Safety and Efficacy of Cangrelor in Acute Stroke Treated with Mechanical Thrombectomy: Endovascular Treatment of Ischemic Stroke Registry and Meta-analysis.

BACKGROUND AND PURPOSE: Rescue therapies are increasingly used in the setting of endovascular therapy for large-vessel occlusion strokes. Among these, cangrelor, a new P2Y12 inhibitor, offers promising pharmacologic properties to join the reperfusion strategies in acute stroke. We assessed the safety and efficacy profiles of cangrelor combined with endovascular therapy in patients with large-vessel-occlusion stroke. MATERIALS AND METHODS: We performed a retrospective patient data analysis in the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France from July 2018 to December 2020 and conducted a systematic review and meta-analysis using several data bases. Indications for cangrelor administration were rescue strategy in case of refractory intracranial occlusion with or without intracranial rescue stent placement, and cervical carotid artery stent placement in case of cervical occlusion (tandem occlusion or isolated cervical carotid occlusion). RESULTS: In the clinical registry, 44 patients were included (median initial NIHSS score, 12; prior intravenous thrombolysis, 29.5%). Intracranial stent placement was performed in 54.5% (n = 24/44), and cervical stent placement, in 27.3% (n = 12/44). Adjunctive aspirin and heparin were administered in 75% (n = 33/44) and 40.9% (n = 18/44), respectively. Rates of symptomatic intracerebral hemorrhage, parenchymal hematoma, and 90-day mortality were 9.5% (n = 4/42), 9.5% (n = 4/42), and 24.4% (n = 10/41). Favorable outcome (90-day mRS, 0-2) was reached in 51.2% (n = 21/41), and successful reperfusion, in 90.9% (n = 40/44). The literature search identified 6 studies involving a total of 171 subjects. In the meta-analysis, including our series data, symptomatic intracerebral hemorrhage occurred in 8.6% of patients (95% CI, 5.0%-14.3%) and favorable outcome was reached in 47.6% of patients (95% CI, 27.4%-68.7%). The 90-day mortality rate was 22.6% (95% CI, 13.6%-35.2%). Day 1 artery patency was observed in 89.7% (95% CI, 81.4%-94.6%). CONCLUSIONS: Cangrelor offers promising safety and efficacy profiles, especially considering the complex endovascular reperfusion procedures in which it is usually applied. Further large prospective data are required to confirm these findings.

A Multicenter Preliminary Study of Cangrelor following Thrombectomy Failure for Refractory Proximal Intracranial Occlusions.

BACKGROUND AND PURPOSE: Rescue endovascular and pharmacologic approaches are increasingly being adopted after recanalization failure of acute large-vessel occlusion strokes with mechanical thrombectomy, with encouraging results. The safety and efficacy of glycoprotein IIb/IIIa inhibitors in ischemic stroke have been investigated, though cangrelor, a recent intravenous P2Y12-receptor inhibitor with a rapid onset/offset of action and a short half-life, may be a valuable option. We compared the safety and efficacy of cangrelor with those of glycoprotein IIb/IIIa inhibitors for refractory occlusions. MATERIALS AND METHODS: We performed a retrospective analysis of the ongoing prospective, multicenter, observational Endovascular Treatment in Ischemic Stroke Registry in France between May 2012 and February 2020. Refractory intracranial occlusions of the anterior and posterior circulation were included and defined as recanalization failure of large-vessel occlusion stroke, perioperative target artery reocclusion, or high risk of early reocclusion related to an arterial wall lesion. The primary end point was a favorable outcome, defined as a 90-day mRS of 0-2. Secondary end points were reperfusion, intracranial hemorrhage, and procedural complications. RESULTS: Among 69 patients, 15 were treated with cangrelor, and 54, with glycoprotein IIb/IIIa inhibitors. The favorable outcome (adjusted OR = 2.22; 95% CI, 0.42-11.75; P = .348) and mortality (adjusted OR = 0.44; 95% CI, 0.06-3.16; P = .411) rates were similar in both groups. There was no difference in the rates of any intracranial hemorrhage (adjusted OR = 0.40; 95% CI, 0.08-2.09; P = .280), symptomatic intracranial hemorrhage (6.7% versus 0.0%, P = .058), or procedural complications (6.7% versus 20.4%, P = .215). Reperfusion rates were higher in the cangrelor group, though the difference did not reach statistical significance (93.3% versus 75.0% for modified TICI 2b-3; adjusted OR =10.88; 95% CI, 0.96-123.84; P = .054). CONCLUSIONS: Cangrelor seems to be as safe as glycoprotein IIb/IIIa inhibitors for managing refractory intracranial occlusion and leads to satisfactory brain reperfusion. Cangrelor is a promising agent in this setting, and additional studies are warranted to confirm our findings.

Fusion Image Guidance for Supra-Aortic Vessel Catheterization in Neurointerventions: A Feasibility Study.

BACKGROUND AND PURPOSE: Endovascular navigation through tortuous vessels can be complex. Tools that can optimise this access phase need to be developed. Our aim was to evaluate the feasibility of supra-aortic vessel catheterization guidance by means of live fluoroscopy fusion with MR angiography or CT angiography. MATERIALS AND METHODS: Twenty-five patients underwent preinterventional diagnostic MRA, and 8 patients underwent CTA. Fusion guidance was evaluated in 35 sessions of catheterization, targeting a total of 151 supra-aortic vessels. The time for MRA/CTA segmentation and fluoroscopy with MRA/CTA coregistration was recorded. The feasibility of fusion guidance was evaluated by recording the catheterizations executed by interventional neuroradiologists according to a standard technique under fluoroscopy and conventional road-mapping independent of the fusion guidance. Precision of the fusion roadmap was evaluated by measuring (on a semiquantitative 3-point scale) the maximum offset between the position of the guidewires/catheters and the vasculature on the virtual CTA/MRA images. The targeted vessels were divided in 2 groups according to their position from the level of the aortic arch. RESULTS: The average time needed for segmentation and image coregistration was 7 ± 2 minutes. The MRA/CTA virtual roadmap overlaid on live fluoroscopy was considered accurate in 84.8% (128/151) of the assessed landmarks, with a higher accuracy for the group of vessels closer to the aortic arch (92.4%; OR, 4.88; 95% CI, 1.83-11.66; P = .003). CONCLUSIONS: Fluoroscopy with MRA/CTA fusion guidance for supra-aortic vessel interventions is feasible. Further improvements of the technique to increase accuracy at the cervical level and further studies are needed for assessing the procedural time savings and decreasing the x-ray radiation exposure.

Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.

Early successful reperfusion after endovascular therapy reduces malignant middle cerebral artery infarction occurrence in young patients with large diffusion-weighted imaging lesions.

BACKGROUND AND PURPOSE: Malignant middle cerebral artery infarction (MMI) is a severe complication of acute ischaemic stroke (AIS). The aim of our study was to assess whether successful reperfusion after endovascular therapy (EVT) in AIS with clinical and imaging predictors of MMI decreased its occurrence. METHODS: Data were collected between January 2014 and July 2018 in a monocentric prospective AIS registry of patients treated with EVT. Patients selected were <65 years old with severe anterior circulation AIS with a National Institutes of Health Stroke Scale score >15, baseline Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score ≤ 6 and baseline diffusion-weighted imaging lesion volume >82 mL within 6 h of symptom onset. Successful reperfusion was defined as a Thrombolysis in Cerebral Ischemia score ≥ 2b. Occurrence of MMI was the primary endpoint. RESULTS: A total of 66 EVT-treated patients were included in our study. MMI occurred in 27 patients (41%). In unadjusted analysis, successful reperfusion was associated with fewer MMIs (31.8% vs. 65.0%; P = 0.015) and with more favorable outcome at 3 months (50% vs. 20%; P = 0.023). In multivariate analysis, successful reperfusion was associated with an adjusted odds ratio (95% confidence intervals) of 0.35 (0.10-1.12) for MMI and 2.77 (0.84-10.43) for 3-month favorable outcome occurrence. CONCLUSIONS: Early successful reperfusion performed in patients with AIS with clinical and imaging predictors of MMI was associated with decreased MMI occurrence. Reperfusion status might be considered in evaluating the need for craniectomy in patients with early predictors of MMI.

Two-layered susceptibility vessel sign is associated with biochemically quantified thrombus red blood cell content.

BACKGROUND AND PURPOSE: Better characterization of the thrombus could be useful to determine acute ischaemic stroke (AIS) aetiology and predict response to thrombolysis and endovascular therapy (EVT). To test the hypothesis that susceptibility vessel sign (SVS) on baseline magnetic resonance imaging (MRI) is related to red blood cell (RBC) content of AIS thrombi, the total haemoglobin contents (HbCs) of AIS thrombi retrieved by EVT from patients with or without SVS or two-layered SVS (TLSVS) were compared. METHODS: Baseline MRI of 84 anterior AIS patients was reviewed by neuro-radiologists blinded to clinical and biochemical data. Thrombi from these patients were retrieved by EVT and analysed for HbC by quantitative enzyme-linked immunosorbent assay and measurement of haem concentration. RESULTS: Susceptibility vessel sign and TLSVS were respectively observed in 85.7% and 50.0% of cases. The median HbC content was 253 µg/mg thrombus (interquartile range 177-333) and the median haem content was 219 µg/mg thrombus (131-264). Thrombus HbC and haem content were highly correlated with thrombus RBC content determined by flow cytometry (r = 0.94). Thrombi from patients with TLSVS weighed more [31.1 (16.5-68.3) mg vs. 17.7 (11.7-33.3) mg; P = 0.005] and had a higher HbC content [278 (221-331) µg/mg vs. 196 (139-301) µg/mg; P = 0.010] compared to thrombi from patients without TLSVS. There was no difference in thrombus weight or HbC content according to SVS status. CONCLUSIONS: Our study shows that TLSVS is significantly associated with a higher thrombus weight and RBC content, as determined by quantitative assays.

Endovascular Treatment for Low-Grade (Spetzler-Martin I-II) Brain Arteriovenous Malformations.

BACKGROUND AND PURPOSE: Surgical resection is usually considered as the first-line curative strategy for low-grade (Spetzler-Martin grade I-II) brain arteriovenous malformations because it has a high cure rate and low complications. The role of endovascular treatment remains to be clarified in this indication, especially after A Randomized Trial of Unruptured Brain Arteriovenous Malformations. Our objective was to assess the safety and efficacy of first-line endovascular treatment in low-grade brain arteriovenous malformation management at our institution. MATERIALS AND METHODS: Patients with low-grade brain arteriovenous malformations treated primarily with embolization in our department between January 2005 and December 2015 were retrieved from our prospectively collected registry. The primary outcome was the brain arteriovenous malformation obliteration rate, and secondary outcomes were disability or death secondary to brain arteriovenous malformation embolization assessed through modification of the modified Rankin Scale. RESULTS: Two hundred twenty-four patients completed endovascular treatment during the study period and represent our study population. Complete exclusion of brain arteriovenous malformations was achieved in 205 patients (92%), including 62.1% of brain arteriovenous malformation exclusions after a single endovascular treatment session. One patient died of a hemorrhagic complication after endovascular treatment, leading to a mortality rate of 0.4%. Twelve patients (5%) kept a permanent neurologic deficit secondary to a complication of the endovascular treatment. An overall good outcome (mRS 0-2) was reported in 179 patients (80%). CONCLUSIONS: Endovascular treatment might be a suitable alternative to surgical resection for complete exclusion of selected low-grade brain arteriovenous malformations.

Application of the DAWN clinical imaging mismatch and DEFUSE 3 selection criteria: benefit seems similar but restrictive volume cut-offs might omit potential responders.

BACKGROUND AND PURPOSE: An external validation of the selection criteria of diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake-up and late-presenting strokes undergoing the Neurointervention with Trevo (DAWN) and the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE3) trials was conducted in a cohort of unknown onset stroke (UOS) patients treated with thrombectomy. METHODS: A validation cohort of UOS patients was selected from a prospectively collected thrombectomy database to match the inclusion criteria of DAWN and DEFUSE 3. Patients with an initial National Institutes of Health Stroke Scale (NIHSS) ≥10 were stratified according to the DAWN selection criteria. Patients ≤90 years old with an initial NIHSS ≥6 were stratified according to the DEFUSE 3 selection criteria. The proportions of patients with a modified Rankin Scale (mRS) ≤2 at 3 months follow-up were compared between DAWN-eligible patients and the DAWN trial thrombectomy group, and between DEFUSE 3-eligible patients and the DEFUSE 3 trial thrombectomy group. RESULTS: Of the 60/102 (59%) DAWN-eligible patients, 26 patients (43%) reached a mRS ≤2 at 3 months follow-up [versus 52/107 patients (49%) in the DAWN trial thrombectomy group; P = 0.52]. Of the 100/117 (85%) DEFUSE 3-eligible patients, 48 patients (48%) reached a mRS ≤2 at 3 months follow-up [versus 41/92 patients (45%) in the DEFUSE 3 trial thrombectomy group; P = 0.67]. Of the DAWN-ineligible and DEFUSE 3-ineligible patients who underwent thrombectomy, 38% (16/42) and 41% (7/17) of patients reached a mRS ≤2, respectively. CONCLUSION: The results of the DAWN and DEFUSE 3 trials were externally validated in a UOS cohort where the trials' selection criteria identified a similar proportion of responders to thrombectomy.

Unknown-onset strokes with anterior circulation occlusion treated by thrombectomy after DWI-FLAIR mismatch selection.

BACKGROUND AND PURPOSE: The DAWN trial recently showed compelling evidence in treating late window and wake-up stroke patients with thrombectomy using a clinical-imaging mismatch. The aim was to evaluate the results of thrombectomy for unknown-onset strokes (UOS) treated in our centres after a diffusion weighted imaging/fluid attenuated inversion recovery (DWI-FLAIR) mismatch based selection. METHODS: A multicentre, cohort study was performed of consecutive UOS treated by thrombectomy between 2012 and 2016. UOS with proximal anterior circulation occlusion discovered beyond 6 h from 'last seen normal' were compared with known-onset strokes (KOS) for whom thrombectomy was started within 6 h from onset. Time intervals were recorded from first time found abnormal. Results were adjusted for age, diabetes, hypertension, National Institutes of Health Stroke Scale, site of occlusion, DWI Alberta Stroke Programme Early CT Score, intravenous thrombolysis and use of general anaesthesia. RESULTS: Amongst 1246 strokes with anterior circulation occlusion treated by thrombectomy, 277 were UOS, with a 'last time seen well' beyond 6 h and DWI-FLAIR mismatch, and 865 were KOS who underwent groin puncture within 6 h. Favourable outcome was achieved less often in UOS than KOS patients (45.2% vs. 53.9%, P = 0.022). After pre-specified adjustment, this difference was not significant (adjusted relative risk 0.91; 95% confidence interval 0.80-1.04; P = 0.17). No differences were found in secondary outcomes. Time intervals from first found abnormal were significantly longer in UOS. CONCLUSION: Thrombectomy of UOS with anterior circulation occlusion and DWI-FLAIR mismatch appears to be as safe and efficient as thrombectomy of KOS within 6 h from onset. This pattern of imaging could be used for patient selection when time of onset is unknown.

Neurologic Complications of Infective Endocarditis: Recent Findings.

PURPOSE OF REVIEW: The purpose of this paper is to provide recent insights in management of neurologic complications of left-sided infective endocarditis (IE). RECENT FINDINGS: Cerebral lesions observed in IE patients are thought to involve synergistic pathophysiological mechanisms including thromboembolism, sepsis, meningitis, and small-vessel cerebral vasculitis. Brain MRI represents a major tool for the detection of asymptomatic events occurring in the majority of patients. The latter can impact therapeutic decisions and prognosis, especially when cardiac surgery is indicated. In patients presenting with neurologic complications, surgery could be safely performed earlier than previously thought. Symptomatic cerebral ischemic or hemorrhagic events occur in 20-55% of IE patients, whereas asymptomatic events are detected in 60-80% of patients undergoing systematic brain MRI. Management of such patients requires an experienced multidisciplinary team. Recent studies suggest that early cardiac surgery, when indicated, can be performed safely in patients with cerebral ischemic events. Other important issues include the appropriate use of anti-infective and anti-thrombotic agents, and endovascular treatment for mycotic aneurysms. Altered mental status at IE onset, which is associated with brain injury, is a major determinant of short-term outcome.

Impact of Modified TICI 3 versus Modified TICI 2b Reperfusion Score to Predict Good Outcome following Endovascular Therapy.

BACKGROUND AND PURPOSE: The TICI score is widely used to evaluate cerebral perfusion before and after the endovascular treatment of stroke. Recent studies showing the effectiveness and safety of mechanical thrombectomy combine modified TICI 2b and modified TICI 3 to assess the technical success of endovascular treatment. The purpose of this study was to determine how much clinical outcomes differ between patients achieving modified TICI 2b and modified TICI 3 reperfusion. MATERIALS AND METHODS: We analyzed 222 consecutive patients with acute large intracranial artery occlusion of the anterior circulation having achieved modified TICI 2b or modified TICI 3 reperfusion after thrombectomy. The primary end point was the rate of favorable outcome defined as the achievement of a modified Rankin Scale score of 0-2 at 3 months. RESULTS: Patients with modified TICI 3 more often had favorable collateral circulation and atherosclerosis etiology, with a shorter time from onset to reperfusion than patients with modified TICI 2b (all P < .05). The number of total passes to achieve reperfusion was higher in the modified TICI 2b group (median, 2; interquartile range, 1-3, 1-9) versus (median, 1; interquartile range, 1-2, 1-8) in the modified TICI 3 group (P = .0002). Favorable outcome was reached more often for patients with modified TICI 3 than for those with modified TICI 2b (71.7% versus 50.5%, P = .001), with a similar difference when considering excellent outcome. In addition, patients with modified TICI 3 had a lower intracerebral hemorrhage rate (23.0% versus 45.0%, P < .001). CONCLUSIONS: Patients with modified TICI 3 reperfusion have better functional outcomes than those with modified TICI 2b. Given the improving reperfusion rates obtained with thrombectomy devices, future thrombectomy trials should consider modified TICI 2b and modified TICI 3 status separately.

Parent artery occlusion in large, giant, or fusiform aneurysms of the carotid siphon: clinical and imaging results.

BACKGROUND AND PURPOSE: Parent artery occlusion has long been considered the reference treatment for large/giant or fusiform aneurysms of the carotid siphon. However, meager recent data exist on this technique, which tends to be replaced by stent-assisted reconstructive techniques. In our department since 2004, we have assessed the safety, efficacy, and complication risk factors of parent artery occlusion by using coils for trapping these aneurysms. MATERIALS AND METHODS: We determined retrospectively the complication rate, factors associated with the occurrence of an ischemic event, changes in symptoms of mass effect, evolution of the aneurysmal size, and the growth of an additional aneurysm after treatment. RESULTS: Fifty-six consecutive patients were included, with a median age of 54 years (range, 25-85 years; 92% women), 48% with giant aneurysms and 75% with infraclinoid aneurysms. There was a permanent morbidity rate of 5% exclusively due to ischemia, a zero mortality rate, an aneurysmal retraction rate of 91%, and an improvement rate for pain of 98% and for cranial nerve palsy of 72%, with a median follow-up of >3 years. Para-/supraclinoid topography of the aneurysm (P = .043) and the presence of cardiovascular risk factors (P = .024) were associated with an excessive risk of an ischemic event, whereas the presence of a mural thrombus had a protective role (P = .033). CONCLUSIONS: In this study, parent artery occlusion by using coils to treat large/giant or fusiform aneurysms of the carotid siphon was safe and effective, especially for giant infraclinoid aneurysms. According to recent meta-analyses, these results suggest that the validation of stent-assisted reconstructive treatments for these aneurysms requires controlled studies with parent occlusion artery.