Background: Venous thromboembolism (VTE) affects nearly 1 million Americans annually, and many benefit from continued anticoagulation after the initial 3- to 6-month treatment period (secondary prevention). Objectives: To determine whether warfarin, apixaban, or rivaroxaban is associated with reduced recurrent VTE hospitalization in the secondary prevention of VTE. Patients/Methods: We performed a retrospective cohort study of participants enrolled in the MarketScan Insurance Database between 2013 and 2017 in those with an incident VTE. In those individuals who continued oral anticoagulation (warfarin, apixaban, or rivaroxaban) beyond 6 months, we determined the relative rate of recurrent VTE hospitalization. Results: Among 119 964 individuals with VTE, 25 419 remained on anticoagulation after 6 months and were matched successfully by age, sex, and date. After adjusting for a propensity score, apixaban versus rivaroxaban (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45-0.94) and apixaban versus warfarin (HR, 0.68; 95% CI, 0.47-1.00) had a reduced risk of recurrent VTE hospitalization, and rivaroxaban versus warfarin (HR, 1.12; 95% CI, 0.94-1.33) had equivalent rates. For the rivaroxaban versus warfarin comparison there was a significant interaction by renal function (P <.01) where rivaroxaban was associated with a lower risk of recurrent VTE hospitalization (HR, 0.65; 95% CI, 0.41-1.03) in those with kidney disease and increased risk in those without kidney disease (HR, 1.24; 95% CI, 1.02-1.50). Conclusions: These data suggest that apixaban has a lower recurrent VTE hospitalization rate than rivaroxaban during the secondary prevention of VTE, and further study of diverse patient populations, especially by kidney function, is warranted.

The association of diabetes mellitus (DM), an established risk factor for dementia in the general population, with incident dementia in patients with atrial fibrillation (AF) has not been explored. We performed a cohort study where we identified subjects with incident AF in the Atherosclerosis Risk in Communities cohort (1987 to 2017) and determined their DM status, fasting blood glucose before AF diagnosis and hemoglobin A1c levels using information from the closest previous study visit. Incident dementia was expert adjudicated using information from cognitive assessments, informant interviews and hospitalization surveillance. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) of incident dementia for each level of exposure using Cox models and adjusting for potential confounders. We analyzed 3,020 patients with AF in the Atherosclerosis Risk in Communities cohort (808 with DM) and 530 had incident dementia after a mean follow-up of 5.3 years after AF diagnosis. After multivariable adjustment, patients with AF with prevalent DM had higher rates of dementia than those without DM, HR 1.45 (95% CI 1.16 to 1.80). A value of hemoglobin A1c ≥6.5% was associated with a HR 1.29 (95% CI 0.97 to 1.71) of dementia. However, fasting blood glucose was not associated with rates of dementia independent of DM status. In conclusion, DM was associated with higher rates of dementia in patients with AF. DM prevention and control could be a promising avenue for reducing risk of dementia in AF.

OBJECTIVE: To examine the cross-sectional associations of individual measures of SES-educational attainment and household income-and the joint effects of SES with PWV, as well as the SES-race interaction, in a cohort of older African American and White adults. METHODS: Data from the Atherosclerosis Risk in Communities (ARIC) Study were used to evaluate the cross-sectional associations of individual and joint SES [education and income] and carotid femoral pulse wave velocity (cfPWV), a subclinical marker of arterial stiffness, and the interaction of SES and race using adjusted multivariable linear regression models in a cohort of 3342 men and women aged 67-89 years free of CVD in 2011-2013. RESULTS: Participants were 64% female, 23% African American, mean cfPWV (12.3±3.5-African American and 11.6±3.9-White participants). Post-graduate education compared to less than high school was significantly associated with lower cfPWV (less stiffness) in African American (β = -1.28 m/s; 95% CI, -1.97, -0.59) but not in White (β = -0.69 m/s; 95% CI, -1.39, 0.01) participants. Income ≥$50K as compared to <$25K, was associated with lower cfPWV both in African American (β = -0.82 m/s; 95% CI, -1.42, -0.22) and White (β = -0.76 m/s; 95% CI, -1.19, -0.32) participants. The interaction of race and individual measures of SES on cfPWV in African American and White adults were not statistically significant (p-value >0.10). CONCLUSIONS: Higher SES was cross-sectionally associated with lower arterial stiffness in this cohort; the data did not support differences by race. Prospective studies of SES and cfPWV are needed to efficiently compare larger racially and regionally diverse populations with a wider range of socioeconomic profiles to better identify subgroup CVD risk.

Background: Inconsistent evidence suggests that use of certain antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), in patients using oral anticoagulants (OACs) might be associated with an elevated risk of bleeding. Objective: This study aims to investigate the risk of bleeding associated with initiation of different types of antidepressants among atrial fibrillation (AF) patients on OAC therapy. Patients and methods: A total of 30,336 AF patients (mean age 72.2 years; 54% female) on OAC therapy that started antidepressant treatment were identified from the Truven Health Analytics MarketScan Commercial and Medicare Databases for the period 2007–2015. Exposure was defined as filling a prescription for antidepressant, and categorized as SSRI, serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants (TCAs), or other antidepressants. The primary outcome was incident hospitalized bleeding. Associations of antidepressant type with bleeding were assessed calculating hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted Cox models in pairwise propensity score-matched cohorts. Results: During a mean follow-up of 21 months, we identified 1612 bleeding episodes. In pairwise comparisons, SSRI use was associated with an increased risk of bleeding when compared to most other antidepressants (HR 1.22, 95% CI 0.96–1.54 vs SNRI; HR 1.10, 95% CI 0.90–1.35 vs SRI; HR 1.03, 95% CI 0.82–1.30 vs TCA). SNRI use was associated with the lowest bleeding risk. Results did not differ by OAC type, age, and sex. Conclusions: Among AF patients on OAC initiating antidepressants, risk of bleeding varied across antidepressant type. This information can inform treatment choices among patients receiving OAC.

The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts. In the AA population, we identified nine novel regions (KLF4-ACTL7B, RAPGEF2-FSTL5, TCF4-LOC100505474, PCDH10, KIAA1751, MYO5B, MIR320B1-CD2, NR5A2-LINC00862, SALL1-C16orf97) that were associated with the sense of smell (P < 5 × 10 −8 ). Many of these regions have been previously linked to neuropsychiatric (schizophrenia or epilepsy) or neurodegenerative (Parkinson’s or Alzheimer’s disease) diseases associated with a decreased sense of smell. In the EA population, we identified two novel loci in or near RASGRP1 and ANXA2P3 associated with sense of smell. In conclusion, this study identified several ancestry-specific loci that are associated with the sense of smell in older adults. While these findings need independent confirmation, they may lead to novel insights into the biology of the sense of smell in older adults and its relationships to neuropsychological and neurodegenerative diseases.

Introduction: Diabetes is prospectively associated with cognitive decline. Whether lower cognitive function and worse brain structure are prospectively associated with incident diabetes is unclear. Methods: We analyzed data for 10,133 individuals with cognitive function testing (1990–1992) and 1212 individuals with brain magnetic resonance imaging (1993–1994) from the Atherosclerosis Risk in Communities cohort. We estimated hazard ratios for incident diabetes through 2014 after adjustment for traditional diabetes risk factors and cohort attrition. Results: Higher level of baseline cognitive function was associated with lower risk for diabetes (per 1 standard deviation, hazard ratio = 0.94; 95% confidence interval = 0.90, 0.98). This association did not persist after accounting for baseline glucose level, case ascertainment methods, and cohort attrition. No association was observed between any brain magnetic resonance imaging measure and incident diabetes. Discussion: This is one of the first studies to prospectively evaluate the association between both cognitive function and brain structure and the incidence of diabetes.

Introduction: Elevated serum uric acid (SUA) is associated with cardiovascular risk factors, which often contribute to dementia and dementia-like morbidity, yet several cross-sectional studies have shown protective associations with cognition, which would be consistent with other work showing benefits of elevated SUA through its antioxidant properties. Methods: We studied 11,169 participants free of dementia and cardiovascular disease from the Atherosclerosis Risk in Communities (ARIC) cohort. SUA was measured in blood samples collected in 1990–92, baseline for this study (age range 47–70 years). Incident dementia was ascertained based on clinical assessments in 2011–13 and 2016–17, surveillance based on dementia screeners conducted over telephone interviews, hospitalization discharge codes, and death certificates. Cognitive function was assessed up to four times between 1990 and 92 and 2016–17. We estimated the association of SUA, categorized into quartiles, with incidence of dementia using Cox regression models adjusting for potential confounders. The association between cognitive decline and SUA was assessed using generalized estimating equations. Results: Over a median follow-up period of 24.1 years, 2005 cases of dementia were identified. High baseline SUA was associated with incident dementia (HR, 1.29; 95% CI, 1.12, 1.47) when adjusted for sociodemographic variables. However, after further adjustment including cardiovascular risk factors, this relationship disappeared (HR, 1.03; 95% CI, 0.88, 1.21). Elevated baseline SUA was associated with faster cognitive decline even after further adjustment (25-year global z-score difference, −0.149; 95% CI, −0.246, −0.052). Conclusion: Higher levels of mid-life SUA were associated with faster cognitive decline, but not necessarily with higher risk of dementia.

Background Long-term data to study recent trends in the incidence of atrial fibrillation (AF), overall and among sex and race groups, are scarce. We evaluated the 30-year trends in the incidence of AF in the ARIC (Atherosclerosis Risk in Communities) study cohort and explored race and sex differences in these trends. Methods and Results We included 15 343 men and women aged 45 to 64 years in 1987 to 1989 without AF from 4 US communities in the ARIC cohort. Incident AF was identified based on study ECGs, hospital discharge codes, and death certificates through 2017. We calculated age and period-specific incidence rates (IRs) of AF. We used Poisson regression to calculate IR ratios of AF over time adjusting for age, sex, and race. A total of 3241 AF cases were identified during a mean (SD) follow-up of 22 years (8.4 years) (599 in Black participants, 2642 in White participants, 1582 in women, and 1659 in men). Overall, the IR of AF in the ARIC cohort was 9.6 per 1000 person-years (6.9 in Black participants, 10.5 in White participants, 8.1 in women, and 11.6 in men). Age-specific IR by time period did not show significant changes over time. In a model adjusted for sex, race, and age group, the rate of AF did not change significantly from 1987 to 1991 compared with 2012 to 2017 (IR ratio, 1.10 [95% CI, 0.88-1.36] comparing 2012-2017 with 1987-1991). Similarly, no evidence of changes over time in AF rates were identified in men and women or White and Black participants separately. Conclusions Even though IRs of AF increase as age increases, our analysis provided evidence suggesting that the overall IRs of AF have not changed over time in a multicenter cohort of Black and White individuals in the United States from 1987 to 2017.

BACKGROUND: Age-related left atrial (LA) structural and functional abnormalities may be related to subclinical cerebral infarcts (SCIs) and stroke. We evaluated the association of 3-dimensional echocardiographic LA contractility parameters with SCIs and stroke across the spectrum of tertiles of age increment in elderly patients with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation. METHODS AND RESULTS: We enrolled 407 participants (mean age, 76±8 years; 40% men) from ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study) undergoing a brain magnetic resonance imaging and 3-dimensional echocardio-graphic examinations in 2011 to 2013. The sample was analyzed among age tertiles and subgroups: no cerebral magnetic resonance imaging– detectable infarcts (n=315), magnetic resonance imaging– diagnosed SCIs (n=58), and clinically diagnosed stroke (n=34). The frequency of SCIs significantly increased over age tertiles (P trend 0.023). LA global longitudinal strain—a 3-dimensional echocardiographic index of LA reservoir function—and E/e’ divided by LA global longitudinal strain—an index of LA stiffness—worsened across age tertiles (P trend 0.014 and 0.001, respectively), and only in the categories of SCIs (P trend <0.001 and 0.045, respectively) and stroke (P trend 0.001 and 0.011, respectively). LA global longitudinal strain was negatively associated with increased odds of SCIs (P=0.036, P=0.008, and P=0.001, respectively) and strokes (P=0.043, P=0.015, and P=0.001, respectively) over age tertiles, with a significant interaction between age tertiles (interaction P=0.043 and P=0.010, respectively). E/e’ divided by LA global longitudinal strain was positively associated with the presence of SCIs (P=0.037, P=0.007, and P=0.001, respectively) and strokes (P=0.045, P=0.007, and P=0.003, respectively) over age tertiles, with a significant interaction only for SCIs (interaction P=0.040) and not for clinical stroke. CONCLUSIONS: In a large cohort study of elderly patients, among participants with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation, measures of worse age-related LA reservoir function and stiffness are associated with higher odds of SCIs and stroke.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.