Endovascular treatment in ischemic strokes with large infarct core: an updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Endovascular treatment (EVT) is recommended for acute ischemic stroke due to large-vessel occlusion (LVO) and an ASPECTs ≥ 6. Recent randomized controlled trials (RCTs) have become available on effect of EVT in patients with LVO-related large core infarct stroke (ASPECTS 0-5). We conducted a systematic review and meta-analysis of trials on patients with large core infarct treated with thrombectomy compared to best medical therapy (BMT). METHODS: The study followed PRISMA guidelines. Primary endpoint was functional independence at 90 days (modified Rankin Scale mRS < 3). Secondary endpoints were 3-month moderate disability (mRS < 4), excellent outcome (mRS < 2) and change in mRS (shift analysis). Safety outcomes were: symptomatic intracranial hemorrhage (sICH) and 3-month mortality. RESULTS: Seven RCTs were included with a total of 1964 patients. Functional independence was significantly more frequent in EVT vs BMT group (19.4% vs 8%; OR = 2.72, 95%CI = 2.06-3.61, pheterogeneity = 0.08; I2: 47%). Moderate outcome was also more prevalent in EVT group (OR = 2.00; 95%CI = 1.61 - 2.48, pheterogeneity = 0.17; I2: 46%) as well as excellent outcome (OR: 1.54, 95%CI = 1.07 - 2.22, pheterogeneity = 0.13; I2: 40%). Shift analysis was also significant with OR 1.59 (CI = 1.33-1.82 and p < 0.001). Finally sICH, that occurred in 68 patients, was more frequent in EVT (OR = 1.63, 95%CI = 0.99 - 2.69, pheterogeneity = 0.68; I2: 0%) while 3 m mortality was reduced in EVT (31% vs 37,1%, OR 0.76 CI = 0.62-0.92). CONCLUSIONS: This updated pooled data show that, in LVO-stroke patients with a large core infarct, EVT plus BMT (as compared to BMT alone) increases significantly the chances of achieving a good functional outcome at 90 days and reduces the 3- month mortality despite a marginal increase in acute sICH.

Predictors and Prognostic Impact of Hematoma Expansion in Infratentorial Cerebral Hemorrhage.

BACKGROUND: Hematoma expansion (HE) is common and predicts poor outcome in patients with supratentorial intracerebral hemorrhage (ICH). We investigated the predictors and prognostic impact of HE in infratentorial ICH. METHODS: We conducted a retrospective analysis of patients with brainstem and cerebellar ICH admitted at seven sites. Noncontrast computed tomography images were analyzed for the presence of hypodensities according to validated criteria, defined as any hypodense region strictly encapsulated within the hemorrhage with any shape, size, and density. Occurrence of HE (defined as > 33% and/or > 6-mL growth) and mortality at 90 days were the outcomes of interest. Their predictors were investigated using logistic regression with backward elimination at p < 0.1. Logistic regression models for HE were adjusted for baseline ICH volume, antiplatelet and anticoagulant treatment, onset to computed tomography time, and presence of hypodensities. The logistic regression model for mortality accounted for the ICH score and HE. RESULTS: A total of 175 patients were included (median age 75 years, 40.0% male), of whom 38 (21.7%) had HE and 43 (24.6%) died within 90 days. Study participants with HE had a higher frequency of hypodensities (44.7 vs. 24.1%, p = 0.013), presentation within 3 h from onset (39.5 vs. 24.8%, p = 0.029), and 90-day mortality (44.7 vs. 19.0%, p = 0.001). Hypodensities remained independently associated with HE after adjustment for confounders (odds ratio 2.44, 95% confidence interval 1.13-5.25, p = 0.023). The association between HE and mortality remained significant in logistic regression (odds ratio 3.68, 95% confidence interval 1.65-8.23, p = 0.001). CONCLUSION: Early presentation and presence of noncontrast computed tomography hypodensities were independent predictors of HE in infratentorial ICH, and the occurrence of HE had an independent prognostic impact in this population.

Using Noncontrast Computed Tomography to Improve Prediction of Intracerebral Hemorrhage Expansion.

BACKGROUND: Noncontrast computed tomography hypodensities are a validated predictor of hematoma expansion (HE) in intracerebral hemorrhage and a possible alternative to the computed tomography angiography (CTA) spot sign but their added value to available prediction models remains unclear. We investigated whether the inclusion of hypodensities improves prediction of HE and compared their added value over the spot sign. METHODS: Retrospective analysis of patients admitted for primary spontaneous intracerebral hemorrhage at the following 8 university hospitals in Boston, US (1994-2015, prospective), Hamilton, Canada (2010-2016, retrospective), Berlin, Germany (2014-2019, retrospective), Chongqing, China (2011-2015, retrospective), Pavia, Italy (2017-2019, prospective), Ferrara, Italy (2010-2019, retrospective), Brescia, Italy (2020-2021, retrospective), and Bologna, Italy (2015-2019, retrospective). Predictors of HE (hematoma growth >6 mL and/or >33% from baseline to follow-up imaging) were explored with logistic regression. We compared the discrimination of a simple prediction model for HE based on 4 predictors (antitplatelet and anticoagulant treatment, baseline intracerebral hemorrhage volume, and onset-to-imaging time) before and after the inclusion of noncontrast computed tomography hypodensities, using receiver operating characteristic curve and De Long test for area under the curve comparison. RESULTS: A total of 2465 subjects were included, of whom 664 (26.9%) had HE and 1085 (44.0%) had hypodensities. Hypodensities were independently associated with HE after adjustment for confounders in logistic regression (odds ratio, 3.11 [95% CI, 2.55-3.80]; P<0.001). The inclusion of noncontrast computed tomography hypodensities improved the discrimination of the 4 predictors model (area under the curve, 0.67 [95% CI, 0.64-0.69] versus 0.71 [95% CI, 0.69-0.74]; P=0.025). In the subgroup of patients with a CTA available (n=895, 36.3%), the added value of hypodensities remained statistically significant (area under the curve, 0.68 [95% CI, 0.64-0.73] versus 0.74 [95% CI, 0.70-0.78]; P=0.041) whereas the addition of the CTA spot sign did not provide significant discrimination improvement (area under the curve, 0.74 [95% CI, 0.70-0.78]). CONCLUSIONS: Noncontrast computed tomography hypodensities provided a significant added value in the prediction of HE and appear a valuable alternative to the CTA spot sign. Our findings might inform future studies and suggest the possibility to stratify the risk of HE with good discrimination without CTA.

Mechanical Thrombectomy in Ischemic Stroke with a Large Infarct Core: A Meta-Analysis of Randomized Controlled Trials.

Background/Objectives: Endovascular treatment (EVT) is recommended for acute ischemic stroke due to large-vessel occlusion (LVO) and an Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6. Randomized controlled trials (RCTs) have recently become available on EVT effects in people with LVO-related large core stroke (ASPECTS 0-5). Here, we provide an updated meta-analysis of the EVT effect on functional neurological status in people with large-core stroke. Methods: The study followed the PRISMA guidelines. PubMed, EMBASE and Cochrane Central were searched for RCTs comparing EVT vs. best medical treatment (BMT) in large-core LVO stroke. The primary outcome was functional independence at 90 days (modified Rankin Scale; mRS 0-2). The secondary outcomes were symptomatic intracranial hemorrhage (sICH), good functional outcome (mRS 0-3) and excellent functional outcome (mRS 0-1). EVT vs. BMT was compared through random effect meta-analysis. Heterogeneity was assessed with the I2 and Q test and risk of bias reported according to the RoB2 tool. Results: Six RCTs were included (n = 1656 patients). All studies had a moderate risk of bias, with blinding bias due to the nature of the intervention, potential allocation bias and incomplete outcome reporting. Functional independence was significantly more frequent in the EVT vs. BMT group (OR = 2.47, 95% CI = 1.52-4.03, p < 0.001). sICH rates (OR = 1.77, 95% CI = 1.01-3.11, p = 0.04) and good functional outcome (OR = 2.20; 95% CI = 1.72-2.81, p < 0.001) were more frequent in the EVT vs. BMT group, while the rates of mRS 0-1 did not differ. Conclusions: In patients with large-core stroke and LVO, EVT plus BMT as compared to BMT alone carries a significant increase in independent ambulation and good functional outcome at 3 months despite the marginal increase in sICH.

Non-contrast CT markers of intracerebral hemorrhage expansion: The influence of onset-to-CT time.

BACKGROUND: Hematoma expansion (HE) is an appealing therapeutic target in intracerebral hemorrhage (ICH) and non-contrast computed tomography (NCCT) features are promising predictors of HE. AIMS: We investigated whether onset-to-CT time influences the diagnostic performance of NCCT markers for HE. METHODS: Retrospective multicentre analysis of patients with primary ICH. The following NCCT markers were analyzed: hypodensities, heterogeneous density, blend sign, and irregular shape. HE was defined as growth ⩾6 mL and/or ⩾33%. We calculated the sensitivity, specificity, positive, and negative predictive values (PPVs and NPVs) of NCCT markers for HE, stratified by onset-to-CT time (<2 h, 2-4 h, 4-6 h, >6 h). RESULTS: We included 1135 patients (median age 69, 53% males), of whom 307 (27%) experienced HE.Overall hypodensities had the highest sensitivity (0.68) and blend sign the highest specificity (0.87) for HE. Hypodensities were more common and had higher sensitivity (0.80) in patients with imaging within 2 h. The same result was observed for heterogeneous density, whereas irregular shape had a similar prevalence across time strata and higher sensitivity (0.79) beyond 6 h from onset. The frequency of blend sign increased with longer onset-to-CT time, whereas its specificity declined after 6 h from onset. CONCLUSION: The diagnostic performance of NCCT markers is influenced by imaging time. Hypodensities identified four out of five patients with HE within 2 h from onset, whereas irregular shape performed better in late presenters. Our findings may improve the use of NCCT markers in future studies and trials targeting HE.

Association Between Hematoma Expansion Severity and Outcome and Its Interaction With Baseline Intracerebral Hemorrhage Volume.

BACKGROUND AND OBJECTIVES: Hematoma expansion (HE) is a major determinant of neurologic deterioration and poor outcome in intracerebral hemorrhage (ICH) and represents an appealing therapeutic target. We analyzed the prognostic effect of different degrees of HE. METHODS: This was a retrospective analysis of patients with ICH admitted at 8 academic institutions in Italy, Germany, Canada, China, and the United States. All patients underwent baseline and follow-up imaging for HE assessment. Relative HE (rHE) was classified as follows: none (<0%), mild (0%-33%), moderate (33.1%-66%), and severe (>66%). Absolute HE (aHE) was classified as none (<0 mL), mild (0-6.0 mL), moderate (6.1-12.5 mL), and severe (>12.5 mL). Predictors of poor functional outcome (90 days modified Rankin Scale 4-6) were explored with logistic regression. RESULTS: We included 2,163 patients, of whom 1,211 (56.0%) had poor outcome. The occurrence of severe aHE or rHE was more common in patients with unfavorable outcome (13.9% vs 6.5%, p < 0.001 and 18.3% vs 7.2%, p < 0.001 respectively). This association was confirmed in logistic regression (rHE odds ratio [OR] 1.98, 95% CI 1.38-2.82, p < 0.001; aHE OR 1.73, 95% CI 1.23-2.45, p = 0.002) while there was no association between mild or moderate HE and poor outcome. The association between severe HE and poor outcome was significant only in patients with baseline ICH volume below 30 mL. DISCUSSION: The strongest association between HE and outcome was observed in patients with smaller initial volume experiencing severe HE. These findings may inform clinical trial design and guide clinicians in selecting patients for antiexpansion therapies.

Imaging markers of intracerebral hemorrhage expansion in patients with unclear symptom onset.

BACKGROUND: Hematoma expansion (HE) is common and associated with poor outcome in intracerebral hemorrhage (ICH) with unclear symptom onset (USO). AIMS: We tested the association between non-contrast computed tomography (NCCT) markers and HE in this population. METHODS: Retrospective analysis of patients with primary spontaneous ICH admitted at five centers in the United States and Italy. Baseline NCCT was analyzed for presence of the following markers: intrahematoma hypodensities, heterogeneous density, blend sign, and irregular shape. Variables associated with HE (hematoma growth > 6 mL and/or > 33% from baseline to follow-up imaging) were explored with multivariable logistic regression. RESULTS: Of 2074 patients screened, we included 646 subjects (median age = 75, 53.9% males), of whom 178 (27.6%) had HE. Hypodensities (odds ratio (OR) = 2.67, 95% confidence interval (CI) = 1.79-3.98), heterogeneous density (OR = 2.16, 95% CI = 1.46-3.21), blend sign (OR = 2.28, 95% CI = 1.38-3.75) and irregular shape (OR = 1.82, 95% CI = 1.21-2.75) were independently associated with a higher risk of HE, after adjustment for confounders (ICH volume, anticoagulation, and time from last seen well (LSW) to NCCT). Hypodensities had the highest sensitivity for HE (0.69), whereas blend sign was the most specific marker (0.90). All NCCT markers were more frequent in early presenters (time from LSW to NCCT ⩽ 6 h, n = 189, 29.3%), and more sensitive in this population as well (hypodensities had 0.77 sensitivity). CONCLUSION: NCCT markers are associated with HE in ICH with USO. These findings require prospective replication and suggest that NCCT features may help the stratification of HE in future studies on USO patients.

Hematoma Expansion in Intracerebral Hemorrhage With Unclear Onset.

OBJECTIVE: To investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO). METHODS: We performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression. RESULTS: We enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, p = 0.269 and 29.9% vs 31.5%, p = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43-4.89, p = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86-6.44, p < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27-5.28, p = 0.009) and replication (OR 2.43, 95% CI 1.42-4.17, p = 0.001) population. CONCLUSION: HE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.

Lacunar stroke syndromes as predictors of lacunar and non-lacunar infarcts on neuroimaging: a hospital-based study.

Lacunar syndromes are usually caused by small ischemic lesions called lacunar infarcts. However, non-lacunar infarcts account for about 20% of lacunar syndromes. The aim of this study was to identify clinical predictors of lacunar syndromes led by non-lacunar infarcts. The following single centre, observational study was conducted on an analysis of the "Perugia hospital-based Stroke Registry" database enrolling consecutive patients admitted with ischemic stroke during the period 2010-2017. We evaluated patient risk factors and clinical features linked to stroke syndrome (lacunar/non-lacunar) and to cerebral infarction (lacunar/non-lacunar). Lacunar syndromes were diagnosed in 478 (26.6%) out of 1796 patients. In 104 (21.1%) patients, lacunar syndromes were caused by non-lacunar infarcts. Lacunar syndromes with lacunar infarcts were primarily linked to diabetes (27.8% vs 16.3%) and obesity (7.7% vs 0.9%), while lacunar syndromes with non-lacunar infarcts were linked to a higher risk of atrial fibrillation (22.1% vs 9.4%) and higher National Institute of Health Stroke Scale scores on admission (mean 5.5 ± 3.7 vs 4.7 ± 2.8). On multivariate analysis, atrial fibrillation (OR 1.67, 95% CI 1.09-2.31; p = 0.002) and higher NIHSS (OR 1.12 for each point increase, 95% CI 1.09-1.15; p < 0.001) were predictors of non-lacunar infarcts in all stroke cases, while lacunar syndromes were inversely associated with non-lacunar infarcts (OR 0.15, 95% CI 0.11-0.20; p < 0.001). Atrial fibrillation was the only predictor of non-lacunar infarcts in patients with lacunar syndromes (OR 2.62, 95% CI 1.33-5.18; p = 0.005). 21% of patients with lacunar syndromes had non-lacunar infarctions. Atrial fibrillation turned out to be a predictor of lacunar syndrome due to non-lacunar infarct.