Endovascular Therapy for Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effectiveness of endovascular therapy in patients with stroke caused by basilar-artery occlusion has not been well studied. METHODS: We randomly assigned patients within 6 hours after the estimated time of onset of a stroke due to basilar-artery occlusion, in a 1:1 ratio, to receive endovascular therapy or standard medical care. The primary outcome was a favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 to 6, with 0 indicating no disability, 3 indicating moderate disability, and 6 indicating death) at 90 days. The primary safety outcomes were symptomatic intracranial hemorrhage within 3 days after the initiation of treatment and mortality at 90 days. RESULTS: A total of 300 patients were enrolled (154 in the endovascular therapy group and 146 in the medical care group). Intravenous thrombolysis was used in 78.6% of the patients in the endovascular group and in 79.5% of those in the medical group. Endovascular treatment was initiated at a median of 4.4 hours after stroke onset. A favorable functional outcome occurred in 68 of 154 patients (44.2%) in the endovascular group and 55 of 146 patients (37.7%) in the medical care group (risk ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.50). Symptomatic intracranial hemorrhage occurred in 4.5% of the patients after endovascular therapy and in 0.7% of those after medical therapy (risk ratio, 6.9; 95% CI, 0.9 to 53.0); mortality at 90 days was 38.3% and 43.2%, respectively (risk ratio, 0.87; 95% CI, 0.68 to 1.12). CONCLUSIONS: Among patients with stroke from basilar-artery occlusion, endovascular therapy and medical therapy did not differ significantly with respect to a favorable functional outcome, but, as reflected by the wide confidence interval for the primary outcome, the results of this trial may not exclude a substantial benefit of endovascular therapy. Larger trials are needed to determine the efficacy and safety of endovascular therapy for basilar-artery occlusion. (Funded by the Dutch Heart Foundation and others; BASICS ClinicalTrials.gov number, NCT01717755; Netherlands Trial Register number, NL2500.).

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.

Sex-Based Analysis of Treatment, Time Metrics and Outcomes in Acute Ischemic Stroke Patients Treated in the Netherlands.

Introduction Sex disparities in stroke treatment have gained increasing interest, especially since women have worse post-stroke functional outcomes compared with men. Existing studies provide conflicting evidence, with some indicating women have longer delays and less often receive acute treatment, whereas others show no differences between men and women. We aimed to explore sex differences in acute treatment modalities and time metrics of patients with acute ischemic stroke (AIS) in a real-world setting. Secondly, we examined whether functional outcomes differed by sex and whether this was influenced by treatment timing. Methods We analyzed data from the Dutch Acute Stroke Audit, a prospective consecutive registry of AIS patients from 72 hospitals in the Netherlands, between 2017 and 2020. We captured data on type of treatment administered (intravenous thrombolysis [IVT] and endovascular thrombectomy [EVT]), time metrics (onset-to-door time [OTDT], door-to-needle and door-to-groin times), and functional outcomes at three months (modified Rankin scale [mRS]). The association between sex and poor outcome (mRS 3-6) was assessed with Cox proportional hazard models stratified by type of treatment and adjusted for age, additionally for National Institute of Health Stroke Scale (NIHSS) and OTDT. Results Of the 58,632 patients, 26,941 (46%) were women. Compared with men, women were, older (mean age 74.6 versus 71.0, p<.001) and presented with slightly higher NIHSS-scores (median 3 [IQR 2-7] versus 3 [IQR 1-6], p<.001). Treatment modalities distribution (no treatment, IVT, EVT) was similar between women and men (64%; 29%; 10% versus 63%; 30%; 9%, p=.16). Women had a slightly longer OTDT (median 145 versus 139 minutes, p<.01). Women had increased odds of poor outcomes (OR 1.49 [95%CI 1.34-1.56]). This was still statistically significant after adjusting for age and NIHSS-score (OR 1.22 [95%CI 1.16-1.28]). Neither treatment modality nor OTDT had an additional influence on this association. Conclusion In this large real-world registry, we observed no differences in distribution of treatment modalities between sexes. We did find a minor pre-hospital delay in women and worse functional outcomes in women. The minor delay in OTDT does not fully explain the observed worse outcomes in women. Our results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Dutch centers.

The relation between vascular risk factors and flow in cerebral perforating arteries. A 7 Tesla MRI study.

INTRODUCTION: Cerebral perforating arteries provide blood supply to the deep regions of the brain. Recently, it became possible to measure blood flow velocity and pulsatility in these small arteries. It is unknown if vascular risk factors are related to these measures. METHODS: We measured perforating artery flow with 2D phase contrast 7 Tesla MRI at the level of the centrum semiovale (CSO) and the basal ganglia (BG) in seventy participants from the Heart Brain Connection study with carotid occlusive disease (COD), vascular cognitive impairment (VCI), or no actual cerebrovascular disease. Vascular risk factors included hypertension, diabetes, hyperlipidemia and smoking. RESULTS: No consistent relations were found between any of the vascular risk factors and either flow velocity or flow pulsatility, although there was a relation between lower diastolic blood pressure and higher pulse pressure and higher cerebral perforator pulsatility (p=0,045 and p=0,044, respectively) at the BG level. Results were similar in stratified analyses for patients with and without a history of cardiovascular disease, or only COD or VCI. CONCLUSION: We conclude that, cross-sectionally, cerebral perforating artery flow velocity and pulsatility are largely independent of the presence of common vascular risk factors in a population with a mixed vascular burden.

Detection of Cardioembolic Sources With Nongated Cardiac Computed Tomography Angiography in Acute Stroke: Results From the ENCLOSE Study.

BACKGROUND: Identifying cardioembolic sources in patients with acute ischemic stroke is important for the choice of secondary prevention strategies. We prospectively investigated the yield of admission (spectral) nongated cardiac computed tomography angiography (CTA) to detect cardioembolic sources in stroke. METHODS: Participants of the ENCLOSE study (Improved Prediction of Recurrent Stroke and Detection of Small Volume Stroke) with transient ischemic attack or acute ischemic stroke with assessable nongated head-to-heart CTA at the University Medical Center Utrecht were included between June 2017 and March 2022. The presence of cardiac thrombus on cardiac CTA was based on a Likert scale and dichotomized into certainly or probably absent versus possibly, probably, or certainly present. The diagnostic certainty of cardiac thrombus was evaluated again on spectral computed tomography reconstructions. The likelihood of a cardioembolic source was determined post hoc by an expert panel in patients with cardiac thrombus on CTA. Parametric and nonparametric tests were used to compare the outcome groups. RESULTS: Forty four (12%) of 370 included patients had a cardiac thrombus on admission CTA: 35 (9%) in the left atrial appendage and 14 (4%) in the left ventricle. Patients with cardiac thrombus had more severe strokes (median National Institutes of Health Stroke Scale score, 10 versus 4; P=0.006), had higher clot burden (median clot burden score, 9 versus 10; P=0.004), and underwent endovascular treatment more often (43% versus 20%; P<0.001) than patients without cardiac thrombus. Left atrial appendage thrombus was present in 28% and 6% of the patients with and without atrial fibrillation, respectively (P<0.001). The diagnostic certainty for left atrial appendage thrombus was higher for spectral iodine maps compared with the conventional CTA (P<0.001). The presence of cardiac thrombus on CTA increased the likelihood of a cardioembolic source according to the expert panel (P<0.001). CONCLUSIONS: Extending the stroke CTA to cover the heart increases the chance of detecting cardiac thrombi and helps to identify cardioembolic sources in the acute stage of ischemic stroke with more certainty. Spectral iodine maps provide additional value for detecting left atrial appendage thrombus. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04019483.

Temporal Trends and Determinants of Stroke Risk in Patients With Medically Treated Asymptomatic Carotid Stenosis.

BACKGROUND: Effectiveness of carotid procedures (surgery and stenting) in patients with asymptomatic carotid artery stenosis (ACAS) depends on the absolute risk reduction that patients might receive from these procedures. We aimed to quantify the risk of ipsilateral ischemic stroke and examined temporal trends and determinants of these risks in patients with ACAS treated conservatively. METHODS: We conducted a systematic review from inception to March 9, 2023, of peer-reviewed trials and cohort studies describing ipsilateral ischemic stroke risk in medically treated patients with ACAS of ≥50%. Risk of bias was assessed with an adapted version of the Quality in Prognosis Studies tool. We calculated the annual incidence rates of ipsilateral ischemic stroke. We explored temporal trends and associations of sex and degree of stenosis with ipsilateral ischemic stroke using Poisson metaregression analysis and incidence rate ratios, respectively. RESULTS: After screening 5915 reports, 73 studies describing ipsilateral ischemic stroke rates of 28 625 patients with midyear of recruitment ranging from 1976 to 2014 were included. The incidence of ipsilateral ischemic stroke was 0.98 (95% CI, 0.93-1.04) per 100 patient-years (median duration of follow-up, 3.3 years). The incidence decreased 24% with every 5 years more recent midyear of recruitment (rate ratio, 0.76 [95% CI, 0.73-0.78]). Incidence rates of ipsilateral ischemic stroke were lower in female patients (rate ratio, 0.74 [95% CI, 0.63-0.87]) and in patients with moderate versus severe stenosis when assessed in cohort studies, with incidence rate ratios of 0.41 ([95% CI, 0.35-0.49] cutoff, 70%) and 0.42 ([95% CI, 0.30-0.59] cutoff, 80%). CONCLUSIONS: Reported risks of ipsilateral ischemic stroke in patients with ACAS have declined 24% every 5 years from mid-1970s onward, further challenging the routine use of carotid procedures. Risks were lower in female patients and more than twice as high with severe compared with moderate ACAS. Inclusion of these findings in individualized risk assessment can help to determine the benefit of carotid procedures in selected individual patients with ACAS. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021222940.

Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.

BACKGROUND: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). METHODS: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. RESULTS: We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. CONCLUSIONS: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Critical analysis of the literature and standards of reporting on stroke after carotid revascularization.

OBJECTIVE: Mechanisms of procedural stroke after carotid endarterectomy (CEA) or carotid artery stenting are surprisingly underresearched. However, understanding the underlying mechanism could (1) assist in balancing the choice for revascularization vs conservative therapy, (2) assist in choosing either open or endovascular techniques, and (3) assist in taking appropriate periprocedural measures to further decrease procedural stroke rate. The purpose of this study was to overview mechanisms of procedural stroke after carotid revascularization and establish reporting standards to facilitate more granular investigation and individual patient data meta-analysis in the future. METHODS: A systematic review was conducted according to the PRISMA statement. RESULTS: The limited evidence in the literature was heterogeneous and of low quality. Thus, no formal data meta-analysis could be performed. Procedural stroke was classified as hemorrhagic or ischemic; the latter was subclassified as hemodynamic, embolic (carotid embolic or cardioembolic) or carotid occlusion derived, using a combination of clinical inference and imaging data. Most events occurred in the first 24 hours after the procedure and were related to hypoperfusion (pooled incidence 10.2% [95% confidence interval (CI), 3.0-17.5] vs 13.9% [95% CI, 0.0-60.9] after CEA vs carotid artery stenting events, respectively) or atheroembolism (28.9% [95% CI, 10.9-47.0]) vs 34.3 [95% CI, 0.0-91.5]). After the first 24 hours, hemorrhagic stroke (11.6 [95% CI, 5.7-17.4] vs 9.0 [95% CI, 1.3-16.7]) or thrombotic occlusion (18.4 [95% CI, 0.9-35.8] vs 14.8 [95% CI, 0.0-30.5]) became more likely. CONCLUSIONS: Although procedural stroke incidence and etiology may have changed over the last decades owing to technical improvements and improvements in perioperative monitoring and quality control, the lack of literature data limits further statements. To simplify and enhance future reporting, procedural stroke analysis and classification should be documented preemptively in research settings. We propose a standardized form enclosing reporting standards for procedural stroke with a systematic approach to inference of the most likely etiology, for prospective use in registries and randomized controlled trials on carotid revascularization.

Lifestyle changes and kidney function: A 10-year follow-up study in patients with manifest cardiovascular disease.

BACKGROUND: Patients with cardiovascular disease (CVD) are at higher risk of kidney function decline. The current study aimed to examine the association of lifestyle changes with kidney function decline in patients with manifest CVD. METHODS: A total of 2260 patients from the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort with manifest CVD who returned for a follow-up visit after a median of 9.9 years were included. The relation between change in lifestyle factors (smoking, alcohol consumption, physical activity and obesity) and change in kidney function (eGFR and uACR) was assessed using linear regression models. RESULTS: An increase in body mass index (ß -2.81; 95% CI -3.98; -1.63 per 5 kg/m2 ) and for men also an increase in waist circumference (ß -0.87; 95% CI -1.28; -0.47 per 5 cm) were significantly associated with a steeper decline in eGFR over 10 years. Continuing smoking (ß -2.44, 95% CI -4.43; -0.45) and recent smoking cessation during follow-up (ß -3.27; 95% CI -5.20; -1.34) were both associated with a steeper eGFR decline compared to patients who remained as non- or previous smokers from baseline. No significant association was observed between physical exercise or alcohol consumption and kidney function decline. No significant relation between any lifestyle factor and change in uACR was observed. CONCLUSIONS: In patients with CVD, continuing smoking, recent smoking cessation and an increase in obesity markers were related to a steeper kidney function decline. Although no definite conclusions from this study can be drawn, the results support the importance of encouraging weight loss and smoking cessation in high-risk patients as a means of slowing down kidney function decline.

Balancing Benefits and Risks of Long-Term Antiplatelet Therapy in Noncardioembolic Transient Ischemic Attack or Stroke.

Background and Purpose: Lifelong treatment with antiplatelet drugs is recommended following a transient ischemic attack or ischemic stroke. Bleeding complications may offset the benefit of antiplatelet drugs in patients at increased risk of bleeding and low risk of recurrent ischemic events. We aimed to investigate the net benefit of antiplatelet treatment according to an individuals' bleeding risk. Methods: We pooled individual patient data from 6 randomized clinical trials (CAPRIE [Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events], ESPS-2 [European Stroke Prevention Study-2], MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance], ESPRIT [European/Australasian Stroke Prevention in Reversible Ischemia Trial], and PRoFESS [Prevention Regimen for Effectively Avoiding Second Strokes]) investigating antiplatelet therapy in the subacute or chronic phase after noncardioembolic transient ischemic attack or stroke. Patients were stratified into quintiles according to their predicted risk of major bleeding with the S2TOP-BLEED score. The annual risk of major bleeding and recurrent ischemic events was assessed per quintile for 4 scenarios: (1) aspirin monotherapy, (2) aspirin-clopidogrel versus aspirin or clopidogrel monotherapy, (3) aspirin-dipyridamole versus clopidogrel, and (4) aspirin versus clopidogrel. Net benefit was calculated for the second, third, and fourth scenario. Results: Thirty seven thousand eighty-seven patients were included in the analyses. Both risk of major bleeding and recurrent ischemic events increased over quintiles of predicted bleeding risk, but risk of ischemic events was consistently higher (eg, from 0.7%/y (bottom quintile) to 3.2%/y (top quintile) for major bleeding on aspirin and from 2.5%/y to 10.2%/y for risk of ischemic events on aspirin). Treatment with aspirin-clopidogrel led to more major bleedings (0.9%­1.7% per year), than reduction in ischemic events (ranging from 0.4% to 0.9/1.0% per year) across all quintiles. There was no clear preference for either aspirin-dipyridamole or clopidogrel according to baseline bleeding risk. Conclusions: Among patients with a transient ischemic attack or ischemic stroke included in clinical trials of antiplatelet therapy, the risk of recurrent ischemic events and of major bleeding increase in parallel. Antiplatelet treatment cannot be individualized solely based on bleeding risk assessment.

Risk, Clinical Course, and Outcome of Ischemic Stroke in Patients Hospitalized With COVID-19: A Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. METHODS: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. RESULTS: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52-2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13-2.15]) than patients without stroke. CONCLUSIONS: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

External applicability of SGLT2 inhibitor cardiovascular outcome trials to patients with type 2 diabetes and cardiovascular disease.

BACKGROUND: Recent treatment guidelines support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and cardiovascular disease based on the results of cardiovascular outcome trials (CVOTs). Applicability of these trials to everyday patients with type 2 diabetes and cardiovascular disease is however unknown. The aim of this study is to assess the external applicability of SGLT2i CVOTs in daily clinical practice type 2 diabetes patients with established cardiovascular disease. METHODS: Trial in- and exclusion criteria from EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS-CV were applied to 1389 type 2 diabetes patients with cardiovascular disease in the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). To evaluate the difference in cardiovascular risk (MACE) and all-cause mortality between trial eligible and ineligible patients, age and sex-adjusted Cox-regression analyses were performed. RESULTS: After applying trial in- and exclusion criteria, 48% of UCC-SMART patients with type 2 diabetes and cardiovascular disease would have been eligible for DECLARE-TIMI 58, 35% for CANVAS, 29% for EMPA-REG OUTCOME and 21% for VERTIS-CV. Without the eligibility criteria of HbA1c, eligibility was 58-88%. For all trials the observed risk for cardiovascular events and all-cause mortality was similar in eligible and ineligible patients after adjustment for age and gender. CONCLUSION: A large proportion of patients with type 2 diabetes and cardiovascular disease in daily clinical practice would have been eligible for participation in the SGLT2i CVOTs. Trial eligible and ineligible patients have the same risk for MACE and all-cause mortality.

Prediction of long-term recurrent ischemic stroke: the added value of non-contrast CT, CT perfusion, and CT angiography.

PURPOSE: The aim of this study was to evaluate whether the addition of brain CT imaging data to a model incorporating clinical risk factors improves prediction of ischemic stroke recurrence over 5 years of follow-up. METHODS: A total of 638 patients with ischemic stroke from three centers were selected from the Dutch acute stroke study (DUST). CT-derived candidate predictors included findings on non-contrast CT, CT perfusion, and CT angiography. Five-year follow-up data were extracted from medical records. We developed a multivariable Cox regression model containing clinical predictors and an extended model including CT-derived predictors by applying backward elimination. We calculated net reclassification improvement and integrated discrimination improvement indices. Discrimination was evaluated with the optimism-corrected c-statistic and calibration with a calibration plot. RESULTS: During 5 years of follow-up, 56 patients (9%) had a recurrence. The c-statistic of the clinical model, which contained male sex, history of hyperlipidemia, and history of stroke or transient ischemic attack, was 0.61. Compared with the clinical model, the extended model, which contained previous cerebral infarcts on non-contrast CT and Alberta Stroke Program Early CT score greater than 7 on mean transit time maps derived from CT perfusion, had higher discriminative performance (c-statistic 0.65, P = 0.01). Inclusion of these CT variables led to a significant improvement in reclassification measures, by using the net reclassification improvement and integrated discrimination improvement indices. CONCLUSION: Data from CT imaging significantly improved the discriminatory performance and reclassification in predicting ischemic stroke recurrence beyond a model incorporating clinical risk factors only.

Variation in perioperative cerebral and hemodynamic monitoring during carotid endarterectomy.

BACKGROUND: Hemodynamic disturbances cause half of the perioperative strokes following carotid endarterectomy (CEA). Guidelines strongly recommend strict pre- and postoperative blood pressure (BP) monitoring in CEA patients, but do not provide firm practical recommendations. Although in the Netherlands 50 centres perform CEA, no national protocol on perioperative hemodynamic, and cerebral monitoring exists. To assess current monitoring policies of all Dutch CEA-centres, a national survey was conducted. METHODS: Between May and July 2017 all 50 Dutch CEA-centres were invited to complete a 42-question survey addressing perioperative hemodynamic and cerebral monitoring during CEA. Nonresponders received a reminder after 1 and 2 months. By November 2017 the survey was completed by all centres. RESULTS: Preoperative baseline BP was based on a single bilateral BP-measurement at the outpatient-clinic in the majority of centres (n = 28). In 43 centres (86%) pre-operative monitoring (transcranial Doppler (TCD, n = 6), electroencephalography (EEG, n = 11), or TCD + EEG (n = 26)) was performed as a baseline reference. Intraoperatively, large diversity for type of anaesthesia (general: 45 vs. local [LA]:5) and target systolic BP (>100 mm hg - 160 mm hg [n = 12], based on preoperative outpatient-clinic or admission BP [n = 18], other [n = 20]) was reported. Intraoperative cerebral monitoring included EEG + TCD (n = 28), EEG alone (n = 13), clinical neurological examination with LA (n = 5), near-infrared spectroscopy with stump pressure (n = 1), and none due to standard shunting (n = 3). Postoperatively, significant variation was reported in standard duration of admission at a recovery or high-care unit (range 3-48 hr, mean:12 hr), maximum accepted systolic BP (range >100 mm hg - 180 mm Hg [n = 32]), postoperative cerebral monitoring (standard TCD [n = 16], TCD on indication [n = 5] or none [n = 24]) and in timing of postoperative cerebral monitoring (range directly postoperative - 24 hr postoperative; median 3 hr). CONCLUSIONS: In Dutch centres performing CEA the perioperative hemodynamic and cerebral monitoring policies are widely diverse. Diverse policies may theoretically lead to over- or under treatment. The results of this national audit may serve as the baseline dataset for development of a standardized and detailed (inter)national protocol on perioperative hemodynamic and cerebral monitoring during CEA.

Treatment Restrictions and the Risk of Death in Patients With Ischemic Stroke or Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Do-not-resuscitate (DNR) orders in the first 24 hours after intracerebral hemorrhage have been associated with an increased risk of early death. This relationship is less certain for ischemic stroke. We assessed the relation between treatment restrictions and mortality in patients with ischemic stroke and in patients with intracerebral hemorrhage. We focused on the timing of treatment restrictions after admission and the type of treatment restriction (DNR order versus more restrictive care). METHODS: We retrospectively assessed demographic and clinical data, timing and type of treatment restrictions, and vital status at 3 months for 622 consecutive stroke patients primarily admitted to a Dutch university hospital. We used a Cox regression model, with adjustment for age, sex, comorbidities, and stroke type and severity. RESULTS: Treatment restrictions were installed in 226 (36%) patients, more frequently after intracerebral hemorrhage (51%) than after ischemic stroke (32%). In 187 patients (83%), these were installed in the first 24 hours. Treatment restrictions installed within the first 24 hours after hospital admission and those installed later were independently associated with death at 90 days (adjusted hazard ratios, 5.41 [95% CI, 3.17-9.22] and 5.36 [95% CI, 2.20-13.05], respectively). Statistically significant associations were also found in patients with ischemic stroke and in patients with just an early DNR order. In those who died, the median time between a DNR order and death was 520 hours (interquartile range, 53-737). CONCLUSIONS: The strong relation between treatment restrictions (including DNR orders) and death and the long median time between a DNR order and death suggest that this relation may, in part, be causal, possibly due to an overall lack of aggressive care.

Cerebral Perfusion and the Burden of Small Vessel Disease in Patients Referred to a Memory Clinic.

BACKGROUND: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of these lesions. OBJECTIVE: The aim of the study was to determine the relationship between cerebral blood flow (CBF) and SVD burden in patients referred to a memory clinic with SVD on MRI. METHOD: We included 132 memory clinic patients (mean age 73 ± 10, 56% male) with SVD on MRI. We excluded patients with large non-lacunar cortical infarcts. Global CBF (mL/min per 100 mL of brain tissue) was derived from 2-dimensional phase-contrast MRI focused on the internal carotid arteries and the basilar artery. SVD burden was defined as the sum of (each 1 point): white matter hyperintensities (WMHs) Fazekas 1 or more, lacunes, microbleeds (MBs), or enlarged perivascular spaces (PVS) presence, and each SVD feature separately. Linear regression analyses were performed to study the association between CBF and SVD burden, age- and sex-adjusted. RESULTS: Median SVD burden score was 2, 36.4% of patients had MBs, 35.6% lacunar infarcts, 48.4% intermediate to severe enlarged PVS, and 57.6% a WMH Fazekas score 2 or more. Median WMH volume was 21.4 mL (25% quartile: 9.6 mL, 75% quartile: 32.5 mL). Mean CBF ± SD was 44.0 ± 11.9 mL/min per 100 mL brain. There was no relation between CBF and overall SVD burden (CBF difference per burden score point [95% CI]: -0.5 [-2.4; 1.4] mL/min/100 mL brain, p = 0.9). CBF did also not differ according to presence or absence or an high burden of any of the individual SVD features. Moreover, there was no significant relation between WMH volume and CBF (CBF difference per ml increase in WMH [95% CI] -0.6 [-1.5; 0.3] mL/min/100 mL brain p = 0.2). CONCLUSION: Global CBF was not related to overall SVD burden or with individual SVD features in this memory clinic cohort, indicating that in this setting these lesions were not primarily due to cerebral hypoperfusion.

Intra-Operative Hypotension is a Risk Factor for Post-operative Silent Brain Ischaemia in Patients With Pre-operative Hypertension Undergoing Carotid Endarterectomy.

OBJECTIVE: Intra-operative haemodynamic instability during carotid endarterectomy (CEA) has been associated with an increased risk of procedural stroke. Diffusion weighted imaging (DWI) lesions have been proposed as a surrogate marker for peri-operative silent cerebral ischaemia. This study aimed to investigate the relationship between peri-operative blood pressure (BP) and presence of post-operative DWI lesions in patients undergoing CEA. METHODS: A retrospective analysis was performed based on patients with symptomatic CEA included in the MRI substudy of the International Carotid Stenting Study. Relative intra-operative hypotension was defined as a decrease of intra-operative systolic BP ≥ 20% compared with pre-operative ('baseline') BP, absolute hypotension was defined as a drop in systolic BP < 80  mmHg. The primary endpoint was the presence of any new DWI lesions on post-operative MRI (DWI positive). The occurrence and duration of intra-operative hypotension was compared between DWI positive and DWI negative patients as was the magnitude of the difference between pre- and intra-operative BP. RESULTS: Fifty-five patients with symptomatic CEA were included, of whom eight were DWI positive. DWI positive patients had a significantly higher baseline systolic (186 ± 31 vs. 158 ± 27 mmHg, p = .011) and diastolic BP (95 ± 15 vs. 84 ± 13 mmHg, p = .046) compared with DWI negative patients. Other pre-operative characteristics did not differ. Relative intra-operative hypotension compared with baseline occurred in 53/55 patients (median duration 34 min; range 0-174). Duration of hypotension did not differ significantly between the groups (p = .088). Mean systolic intra-operative BP compared with baseline revealed a larger drop in BP (-37 ± 29 mmHg) in DWI positive compared with DWI negative patients (-14 ± 26 mmHg, p = .024). Absolute intra-operative systolic BP values did not differ between the groups. CONCLUSION: In this exploratory study, high pre-operative BP and a larger drop of intra-operative BP were associated with peri-procedural cerebral ischaemia as documented with DWI. These results call for confirmation in an adequately sized prospective study, as they suggest important consequences for peri-operative haemodynamic management in carotid revascularisation.

Cerebral Small Vessel Disease in Standard Pre-operative Imaging Reports Is Independently Associated with Increased Risk of Cardiovascular Death Following Carotid Endarterectomy.

OBJECTIVE: Cerebral white matter lesions (WMLs) and lacunar infarcts are surrogates of cerebral small vessel disease (SVD). WML severity as determined by trained radiologists predicts post-operative stroke or death in patients undergoing carotid endarterectomy (CEA). It is unknown whether routine pre-operative brain imaging reports as part of standard clinical practice also predict short and long term risk of stroke and death after CEA. METHODS: Consecutive patients from the Athero-Express biobank study that underwent CEA for symptomatic high degree stenosis between March 2002 and November 2014 were included. Pre-operative brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) reports were reviewed for reporting of SVD, defined as WMLs or any lacunar infarcts. The primary outcome was defined as any stroke or any cardiovascular death over three year follow up. The secondary outcome was defined as the 30 day peri-operative risk of stroke or cardiovascular death. RESULTS: A total of 1038 patients were included (34% women), of whom 659 (63.5%) had CT images and 379 (36.5%) MRI images available. Of all patients, 697 (67%) had SVD reported by radiologists. Patients with SVD had a higher three year risk of cardiovascular death than those without (6.5% vs. 2.1%, adjusted HR 2.52 [95% CI 1.12-5.67]; p = .026) but no association was observed for the three year risk of stroke (9.0% vs. 6.7%, for patients with SVD vs. those without, adjusted HR 1.24 [95% CI 0.76-2.02]; p = .395). No differences in 30 day peri-operative risk were observed for stroke (4.4% vs. 2.9%, for patients with vs. those without SVD; adjusted HR 1.49 [95% CI 0.73-3.05]; p = .28), and for the combined stroke/cardiovascular death risk (4.4% vs. 3.5%, adjusted HR 1.20 [95% CI 0.61-2.35]; p = .59). CONCLUSION: Presence of SVD in pre-operative brain imaging reports can serve as a predictor for the three year risk of cardiovascular death in symptomatic patients undergoing CEA but does not predict peri-operative or long term risk of stroke.

Computed Tomography Perfusion Data for Acute Ischemic Stroke Evaluation Using Rapid Software: Pitfalls of Automated Postprocessing.

Computed tomography perfusion (CTP) is increasingly used to determine treatment eligibility for acute ischemic stroke patients. Automated postprocessing of raw CTP data is routinely used, but it can fail. In reviewing 176 consecutive acute ischemic stroke patients, failures occurred in 20 patients (11%) during automated postprocessing by the RAPID software. Failures were caused by motion (n = 11, 73%), streak artifacts (n = 2, 13%), and poor contrast bolus arrival (n = 2, 13%). Stroke physicians should review CTP results with care before they are being integrated in their decision-making process.