Citations

Background: Left ventricular (LV) injury is a cardioembolic etiology of ischemic stroke. We aimed to 1) evaluate recurrent stroke risk among patients with cryptogenic stroke and LV injury, and 2) determine if there is a treatment effect with anticoagulation in this population. Methods: We analyzed the multicenter, retrospective Cardiac Abnormalities in Stroke Prevention and Recurrence cohort of patients with cryptogenic ischemic stroke. The exposure was LV injury defined by 1) LV ejection fraction (EF) 20-40% and/or 2) LV wall motion abnormality (hypokinesis or akinesis). The primary composite outcome included recurrent stroke, major bleeding, or death. Cox proportional hazard models were built and sequentially adjusted for 1) age and sex (Model 1), and 2) age, sex, race, ethnicity, anti-thrombotic use, and vascular risk factors (Model 2). We then assessed if there was heterogeneity in treatment effect by LV injury status with an interaction term of LV injury and oral anticoagulation use in Model 2. Results: Of 2,641 patients in CASPR, the analytic cohort included 2,191 patients with complete exposure and outcome data (median age 65 years, 49.8% female, median follow-up 1.55 years). There were 113 (5.2%) patients with LV injury (median LVEF 30%, interquartile range 25-34%). There were 559 incident events (321 recurrent strokes [288 ischemic], 71 major hemorrhages, 250 deaths). Among patients with LV injury, 15.9% were prescribed an anticoagulant within 7 days of index stroke (vs 9.6% without LV injury, p=0.03). The unadjusted risk of the primary outcome was non-significantly higher among patients with LV injury vs without (HR 1.40; 95% confidence interval [CI], 0.98-2.00), but became significant in Model 1 (HR 1.50; 95% CI, 1.21-1.85) and in Model 2 (HR 1.35, 95% CI, 1.11-1.64). In the LV injury subgroup, anticoagulation vs antiplatelet therapy was associated with a significant reduction in the primary outcome (HR 0.63, 95% CI, 0.43-0.94). In patients without LV injury, anticoagulation was associated with a higher risk of the composite outcome (HR 4.35, 95% CI, 1.69-11.16, p[interaction]=0.002). Conclusion: In this observational study, there was an increased risk of the primary outcome which included recurrent stroke among patients with cryptogenic stroke and LV injury. Anticoagulation use in LV injury is associated with a significant reduction in the risk of the primary outcome. These findings warrant confirmation in a dedicated randomized controlled trial.

Introduction: Malignancy represents an important subgroup of embolic stroke of undetermined source (ESUS). We aim to compare infarct features, potential embolic sources, and long-term outcomes in ESUS patients with and without malignancy. Methods: In this pre-specified secondary analysis of the Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) retrospective cohort study, active cancers were identified by site investigators and adjudicated as malignant if they were non-squamous or non-basal cell skin cancers. We compared the prevalence of various potential embolic sources (e.g., patent foramen ovale, left ventricular dysfunction, post-stroke atrial fibrillation) among patients with and without malignancy. The risk of recurrent stroke, major bleeding, or death was evaluated using adjusted Cox proportional hazards models, accounting for age, sex, vascular risk factors, competing potential embolic sources, and initial treatment with anticoagulation versus non-anticoagulant (e.g., antiplatelet) regimen. Results: Of the 2201 patients followed over a median of 564 days, 236 (10.7%) were diagnosed with cancer at the time of stroke. Patients with malignancy were older, more frequently hypertensive and did not differ with regards to prevalence of specific infarct patterns or potential cardiac embolic sources. No difference was observed in the composite outcome of recurrent stroke, major bleeding, or death (adjusted HR 1.02, 95% CI, 0.71-1.46). Age (adjusted HR per year 1.02, 95% CI, 1.01-1.03), baseline stroke severity (adjusted HR 1.03 per NIHSS point, 95% CI, 1.01-1.05), prior stroke (adjusted HR 1.68, 95% CI, 1.38-2.05), and multi-territorial infarct pattern (adjusted HR 1.67, 95% CI, 1.33-2.08) were significantly associated with this composite outcome, but anticoagulation was not. There was a nominally lower rate of major bleeding with malignancy (adjusted HR 0.45, 95% CI, 0.19-1.04), a significantly higher rate of death (adjusted HR 1.58, 95% CI, 1.09-2.30), but no significant difference in recurrent ischemic stroke (p=0.31). Conclusions: Patients with malignancy and ESUS had higher mortality but did not differ in recurrent stroke risk or major bleeding when compared to patients without malignancy. Anticoagulation was not independently associated with better outcomes. Further analysis of infarct topology and risk factors may better identify patients for whom anticoagulation may benefit.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Background: Collateral blood flow, modulated by inflammation and arteriogenesis, alters ischemic injury in intracranial atherosclerosis. We investigated the potential link between several inflammatory and arteriogenic biomarkers with angiographic findings at enrollment in BIOSIS/SAMMPRIS. Methods: Baseline angiography and blood biomarkers of BIOSIS/SAMMPRIS, which included subjects with stroke or TIA due to 70-99% intracranial stenosis were analyzed. Collateral blood flow status at angiography was categorized by the combination of antegrade flow (TICI) and corresponding extent of collaterals (ASITN/SIR). Collateral status was analyzed with respect to blood progenitor cell markers (CD34) at baseline and inflammatory biomarkers (Plasminogen Activator Inhibitor-1 (PAI-1), E-selectin, high sensitivity C-reactive protein (hsCRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) activity and concentrations) at baseline, 30 days and 4 months. Results: 376 subjects (mean age 60.44 years SD 11; 149/376 (39.6%) women) enrolled in BIOSIS/SAMMPRIS had angiography of collaterals and biomarker data. Collateral perfusion was impaired in 71 (19%) and intermediate in 188 (50%), with robust collaterals in 117 (30%) subjects. Better collateral status was associated with younger age (p=0.001), male sex (p=0.029) and greater baseline physical activity (p=0.007). Baseline blood progenitor cell (CD34+) counts were unrelated to angiographic features at enrollment, whereas inflammatory Lp-PLA 2 activity was linked (p=0.059) with blood flow categories, and lower hsCRP (p=0.025) with better collaterals. Lp-PLA 2 activity was lowest in those with robust collaterals at 30 days (p=0.070) and 4 months (p=0.120). Those with robust collaterals had the greatest decrease in Lp-PLA 2 activity (p=0.021) and concentration (p=0.027) by 30 days, with a continued decline of Lp-PLA 2 activity (p=0.037) to 4 months. Disparate trends in inflammatory markers were seen in the medical and stenting arms. Conclusions: Inflammatory biomarkers are linked with collateral blood flow status in intracranial atherosclerosis. The impact of physical activity, medications and other therapeutic investigations may disclose important mechanisms to avert ischemia.

Background and Purpose: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. Methods: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. Results: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09–1.21]; P =0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32–1.34]; P =0.25) among noncarriers. There was no significant interaction by genotype for major ischemia ( P =0.36) or stroke ( P =0.33). Conclusions: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00991029.