Randomized Clinical Trials in Cerebrovascular Neurosurgery From 2018 to 2022

There has been an exponential increase in randomized controlled trials (RCTs) on cerebrovascular disease within neurosurgery. The goal of this study was to review, outline the scope, and summarize all phase 2b and phase 3 RCTs impacting cerebrovascular neurosurgery practice since 2018. We searched PubMed, MEDLINE, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for relevant RCTs published between January 1, 2018, and July 1, 2022. We searched for studies related to eight major cerebrovascular disorders relevant to neurosurgery, including acute ischemic stroke, cerebral aneurysms and subarachnoid hemorrhage, intracerebral hemorrhage, subdural hematomas, cerebral venous thrombosis, arteriovenous malformations, Moyamoya disease and extracranial-intracranial bypass, and carotid and intracranial atherosclerosis. We limited our search to phase 2b or 3 RCTs related to cerebrovascular disorders published during the study period. The titles and abstracts of all relevant studies meeting our search criteria were included. Pediatric studies, stroke studies related to rehabilitation or cardiovascular disease, study protocols without published results, prospective cohort studies, registry studies, cluster randomized trials, and nonrandomized pivotal trials were excluded. From an initial total of 2,797 records retrieved from the database searches, 1,641 records were screened after duplicates and studies outside of our time period were removed. After screening, 511 available reports within our time period of interest were assessed for eligibility. Pediatric studies, stroke studies related to rehabilitation or cardiovascular disease, study protocols without published results, prospective cohort studies, registry studies, cluster randomized trials, and nonrandomized pivotal trials were excluded. We found 80 unique phase 2b or 3 RCTs that fit our criteria, with 165 topic-relevant articles published within the study period. Numerous RCTs in cerebrovascular neurosurgery have been published since 2018. Ischemic stroke, including mechanical thrombectomy and thrombolysis, accounted for a majority of publications, but there were large trials in intracerebral hemorrhage, subdural hemorrhage, aneurysms, subarachnoid hemorrhage, and cerebral venous thrombosis, among others. This review helps define the scope of the large RCTs published in the last four years to guide future research and clinical care.


Introduction And Background
Earlier research conducted by our team comprehensively reviewed randomized controlled trials (RCTs) in cerebrovascular neurosurgery published between 2016 and 2017 [1].At the time, studies covered management for ischemic stroke, aneurysms, subarachnoid hemorrhage, intracerebral hemorrhage, and carotid stenosis.Many important RCTs in cerebrovascular neurosurgery have been published since.These studies further explore questions surrounding indications and timing of mechanical thrombectomy for acute ischemic stroke, as well as new devices and additional strategies for acute management.Controversies regarding clipping versus coiling and endovascular versus surgical intervention for intracranial aneurysms continue, with the ongoing development of new technology.Sequelae of subarachnoid hemorrhage, such as delayed cerebral ischemia and vasospasm, also remain significant clinical challenges.Busy clinicians may benefit from a study outlining the scope of the newest RCTs published in the field and a brief summary of major trials affecting clinical practice.The goal of this study was to review, outline, and summarize all of the high-quality phase 2b and phase 3 RCTs impacting cerebrovascular neurosurgery practice between 2018 and 2022.

Review Materials and methods
We searched PubMed, MEDLINE, Embase, ClinicalTrials.gov,and the Cochrane Central Register of  Eight phase 2b or 3 RCTs with 165 articles published within the study period were included.The majority of trials reviewed (44/80, 54%) were in ischemic stroke, while aneurysm or subarachnoid hemorrhage trials were the second most common (17/80, 22%), with fewer trials in other categories.

Timing and Indications
Strong data from previously published RCTs support mechanical thrombectomy (MT) for acute ischemic stroke (AIS) due to large vessel occlusion (LVO), including MR CLEAN [2], EXTEND-IA [3], ESCAPE [4], REVASCAT [5], SWIFT PRIME [6], and THRACE [7].DAWN [8] and DEFUSE-3 [9] extend the time window for intra-arterial thrombectomy (IAT) to 24 hours and reinforce the role of perfusion imaging in selecting patients for MT.In DAWN, IAT plus standard medical care 6 to 24 hours after LVO was superior to medical management alone [8].In DEFUSE-3 [9], thrombectomy plus medical therapy 6 to 16 hours after the lastknown well (LKW) lowered 90-day modified Rankin scale (mRS) and mortality rates [9].The Brazilian RESILIENT [10] trial showed that IAT for LVO was feasible, safe, and effective at a large scale in a lowresource public healthcare setting [10].RESCUE-Japan [11] randomized 203 patients with low Alberta Stroke Program Early CT Scores (ASPECTS) of 3 to 5 to either MT plus maximal medical management or maximal medical management alone and found a significant increase in the percentage of patients with an mRS score of 0 to 3 at 90 days (31% endovascular-therapy group versus 12.7% medical care group; relative risk [RR] 2.43; 95% confidence interval [CI], 1.35-4.37;P = 0.002).

Upcoming and Late-Breaking Trials
ANGEL-ASPECTS, TENSION, and SELECT2 are prospective, open-label, blinded endpoint (PROBE) RCTs in China, the European Union (EU), and an international group comprising North America, the EU, the UK, and New Zealand.The primary objective of these trials is to compare the safety and effectiveness of thrombectomy versus maximal medical management alone in patients with low ASPECTS scores of 3 to 5 (NCT04551664; NCT03094715; NCT03876457).ANGEL-ASPECTS results were published in April 2023 and found that patients with large infarctions (ASPECTS score of 3-5 or core infarct volume of 70-100 cc) who underwent endovascular treatment within 24 hours had better outcomes (generalized odds ratio [OR], 1.37; 95% CI, 1.11-1.69;P = 0.004) but more intracerebral hemorrhages than patients randomized to medical management alone [12].SELECT2 results were also published in April 2023 and showed similar results with better 90-day outcomes in favor of MT in 352 patients with large-volume ischemic strokes (ASPECTS score of 3-5 or core infarct volume >50 cc) randomized 1:1 to endovascular therapy (EVT) within 24 hours or medical management alone (generalized OR 1.51; 95% CI, 1.20-1.89;P < 0.001) [13].
The COMPASS trial [18] randomized 134 patients to a direct aspiration first-pass technique (ADAPT) with the Penumbra aspiration system and 136 patients to a stent-retriever first line (SRFL) technique with Solitaire (Medtronic, Minneapolis, MN) or Trevo (Stryker, Kalamazoo, MI) device (balloon guide and/or aspiration used at the discretion of the treating physician) [19].The COMPASS trial demonstrated non-inferior 90-day functional outcomes using ADAPT compared to SRFL (52% vs. 50%; P non-inferiority = 0.0014) [18].

Upcoming Trials
Retrospective analysis of ADAPT using SOFIA catheters (Microvention, Aliso Viejo, CA) suggested that the device was safe and effective with TICI 2b/3 reperfusion in 86.1%, after first pass in 24.2%, and with rescue stent-retriever in 29.7% of cases [20].The REal-World Analyses of Stroke-Thrombus Occlusion REtrieval (RESTORE) trial using the SOFIA aspiration system are currently being recruited (NCT04451525).

New Stent-Retrievers
The REDIRECT trial [21] randomized 136 patients with AIS due to LVO within eight hours of symptom onset to evaluate the efficacy of the RECO flow restoration (FR) device (Genesis MedTech, Singapore) compared to the Solitaire stent-retriever.There were similar rates of 90-day functional independence (mRS 0-2), 90-day all-cause mortality, and procedure duration between the two groups [21].
The Tonbridge stent (Tonbridge Medical Technology, Guangzhou, China) was compared to the Solitaire stent-retriever in 208 patients with AIS due to LVO within 6 hours of symptom onset.The Tonbridge device showed non-inferiority, with similar rates of all-cause mortality and 90-day mRS of 0-2 [22].

Prospective Trials
The TIGER trial [23] was a single-arm, multicenter, prospective study of the Tigertriever device (Rapid Medical, Sunrise, FL) involving 160 patients with a National Institutes of Health Stroke Scale (NIHSS) score of ≥8 and AIS due to LVO within eight hours of symptom onset.About 95.7% of patients achieved TICI ≥ 2b reperfusion and 58% of patients had 90-day mRS of 0-2 [23].

Posterior Circulation
The BEST trial aimed to evaluate the efficacy of IAT for basilar occlusion but was terminated early after randomization of 131 patients due to high rates of crossover, poor recruitment, and loss of equipoise [24].
ATTENTION [25] randomized 340 adults with acute basilar artery occlusion (BAO) within 12 hours of symptom onset to EVT or maximal medical management and demonstrated a significantly higher rate of good 90-day functional outcome in the endovascular group (46%) compared to the medical group (23%; P < 0.001).
Similarly, BAOCHE [26] randomized 217 adults with BAO to IAT or maximal medical management within 6 to 24 hours of symptom onset.Functional outcomes were significantly better with IAT (46%) compared to medical management (24%; P < 0.001).

Anesthesia
The General or Local Anesthesia in Intra-Arterial Therapy (GOLIATH) trial [27] was a singlecenter PROBE trial comparing general anesthesia to conscious sedation in 128 patients undergoing IAT for AIS due to LVO and found similar outcomes between the two groups [27].

Thrombectomy With or Without Thrombolysis
Additional trials have focused on the role of intravenous alteplase (IV-tPA or intravenous tissue plasminogen activator) plus IAT compared to IAT alone.The DIRECT-MT trial [28] was a randomized PROBE trial that enrolled 656 eligible patients with AIS within 4.5 hours of LKW.The trial, conducted at 41 academic tertiary care centers in China, demonstrated the non-inferiority of IAT alone compared to a combination of IV-tPA followed by thrombectomy [28].
MR CLEAN NO-IV [29] was an open-label, multicenter, RCT in Europe involving 539 patients who underwent IAT alone or IV-tPA followed by IAT and also demonstrated non-inferiority of IAT alone with similar 90-day outcomes and disability scores [29].The DEVT [30] trial, conducted at 33 stroke centers in China, also demonstrated non-inferiority of IAT alone compared to IV-tPA plus IAT in 90-day functional independence [30].
The SKIP [31] trial, however, failed to demonstrate non-inferiority of IAT alone compared to IAT following IV thrombolysis among 204 patients with acute LVO.With IAT alone, 59.4% of patients had a favorable functional outcome compared to 57.3% with IV thrombolysis plus IAT (OR, 1.09; 95% CI, 0.63 to ∞), but may have been underpowered [31].The SWIFT DIRECT [32] trial also failed to demonstrate the non-inferiority of IAT alone compared to IV-tPA plus IAT.A total of 408 patients with anterior circulation LVO within 4.5 hours of symptom onset and NIHSS ≥ 5 were randomized, and thrombectomy alone had decreased rates of TICI 2b/3 reperfusion compared to IV-tPA followed by IAT (91% vs. 96%; P = 0.047) [32].

Other Trials
The CHOICE [33] trial was a phase 2b randomized, placebo-controlled, double-blind trial of intraarterial alteplase compared to placebo in 121 patients after IAT, which demonstrated a greater likelihood of excellent 90-day neurological outcome (mRS 0-1) in the treatment arm compared to placebo (59% vs. 40.4%;P = 0.047) [33].

Upcoming Trials
DIRECT-SAFE [34] is an international multicenter PROBE non-inferiority trial that aims to randomize 780 patients presenting within 4.5 hours of LKW to either direct IAT or IV-tPA followed by IAT (NCT03494920).

Ischemic stroke/thrombolysis
Time Window and Wake-Up Strokes ECASS-4 [35] enrolled 119 patients with LVO stroke between 4.5 and 9 hours after symptom onset to either IV-tPA or placebo.The trial was stopped early due to slow recruitment and failed to show a significant benefit over placebo during the extended time window [35].
The WAKE-UP [36] trial compared IV-tPA to placebo in patients with unknown symptom onset.Patients with diffusion restriction on MRI but no corresponding finding on FLAIR were randomized.Alteplase demonstrated significantly improved functional outcomes but higher rates of ICH compared to placebo [36].
The EXTEND [37] trial had a similar aim of MRI-guided thrombolysis for LVO stroke patients presenting with an unknown LKW time but was stopped early after the WAKE-UP [36] trial was published in 2018.In patients with a mismatch between DWI and FLAIR on MRI, IV-tPA demonstrated a significant improvement in functional outcome resulting in higher rates of any intracranial hemorrhage (ICH) event at 90 days compared to placebo [37].
Similarly, THAWS [38] also aimed to evaluate MRI-guided thrombolysis with IV-tPA in patients with unknown LKW but was stopped early when the WAKE-UP [36] trial was published.Early results failed to show any significant benefit of alteplase over placebo but demonstrated comparable safety [38].
Tenecteplase NOR-TEST 2 [39] was a non-inferiority phase 3 PROBE trial following the NOR-TEST trial [40], which showed 0.4 mg/kg of tenecteplase was similar to 0.9 mg/kg of IV alteplase [40].NOR-TEST 2 was stopped early due to worse safety and functional outcomes with 0.4 mg/kg tenecteplase compared to the standard alteplase dose.NOR-TEST 2 Part B, with an IV tenecteplase dose of 0.25 mg/kg, is ongoing (NCT01949948).
The original EXTEND-IA TNK trial [42] was a phase 2 multicenter PROBE trial demonstrating that 0.25 mg/kg IV tenecteplase (maximum dose 25 mg) improved reperfusion in patients with LVO within 4.5 hours of symptom onset compared to standard dose IV alteplase [42].
EXTEND-IA TNK Part 2 [43] compared IV tenecteplase at 0.40 to 0.25 mg/kg in patients with LVO due to AIS within 4.5 hours of LKW who subsequently underwent endovascular thrombectomy and demonstrated similar rates of all-cause mortality and symptomatic ICH within 36 hours [43].Thus, a higher dose of IV tenecteplase did not confer an advantage in patients in whom IAT was planned [43].

Upcoming Trials
TEMPO-2 is an RCT of tenecteplase versus standard of care for minor ischemic stroke or transient ischemic attack (TIA) within 12 hours of onset that is currently recruiting (NCT02398656).
TASTE is an ongoing multicenter PROBE trial comparing 0.25 mg/kg IV tenecteplase to the standard dose of alteplase for patients with large vessel occlusion (LVO) stroke within 4.5 hours of symptom onset (ACTRN12613000243718).

Alternative Thrombolytics
The FRIDA [44] trial was an open-label, non-inferiority RCT conducted at 18 sites in Russia that enrolled 385 patients and compared nonimmunogenic staphylokinase to standard alteplase within 4.5 hours of stroke onset.Staphylokinase was non-inferior to alteplase with similar rates of serious adverse events [44].

Ischemic stroke/TIA
Several trials have investigated the safety and efficacy of dual antiplatelet therapy with clopidogrel or ticagrelor plus aspirin compared to aspirin alone for secondary prevention of stroke following TIA or minor ischemic stroke.

Dual Antiplatelet Therapy
The POINT [45] trial randomized 4,881 patients with minor ischemic stroke or high-risk TIA to either clopidogrel plus aspirin or aspirin alone and was halted early due to a significantly decreased risk of stroke in the dual antiplatelet group at 90 days [45].However, there was a higher risk of major hemorrhage at 90 days in the dual antiplatelet group (0.9%) compared to aspirin alone (0.4%; hazard ratio, 2.32; 95% CI, 1.10-4.87;P = 0.02) [45].
The THALES [46] trial randomized 11,016 patients with minor ischemic stroke or TIA who did not undergo thrombectomy to either ticagrelor plus aspirin or aspirin alone.Ticagrelor added to aspirin was superior to aspirin alone in preventing recurrent stroke [46] as well as disabling stroke and death at 30 days [47].
The TARDIS [48] trial compared triple antiplatelet therapy (aspirin, clopidogrel, and dipyridamole) with either clopidogrel alone or combined aspirin and dipyridamole in patients with ischemic stroke or TIA within 48 hours of onset.They found no difference in the rate or severity of recurrent TIAs or strokes but did find a significant increase in the risk of major bleeding among the triple antiplatelet group [48].CHANCE-2 [49] was a double-blind, placebo-controlled RCT that compared ticagrelor plus aspirin to clopidogrel plus aspirin in carriers of the CYP2C19 loss-of-function mutation that presented with minor ischemic stroke or TIA.Results demonstrated a decreased risk of stroke at 90 days with ticagrelor compared to clopidogrel in patients with the CYP2C19 loss-of-function mutation [49].

Updates
The CHANCE [50] trial, first published in 2013, demonstrated the superiority of aspirin plus clopidogrel over aspirin alone for the prevention of recurrent stroke in patients with TIA or minor ischemic stroke treated within 24 hours.A 2018 subgroup analysis found a 50% risk reduction in stroke recurrence in patients with multiple acute infarctions treated with both aspirin and clopidogrel compared with aspirin alone -a finding not seen in patients with one or fewer acute infarctions [51].

Minor Nondisabling Strokes
Among 313 patients with minor non-disabling strokes (NIHSS 0-5), the PRISMS study [52] concluded that alteplase or aspirin had no significant effect on 90-day functional outcomes.However, the study was terminated early precluding any definitive conclusions [52].

Blood Pressure Goals
The ENCHANTED [53] trial randomized 2,227 patients within six hours of AIS onset to either intensive systolic blood pressure (SBP) management (SBP 130-140 mmHg) or standard therapy (SBP < 180 mmHg) for 72 hours.Although intensive BP management was safe with fewer intracerebral hemorrhage events than the intensive group (14.8% vs. 18.7%;P = 0.0137), there was no difference in 90-day functional status.The CHASE [54] trial also failed to demonstrate a significant benefit with a 10% to 15% SBP reduction compared to standard SBP in 90-day rates of dependence or death [54].BP-TARGET [55] did not find a significant reduction in the rate of intraparenchymal hemorrhage or hypotensive events after intensive SBP lowering (SBP 100-129 mmHg) compared to a standard SBP target (SBP 130-185 mmHg) after successful IAT in patients with LVO stroke [55].

Upcoming Trials
INDIVIDUATE [56] is a single-center PROBE trial that randomized 250 patients with LVO undergoing IAT to either a standard intraprocedural SBP goal (SBP 140-180 mmHg) or an individualized approach of SBP maintained at the level on presentation (±10 mmHg).

Mobile Stroke Units
Several studies have investigated prehospital interventions for stroke management, including mobile stroke units (MSUs) for triage and intervention.RACECAT [57] randomized 1,401 patients with suspected LVO stroke to either a thrombectomy-capable center or the closest local stroke center and found no significant difference in 90-day neurological outcomes [57].The Mobile Stroke Unit (MSU) in Rural Areas [57] trial, however, was able to demonstrate that MSUs are valuable for enabling accurate triage decisions for patients with stroke-like symptoms [58].The RIGHT-2 [59] trial evaluated the safety and efficacy of prehospital administration of transdermal glyceryl trinitrate (GTN) but did not find any improvement in functional outcomes in patients with presumed stroke [59].

Statins
There was no difference in clinical outcomes at 90 days in 65 patients with AIS randomized to high-dose or low-dose simvastatin within 24 hours of symptom onset [60].

Glucose Control
The SHINE [61] trial randomized 1,151 patients with AIS within 12 hours of symptom onset to intensive blood glucose control (80-130 mg/dL) or standard glucose control (80-179 mg/dL) for up to 72 hours with no significant difference in favorable functional outcome at 90 days.Hypoglycemia or other adverse events occurred in 11.2% of patients in the intensive arm compared to only 3.2% of patients in the standard treatment arm, and the trial was terminated early as a result [61].

Sonothrombolysis
CLOTBUST-ER [62] randomized 335 patients to sonothrombolysis for patients with AIS due to LVO who were treated with alteplase compared to 341 patients in the control group and found no significant clinical benefit at 90 days [62].

Sphenopalatine Ganglion Stimulation
The ImpACT-24A [63] and ImpACT-24B [64] trials enrolled patients with AIS due to LVO who were not eligible for IAT to sphenopalatine ganglion stimulation 8 to 24 hours after symptom onset.No significant difference in outcomes was found.Subgroup analysis suggested a trend toward improved functional outcomes in patients with radiographic evidence of cortical involvement at presentation.

Ischemia Reperfusion
In the ESCAPE-NA1 [65] trial, IV nerinetide, a neuroprotectant, administered following IAT did not improve functional outcomes at 90 days.Secondary outcomes, including functional and neurological measures of disability, were also similar between groups [65].

Aneurysms
Management An interim analysis of the ISAT-2 [66] trial, which was a randomized trial of endovascular versus surgical management of ruptured intracranial aneurysms, found complete aneurysm obliteration in 85% (23/27) of the surgical patients compared to 67% (18/27) of the endovascular coiling patients at one-year follow-up, but a higher rate of hospital stays exceeding 20 days in the surgical group (47%) compared to the endovascular group (19%) [66].

Updates
An intent-to-treat analysis of the BRAT [67] trial showed similar mRS scores at any follow-up time for surgical clipping or endovascular coiling but significantly lower rates of retreatment in the surgical group [68].Ten-year outcomes of the BRAT trial demonstrated better obliteration rates in the surgical group but similar long-term outcomes between groups [69].A subgroup analysis found better clinical outcomes in posterior circulation aneurysms treated endovascularly at one year, but no difference beyond one year [69].

Upcoming Trials
MCAAT [70] is a multicenter, parallel-group, prospective RCT of the ruptured and unruptured middle cerebral artery (MCA) aneurysms randomized to surgical or endovascular treatment (NCT05161377).

Seizure Prophylaxis
The SPAR [71] trial found no reduction in the rate of early seizures after seven days of perioperative seizure prophylaxis with levetiracetam in patients undergoing surgical treatment of unruptured intracranial aneurysms compared to those who did not receive levetiracetam [71].
The GREAT [73] trial investigated the efficacy of second-generation hydrogel coils compared to bare metal coils and found a significant reduction in aneurysm recurrence, retreatment, morbidity, and death during treatment and follow-up [73].The HEAT [74] trial similarly found a decreased rate of aneurysm recurrence in patients with small-to-medium aneurysms treated with the second-generation HydroCoil Embolic System (HES; MicroVention, Inc., Aliso Viejo, CA) compared to bare platinum coils [74].

Prospective Cohort Studies
The WEB-IT [75] trial found that the WEB device (MicroVention, Inc.) was safe and effective for wide-neck bifurcation aneurysms [75].In the TARGET [76] trial of TARGET-360° or helical coils (Penumbra) more than two-thirds of aneurysms achieved long-term complete occlusion [76].The SCENT [77] trial evaluated the Surpass FD (Stryker Neurovascular, Portage, MI).The CERUS [78] trial investigated the Contour Neurovascular System (Cerus Endovascular, Fremont, CA), and the FRED [79] trial investigated the safety and efficacy of the Flow Redirection Endoluminal Device (MicroVention, Inc.) in the treatment of intracranial aneurysms.

Updates
A five-year update of outcomes from the MAPS [80] trial demonstrated that Matrix2 coils (Boston Scientific, Natick, MA) were non-inferior to bare metal coils but with no significant difference in radiographic or clinical outcomes [81].
A three-year analysis of the WEBCAST and WEBCAST-2 registries found a high safety profile of WEB with adequate occlusion (complete occlusion or neck remnant) in 83.6% of cases [82].

Endovascular Coiling
The DELTA [83] trial demonstrated that 15-caliber coils significantly improved the packing density in 4 to 12 mm unruptured aneurysms compared with 10-caliber coils but had no significant impact on radiographic or clinical outcomes at one year [83].

Prospective Cohort Registry
Long-term results of a post-market, prospective, multicenter registry of the Penumbra SMART COIL system (Penumbra) demonstrated Raymond Roy occlusion I or II in 90.0% of aneurysms and a 6.8% re-treatment rate at one year [84].

Anesthesia
The Deep NMB [85] trial demonstrated improved angiographic image quality during endovascular coiling of unruptured cerebral aneurysm in the group randomized to deep neuromuscular blockade (NMB) compared to the moderate NMB group [85].

Aneurysm Re-bleeding
In the ULTRA [86] trial, tranexamic acid (TXA) did not improve clinical outcomes at six months in aneurysmal SAH (aSAH) patients.While no significant difference in the re-bleeding rate was appreciated, there was a favorable trend toward decreased re-bleeding in the TXA group [86].

Upcoming Trials
FIVHeMA [87] is an upcoming trial investigating the safety and efficacy of intraventricular fibrinolysis in aSAH.

Cerebral Vasospasm and Delayed Cerebral Ischemia
Atorvastatin reduced the rate of cerebral vasospasm and infarction in ruptured aneurysms with SAH but did not improve six-month clinical outcomes [88].Similar findings were seen with pitavastatin, which reduced the rate of radiographic vasospasm compared to placebo (14.8% vs. 33.3%;OR, 0.32; 95% CI, 0.11-0.87;P = 0.042) but did not significantly reduce the rate of delayed cerebral ischemia (DCI) or new neurologic deficits [89].
IV magnesium sulfate infusion plus oral nimodipine reduced the incidence of DCI and new neurological deficits but did not decrease the incidence of re-hemorrhage or death [90].A separate study of IV hydrogen therapy plus intracisternal magnesium sulfate infusion in poor-grade SAH patients undergoing surgery similarly demonstrated a reduced incidence of vasospasm and ischemia [91].
In the HIMALAIA [92] trial, patients with aSAH and clinical signs or symptoms of DCI were randomized to induced hypertension or no intervention, but the trial was stopped early due to a lack of effect on cerebral perfusion and slow recruitment.The adjusted risk ratio for poor outcome was 1.0 (95% CI, 0.6-1.8)and the risk ratio for serious adverse events (SAEs) was 2.1 (95% CI, 0.9-5.0),suggesting no significant benefit and an increased risk of SAEs in the treatment group [92].
The PiSAH trial [93] randomized 108 patients to a control group or goal-directed hemodynamic therapy (GDHT) to optimize mean arterial pressure, cardiac index, global end-diastolic index, and extravascular lung water index using vasopressor, inotropes, and crystalloid with specific goals in the presence or absence of vasospasm [93].Results showed GDHT reduced the rate of DCI after aSAH from 32% in the control group to 13% in the GDHT group (OR, 0.32; 95% CI, 0.11-0.86;P = 0.021), with improved functional outcome three months after discharge.

Tranexamic Acid
The TXA for hyperacute primary Intracerebral Hemorrhage (TICH-2) [94] trial randomized 2,325 participants to 1 g of IV-TXA followed by an eight-hour infusion or a matching placebo administered within eight hours of symptom onset.The trial found a reduction in early deaths at seven days but no significant difference in functional status at 90 days [94].

Hematoma Evacuation
MISTIE III [95] was an international, multicenter, phase 3 PROBE trial that included 499 adult patients with spontaneous supratentorial ICH of 30 cc or greater and compared minimally invasive catheter evacuation followed by thrombolysis to standard medical management.The study group found that ICH evacuation was safe but not effective at improving functional outcomes for one year [95].

Fluoxetine
The FMRICH [96] trial found that fluoxetine initiated within 10 days of symptomatic ICH and maintained for three months was safe and effective at increasing motor recovery at 90 days [96].

Upcoming Trials
Hematoma evacuation: The Endoscopic IVH [97] trial is a multicenter, prospective, RCT in China that will randomize 956 patients with moderate-to-severe intraventricular hemorrhage (IVH) to either endoscopic evacuation or external ventricular drainage, with a primary endpoint of survival at 12 months (NCT04037267).
Critical care/anesthesia: The ASSICHH [98] trial is a multicenter, prospective, RCT in China that aims to enroll 354 subjects in early, rapid blood pressure stabilization with either analgesic (remifentanil and dexmedetomidine) or antihypertensive (urapidil, nicardipine, and labetalol) medications.

Dexamethasone
In an interim analysis of the first registered prospective randomized placebo-controlled trial (PRPCT) of adjuvant dexamethasone [99], 47 patients who underwent evacuation and drainage for chronic subdural hematoma (cSDH) were randomized to either a two-week dexamethasone taper or placebo [99].There were fewer recurrences in the dexamethasone group (0/23, 0%) compared to the placebo group (5/24, 20.83%; P = 0.049) and no significant difference in morbidity, mortality, or length of stay [99].

Prednisone
The HEMACORT [101] trial found that postoperative prednisone administered at a dose of 1 mg/kg/day followed by weekly stepwise tapering of 10 mg/day demonstrated an earlier radiographic resolution but led to increased rates of SAEs including sleep disorders.

Subdural Drains
In the cSDH-Drain trial [103], subperiosteal drains (SPDs) were non-inferior to subdural drains (SDDs) after the burr-hole evacuation of cSDH, although there was a trend toward lower recurrence, fewer surgical infections, and fewer drain misplacements with SPDs [103].

Anesthesia
The inhalational anesthesia [104] trial demonstrated that total IV-propofol infusion provided better brain relaxation, lower intracranial pressure, and better hemodynamics to inhalational anesthesia with sevoflurane in patients with acute subdural hematoma undergoing emergency evacuation [104].

Hypothermia
In patients with acute subdural hematomas requiring emergent evacuation, the HOPES [105] trial found no statistically significant difference in functional outcome between patients randomized to a core temperature of 35 °C before dura opening followed by 33 °C for 48 hours compared with normothermia of 37 °C [105].

Endovascular Therapy
The TO-ACT [106] trial was a multicenter, international RCT that enrolled 67 patients with symptomatic or deep CVT to either EVT or standard medical management.The trial failed to show any significant improvement in functional outcomes in the EVT group.There was no significant difference in morbidity or mortality between the two groups.Due to a small sample size, future trials should investigate the role of EVT in symptomatic or deep CVT [106].

ARUBA Final Follow-Up
A final follow-up of the ARUBA trial published in the Lancet in 2020 [109] found that multimodal treatment of selected patients with brain AVMs did better than the ARUBA intervention arm and similar to the ARUBA medical arm at five years, suggesting that the controversial results of the original ARUBA trial [110,111] remain in question.

Anesthesia
The SedLine [112] trial evaluated processed electroencephalogram (EEG)-guided anesthesia management in patients undergoing carotid endarterectomy (CEA) and found a reduced risk of postoperative delirium in these patients.
In the SONOBIRDIE [113] trial, 210 patients were randomized 1:1 to CEA with local anesthesia (LA) or general anesthesia (GA).The study authors found an increased rate of clinically silent radiographic strokes in the GA group compared to the LA group but no difference in clinical outcomes or other complications [113].

Endovascular Stenting
The Vertebral Artery Ischemia Stenting RCT (VIST RCT) [114] was a PROBE clinical trial comparing vertebral artery angioplasty and stenting to best medical management in 182 patients with symptomatic vertebral artery stenosis of at least 50% or more.The trial found no difference in risk of the primary endpoint between the two groups but failed to meet its target recruitment and suffered from a high rate of unconfirmed stenosis in the stented group [114].

Anesthesia
Only two studies were published on extracranial-intracranial (EC-IC) bypass.The dobutamine versus phenylephrine [115] trial was a randomized crossover study that found both dobutamine and phenylephrine increased graft flow during EC-IC bypass surgery.The sevoflurane and hyperperfusion syndrome [116] study found that sevoflurane post-conditioning did not increase the rate of symptomatic cerebral hyperperfusion (SCH) after EC-IC bypass in patients with Moyamoya disease [116].

Limitations
Our literature review has some limitations.To make our review more feasible, we were only able to include phase 2b or 3 trials and excluded other types of RCTs.Despite efforts to create a comprehensive search strategy, the possibility of excluding pertinent studies remains.The inclusion of our search terms for reproducibility, while not universally converted across all databases, restricts our reporting to the overall number of articles reviewed.It is crucial to acknowledge the enormity of this review, and our findings are current only as of July 1, 2022.A summary of the major trials is given in Table 1.Routine seizure prophylaxis did not improve clinical outcomes for unruptured intracranial aneurysms undergoing surgical intervention and TXA for subarachnoid hemorrhage showed promising but not significant results in the ULTRA trial.TXA and clot evacuation were not successful at improving outcomes in intracerebral hemorrhage patients.In subdural hematoma patients, dexamethasone was associated with worse clinical outcomes but fewer recurrences or repeat surgeries.TO-ACT failed to demonstrate the efficacy of endovascular therapy for CVT, and RE-SPECT CVT showed that both dabigatran and warfarin may be safe and effective treatments for CVT.Although many trials have been performed in stroke, mechanical thrombectomy, and thrombolysis, the remainder of cerebrovascular neurosurgery faces a shortage of RCTs due to numerous limitations.This review helps define the scope of the large RCTs published in the last four years to guide future research and clinical practice.

FIGURE 1 :
FIGURE 1: PRISMA flowchart details the results of the literature search for all randomized controlled trials (RCTs) in cerebrovascular neurosurgery published between January 1, 2018, and July 1, 2022.PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

FIGURE 2 :
FIGURE 2: Breakdown of randomized controlled trials (RCTs) included in the review.

TIA, transient ischemic attack Conclusions Numerous
RCTs were published in cerebrovascular neurosurgery between 2018 and July 2022.RCTs on the management of ischemic stroke, including mechanical thrombectomy and thrombolysis, accounted for the majority of publications.Mechanical thrombectomy within 24 hours was more effective than medical management alone in the DAWN, DEFUSE, and RESILIENT trials.The RESCUE-Japan trial expanded indications for mechanical thrombectomy in patients with low ASPECTS.The demonstrated non-inferiority of IAT alone compared to IV alteplase followed by IAT in the DIRECT-MT, MR CLEAN NO-IV, and DEVT trials directly influenced clinical care.Several trials, including AcT, EXTEND-IA TNK, and EXTEND-IA TNK Part 2, showed non-inferiority of 0.25 mg/kg of IV tenecteplase compared to IV alteplase for LVO stroke within 4.5 hours of symptom onset.