients across the five trials received intravenous-rtPA (1090/1278, 85%). Clinical outcomes favored mechanical thrombectomy in both subgroups (common OR 2.45, 95% CI 1.68-3.57 in the group receiving intravenous-rtPA and common OR 2.43, 95% CI 1.30-4.55 in the group not receiving intravenous-rtPA). Given this, the authors concluded that endovascular eligibility should be decided irrespective of eligibility for alteplase. HERMES analysis of NIHSS subgroups favored mechanical thrombectomy for higher NIHSS subgroups (11-15, 16-20, 21 or higher), whereas the benefit of mechanical thrombectomy in the lower NIHSS subgroup (10 or lower) was not statistically significant. The lack of conclusive efficacy of mechanical thrombectomy in the lower NIHSS subgroup may be due to insufficient patient enrollment.

The extent of pretreatment core infarction on initial diagnostic imaging has been recognized as a critical determinant of clinical outcome in patients who have had acute ischemic stroke and are receiving reperfusion therapies (either systemic thrombolysis or mechanical thrombectomy). Across all five trials, average ASPECTS was 9. Four of the trials required specific criterion to exclude patients with large core infarction on baseline imaging. Three of the trials (ESCAPE, SWIFT PRIME, REVASCAT) excluded patients with low ASPECTS scores (lower than 6) whereas EXTEND-IA selected patients with small core infarcts and salvageable brain tissue. MR CLEAN allowed enrollment across the spectrum of ASPECTS scores, thus, allowing subgroup analysis of patients with low ASPECTS scores (0 to 5). The HERMES analysis concluded that similar favorable outcomes with mechanical thrombectomy were seen in subgroups with high baseline ASPECTS scores (9 to 10) and moderate baseline ASPECTS scores (6 t 10). The subgroup with baseline ASPECTS scores 0 to 5, although underpowered, did not favor mechanical thrombectomy (common OR 1.24, 95% CI 0.62-2.49). However, a retrospective study demonstrated that patients with low ASPECTS may still benefit from thrombectomy (45).

Three of the 2015 studies (MR CLEAN, EXTEND-IA, SWIFT PRIME) required a 6-hour window from stroke onset to randomization. REVASCAT and ESCAPE included patients up to 8 and 12 hours, respectively, from stroke onset to randomization. It should be emphasized that the median time-of-onset to reperfusion time was approximately 4.5 hours. Indeed, the HERMES analysis also demonstrated efficiency of thrombectomy for patients randomized beyond 5 hours after stroke onset (common OR: 1.76, 95% CI: 1.05–2.97), including up to 7 hours.

The cumulative findings of these five trials provided American Heart Association (AHA) class 1 level of evidence for acute stroke intervention in carefully selected patients with large vessel occlusions (Mulder et al 2015). Per the 2018 AHA guidelines, there is Class 1a evidence for mechanical thrombectomy with a stent retriever if patients meet all of the following criteria: (1) prestroke mRS score 0 to 1; (2) causative occlusion of the internal carotid artery or MCA segment 1(M1); (3) age older than 18 years (4) NIHSS score higher than 6; and (6) treatment can be initiated (groin puncture) within 6 hours of symptom onset (41).

Endovascular treatment in the posterior circulation

ATTENTION and BAOCHE, two randomized controlled trials of basilar artery occlusion published in 2022, shed light on the effectiveness of endovascular thrombectomy versus best medical management (25; 50). In ATTENTION, a study involving Chinese patients within 0 to 12 hours of stroke onset, the endovascular therapy group exhibited a significantly improved primary endpoint of modified Rankin score at 90 days compared to best medical management, despite a trend towards more symptomatic intracerebral hemorrhage with thrombectomy. The BAOCHE trial recruited patients within 6 to 24 hours of symptom onset and was terminated early due to significant differences, showing a nearly 2-fold greater proportion of patients achieving the primary outcome in the endovascular group compared to medical management. Despite an increase in symptomatic intracerebral hemorrhage and early mortality, BAOCHE was the first endovascular thrombectomy trial to demonstrate a reduction in 90-day mortality for basilar artery occlusion. These two trials collectively provide compelling evidence that thrombectomy enhances outcome in basilar artery occlusion up to 24 hours after symptom onset.

Regarding endovascular treatment, specifically of posterior cerebral artery (PCA) occlusions, retrospective analyses for proximal PCA occlusion (P1 or P2 segments) demonstrate trends towards improved outcomes with endovascular thrombectomy compared to best medical treatment. A similar trend was observed in the TOPMOST study, which evaluated distal PCA occlusions (P2 and P3 segments), without an increase in symptomatic intracranial hemorrhage with endovascular thrombectomy in any of these studies (31).

Extended time window thrombectomy

Two landmark studies published in early 2018 addressed the efficacy of mechanical thrombectomy in the extended window (more than 6-hour) period: the DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-up and Late Presenting Strokes Undergoing Neurointervention with Trevo trial (DAWN) (34) and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trial (DEFUSE 3) (01). Although each had specific inclusion criteria, the overall paradigm was focused on selecting patients beyond 6 hours with large mismatches between the ischemic core and salvageable penumbra.

In DAWN, patients with large vessel occlusion of the anterior circulation who were last known well in the previous 6 to 24 hours were randomly assigned to thrombectomy plus standard medical care or standard care alone. To qualify, patients needed to exhibit a mismatch between clinical deficits and infarct volume as determined by MRI or CT perfusion. The mismatch criteria were defined according to age, with patients older than 80 years needing a NIHSS greater than 10 and a core infarct volume less than 20 ml to qualify. Patients between 18 and 80 years of age needed a NIHSS greater than 10 and a core volume less than 30 ml or a NIHSS greater than 20 and a core volume less than 50 ml. Primary endpoints included the rate of functional independence (defined as mRS 0 to 2) at 90 days.

Patients were well-matched in both groups, with median age of 70 years, median NIHSS of 17, and core volume of approximately 8 ml. The occluded vessel was most commonly the first segment of the MCA (80%), followed by the intracranial internal carotid artery (20%). The median time between last known well and study randomization was 12.2 hours in the thrombectomy group and 13.3 hours in the control group. The median time from last known well to recanalization was 13.6 hours. The trial was stopped early at 31 months after interim analysis of the first 200 enrolled patients demonstrated clear superiority of mechanical thrombectomy. Compared to standard medical care, thrombectomy greatly increased rates of functional independence (49% vs. 13%; ARR 35) with a number needed to treat of only 2.8 patients for every one patient with preserved functional independence at 90 days. These benefits were maintained across multiple subgroups, including sex, age, baseline NIHSS, and time between onset and randomization (less than 12 hours and 12 to 24 hours). Change in median infarct volume at 24 hours was significantly larger in the control group. There was no difference in serious adverse events, including symptomatic intracerebral hemorrhage or 90-day mortality, between the two groups.

DEFUSE3, published several months after DAWN, randomized patients presenting with large vessel occlusion of the anterior circulation who were last known well between 6 and 16 hours to thrombectomy plus standard medical therapy versus medical therapy alone. The main inclusion criteria were a core less than 70 ml, a penumbra volume greater than 15 ml, and a penumbra-to-core ratio greater than 1.8. Thrombectomy was performed with any FDA-approved device, and carotid stenting was allowed, if necessary. Primary outcome was ordinal score on the modified Rankin Scale. Like DAWN, both groups in DEFUSE had the median age of 70 years and NIHSS score of 16. In the thrombectomy group, the median time from symptom onset to baseline imaging was 10 hours and 29 minutes, with a median ischemic core and penumbra volumes of 9.4 ml and 114.7 ml respectively. In the control group, median time from symptom onset to baseline imaging was 9 hours and 55 minutes, with core and penumbra volumes of 10.1 ml and 116.1 ml respectively.

The DEFUSE3 trial was also stopped early after interim analysis of first 182 patients demonstrated clear efficacy for mechanical thrombectomy. The thrombectomy group had lower median mRS score at 90 days (3 vs. 4; OR 2.77) and had a higher percentage of patients who were functionally independent (mRS 0- to 2) at 90 days (45% vs. 17%; ARR 28%), with 3.6 treated patients needed to preserve functional independence in one patient. Thrombectomy patients were more likely to have complete recanalization at 24 hours. There was a trend towards lower median infarct growth at 24 hours. Unlike in the DAWN trial, DEFUSE3 demonstrated a clear all-cause mortality benefit at 90 days. There were no differences in adverse events or symptomatic intracranial hemorrhages between the intervention and control groups.

Overall, both studies demonstrated the superiority of endovascular thrombectomy in the treatment of large vessel occlusions of the anterior circulation in carefully selected and imaging-selected patients beyond the traditional intervention period of 6 to 8 hours from last known well. Both studies focused on selecting patients with large mismatches between core lesion and salvageable penumbra. Although similar in design, both studies also had some key differences. Foremost, DAWN had a larger time window, including patients up to 24 hours from last known well. DEFUSE3 had broader inclusion criteria, including lower functioning baseline (mRS 0–2 vs mRS 0–1), milder clinical deficits (NIHSS greater than 6 vs. 10), and larger maximum core volume (70 mL vs. 50 mL) and did not qualify different mismatch criteria based on age. Additionally, DAWN required thrombectomies be performed with the Trevo device whereas DEFUSE3 allowed any FDA-approved thrombectomy device and allowed for concomitant cervical internal carotid artery stenting.

As a result of these two landmark studies, the 2018 AHA/ASA guidelines provide class 1a evidence for mechanical thrombectomy in select patients with acute ischemic strokes within 6 to 16 hours of last known well (41). Given the discrepancy in interventional time frame between the two studies, endovascular thrombectomy in patients presenting within 16 to 24 hours since last known well merits class IIa evidence.

Thrombectomy without intravenous thrombolysis

Currently, patients who present with large vessel occlusion within 4.5 hours of onset are eligible for both intravenous thrombolysis and endovascular therapy. There is uncertainty regarding the role of thrombolysis administered before and during thrombectomy in patients with ischemic stroke. Potential complications of this combination therapy include distal embolization from thrombolysis and increased risk of cerebral hemorrhage. A multicenter, randomized, noninferiority trial was conducted to compare outcomes of thrombectomy with or without thrombolysis (using alteplase) in 656 eligible patients (51). Overall, endovascular monotherapy was considered noninferior to combination therapy with thrombolysis for modified Rankin scale scores between 0 and 3 and mortality at 90 days. However, the combination therapy resulted in significantly higher rates of successful reperfusion before thrombectomy and overall successful reperfusion. Similar research from the SWIFT-DIRECT trial found that thrombectomy alone was not shown to be noninferior to intravenous alteplase plus thrombectomy and also resulted in decreased reperfusion rates (16).

A 2020 study explored incomplete mechanical thrombectomy followed by intraarterial urokinase administration and found that the patients treated with intraarterial urokinase during endovascular therapy showed no increased risk of symptomatic intracranial hemorrhage or mortality (26). Notably, there was a significantly higher mRS 0–2 incidence at 3 months. The study suggests considering urokinase in cases with tortuous distal anatomy, but validation in larger studies, such as the upcoming Multi-arm Optimization of Stroke Thrombolysis (MOST) study, is crucial.

In the CHOICE trial, patients with acute ischemic stroke and large vessel occlusion within 24 hours of symptom onset underwent successful thrombectomy and were randomized to intraarterial alteplase or placebo (53). The primary outcome favored intraarterial alteplase (59% vs 40% achieving mRS 0–1 at 90 days), with no increase in symptomatic intracranial hemorrhage within 24 hours. Furthermore, ongoing studies, like BRETIS-TNK II and TECNO, are investigating the use of intraarterial tenecteplase during thrombectomy.

Adjuvant management

As the field of endovascular therapy for acute ischemic strokes has matured, several studies have looked at perioperative management and adjuvant therapies to optimize outcomes. These have focused particularly on perioperative sedation and thrombolysis.

The two primary modes of perioperative sedation during endovascular therapy are generalized anesthesia via endotracheal intubation and moderate sedation using intravenous benzodiazepines. Generalized anesthesia allows for greater technical success by helping to prevent patient movement during the procedure, particularly those with a dominant hemispheric stroke that interferes with verbal comprehension. However, anesthetic induction and positive pressure mechanical ventilation may result in perioperative hypotension, a potentially deleterious effect in patients with acute ischemic stroke.

Since 2016, three randomized clinical trials have attempted to address this controversy between generalized anesthesia and moderate sedation: Sedation vs. Intubation for Endovascular Stroke Treatment (SIESTA), Anesthesia During Stroke (ANSTROKE), and General or Local Anesthesia in Intra-Arterial Therapy (GOLIATH). The trials failed to demonstrate significant differences in patient outcomes; however, all were single center with limited sample size. Given these issues, a meta-analysis combining all three studies using 365 individual patient data was preformed (44). Overall, general anesthesia was associated with a significant decrease in mean arterial pressure (MAP), including lower periprocedural mean MAP values (96 vs. 100 mmHg, p< 0.01) and episodes of MAP below 70 mmHg (32% vs. 14%, p< 0.001). Sedation type did not affect patient outcome, yet a significant relationship was demonstrated between periprocedural hemodynamics and outcomes. A U-shaped association was demonstrated, with poor outcomes associated with critical MAP threshold of less than 70 mmHg for more than 10 minutes and greater than 90 mmHg for more than 45 minutes. Although it is still unclear if generalized anesthesia is superior to conscious sedation, these studies demonstrated the need to maintain periprocedural MAP between 70 to 90 mmHg.

Future directions

Given the success of the trials in 2015 and 2018, research into endovascular and systemic therapy for acute ischemic stroke is projected to expand to support and extend the effectiveness of acute stroke treatment. As presented in the last International Stroke Conference in 2024, the 57-center U.S. MOST (Multi-Arm Optimization of Stroke Thrombolysis) trial was discontinued following an evaluation by an independent data and safety board. The analysis, based on the initial 500 participants out of the intended 1200 acute ischemic stroke patients eligible for intravenous thrombolysis, concluded that completing the research was highly unlikely to reveal any benefits. The study aimed to assess improvement in functional outcomes at the 90-day mark after adding the intravenous direct thrombin inhibitor argatroban or the G2b/3a inhibitor eptifibatide to intravenous rtPA. The risk of symptomatic intracranial hemorrhage did not significantly increase; 44% of the patients across all three groups were treated with endovascular thrombectomy as per usual care. For the patient undergoing endovascular thrombectomy, studies are underway to investigate whether intraarterial administration of blood thinners directly into the affected artery may improve outcomes.

Ongoing clinical trials are investigating increasing the intervention window beyond 24 hours in patients with salvageable penumbras. The adage of “time is tissue” may well be replaced with “penumbra is tissue.” In November 2023, the TENSION trial was published (07). The trial included patients with a large core infarct indicated by an ASPECTS of 3 to 5 who were randomly assigned using a central web-based system to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 hours from stroke onset; 253 participants underwent random assignment, with 125 individuals allocated to endovascular thrombectomy and 128 to exclusive medical treatment. The trial was stopped early for efficacy after the first interim analysis. At the 90-day endpoint, endovascular thrombectomy demonstrated a favorable shift in the distribution of scores on the modified Rankin Scale, indicating better outcomes along with reduced mortality. Symptomatic intracranial hemorrhage was similar in the two groups at 5% to 6%. This randomized controlled trial indicates that patients with acute ischemic stroke and large vessel occlusion, up to 12 hours from stroke onset, may benefit from thrombectomy despite having a low ASPECT score, which would have previously barred them from interventional treatment.

Further studies are also investigating the efficacy of thrombectomy for more distal vessel occlusions. Of the five major 2015 thrombectomy trials, only MR CLEAN and EXTEND-IA included patients with distal middle cerebral artery occlusions (M2 segment). Three major trials are currently investigating this topic: EnDovascular Therapy Plus Best Medical Treatment (BMT) Versus BMT Alone for MedIum VeSsel Occlusion sTroke (DISTAL), Evaluation of Mechanical Thrombectomy in Acute Ischemic Stroke Related to a Distal Arterial Occlusion (DISCOUNT), and EndovaSCular TreAtment to imProve outcomEs for Medium Vessel Occlusions (ESCAPE-MeVO). The first results are expected by the end of 2024.

Another topic for further investigation is acute ischemic stroke related to intracranial atherosclerotic disease (05). Failed reperfusion happens in 10% to 20% of mechanical thrombectomy cases, and one of the reasons for this failure is underlying intracranial stenosis due to atherosclerotic disease, rendering the vessel much more likely to instantly re-occlude because of in situ thrombosis. A potential solution to this challenge lies in the utilization of intracranial rescue stenting (02). The hypothesis is that with the help of the stent, the vessel lumen will remain open, allowing reperfusion of the affected brain tissue. This approach is adapted from the treatment of myocardial infarction, whereby permanent stenting is the established practice. Although retrospective and prospective registry data (04) show promising reperfusion results, debate is ongoing about the safety of the procedure due to the need of dual antiplatelet therapy during and after stenting, especially in the setting of intravenous thrombolysis. Temporary dilatation while allowing reperfusion is also being explored (36). Due to insufficient data, the expert consensus recommendation from the 2022 European Stroke Organization Guidelines on the treatment of patients with intracranial atherosclerotic disease (42) is that patients should be enrolled in dedicated randomized controlled clinical trials, if possible. Currently, no suggestion is made for or against rescue therapy after unsuccessful thrombectomy in patients with an acute ischemic stroke suspected to be caused by underlying intracranial atherosclerotic disease.