Mulder, Hillary

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

Objective: We aimed to characterize seasonal variation in US population-based blood pressure (BP) control and BP-related metrics and evaluate the association between outdoor temperature and BP control variation. Methods: We queried electronic health records (EHRs) from 26 health systems, representing 21 states, to summarize BP metrics by quarters of 12-month periods from January 2017 to March 2020. Patients with at least one ambulatory visit during the measurement period and a hypertension diagnosis during the first 6 months or prior to the measurement period were included. Changes in BP control, BP improvement, medication intensification, average SBP reduction after medication intensification across quarters and association with outdoor temperature were analyzed using weighted generalized linear models with repeated measures. Results: Among 1 818 041 people with hypertension, the majority were more than 65 years of age (52.2%), female (52.1%), white non-Hispanic (69.8%) and had stage 1/2 hypertension (64.8%). Overall, BP control and process metrics were highest in quarters 2 and 3, and lowest in quarters 1 and 4. Quarter 2 had the highest percentage of improved BP (31.95 ± 0.90%) and average SBP reduction after medication intensification (16 ± 0.23 mmHg). Quarter 3 had the highest percentage of BP controlled (62.25 ± 2.55%) and lowest with medication intensification (9.73 ± 0.60%). Results were largely consistent in adjusted models. Average temperature was associated with BP control metrics in unadjusted models, but associations were attenuated following adjustment. Conclusion: In this large, national, EHR-based study, BP control and BP-related process metrics improved during spring/summer months, but outdoor temperature was not associated with performance following adjustment for potential confounders.

Introduction: Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease (ASCVD), yet little is known about Lp(a) testing patterns in real-world practice. We hypothesized that Lp(a) testing occurs in a different population than calculated low density lipoprotein (LDL-C) testing alone, and that elevated Lp(a) is associated with greater lipid-lowering therapy (LLT) initiation and cardiovascular (CV) events. Methods: We used data from 11 health systems participating in the National Patient-Centered Clinical Research Network. We created two cohorts based on lab tests from Jan 1, 2015 to Dec 31, 2019: 1) the Lp(a) cohort, of adults with an Lp(a) test and 2) the LDL-C cohort, of 4:1 date- and site-matched adults with an LDL-C test, but no Lp(a) test. We used logistic regression to assess the relationship between Lp(a) levels (< 50, 50-100, and > 100mg/dL) and initiation of LLT within 3 months; and cox proportional hazards to evaluate Lp(a) levels and time to all-cause hospitalization and the composite of MI, revascularization and ischemic stroke hospitalization. Results: Overall, 20,551 patients (0.06% per year) had Lp(a) tests, with median Lp(a) value 17.5mg/dL (Q1, Q3: 7.0, 56.0). Compared with the LDL-C cohort (N=82,204), the Lp(a) cohort more frequently had ASCVD (24.3% vs. 8.5%) or multiple prior CV events (8.6% vs. 2.6%). Elevated Lp(a) was associated with greater odds of LLT initiation (Figure 1). Elevated Lp(a) was not significantly associated with all-cause hospitalization; however, Lp(a) > 100mg/dL was correlated with composite CV hospitalization compared with Lp(a) < 50mg/dL [adj HR (95% CI): 1.24 (1.06-1.44), p=0.006]. Conclusions: Lp(a) testing occurs more often in adults with ASCVD and multiple CV events, but testing is infrequent. Elevated Lp(a) was associated with LLT initiation, including niacin, despite lack of evidence of CV benefit. There was an association between elevated Lp(a) and CV hospitalization outcomes.

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin. Methods: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models. Results: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11–2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16–2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome. Conclusions: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Objective To assess stroke/systemic embolism, major bleeding and other outcomes, and treatment effect of apixaban versus warfarin, in patients with atrial fibrillation (AF) and different types of valvular heart disease (VHD), using data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Methods There were 14 793 patients with known VHD status, categorised as having moderate or severe mitral regurgitation (MR) (n=3382), aortic regurgitation (AR) (n=842) or aortic stenosis (AS) (n=324); patients with moderate or severe mitral stenosis were excluded from the trial. Baseline characteristics, efficacy and safety outcomes were compared between each type and no significant VHD. Treatment effect was assessed using an adjusted model. Results Patients with MR or AR had similar rates of stroke/systemic embolism and bleeding compared with patients without MR or AR, respectively. Patients with AS had significantly higher event rates (presented as rate per 100 patient-years of follow-up) of stroke/systemic embolism (3.47 vs 1.36; adjusted HR (adjHR) 2.21, 95% CI 1.35 to 3.63), death (8.30 vs 3.53; adjHR 1.92, 95% CI 1.41 to 2.61), major bleeding (5.31 vs 2.53; adjHR 1.80, 95% CI 1.19 to 2.75) and intracranial bleeding (1.29 vs 0.51; adjHR 2.54, 95% CI 1.08 to 5.96) than patients without AS. The superiority of apixaban over warfarin on stroke/systemic embolism was similar in patients with versus without MR (HR 0.69, 95% CI 0.46 to 1.04 vs HR 0.79, 95% CI 0.63 to 1.00; interaction P value 0.52), with versus without AR (HR 0.57, 95% CI 0.27 to 1.20 vs HR 0.78, 95% CI 0.63 to 0.96; interaction P value 0.52), and with versus without AS (HR 0.44, 95% CI 0.17 to 1.13 vs HR 0.79, 95% CI 0.64 to 0.97; interaction P value 0.19). For each of the primary and secondary efficacy and safety outcomes, there was no evidence of a different effect of apixaban over warfarin in patients with any VHD subcategory. Conclusions In anticoagulated patients with AF, AS is associated with a higher risk of stroke/systemic embolism, bleeding and death. The efficacy and safety benefits of apixaban compared with warfarin were consistent, regardless of presence of MR, AR or AS. Clinical trial registration ARISTOTLE clinical trial number NCT00412984.

Background and Purpose— Few data exist on the long-term outcomes of patients with spontaneous echo contrast (SEC), left atrial/left atrial appendage (LA/LAA) thrombus, and complex aortic plaque (CAP), in patients with atrial fibrillation receiving oral anticoagulation. We explored the relationship between these 3 echocardiographic findings and clinical outcomes, and the comparative efficacy and safety of apixaban and warfarin for each finding. Methods— Patients from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) with SEC, LA/LAA thrombus, or CAP diagnosed by either transthoracic or transesophageal echocardiography were compared with patients with none of these findings on transesophageal echocardiography. Results— A total of 1251 patients were included: 217 had SEC, 127 had LA/LAA thrombus, 241 had CAP, and 746 had none. The rates of stroke/systemic embolism were not significantly different among patients with and without these echocardiographic findings (hazard ratio, 0.96; 95% confidence interval, 0.25–3.60 for SEC; hazard ratio, 1.27; 95% confidence interval, 0.23–6.86 for LA/LAA thrombus; hazard ratio, 2.21; 95% confidence interval, 0.71–6.85 for CAP). Rates of ischemic stroke, myocardial infarction, cardiovascular death, and all-cause death were also not different between patients with and without these findings. For patients with either SEC or CAP, there was no evidence of a differential effect of apixaban over warfarin. For patients with LA/LAA thrombus, there was also no significant interaction, with the exception of all-cause death and any bleeding where there was a greater benefit of apixaban compared with warfarin among patients with no LA/LAA thrombus. Conclusions— In anticoagulated patients with atrial fibrillation and risk factors for stroke, echocardiographic findings do not seem to add to the risk of thromboembolic events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Background Prior studies have demonstrated a link between the metabolic syndrome and increased risk of cardiovascular mortality. Whether the metabolic syndrome is associated with sudden cardiac death is uncertain. Methods and Results We characterized the relationship between sudden cardiac death and metabolic syndrome status among participants of the ARIC (Atherosclerosis Risk in Communities) Study (1987–2012) free of prevalent coronary heart disease or heart failure. Among 13 168 participants, 357 (2.7%) sudden cardiac deaths occurred during a median follow‐up of 23.6 years. Participants with the metabolic syndrome (n=4444) had a higher cumulative incidence of sudden cardiac death than those without it (n=8724) (4.1% versus 2.3%, P <0.001). After adjustment for participant demographics and clinical factors other than components of the metabolic syndrome, the metabolic syndrome was independently associated with sudden cardiac death (hazard ratio, 1.70, 95% confidence interval, 1.37–2.12, P <0.001). This relationship was not modified by sex (interaction P =0.10) or race (interaction P =0.62) and was mediated by the metabolic syndrome criteria components. The risk of sudden cardiac death varied according to the number of metabolic syndrome components (hazard ratio 1.31 per additional component of the metabolic syndrome, 95% confidence interval, 1.19–1.44, P <0.001). Of the 5 components, elevated blood pressure, impaired fasting glucose, and low high‐density lipoprotein were independently associated with sudden cardiac death. Conclusions We observed that the metabolic syndrome was associated with a significantly increased risk of sudden cardiac death irrespective of sex or race. The risk of sudden cardiac death was proportional to the number of metabolic syndrome components.