Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6.

BACKGROUND: GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk. METHODS: SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke. RESULTS: A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (Pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (Pinteraction >0.05 for all). CONCLUSIONS: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01720446 and NCT02692716.

Outcome and safety of mechanical thrombectomy in patients with acute ischemic stroke due to internal carotid artery dissection.

BACKGROUND: Mechanical thrombectomy (MT) in patients with symptoms of acute ischemic stroke (AIS) due to internal carotid artery dissection (ICAD) remains controversial. In this study, we present clinical outcome and safety of MT in acute ICAD compared to other acute carotid artery pathology. METHODS: Patients with symptoms of AIS due to internal carotid artery pathology, treated with MT from 2017-2021, were categorized as ICAD or non-ICAD. Baseline and procedural characteristics, complications, and functional outcome at 90 days were compared between the two groups. Factors associated with a favorable outcome (modified Rankin Scale 0-2) were analyzed using multivariate logistic regression. Safety analyses included in-stent thrombosis, perforation, intracranial hemorrhage, and mortality. RESULTS: Sixty-seven ICAD patients (14.8%) and 387 non-ICAD patients (85.2%) were enrolled. ICAD patients were younger, median age 53 years (interquartile range (IQR) 47-61) vs. non-ICAD 72 years (IQR 64-79), p < 0.001. Favorable outcome was more common in ICAD patients, 49 ICAD patients (76.6%) vs. 158 non-ICAD patients (42.4%), p < 0.001. Post-procedural symptomatic intracranial hemorrhage occurred in 41 patients, 5 (7.5%) ICAD patients vs. 36 (9.3%) non-ICAD patients, p = 0.6. Mortality differed significantly, 6 (9%) ICAD patients vs. 94 (24.3%) non-ICAD patients, p = 0.01. ICAD was not associated with functional outcome in multivariate analysis, OR = 1.25 [95%confidence interval:0.55-2.86]. CONCLUSION: ICAD patients achieved a better 90-day functional outcome compared with non-ICAD patients. ICAD patients did not perform worse in safety measures than non-ICAD patients. Our data provide indirect evidence that MT is of clinical benefit in ICAD patients with symptoms of AIS.

Randomized Trial of Surgical Left Atrial Appendage Closure: Protection Against Cerebrovascular Events.

Following open-heart surgery, atrial fibrillation and stroke occur frequently. Left atrial appendage closure added to elective open-heart surgery could reduce the risk of ischemic stroke. We aim to examine if routine closure of the left atrial appendage in patients undergoing open-heart surgery provides long-term protection against cerebrovascular events independently of atrial fibrillation history, stroke risk, and oral anticoagulation use. Long-term follow-up of patients enrolled in the prospective, randomized, open-label, blinded evaluation trial entitled left atrial appendage closure by surgery (NCT02378116). Patients were stratified by oral anticoagulation status and randomized (1:1) to left atrial appendage closure in addition to elective open-heart surgery vs standard care. The primary composite endpoint was ischemic stroke events, transient ischemic attacks, and imaging findings of silent cerebral ischemic lesions. Two neurologists blinded for treatment assignment adjudicated cerebrovascular events. In total, 186 patients (82% males) were reviewed. At baseline, mean (standard deviation (SD)) age was68 (9) years and 13.4% (n = 25/186) had been diagnosed with atrial fibrillation. Median [interquartile range (IQR)] CHA2DS2-VASc was 3 [2,4] and 25.9% (n = 48/186) were receiving oral anticoagulants. Mean follow-up was 6.2 (2.5) years. The left atrial appendage closure group experienced fewer cerebrovascular events; intention-to-treat 11 vs 19 (P = 0.033, n = 186) and per-protocol 9 vs 17 (P = 0.186, n = 141). Left atrial appendage closure as an add-on open-heart surgery, regardless of pre-surgery atrial fibrillation and oral anticoagulation status, seems safe and may reduce cerebrovascular events in long-term follow-up. More extensive randomized clinical trials investigating left atrial appendage closure in patients without atrial fibrillation and high stroke risk are warranted.

Early Life Body Size in Relation to First Intracerebral or Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: As risk of hemorrhagic stroke may have early life origins, we investigated associations of birth weight and childhood body mass index (BMI) with adult intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH). METHODS: We included 240,234 Danish schoolchildren, born 1936 to 1989, with information on birth weight and measured weights and heights from 7 to 13 years. We calculated hazard ratios (HRs) and confidence intervals (CIs) for the associations between early life anthropometrics and ICH or SAH, identified through linkage with national registers. RESULTS: During the study period, 1,947 individuals (39% women) experienced an ICH and 797 individuals (64% women) experienced a SAH. Per 500 g increase in birth weight, women had a 10% decreased risk of SAH (HR, 0.90; 95% CI, 0.83 to 0.97) and men had a 10% decreased risk of ICH (HR, 0.90; 95% CI, 0.85 to 0.95). Birth weight was not associated with risks of ICH in women or SAH in men. In men, a childhood BMI below average (BMI z-score <0) was associated with increased risks of ICH. The association was stronger at older childhood ages, and at 13 years a BMI z-score of -1 was associated with a HR of 1.17 (95% CI, 1.06 to 1.28), and a BMI z-score of -2 with a HR of 1.46 (95% CI, 1.17 to 1.82) for ICH. Childhood BMI was not associated with risks of ICH in women or with risks of SAH in both sexes. CONCLUSION: s Early life body size is associated with ICH and SAH, and the associations differ by sex.

Atrial fibrillation in cryptogenic stroke and transient ischaemic attack - The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Rationale and design.

PURPOSE: Paroxysmal atrial fibrillation is often suspected as a probable cause of cryptogenic stroke. Continuous long-term ECG monitoring using insertable cardiac monitors is a clinically effective technique to screen for atrial fibrillation and superior to conventional follow-up in cryptogenic stroke. However, more studies are needed to identify factors which can help selecting patients with the highest possibility of detecting atrial fibrillation with prolonged rhythm monitoring. The clinical relevance of short-term atrial fibrillation, the need for medical intervention and the evaluation as to whether intervention results in improved clinical outcomes should be assessed. METHOD: The Nordic Atrial Fibrillation and Stroke Study is an international, multicentre, prospective, observational trial evaluating the occurrence of occult atrial fibrillation in cryptogenic stroke and transient ischaemic attack. Patients with cryptogenic stroke or transient ischaemic attack from the Nordic countries are included and will have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for atrial fibrillation detection. Biomarkers which can be used as predictors for atrial fibrillation and may identify patients, who could derive the most clinical benefit from the detection of atrial fibrillation by prolonged monitoring, are being studied. CONCLUSION: The primary endpoint is atrial fibrillation burden within 12 months of continuous rhythm monitoring. Secondary endpoints are atrial fibrillation burden within six months, levels of biomarkers predicting atrial fibrillation, CHA2DS2-VASc score, incidence of recurrent stroke or transient ischaemic attack, use of anticoagulation and antiarrhythmic drugs, and quality of life measurements. The clinical follow-up period is 12 months. The study started in 2017 and the completion is expected at the end of 2020.

Association of Childhood Body Mass Index and Change in Body Mass Index With First Adult Ischemic Stroke.

Importance: The incidence of ischemic stroke among young adults is rising and is potentially due to an increase in stroke risk factors occurring at younger ages, such as obesity. Objectives: To investigate whether childhood body mass index (BMI) and change in BMI are associated with adult ischemic stroke and to assess whether the associations are age dependent or influenced by birth weight. Design, Setting, and Participants: This investigation was a population-based cohort study of schoolchildren born from 1930 to 1987, with follow-up through national health registers from 1977 to 2012 in Denmark. Participants were 307 677 individuals (8899 ischemic stroke cases) with measured weight and height at ages 7 to 13 years. The dates of the analysis were September 1, 2015, to May 27, 2016. Main Outcomes and Measures: Childhood BMI, change in BMI, and birth weight. Ischemic stroke events were divided into early (≤55 years) or late (>55 years) age at diagnosis. Results: The study cohort comprised 307 677 participants (approximately 49% female and 51% male). During the study period, 3529 women and 5370 men experienced an ischemic stroke. At all ages from 7 to 13 years, an above-average BMI z score was positively associated with early ischemic stroke. At age 13 years, a BMI z score of 1 was associated with hazard ratios (HRs) of 1.26 (95% CI, 1.11-1.43) in women and 1.21 (95% CI, 1.10-1.33) in men. No significant associations were found for below-average BMI z scores. Among children with above-average BMI z scores at age 7 years, a score increase of 0.5 from ages 7 to 13 years was positively associated with early ischemic stroke in women (HR, 1.10; 95% CI, 1.01-1.20) and in men (HR, 1.08; 95% CI, 1.00-1.16). Similarly, among children with below-average BMI z scores at age 7 years, a score increase of 0.5 from ages 7 to 13 years was positively associated with early ischemic stroke in women (HR, 1.14; 95% CI, 1.06-1.23) and in men (HR, 1.10; 95% CI, 1.04-1.18). Adjusting for birth weight minimally affected the associations. Conclusions and Relevance: Independent of birth weight, above-average childhood BMI and increases in BMI during childhood are positively associated with early adult ischemic stroke. To avoid the occurrence of early ischemic stroke associated with childhood overweight and obesity, these results suggest that all children should be helped to attain and maintain healthy weights.