Lower haemoglobin concentrations are associated with impaired cognition in patients with carotid artery occlusion.

Background: Patients with carotid artery occlusion (CAO) are vulnerable to cognitive impairment (CI). Anaemia is associated with CI in the general population. We hypothesized that lower haemoglobin is associated with cognitive impairment (CI) in patients with CAO and that this association is accentuated by cerebral blood flow (CBF). Methods: 104 patients (mean age 66±8 years, 77% men) with complete CAO from the Heart-Brain Connection study were included. Anaemia was defined as haemoglobin < 12 g/dL for women and < 13 g/dL for men. Cognitive test results were standardized into z-scores (using a reference group) in four cognitive domains. Patients were classified as cognitively impaired when ≥ one domain was impaired. The association between lower haemoglobin and both cognitive domain z-scores and the presence of CI was assessed with adjusted (age, sex, education and ischaemic stroke) regression models. Total CBF (measured with phase contrast MRI) and the interaction term haemoglobin*CBF were additionally added to the analyses. Results: Anaemia was present in 6 (6%) patients and was associated with CI (RR 2.54, 95% CI 1.36; 4.76). Lower haemoglobin was associated with the presence of CI (RR per minus 1 g/dL haemoglobin 1.15, 95% CI 1.02; 1.30). This association was strongest for the attention-psychomotor speed domain (RR for impaired attention-psychomotor speed functioning per minus 1 g/dL haemoglobin 1.27, 95% CI 1.09;1.47) and ß for attention-psychomotor speed z-scores per minus 1 g/dL haemoglobin -0.19, 95% CI -0.33; -0.05). Adjustment for CBF did not affect these results and we found no interaction between haemoglobin and CBF in relation to cognition. Conclusion: Lower haemoglobin concentrations are associated with CI in patients with complete CAO, particularly in the domain attention-psychomotor speed. CBF did not accentuate this association. If validated in longitudinal studies, haemoglobin might be a viable target to prevent cognitive deterioration in patients with CAO.

Aneurysm Prevalence and Quality of Life During Screening in Relatives of Patients With Unruptured Intracranial Aneurysms: A Prospective Study.

BACKGROUND AND OBJECTIVES: Screening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives (FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening is also effective for FDRs of patients with UIA is unknown. We determined the yield of screening in such FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, identified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL). METHODS: In this prospective cohort study, we included FDRs, aged 20-70 years, of patients with UIA without a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 participating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magnetic resonance angiography between 2017 and 2021. We determined UIA prevalence and developed a prediction model for UIA risk at screening using multivariable logistic regression. QoL was evaluated with questionnaires 6 times during the first year after screening and assessed with a linear mixed-effects model. RESULTS: We detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI 3.2-7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2-4 mm), and the median 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%-0.9%). All UIAs received follow-up imaging, and none were treated preventively. After a median follow-up of 24 months (IQR 13-38 months), no UIA had changed. Predicted UIA risk at screening ranged between 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcohol consumption (c-statistic: 0.76; 95% CI 0.65-0.88). At all survey moments, health-related QoL and emotional functioning were comparable with those in a reference group from the general population. One FDR with a positive screening result expressed regret about screening. DISCUSSION: Based on the current data, we do not advise screening FDRs of patients with UIA because all identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. A longer follow-up should determine the risk of aneurysm growth requiring preventive treatment.

A Delphi consensus checklist helped assess the need to develop rapid guideline recommendations.

BACKGROUND AND OBJECTIVES: We aimed to develop a checklist to aid guideline developers in determining which scientific or societal cause ("triggers") are relevant when considering to initiate a rapid recommendation procedure. METHODS: We conducted a two-round modified Delphi procedure with a panel of Dutch guideline experts, clinicians, and patient representatives. A previously conducted systematic literature review and semistructured interviews with four science journalists were used to generate a list of potential items. This item list was submitted to the panel for discussion, reduction and refinement into a checklist. RESULTS: Thirteen experts took part. Two questionnaires were completed in which participants scored an initial list of 64 items based on relevance. During two online meetings, the scores were discussed, irrelevant items were removed, and relevant items were reformulated into seven questions. The final "quickscan assessment of the need for a rapid recommendation" covers user perspective, scientific evidence, clinical relevance, clinical practice variation, applicability, quality of care and public health outcomes, and ethical/legal considerations. CONCLUSION: The quickscan aids guideline developers in systematically assessing whether a trigger expresses a valid need for developing a rapid recommendation. Future research could focus on the applicability and validity of the checklist within guideline development programs.

Risk Prediction of New Intracranial Aneurysms at Follow-Up Screening in People With a Positive Family History.

BACKGROUND: In first-degree relatives of patients with aneurysmal subarachnoid hemorrhage (aSAH), the risk of an intracranial aneurysm can be predicted at initial screening but not at follow-up screening. We aimed to develop a model for predicting the probability of a new intracranial aneurysm after initial screening in people with a positive family history of aSAH. METHODS: In a prospective study, we obtained data from follow-up screening for aneurysms of 499 subjects with ≥2 affected first-degree relatives. Screening took place at the University Medical Center Utrecht, the Netherlands, and the University Hospital of Nantes, France. We studied associations between potential predictors and the presence of aneurysms using Cox regression analysis and the predictive performance at 5, 10, and 15 years after initial screening using C statistics and calibration plots, while correcting for overfitting. RESULTS: In 5050 person-years of follow-up, intracranial aneurysms were found in 52 subjects. The risk of aneurysm at 5 years was 2% to 12%, at 10 years, 4% to 28%, and at 15 years, 7% to 40%. Predictors were female sex, history of intracranial aneurysms/aneurysmal subarachnoid hemorrhage, and older age. The sex, previous history of intracranial aneurysm/aSAH, older age score had a C statistic of 0.70 (95% CI, 0.61-0.78) at 5 years, 0.71 (95% CI, 0.64-0.78) at 10 years, and 0.70 (95% CI, 0.63-0.76) at 15 years and showed good calibration. CONCLUSIONS: The sex, previous history of intracranial aneurysm/aSAH, older age score provides risk estimates for finding new intracranial aneurysms at 5, 10, and 15 years after initial screening, based on 3 easily retrievable predictors; this can help to define a personalized screening strategy after initial screening in people with a positive family history for aSAH.

Development of the SAFETEA Scores for Predicting Risks of Complications of Preventive Endovascular or Microneurosurgical Intracranial Aneurysm Occlusion.

OBJECTIVE: Preventive unruptured intracranial aneurysm occlusion can reduce the risk of subarachnoid hemorrhage, but both endovascular and microneurosurgical treatment carry a risk of serious complications. To improve individualized management decisions, we developed risk scores for complications of endovascular and microneurosurgical treatment based on easily retrievable patient, aneurysm, and treatment characteristics. METHODS: For this multicenter cohort study, we combined individual patient data from unruptured intracranial aneurysm patients ≥18 years undergoing preventive endovascular treatment (standard, balloon-assisted or stent-assisted coiling, Woven EndoBridge-device, or flow-diverting stent) or microneurosurgical clipping at one of 10 participating centers from three continents between 2000-2018. The primary outcome was death from any cause or clinical deterioration from neurological complications ≤30 days. We selected predictors based on previous knowledge about relevant risk factors and predictor performance and studied the association between predictors and complications with logistic regression. We assessed model performance with calibration plots and concordance (c) statistics. RESULTS: Of 1282 included patients, 94 (7.3%) had neurological symptoms that resolved <30 days, 140 (10.9%) had persisting neurological symptoms, and 6 died (0.5%)). At 30 days, 52 patients (4.1%) were dead or dependent. Predictors of procedural complications were: size of aneurysm, aneurysm location, familial subarachnoid hemorrhage, earlier atherosclerotic disease, treatment volume, endovascular modality (for endovascular treatment) or extra aneurysm configuration factors (for microneurosurgical treatment; branching artery from aneurysm neck or unfavorable dome-to-neck ratio), and age (acronym: SAFETEA). For endovascular treatment (n=752), the c-statistic was 0.72 (95%CI:0.67-0.77) and the absolute complication risk ranged from 3.2% (95%CI:1.6%-14.9%;≤1 point) to 33.1% (95%CI:25.4%-41.5%;≥6 points). For microneurosurgical treatment (n=530), the c-statistic was 0.72 (95%CI:0.67-0.77) and the complication risk ranged from 4.9% (95%CI:1.5%-14.9%;≤1 point) to 49.9% (95%CI:39.4%-60.6%;≥6 points). CONCLUSIONS: The SAFETEA risk scores for endovascular and microneurosurgical treatment are based on seven easily retrievable risk factors to predict the absolute risk of procedural complications in patients with unruptured intracranial aneurysms. The scores need external validation before the predicted risks can be properly used to support decision making in clinical practice.

Risk evaluation of cognitive impairment in patients with heart failure: A call for action.

Background: Cognitive impairment (CI) is common in patients with heart failure (HF) and impacts treatment adherence and other aspects of patient life in HF. Recognition of CI in patients with HF is therefore important. We aimed to develop a risk model with easily available patient characteristics, to identify patients with HF who are at high risk to be cognitively impaired and in need for further cognitive investigation. Methods & results: The risk model was developed in 611 patients ≥ 60 years with HF from the TIME-CHF trial. Fifty-six (9 %) patients had CI (defined as Hodkinson Abbreviated Mental Test ≤ 7). We assessed the association between potential predictors and CI with least-absolute-shrinkage-and-selection-operator (LASSO) regression analysis. The selected predictors were: older age, female sex, NYHA class III or IV, Charlson comorbidity index ≥ 6, anemia, heart rate ≥ 70 bpm and systolic blood pressure ≥ 145 mmHg. A model that combined these variables had a c-statistic of 0.70 (0.63-0.78). The model was validated in 155 patients ≥ 60 years with HF from the ECHO study. In the validation cohort 51 (33 %) patients had CI (defined as a Mini Mental State Exam ≤ 24). External validation showed an AUC of 0.56 (0.46-0.66). Conclusions: This risk model with easily available patient characteristics has poor predictive performance in external validation, which may be due to case-mix variation. These findings underscore the need for active screening and standardized assessment for CI in patients with HF.

Quality of life outcomes over time in patients with unruptured intracranial aneurysms with and without preventive occlusion: a prospective cohort study.

OBJECTIVE: In counselling patients with an unruptured intracranial aneurysm (UIA), quality-of-life (QoL) outcomes are important for informed decision-making. We evaluated QoL outcomes in patients with and without preventive aneurysm occlusion at multiple time points during the first year after UIA diagnosis and studied predictors of QoL outcomes. METHODS: We performed a prospective cohort study in patients ≥18 years old with a newly diagnosed UIA in two tertiary referral centers in the Netherlands between 2017 and 2019. Patients were sent QoL questionnaires at 7 (aneurysm occlusion) or 5 (no occlusion) moments during the first year after diagnosis. We collected baseline data on patient and aneurysm characteristics, passive coping style (Utrecht Coping List), occlusion modality, and neurological complications. We assessed health-related QoL (HRQoL) with the EuroQol 5-dimensions (EQ-5D), emotional functioning with the Hospital Anxiety and Depression Scale (HADS), and restrictions in daily activities with the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P). We used a linear mixed effects model to assess the course of QoL over time and to explore predictors of QoL outcomes. RESULTS: Of 153 eligible patients, 99 (65%) participated, of whom 30/99 (30%) underwent preventive occlusion. Patients undergoing occlusion reported higher baseline levels of passive coping, anxiety and depression, and restrictions than patients without occlusion. During recovery after occlusion, patients reported more restrictions compared to baseline (adjusted USER-P decrease one-month post-occlusion: -12.8 (95%CI:-23.8- -1.9). HRQoL and emotional functioning gradually improved after occlusion (EQ-5D increase at one-year: 8.6 (95%CI:0.1-17.0) and HADS decrease at one-year: -5.4 (95%CI:-9.4- -1.5)). In patients without occlusion, the largest HRQoL improvement occurred directly after visiting the outpatient aneurysm clinic (EQ-5D increase: 9.2 (95%CI:5.5-12.8)). At one-year, QoL outcomes were comparable in patients with and without occlusion. Factors associated with worse QoL outcomes were a passive coping style in all patients, complications in patients with occlusion and higher rupture risks in patients without occlusion. CONCLUSIONS: After UIA diagnosis, QoL improves gradually after preventive occlusion and directly after counselling at the outpatient clinic in patients without occlusion, resulting in comparable one-year QoL outcomes. A passive coping style is an important predictor of poor QoL outcomes in all UIA patients.

Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage.

BACKGROUND: Persons with a positive family history of aneurysmal subarachnoid hemorrhage are at increased risk of aneurysmal subarachnoid hemorrhage. Preventive screening for intracranial aneurysms (IAs) in these persons is cost-effective but not very efficient. We aimed to develop and externally validate a model for predicting the probability of an IA at first screening in persons with a positive family history of aneurysmal subarachnoid hemorrhage. METHODS: For model development, we studied results from initial screening for IA in 660 prospectively collected persons with ≥2 affected first-degree relatives screened at the University Medical Center Utrecht. For validation, we studied results from 258 prospectively collected persons screened in the University Hospital of Nantes. We assessed potential predictors of IA presence in multivariable logistic regression analysis. Predictive performance was assessed with the C statistic and a calibration plot and corrected for overfitting. RESULTS: IA were present in 79 (12%) persons in the development cohort. Predictors were number of affected relatives, age, smoking, and hypertension (NASH). The NASH score had a C statistic of 0.68 (95% CI, 0.62-0.74) and showed good calibration in the development data. Predicted probabilities of an IA at first screening varied from 5% in persons aged 20 to 30 years with two affected relatives, without hypertension who never smoked, up to 36% in persons aged 60 to 70 years with ≥3 affected relatives, who have hypertension and smoke(d). In the external validation data IA were present in 67 (26%) persons, the model had a C statistic of 0.64 (95% CI, 0.57-0.71) and slightly underestimated IAs risk. CONCLUSIONS: For persons with ≥2 affected first-degree relatives, the NASH score improves current predictions and provides risk estimates for an IA at first screening between 5% and 36% based on 4 easily retrievable predictors. With the information such persons can now make a better informed decision about whether or not to undergo preventive screening.

Development of a questionnaire to identify persons with a family history of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Preventive screening for intracranial aneurysms is effective in persons with a positive family history of aneurysmal subarachnoid hemorrhage (aSAH), but for many relatives of aSAH patients, it can be difficult to assess whether their relative had an aSAH or another type of stroke. AIM: We aimed to develop a family history questionnaire for people in the population who believe they have a first-degree relative who had a stroke and to assess its accuracy to identify relatives of aSAH patients. METHODS: A questionnaire to distinguish between aSAH and other stroke types (ischemic stroke and intracerebral hemorrhage) was developed by a team of clinicians and consumers. The level of agreement between the questionnaire outcome and medical diagnosis was pilot tested in 30 previously admitted aSAH patients. Next, the sensitivity and specificity of the questionnaire were assessed in 91 first-degree relatives (siblings/children) of previously admitted stroke patients. RESULTS: All 30 aSAH patients were identified by the questionnaire in the pilot study; 29 of 30 first-degree relatives of aSAH patients were correctly identified. The questionnaire had a sensitivity of 97% (95% confidence interval (CI) = 83-100%) and a specificity of 93% (95% CI = 84-98%) when tested in the first-degree relatives of stroke patients. CONCLUSION: Our questionnaire can help persons to discriminate an aSAH from other types of stroke in their affected relative. This family history questionnaire is developed in the Netherlands but could also be used in other countries after validation.

Sex Difference and Rupture Rate of Intracranial Aneurysms: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture. METHODS: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage. RESULTS: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89-1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58-0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07-1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02-1.90). CONCLUSIONS: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women.

External Validation of Risk Prediction Models to Improve Selection of Patients for Carotid Endarterectomy.

BACKGROUND AND PURPOSE: The net benefit of carotid endarterectomy (CEA) is determined partly by the risk of procedural stroke or death. Current guidelines recommend CEA if 30-day risks are <6% for symptomatic stenosis and <3% for asymptomatic stenosis. We aimed to identify prediction models for procedural stroke or death after CEA and to externally validate these models in a large registry of patients from the United States. METHODS: We conducted a systematic search in MEDLINE and EMBASE for prediction models of procedural outcomes after CEA. We validated these models with data from patients who underwent CEA in the American College of Surgeons National Surgical Quality Improvement Program (2011-2017). We assessed discrimination using C statistics and calibration graphically. We determined the number of patients with predicted risks that exceeded recommended thresholds of procedural risks to perform CEA. RESULTS: After screening 788 reports, 15 studies describing 17 prediction models were included. Nine were developed in populations including both asymptomatic and symptomatic patients, 2 in symptomatic and 5 in asymptomatic populations. In the external validation cohort of 26 293 patients who underwent CEA, 702 (2.7%) developed a stroke or died within 30-days. C statistics varied between 0.52 and 0.64 using all patients, between 0.51 and 0.59 using symptomatic patients, and between 0.49 to 0.58 using asymptomatic patients. The Ontario Carotid Endarterectomy Registry model that included symptomatic status, diabetes, heart failure, and contralateral occlusion as predictors, had C statistic of 0.64 and the best concordance between predicted and observed risks. This model identified 4.5% of symptomatic and 2.1% of asymptomatic patients with procedural risks that exceeded recommended thresholds. CONCLUSIONS: Of the 17 externally validated prediction models, the Ontario Carotid Endarterectomy Registry risk model had most reliable predictions of procedural stroke or death after CEA and can inform patients about procedural hazards and help focus CEA toward patients who would benefit most from it.

Difference in Rupture Risk Between Familial and Sporadic Intracranial Aneurysms: An Individual Patient Data Meta-analysis.

BACKGROUND AND OBJECTIVES: We combined individual patient data (IPD) from prospective cohorts of patients with unruptured intracranial aneurysms (UIAs) to assess to what extent patients with familial UIA have a higher rupture risk than those with sporadic UIA. METHODS: For this IPD meta-analysis, we performed an Embase and PubMed search for studies published up to December 1, 2020. We included studies that (1) had a prospective study design; (2) included 50 or more patients with UIA; (3) studied the natural course of UIA and risk factors for aneurysm rupture including family history for aneurysmal subarachnoid haemorrhage and UIA; and (4) had aneurysm rupture as an outcome. Cohorts with available IPD were included. All studies included patients with newly diagnosed UIA visiting one of the study centers. The primary outcome was aneurysmal rupture. Patients with polycystic kidney disease and moyamoya disease were excluded. We compared rupture rates of familial vs sporadic UIA using a Cox proportional hazard regression model adjusted for PHASES score and smoking. We performed 2 analyses: (1) only studies defining first-degree relatives as parents, children, and siblings and (2) all studies, including those in which first-degree relatives are defined as only parents and children, but not siblings. RESULTS: We pooled IPD from 8 cohorts with a low and moderate risk of bias. First-degree relatives were defined as parents, siblings, and children in 6 cohorts (29% Dutch, 55% Finnish, 15% Japanese), totaling 2,297 patients (17% familial, 399 patients) with 3,089 UIAs and 7,301 person-years follow-up. Rupture occurred in 10 familial cases (rupture rate: 0.89%/person-year; 95% confidence interval [CI] 0.45-1.59) and 41 sporadic cases (0.66%/person-year; 95% CI 0.48-0.89); adjusted hazard ratio (HR) for familial cases 2.56 (95% CI 1.18-5.56). After adding the 2 cohorts excluding siblings as first-degree relatives, resulting in 9,511 patients, the adjusted HR was 1.44 (95% CI 0.86-2.40). DISCUSSION: The risk of rupture of UIA is 2.5 times higher, with a range from a 1.2 to 5 times higher risk, in familial than in sporadic UIA. When assessing the risk of rupture in UIA, family history should be taken into account.

Sex and Cardiovascular Function in Relation to Vascular Brain Injury in Patients with Cognitive Complaints.

BACKGROUND: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. OBJECTIVE: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. METHODS: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). RESULTS: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05). CONCLUSION: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Dementia risk in the general population: large-scale external validation of prediction models in the AGES-Reykjavik study.

We aimed to evaluate the external performance of prediction models for all-cause dementia or AD in the general population, which can aid selection of high-risk individuals for clinical trials and prevention. We identified 17 out of 36 eligible published prognostic models for external validation in the population-based AGES-Reykjavik Study. Predictive performance was assessed with c statistics and calibration plots. All five models with a c statistic > .75 (.76-.81) contained cognitive testing as a predictor, while all models with lower c statistics (.67-.75) did not. Calibration ranged from good to poor across all models, including systematic risk overestimation or overestimation for particularly the highest risk group. Models that overestimate risk may be acceptable for exclusion purposes, but lack the ability to accurately identify individuals at higher dementia risk. Both updating existing models or developing new models aimed at identifying high-risk individuals, as well as more external validation studies of dementia prediction models are warranted.

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.

Management decisions on unruptured intracranial aneurysms before and after implementation of the PHASES score.

BACKGROUND: In management decisions on saccular unruptured intracranial aneurysms (UIAs) the risk of rupture is an important factor. The PHASES score, introduced in 2014, provides absolute 5-year risks of rupture based on six easily retrievable patient and aneurysm characteristics. We assessed whether management decisions on UIAs changed after implementation of the PHASES score. PATIENT AND METHODS: We included all patients with UIAs who were referred to two Dutch tertiary referral centers for aneurysm care in the Netherlands (University Medical Center Utrecht (UMCU) and Leiden University Medical Center (LUMC)) between 2011 and 2017. Analyses were done on an aneurysm level. We calculated the overall proportion of UIAs with a decision to treat before and after PHASES implementation and studied the influence of age and center on post-implementation management changes. RESULTS: We included 623 patients with 803 UIAs. The proportion of UIAs with a decision to treat was 123/360 (34.2%) before and 117/443 (26.4%) after PHASES implementation (absolute risk difference: -7.8%; 95% CI: -14.1 to -1.4). The decision to treat was made at a higher median PHASES score after implementation (7 points (IQR 5;10) pre- versus 8 points (IQR 5;10) post-implementation; p = 0.14). The reduced proportion with a treatment decision after implementation was most pronounced in patients <50 years (-22.3%; 95% CI: -39.2 to -3.4) and was restricted to treatment decisions made at the UMCU (-10.6%; 95% CI: -18.5 to -2.5). DISCUSSION AND CONCLUSIONS: Management of UIAs changed following implementation of the PHASES score, but the impact of PHASES implementation on treatment decisions differed across age subgroups and centers.

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials.

BACKGROUND AND PURPOSE: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. METHODS: Data from the Carotid Stenosis Trialists' Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P≤0.10. RESULTS: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant (P=0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. CONCLUSIONS: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).

Surgical Decompression for Space-Occupying Hemispheric Infarction: A Systematic Review and Individual Patient Meta-analysis of Randomized Clinical Trials.

Importance: In patients with space-occupying hemispheric infarction, surgical decompression reduces the risk of death and increases the chance of a favorable outcome. Uncertainties, however, still remain about the benefit of this treatment for specific patient groups. Objective: To assess whether surgical decompression for space-occupying hemispheric infarction is associated with a reduced risk of death and an increased chance of favorable outcomes, as well as whether this association is modified by patient characteristics. Data Sources: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Stroke Trials Registry were searched from database inception to October 9, 2019, for English-language articles that reported on the results of randomized clinical trials of surgical decompression vs conservative treatment in patients with space-occupying hemispheric infarction. Study Selection: Published and unpublished randomized clinical trials comparing surgical decompression with medical treatment alone were selected. Data Extraction and Synthesis: Patient-level data were extracted from the trial databases according to a predefined protocol and statistical analysis plan. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the Cochrane Collaboration's tool for assessing risk of bias were used. One-stage, mixed-effect logistic regression modeling was used for all analyses. Main Outcomes and Measures: The primary outcome was a favorable outcome (modified Rankin Scale [mRS] score ≤3) at 1 year after stroke. Secondary outcomes included death, reasonable (mRS score ≤4) and excellent (mRS score ≤2) outcomes at 6 months and 1 year, and an ordinal shift analysis across all levels of the mRS. Variables for subgroup analyses were age, sex, presence of aphasia, stroke severity, time to randomization, and involved vascular territories. Results: Data from 488 patients from 7 trials from 6 countries were available for analysis. The risk of bias was considered low to moderate for 6 studies. Surgical decompression was associated with a decreased chance of death (adjusted odds ratio, 0.16; 95% CI, 0.10-0.24) and increased chance of a favorable outcome (adjusted odds ratio, 2.95; 95% CI, 1.55-5.60), without evidence of heterogeneity of treatment effect across any of the prespecified subgroups. Too few patients were treated later than 48 hours after stroke onset to allow reliable conclusions in this subgroup, and the reported proportions of elderly patients reaching a favorable outcome differed considerably among studies. Conclusions and Relevance: The results suggest that the benefit of surgical decompression for space-occupying hemispheric infarction is consistent across a wide range of patients. The benefit of surgery after day 2 and in elderly patients remains uncertain.

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.

Hypertensive Exposure Markers by MRI in Relation to Cerebral Small Vessel Disease and Cognitive Impairment.

OBJECTIVES: This study sought to investigate the extent of hypertensive exposure as assessed by cardiovascular magnetic resonance imaging (MRI) in relation to cerebral small vessel disease (CSVD) and cognitive impairment, with the aim of understanding the role of hypertension in the early stages of deteriorating brain health. BACKGROUND: Preserving brain health into advanced age is one of the great challenges of modern medicine. Hypertension is thought to induce vascular brain injury through exposure of the cerebral microcirculation to increased pressure/pulsatility. Cardiovascular MRI provides markers of (subclinical) hypertensive exposure, such as aortic stiffness by pulse wave velocity (PWV), left ventricular (LV) mass index (LVMi), and concentricity by mass-to-volume ratio. METHODS: A total of 559 participants from the Heart-Brain Connection Study (431 patients with manifest cardiovascular disease and 128 control participants), age 67.8 ± 8.8 years, underwent 3.0-T heart-brain MRI and extensive neuropsychological testing. Aortic PWV, LVMi, and LV mass-to-volume ratio were evaluated in relation to presence of CSVD and cognitive impairment. Effect modification by patient group was investigated by interaction terms; results are reported pooled or stratified accordingly. RESULTS: Aortic PWV (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.05 to 1.30 in patient groups only), LVMi (in carotid occlusive disease, OR: 5.69; 95% CI: 1.63 to 19.87; in other groups, OR: 1.30; 95% CI: 1.05 to 1.62]) and LV mass-to-volume ratio (OR: 1.81; 95% CI: 1.46 to 2.24) were associated with CSVD. Aortic PWV (OR: 1.07; 95% CI: 1.02 to 1.13) and LV mass-to-volume ratio (OR: 1.27; 95% CI: 1.07 to 1.51) were also associated with cognitive impairment. Relations were independent of sociodemographic and cardiac index and mostly persisted after correction for systolic blood pressure or medical history of hypertension. Causal mediation analysis showed significant mediation by presence of CSVD in the relation between hypertensive exposure markers and cognitive impairment. CONCLUSIONS: The extent of hypertensive exposure is associated with CSVD and cognitive impairment beyond clinical blood pressure or medical history. The mediating role of CSVD suggests that hypertension may lead to cognitive impairment through the occurrence of CSVD.