Common and specific proteins and pathways in heart and cerebral ischemia.

OBJECTIVE: To understand the similarities and differences between acute ischemic stroke and acute myocardial infarction (AMI) to help in the development of specific or common treatment strategies. METHODS: Using an aptamer-based proteomic array, we measured and compared 1310 circulating proteins in the blood of 40 patients with AIS, 9 patients with AMI, and 31 healthy controls. Pathway enrichment analysis was performed using GSEA and g:profiler. RESULTS: Ninety-four proteins were differentially expressed in AIS, and 284 were differentially expressed in AMI. Of these, 8 were specific to cerebral ischemia, and 197 were specific to myocardial infarction. Forty-two proteins were altered in both ischemia processes. Most altered pathways in AIS could be classified as immune response, cell cycle processing, molecular transport, or signaling. Pathways altered in AMI were mostly related to lipid metabolism and transport, highlighting cholesterol metabolic processes and estrogen signaling. In both types of ischemia, we found pathways related to metabolism, specifically purine metabolism, and signaling processes, such as TNF signaling or MAPK1/3. CONCLUSIONS: The present study revealed proteins and pathways that were specifically altered in cerebral ischemia, in cardiac ischemia, or in both diseases, providing information on the similarities and differences of ischemic conditions. The role of common and specific proteins and pathways should be explored in detail to find possible therapeutic targets.

Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients.

BACKGROUND: Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk. METHODS: The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score ≤1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany. RESULTS: 45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.99-23.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment. CONCLUSIONS: BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.

The SITS Open Study: A Prospective, Open Label Blinded Evaluation Study of Thrombectomy in Clinical Practice.

BACKGROUND AND PURPOSE: We designed SITS (Safe Implementation of Treatment in Stroke) Open to determine benefit and safety of thrombectomy in clinical practice for large artery occlusion stroke, using selected stent retrievers plus standard care versus standard care alone. METHODS: SITS Open was a prospective, open, blinded evaluation, international, multicenter, controlled, nonrandomized registry study. Centers lacking access to thrombectomy contributed controls. Primary end point was categorical shift in modified Rankin Scale score at 3 months in the per protocol (PP) population. Principal secondary outcomes were symptomatic intracranial hemorrhage, functional independency (modified Rankin Scale score 0-2) and death at 3 months. Patients independently evaluated by video-recorded modified Rankin Scale interviews blinded to treatment or center identity by central core laboratory were regarded as PP population. Propensity score matching with covariate adjusted analysis was performed. RESULTS: During 2014 to 2017, 293 patients (257 thrombectomy, 36 control) from 26 centers in 10 countries fulfilled intention-to-treat and 200 (170 thrombectomy, 30 control) PP criteria; enrollment of controls was limited by rapid uptake of thrombectomy. In PP analysis, median age was 71 versus 71 years, and baseline National Institutes of Health Stroke Scale 17 versus 17 in the thrombectomy and control arms, respectively. The propensity score matching analysis for PP showed a significant shift for modified Rankin Scale at 3 months favoring the thrombectomy group (odds ratio, 3.8 [95% CI, 1.61-8.95]; P=0.002). Regarding safety, there were 4 cases of symptomatic intracranial hemorrhage in the thrombectomy group (2.4%) and none in the control group. CONCLUSIONS: In clinical practice, thrombectomy for patients with large artery occlusion stroke is superior to standard of care in our study. Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT02326428.

Effect of Recanalization on Cerebral Edema in Ischemic Stroke Treated With Thrombolysis and/or Endovascular Therapy.

Background and Purpose- A large infarct and expanding cerebral edema (CED) due to a middle cerebral artery occlusion confers a 70% mortality unless treated surgically. Reperfusion may cause blood-brain barrier disruption and a risk for cerebral edema and secondary parenchymal hemorrhage (PH). We aimed to investigate the effect of recanalization on development of early CED and PH after recanalization therapy. Methods- From the SITS-International Stroke Treatment Registry, we selected patients with signs of artery occlusion at baseline (either Hyperdense Artery Sign or computed tomography/magnetic resonance imaging angiographic occlusion). We defined recanalization as the disappearance of radiological signs of occlusion at 22 to 36 hours. Primary outcome was moderate to severe CED and secondary outcome was PH on 22- to 36-hour imaging scans. We used logistic regression with adjustment for baseline variables and PH. Results- Twenty two thousand one hundred eighty-four patients fulfilled the inclusion criteria (n=18 318 received intravenous thrombolysis, n=3071 received intravenous thrombolysis+thrombectomy, n=795 received thrombectomy). Recanalization occurred in 64.1%. Median age was 71 versus 71 years and National Institutes of Health Stroke Scale score 15 versus 16 in the recanalized versus nonrecanalized patients respectively. Recanalized patients had a lower risk for CED (13.0% versus 23.6%), adjusted odds ratio (aOR), 0.52 (95% CI, 0.46-0.59), and a higher risk for PH (8.9% versus 6.5%), adjusted odds ratio, 1.37 (95% CI, 1.22-1.55), than nonrecanalized patients. Conclusions- In patients with acute ischemic stroke, recanalization was associated with a lower risk for early CED even after adjustment for higher rate for PH in recanalized patients.

Break in the Stroke Chain of Survival due to COVID-19.

BACKGROUND AND PURPOSE: Emergency measures to treat patients with coronavirus disease 2019 (COVID-19) and contain the outbreak is the main priority in each of our hospitals; however, these measures are likely to result in collateral damage among patients with other acute diseases. Here, we investigate whether the COVID-19 pandemic affects acute stroke care through interruptions in the stroke chain of survival. METHODS: A descriptive analysis of acute stroke care activity before and after the COVID-19 outbreak is given for a stroke network in southern Europe. To quantify the impact of the pandemic, the number of stroke code activations, ambulance transfers, consultations through telestroke, stroke unit admissions, and reperfusion therapy times and rates are described in temporal relationship with the rising number of COVID-19 cases in the region. RESULTS: Following confinement of the population, our stroke unit activity decreased sharply, with a 25% reduction in admitted cases (mean number of 58 cases every 15 days in previous months to 44 cases in the 15 days after the outbreak, P<0.001). Consultations to the telestroke network declined from 25 every 15 days before the outbreak to 7 after the outbreak (P<0.001). The increasing trend in the prehospital diagnosis of stroke activated by 911 calls stopped abruptly in the region, regressing to 2019 levels. The mean number of stroke codes dispatched to hospitals decreased (78% versus 57%, P<0.001). Time of arrival from symptoms onset to stroke units was delayed >30 minutes, reperfusion therapy cases fell, and door-to-needle time started 16 minutes later than usual. CONCLUSIONS: The COVID-19 pandemic is disruptive for acute stroke pathways. Bottlenecks in the access and delivery of patients to our secured stroke centers are among the main challenges. It is critical to encourage patients to continue seeking emergency care if experiencing acute stroke symptoms and to ensure that emergency professionals continue to use stroke code activation and telestroke networks.

Safety of Early Carotid Artery Stenting for Symptomatic Stenosis in Daily Practice.

OBJECTIVE/BACKGROUND: In 2006, the American Heart Association recommended that for preference carotid endarterectomy (CEA) or, alternatively, carotid angioplasty and stenting (CAS) for symptomatic carotid artery stenosis should ideally occur within 14 days of an ischaemic event. The aim was to determine the safety of CAS according to those recommendations in daily practice. METHODS: A retrospective analysis was performed of all consecutive patients (2000-16), with ipsilateral carotid symptoms who underwent CAS for extracranial carotid stenosis ≥70%, who were previously included in a prospective database. Thirty day morbidity was assessed (any stroke without transient ischaemic attack [TIA]/amaurosis fugax), along with mortality of the procedure in the early (≤14 days after stroke onset) and delayed phases (15-180 days after stroke onset). Patients who received CAS and/or mechanical thrombectomy for acute ischaemic stroke treatment were not included. RESULTS: In total, 1227 patients with symptomatic carotid stenosis who underwent CAS were identified. Early and delayed CAS was performed in 291 and 936 patients, respectively. Morbidity (any stroke) and mortality was 2.2% (n = 27) in the whole cohort (n = 8 [2.7%] in early vs. n = 19 [2%] in delayed CAS; p = .47). There were no differences in morbidity between early and delayed CAS regarding TIA (n = 15 vs. 36 [5.2% vs. 3.9%]; p = .33), minor stroke (n = 4 vs. 5 [1.4% vs. 0.5%]; p = .14), or major stroke (n = 2 vs. 6 [0.7% vs. 0.6%]; p = .59). Two patients (0.7%) died after early CAS and eight (0.9%) after delayed CAS (p = .56). CONCLUSION: CAS may be safely performed in the early phase after an ischaemic stroke with low clinical complication rates. Further studies are needed to validate CAS safety conducted even earlier in the acute phase of ischaemic stroke.

External Validation of the ISAN, A2DS2, and AIS-APS Scores for Predicting Stroke-Associated Pneumonia.

BACKGROUND: The Prestroke Independence, Sex, Age, National Institutes of Health Stroke Scale (ISAN), Age, Atrial Fibrillation, Dysphagia, male sex, and National Institutes of Health Stroke Scale (A2DS2), and acute ischemic stroke-associated pneumonia score (AIS-APS) scores were created to predict stroke-associated pneumonia (SAP), one of the most important medical stroke complications. External validation of all such scores in an acute stroke population was the aim of our study. METHODS: Patients with ischemic or hemorrhagic stroke were prospectively enrolled in the multicenter Stroke-Induced Pneumonia in Andalucía project between October 2014 and May 2016. Receiver operating characteristic curves and linear regression analyses were used to determine discrimination ability of the scores. The Hosmer-Lemeshow goodness-of-fit test and the plot of observed versus predicted SAP risk were used to assess model calibration. RESULTS: Among 201 included patients, SAP rate was 15.5% (31). Higher ISAN, A2DS2, and AIS-APS scores were related to SAP (all P < .001). The C statistic was .83 (95% confidence interval [CI], .76-.91) for the ISAN score, .80 (95% CI, .70-.89) for the A2DS2 score, and .82 (95% CI, .74-.90) for the AIS-APS score, suggesting good discrimination. The ISAN and AIS-APS scores showed good calibration (Cox and Snell R2 = .206 and .174, respectively). The A2DS2 score showed the highest sensitivity (87%), and the AIS-APS score showed the highest specificity (92.8%). CONCLUSIONS: In our cohort, the external validation of ISAN, A2DS2, and AIS-APS scores have demonstrated their accurate prediction of SAP and the ability of these scores as screening tools to better manage SAP. The AIS-APS score would be recommendable for the development of future clinical trials.

Predictors of Restenosis Following Carotid Angioplasty and Stenting.

BACKGROUND AND PURPOSE: Restenosis after carotid angioplasty (with or without stent) is associated with increased rate of stroke and death. Our aim was to determine risk and predictive factors related to carotid restenosis post carotid angioplasty and its association to recurrent cerebrovascular events. METHODS: All consecutive patients with carotid stenosis treated with angioplasty (n=1060) in a single University Hospital were included (from 2002 to 2013). Follow-up was done prospectively evaluating restenosis, ipsilateral stroke, or death. Restenosis was defined as a narrowing of ≥70% of a previously treated vessel evaluated by ultrasonography. RESULTS: Of the 1060 patients treated, 9.2% (97) of patients experienced restenosis during follow up (median 12 [9-32] months). Occurrence of restenosis was associated with ipsilateral stroke during follow-up (P=0.049). After Cox regression analysis, hypertension (hazard ratio, 6.2 [1.9-19.9]; P=0.002), impaired vasoreactivity (hazard ratio, 1.7 [1.09-2.8]; P=0.019), and angioplasty without stent (hazard ratio, 2.9 [1.2-6.8]; P=0.012) were independent risk predictors of >70% restenosis. CONCLUSIONS: Carotid restenosis after carotid angioplasty is associated with ipsilateral stroke occurrence. In our sample, hypertension, angioplasty without stent, and impaired vasoreactivity identify patients at high risk of restenosis and could help to select patients for follow-up ultrasonography imaging.

Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

Atrial fibrillation and stroke: A review and new insights.

The link between heart and brain continues to be a matter of great interest for the scientific community. One of the most established associations between the two is that the heart is a significant source of emboli and is responsible for 20-25% of all ischemic strokes. The most frequent underlying cause of cardioembolic stroke is atrial fibrillation (AF), a disease that affects almost 3 million people in the USA and 4.5 million in Europe. AF increases the risk of ischemic stroke by a factor of 3 to 5 times. It is estimated that AF is responsible for 15% of all strokes worldwide. A more comprehensive understanding of this association and development of intensive stroke prevention measures are needed, as we know that AF incidence and prevalence will increase over the coming years, becoming one of the largest epidemics and public health challenges we face.

Association of cholesterol levels with hemorrhagic transformation and cerebral edema after reperfusion therapies.

Background: The association between cholesterol levels and cerebral edema (CED) or hemorrhagic transformation (HT) as an expressions of blood-brain barrier (BBB) dysfunction after ischemic stroke is not well established. The aim of this study is to determine the association of total cholesterol (TC) levels with the incidence of HT and CED after reperfusion therapies. Methods: We analyzed SITS Thrombolysis and Thrombectomy Registry data from January 2011 to December 2017. We identified patients with data on TC levels at baseline. TC values were categorized in three groups (reference group ⩾200 mg/dl). The two primary outcomes were any parenchymal hemorrhage (PH) and moderate to severe CED on follow up imaging. Secondary outcomes included death and functional independence (mRS 0-2) at 3 months. Multivariable logistic regression analysis adjusted for baseline factors including statin pretreatment was used to assess the association between TC levels and outcomes. Results: Of 35,314 patients with available information on TC levels at baseline, 3372 (9.5%) presented with TC levels ⩽130 mg/dl, 8203 (23.2%) with TC 130-200 mg/dl and 23,739 (67.3%) with TC ⩾ 200 mg/dl. In the adjusted analyses, TC level as continuous variable was inversely associated with moderate to severe CED (OR 0.99, 95% CI 0.99-1.00, p = 0.025) and as categorical variable lower TC levels were associated with a higher risk of moderate to severe CED (aOR 1.24, 95% CI 1.10-1.40, p = 0.003). TC levels were not associated with any PH, functional independence, and mortality at 3 months. Conclusions: Our findings indicate an independent association between low levels of TC and higher odds of moderate/severe CED. Further studies are needed to confirm these findings.

Reperfusion by endovascular thrombectomy and early cerebral edema in anterior circulation stroke: Results from the SITS-International Stroke Thrombectomy Registry.

BACKGROUND: A large infarct and expanding cerebral edema (CED) due to a middle cerebral artery occlusion confers a 70% mortality unless treated surgically. There is still conflicting evidence whether reperfusion is associated with a lower risk for CED in acute ischemic stroke. AIM: To investigate the association of reperfusion with development of early CED after stroke thrombectomy. METHODS: From the SITS-International Stroke Thrombectomy Registry, we selected patients with occlusion of the intracranial internal carotid or middle cerebral artery (M1 or M2). Successful reperfusion was defined as mTICI ⩾ 2b. Primary outcome was moderate or severe CED, defined as focal brain swelling ⩾1/3 of the hemisphere on imaging scans at 24 h. We used regression methods while adjusting for baseline variables. Effect modification by severe early neurological deficits, as indicators of large infarct at baseline and at 24 h, were explored. RESULTS: In total, 4640 patients, median age 70 years and median National Institutes of Health Stroke Score (NIHSS) 16, were included. Of these, 86% had successful reperfusion. Moderate or severe CED was less frequent among patients who had reperfusion compared to patients without reperfusion: 12.5% versus 29.6%, p < 0.05, crude risk ratio (RR) 0.42 (95% confidence interval (CI): 0.37-0.49), and adjusted RR 0.50 (95% CI: 0.44-0.57). Analysis of effect modification indicated that severe neurological deficits weakened the association between reperfusion and lower risk of CED. The RR reduction was less favorable in patients with severe neurological deficits, defined as NIHSS score 15 or more at baseline and at 24 h, used as an indicator for larger infarction. CONCLUSION: In patients with large artery anterior circulation occlusion stroke who underwent thrombectomy, successful reperfusion was associated with approximately 50% lower risk for early CED. Severe neurological deficit at baseline seems to be a predictor for moderate or severe CED also in patients with successful reperfusion by thrombectomy.

Cerebral Edema in Patients with severe Hemispheric Syndrome: Incidence, Risk Factors, and Outcomes-Data from SITS-ISTR.

BACKGROUND AND PURPOSE: Cerebral edema (CED) in ischemic stroke can worsen prognosis and about 70% of patients who develop severe CED die if treated conservatively. We aimed to describe incidence, risk factors and outcomes of CED in patients with extensive ischemia. METHODS: Oservational study based on Safe Implementation of Treatments in Stroke-International Stroke Treatment Registry (2003-2019). Severe hemispheric syndrome (SHS) at baseline and persistent SHS (pSHS) at 24 hours were defined as National Institutes of Health Stroke Score (NIHSS) >15. Outcomes were moderate/severe CED detected by neuroimaging, functional independence (modified Rankin Scale 0-2) and death at 90 days. RESULTS: Patients (n=8,560) presented with SHS and developed pSHS at 24 hours; 82.2% received intravenous thrombolysis (IVT), 10.5% IVT+thrombectomy, and 7.3% thrombectomy alone. Median age was 77 and NIHSS 21. Of 7,949 patients with CED data, 3,780 (47.6%) had any CED and 2,297 (28.9%) moderate/severe CED. In the multivariable analysis, age <50 years (relative risk [RR], 1.56), signs of acute infarct (RR, 1.29), hyperdense artery sign (RR, 1.39), blood glucose >128.5 mg/dL (RR, 1.21), and decreased level of consciousness (RR, 1.14) were associated with moderate/severe CED (for all P<0.05). Patients with moderate/severe CED had lower odds to achieve functional Independence (adjusted odds ratio [aOR], 0.35; 95% confidence interval [CI], 0.23 to 0.55) and higher odds of death at 90 days (aOR, 2.54; 95% CI, 2.14 to 3.02). CONCLUSIONS: In patients with extensive ischemia, the most important predictors for moderate/ severe CED were age <50, high blood glucose, signs of acute infarct, hyperdense artery on baseline scans, and decreased level of consciousness. CED was associated with worse functional outcome and a higher risk of death at 3 months.

Association of statin pre-treatment with baseline stroke severity and outcome in patients with acute ischemic stroke and received reperfusion treatment: An observational study.

BACKGROUND: Statins have an important role in stroke prevention, especially in high-risk populations and may also affect the initial stroke severity and outcomes in patients taking them before an ischemic stroke. AIMS: Our aim was to evaluate the association of statin pre-treatment with the severity in acute ischemic stroke (AIS). METHODS: We analyzed AIS patients received intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT) and recorded in the SITS International Thrombolysis and Thrombectomy Registry from 2011 to 2017. We identified patients with statin information at baseline. The primary outcome was baseline National Institutes of Health Stroke Scale (NIHSS) score. Secondary outcomes were NIHSS score at 24 h, symptomatic intracerebral hemorrhage (SICH) and functional outcome at 90 days after acute intervention. Multivariable linear and logistic regression and propensity score matching (PSM) was used to quantify the effect of statin pre-treatment. RESULTS: Of 93,849 patients, 23,651 (25.2%) were treated with statins prior the AIS. Statin pre-treatment group was older and had higher comorbidity. Median NIHSS at baseline was similar between groups. In the adjusted and PSM analysis, statin pre-treatment was inversely associated with baseline NIHSS (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.6-0.99 and OR for PSM 0.73, 95% CI = 0.54-0.99, p = 0.004) and independently associated with mild stroke defined as NIHSS ⩽8 in adjusted and PSM analysis (OR = 1.21, 95% CI = 1.1-1.34, p < 0.001 and OR for PSM 1.17, 95% CI = 1.05-1.31, p = 0.007). Regarding secondary outcomes, there were no differences in functional outcomes, death nor SICH rates between groups. CONCLUSION: Prior treatment with statins was associated with lower NIHSS at baseline. However, this association did not translate into any difference regarding functional outcome at 90 days. No association was found regarding SICH. These findings indicate the need of further studies to assess the effect on statin pre-treatment on initial stroke severity.

Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial.

BACKGROUND: Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. METHODS: The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. FINDINGS: Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. INTERPRETATION: Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. FUNDING: Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

Mediterranean Diet and its Effects on Silent Brain Infarcts in a Cohort of Patients With Atrial Fibrillation.

Background and Aims: The benefits of Mediterranean Diet (MeDiet) in prevention of cardiovascular diseases (CVD) in general and ischemic stroke (IS) have been extensively studied and reported. We hypothesize that the consumption of nutrients typical of MeDiet would also reduce the rate of silent brain infarcts (SBI) among AF patients. Methods and Results: Patients with a history of AF who scored 0 to 1 in the CHADS2 score, ⩾50 years and with absence of neurological symptoms were selected from Seville urban area using the Andalusian electronic healthcare database. A 3T brain MRI was performed to all participants. Demographic and clinical data and food-frequency questionnaire (FFQ) were collected. Of the 443 scanned patients, 66 presented SBI. Of them 52 accepted to be scheduled for a clinical visit and were included in the diet sub study and 41 controls were matched per age and sex. There were no statistically significant differences in baseline characteristics. After logistic regression analysis, we found that a higher consumption of fiber from fruit was independently associated with a lower risk of SBI, while a higher consumption of high glycemic load (GL) foods was associated with a higher risk of SBI in a population with AF. Conclusion: Our findings support that MeDiet could be suggested as a prevention strategy for SBI in patients with AF.

Safety and Outcomes of Thrombectomy in Ischemic Stroke With vs Without IV Thrombolysis.

OBJECTIVE: To test the hypothesis that IV thrombolysis (IVT) treatment before endovascular thrombectomy (EVT) is associated with better outcomes in patients with anterior circulation large artery occlusion (LAO) stroke, we examined a large real-world database, the Safe Implementation of Treatment in Stroke-International Stroke Thrombectomy Register (SITS-ISTR). METHODS: We identified centers recording ≥10 consecutive patients in the SITS-ISTR, with at least 70% available modified Rankin Scale (mRS) scores at 3 months during 2014 to 2019. We defined LAO as intracranial internal carotid artery, first and second segment of middle cerebral artery, and first segment of anterior cerebral artery. Main outcomes were functional independence (mRS score 0-2) and death at 3 months and symptomatic intracranial hemorrhage (SICH) per modified SITS-Monitoring Study. We performed propensity score-matched (PSM) and multivariable logistic regression analyses. RESULTS: Of 6,350 patients from 42 centers, 3,944 (62.1%) received IVT. IVT + EVT-treated patients had less frequent atrial fibrillation, ongoing anticoagulation, previous stroke, heart failure, and prestroke disability. PSM analysis showed that IVT + EVT-treated patients had a higher rate of functional independence than patients treated with EVT alone (46.4% vs 40.3%, p < 0.001) and a lower rate of death at 3 months (20.3% vs 23.3%, p = 0.035). SICH rates (3.5% vs 3.0%, p = 0.42) were similar in both groups. Multivariate adjustment yielded results consistent with PSM. CONCLUSION: Pretreatment with IVT was associated with favorable outcomes in EVT-treated LAO stroke in the SITS-ISTR. These findings, while indicative of international routine clinical practice, are limited by observational design, unmeasured confounding, and possible residual confounding by indication. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVT before EVT increases the probability of functional independence at 3 months compared to EVT alone.

Dabigatran initiation in patients with non-valvular AF and first acute ischaemic stroke: a retrospective observational study from the SITS registry.

BACKGROUND AND OBJECTIVE: The optimal timing for initiation of dabigatran after acute ischaemic stroke (AIS) is not established. We aimed to evaluate initiation timing and clinical outcomes of dabigatran in AIS patients with non-valvular atrial fibrillation (NVAF). DESIGN: Retrospective study based on prospectively collected data in SITS (Safe Implementation of Treatment in Stroke) Thrombolysis and Thrombectomy Registry from July 2014 to July 2018. PARTICIPANTS: European NVAF patients (≥18 years) hospitalised after first-ever ischaemic stroke. SETTING: A multinational, observational monitoring register. INTERVENTION: Dabigatran initiation within 3 months after the ischaemic stroke. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was time from first-ever ischaemic stroke (index event) to dabigatran initiation. Additional outcomes included physicians' reasons for delaying dabigatran initiation beyond acute hospital discharge and outcomes within 3 months of index event. METHODS: We identified patients with NVAF who received dabigatran within 3 months of the index event. We performed descriptive statistics for baseline and demographic data and clinical outcomes after dabigatran initiation. RESULTS: In total, 1489 patients with NVAF received dabigatran after AIS treated with thrombolysis and/or thrombectomy. Of these, 1240 had available initiation time. At baseline, median age was 75 years; 53% of patients were women, 15% were receiving an oral anticoagulant, 29% acetylsalicylic acid and 4% clopidogrel. Most patients (82%) initiated dabigatran within 14 days after the index event. Patients initiating earlier had lower stroke severity from median NIHSS 8 (IQR 6-13) if initiated within 7 days to NIHSS 15 (9-19) if initiated between 28 days and 3 months. Most common reasons for delaying initiation were haemorrhagic transformation or intracranial haemorrhage, stroke severity and infarct size. Few thrombotic/haemorrhagic events occurred within 3 months after the index event (20 of 926 patients, 2.2% with the available data). CONCLUSIONS: Our findings, together with previous observational studies, indicate that dabigatran initiated within the first days after an AIS is safe in patients treated with intravenous thrombolysis, endovascular thrombectomy or both. TRIAL REGISTRATION NUMBER: SITS Thrombolysis and Thrombectomy Registry (NCT03258645).

Prevalence and risk factors of silent brain infarcts in patients with AF detected by 3T-MRI.

BACKGROUND: Silent brain infarcts (SBI), a finding on neuroimaging, are associated with higher risk of future stroke. Atrial Fibrillation (AF) has been previously identified as a cause of SBI. OBJECTIVES: The aim of this study is to determine the prevalence of and risk factors for SBI in patients with AF and low-to-moderate embolic risk according to CHADS2 and CHA2DS2VASc score. METHODS: Patients with a history of AF based on medical records who scored 0-1 in the CHADS2 score were selected from the Seville urban area using the Andalusian electronic healthcare database (DIRAYA). Demographic and clinical data were collected and a 3T brain MRI was performed on patients older than 50 years and with absence of neurological symptoms. RESULTS: 66 of the initial 443 patients (14.9%) and 41 of the 349 patients with low risk according to CHA2DS2VASc score (11.7%) presented at least 1 SBI. After adjusted multivariable analysis, an older age (OR 3.84, 95% CI 1.07-13.76) and left atrial (LA) enlargement (OR 3.13, 95% CI 1.15-8.55) were associated with SBI in the whole cohort, while only LA enlargement was associated with SBI in the low-risk cohort (OR 3.19, 95% CI 1.33-7.63). CONCLUSIONS: LA enlargement on echocardiogram was associated with SBI in patients with AF and low or moderate embolic risk according to CHADS2 and in the low-risk population according to CHA2DS2VASc. Although further studies are needed, a neuroimaging screening might be justified in these patients to guide medical therapies to improve stroke prevention.