Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Mechanical Thrombectomy in Nonagenarians: A Propensity Score Matched Analysis.

BACKGROUND: Little data exists on outcomes of mechanical thrombectomy (MT) in nonagenarians. We aimed to compare the procedural and discharge outcomes of MT for acute ischemic stroke (AIS) in nonagenarians versus younger patients. METHODS: Procedural outcomes and discharge disposition were compared in propensity score-matched groups of nonagenarians versus patients aged≤69 with AIS who underwent MT. Patients aged 70-89 were excluded in order to compare nonagenarians to a younger cohort that most closely approximates the age of patients in the seminal MT trials. Good discharge disposition was defined as a discharge to home or acute rehabilitation. RESULTS: Of 3010 AIS patients, 46/297(16%) nonagenarians underwent MT compared to 159/1337(12%) aged≤69 (P = 0.091). Of 78 propensity score-matched patients (N = 39 ≥90, N = 39 ≤69), the median admission NIHSS was 22 versus 20, median ASPECTS was 9 versus 9, pre-stroke mRS<4 was 82% versus 87%, 18% versus 8% received IV tPA, and mTICI≥2b was 90% versus 90%, respectively (all P>0.05). Revascularization time (569 versus 372 min), door to groin puncture time (82 versus 71 min) and groin puncture to revascularization times (39 versus 24 min) were similar in between nonagenarians and ≤69, respectively (both P>0.05). Symptomatic ICH (2.6% versus 10.3%; p = 0.165) and in-hospital death rates (10% vs 26%; p = 0.077) trended lower among nonagenarians versus aged≤69. Good discharge disposition occurred in 44% of nonagenarians versus 51% aged≤69 years (p = 0.496). CONCLUSIONS: In propensity score analysis, 90% of nonagenarians achieved successful recanalization and almost half (44%) were discharged to home/acute rehabilitation, which was similar to a younger (aged≤69 years) cohort.

The critical care management of spontaneous intracranial hemorrhage: a contemporary review.

Spontaneous intracerebral hemorrhage (ICH), defined as nontraumatic bleeding into the brain parenchyma, is the second most common subtype of stroke, with 5.3 million cases and over 3 million deaths reported worldwide in 2010. Case fatality is extremely high (reaching approximately 60 % at 1 year post event). Only 20 % of patients who survive are independent within 6 months. Factors such as chronic hypertension, cerebral amyloid angiopathy, and anticoagulation are commonly associated with ICH. Chronic arterial hypertension represents the major risk factor for bleeding. The incidence of hypertension-related ICH is decreasing in some regions due to improvements in the treatment of chronic hypertension. Anticoagulant-related ICH (vitamin K antagonists and the newer oral anticoagulant drugs) represents an increasing cause of ICH, currently accounting for more than 15 % of all cases. Although questions regarding the optimal medical and surgical management of ICH still remain, recent clinical trials examining hemostatic therapy, blood pressure control, and hematoma evacuation have advanced our understanding of ICH management. Timely and aggressive management in the acute phase may mitigate secondary brain injury. The initial management should include: initial medical stabilization; rapid, accurate neuroimaging to establish the diagnosis and elucidate an etiology; standardized neurologic assessment to determine baseline severity; prevention of hematoma expansion (blood pressure management and reversal of coagulopathy); consideration of early surgical intervention; and prevention of secondary brain injury. This review aims to provide a clinical approach for the practicing clinician.

Validation of Carotid Artery Revascularization Coding in Ontario Health Administrative Databases.

PURPOSE: The positive predictive value (PPV) of carotid endarterectomy (CEA) and carotid artery stenting (CAS) procedure and post-operative complication coding were assessed in Ontario health administrative databases. METHODS: Between 1 April 2002 and 31 March 2014, a random sample of 428 patients were identified using Canadian Classification of Health Intervention (CCI) procedure codes and Ontario Health Insurance Plan (OHIP) billing codes from administrative data. A blinded chart review was conducted at two high-volume vascular centers to assess the level of agreement between the administrative records and the corresponding patients' hospital charts. PPV was calculated with 95% confidence intervals (CIs) to estimate the validity of CEA and CAS coding, utilizing hospital charts as the gold standard. Sensitivity of CEA and CAS coding were also assessed by linking two independent databases of 540 CEA-treated patients (Ontario Stroke Registry) and 140 CAS-treated patients (single-center CAS database) to administrative records. RESULTS: PPV for CEA ranged from 99% to 100% and sensitivity ranged from 81.5% to 89.6% using CCI and OHIP codes. A CCI code with a PPV of 87% (95% CI, 78.8-92.9) and sensitivity of 92.9% (95% CI, 87.4-96.1) in identifying CAS was also identified. PPV for post-admission complication diagnosis coding was 71.4% (95% CI, 53.7-85.4) for stroke/transient ischemic attack, and 82.4% (95% CI, 56.6-96.2) for myocardial infarction. CONCLUSIONS: Our analysis demonstrated that the codes used in administrative databases accurately identify CEA and CAS-treated patients. Researchers can confidently use administrative data to conduct population-based studies of CEA and CAS.

The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale-the VASOGRADE-for prediction of DCI. METHODS: We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale [WFNS] 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1-3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots. RESULTS: In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio [OR], 1.31; 95% CI, 0.77-2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07-4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration. CONCLUSIONS: The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.

Aneurysmal subarachnoid haemorrhage from a neuroimaging perspective.

Neuroimaging is a key element in the management of patients suffering from subarachnoid haemorrhage (SAH). In this article, we review the current literature to provide a summary of the existing neuroimaging methods available in clinical practice. Noncontrast computed tomography is highly sensitive in detecting subarachnoid blood, especially within 6 hours of haemorrhage. However, lumbar puncture should follow a negative noncontrast computed tomography scan in patients with symptoms suspicious of SAH. Computed tomography angiography is slowly replacing digital subtraction angiography as the first-line technique for the diagnosis and treatment planning of cerebral aneurysms, but digital subtraction angiography is still required in patients with diffuse SAH and negative initial computed tomography angiography. Delayed cerebral ischaemia is a common and serious complication after SAH. The modern concept of delayed cerebral ischaemia monitoring is shifting from modalities that measure vessel diameter to techniques focusing on brain perfusion. Lastly, evolving modalities applied to assess cerebral physiological, functional and cognitive sequelae after SAH, such as functional magnetic resonance imaging or positron emission tomography, are discussed. These new techniques may have the advantage over structural modalities due to their ability to assess brain physiology and function in real time. However, their use remains mainly experimental and the literature supporting their practice is still scarce.

Safety of early pharmacological thromboprophylaxis after subarachnoid hemorrhage.

OBJECTIVE: The recent guidelines on management of aneurysmal subarachnoid hemorrhage (aSAH) advise pharmacological thromboprophylaxis (PTP) after aneurysm obliteration. However, no study has addressed the safety of PTP in the aSAH population. Therefore, the aim of this study was to assess the safety of early PTP after aSAH. METHODS: Retrospective cohort of aSAH patients admitted between January 2012 and June 2013 in a single high-volume aSAH center. Traumatic SAH and perimesencephalic hemorrhage patients were excluded. Patients were grouped according to PTP timing: early PTP group (PTP within 24 hours of aneurysm treatment), and delayed PTP group (PTP started > 24 hours). RESULTS: A total of 174 SAH patients (mean age 56.3±12.5 years) were admitted during the study period. Thirty-nine patients (22%) did not receive PTP, whereas 135 patients (78%) received PTP after aneurysm treatment or negative angiography. Among the patients who received PTP, 65 (48%) had an external ventricular drain. Twenty-eight patients (21%) received early PTP, and 107 (79%) received delayed PTP. No patient in the early treatment group and three patients in the delayed PTP group developed an intracerebral hemorrhagic complication. Two required neurosurgical intervention and one died. These three patients were on concomitant PTP and dual antiplatelet therapy. CONCLUSIONS: The initiation of PTP within 24 hours may be safe after the treatment of a ruptured aneurysm or in angiogram-negative SAH patients with diffuse aneurysmal hemorrhage pattern. We suggest caution with concomitant use of PTP and dual antiplatelet agents, because it possibly increases the risk for intracerebral hemorrhage.

Characteristics of a COVID-19 Cohort With Large Vessel Occlusion: A Multicenter International Study.

BACKGROUND: The mechanisms and outcomes in coronavirus disease (COVID-19)-associated stroke are unique from those of non-COVID-19 stroke. OBJECTIVE: To describe the efficacy and outcomes of acute revascularization of large vessel occlusion (LVO) in the setting of COVID-19 in an international cohort. METHODS: We conducted an international multicenter retrospective study of consecutively admitted patients with COVID-19 with concomitant acute LVO across 50 comprehensive stroke centers. Our control group constituted historical controls of patients presenting with LVO and receiving a mechanical thrombectomy between January 2018 and December 2020. RESULTS: The total cohort was 575 patients with acute LVO; 194 patients had COVID-19 while 381 patients did not. Patients in the COVID-19 group were younger (62.5 vs 71.2; P < .001) and lacked vascular risk factors (49, 25.3% vs 54, 14.2%; P = .001). Modified thrombolysis in cerebral infarction 3 revascularization was less common in the COVID-19 group (74, 39.2% vs 252, 67.2%; P < .001). Poor functional outcome at discharge (defined as modified Ranklin Scale 3-6) was more common in the COVID-19 group (150, 79.8% vs 132, 66.7%; P = .004). COVID-19 was independently associated with a lower likelihood of achieving modified thrombolysis in cerebral infarction 3 (odds ratio [OR]: 0.4, 95% CI: 0.2-0.7; P < .001) and unfavorable outcomes (OR: 2.5, 95% CI: 1.4-4.5; P = .002). CONCLUSION: COVID-19 was an independent predictor of incomplete revascularization and poor outcomes in patients with stroke due to LVO. Patients with COVID-19 with LVO were younger, had fewer cerebrovascular risk factors, and suffered from higher morbidity/mortality rates.

Recurrence and Coniglobus Volumetric Resolution of Subacute and Chronic Subdural Hematoma Post-Middle Meningeal Artery Embolization.

OBJECTIVE: To study the efficacy of middle meningeal artery (MMA) embolization for the treatment of chronic subdural hematoma (SDH) and characterize its post-embolization volumetric resolution. METHODS: Ten patients diagnosed with 13 cSDH underwent MMA embolization. SDH volumes were measured from time of initial discovery on imaging to pre-operative, post-operative, short-term and long-term follow-up. Time between procedure to obliteration was also measured. Volumetric analysis was done using the coniglobus formula, and recurrence rate as well as resolution timeline was defined using best-fit models. RESULTS: Out of 10 patients, five were recurrent lesions, three were bilateral and seven unilateral cSDH. Average and median pre-operative volumes were 105.3 cc and 97.4 cc, respectively. Embolization on average was performed 21 days after discovery. Sixty percent of patients had concurrent antiplatelets or anticoagulation use. Forty percent underwent embolization treatment as the primary therapy. Recurrence was not seen in any patients treated with embolization. There were no peri- or post-operative complications. Five patients experienced complete or near-complete obliteration, while those with partial resolution showed a composite average of 75% volumetric reduction in 45 days. Post-embolization, the volumetric resolution followed an exponential decay curve over time and was independent of initial volume. CONCLUSION: MMA embolization contributed to a marked reduction in SDH volume post-operatively and can be used as a curative therapy for primary or recurrent chronic SDH.

Stroke Treatment Delay Limits Outcome After Mechanical Thrombectomy: Stratification by Arrival Time and ASPECTS.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) has helped many patients achieve functional independence. The effect of time-to-treatment based in specific epochs and as related to Alberta Stroke Program Early CT Score (ASPECTS) has not been established. The goal of the study was to evaluate the association between last known normal (LKN)-to-puncture time and good functional outcome. METHODS: We conducted a retrospective cohort study of prospectively collected acute ischemic stroke patients undergoing MT for large vessel occlusion. We used binary logistic regression models adjusted for age, Modified Treatment in Cerebral Ischemia score, initial National Institutes of Health Stroke Scale, and noncontrast CT ASPECTS to assess the association between LKN-to-puncture time and favorable outcome defined as Modified Rankin Score 0-2 on discharge. RESULTS: Among 421 patients, 328 were included in analysis. Increased LKN-to-puncture time was associated with decreased probability of good functional outcome (adjusted odds ratio [aOR] ratio per 15-minute delay = .98; 95% confidence interval [CI], .97-.99; P = .001). This was especially true when LKN-puncture time was 0-6 hours (aOR per 15-minute delay = .94; 95% CI, .89-.99; P = .05) or ASPECTS 8-10 (aOR = .98; 95% CI, .97-.99; P = .002) as opposed to when LKN-puncture time was 6-24 hours (aOR per 15-minute delay = .99; 95% CI, .97-1.00; P = .16) and ASPECTS <8 (aOR = .98; 95% CI, .93-1.03; P = .37). CONCLUSION: Decreased LKN-groin puncture time improves outcome particularly in those with good ASPECTS presenting within 6 hours. Strategies to decrease reperfusion times should be investigated, particularly in those in the early time window and with good ASPECTS.

Managing aneurysmal subarachnoid hemorrhage: It takes a team.

Patients with aneurysmal subarachnoid hemorrhage are at high risk of complications, including rebleeding, delayed cerebral ischemia, cerebral infarction, and death. This review presents a practical approach for managing this condition and its complications.