Influence of Opioid Prescription Policy on Overdoses and Related Adverse Effects in a Primary Care Population.

BACKGROUND: In response to the opioid epidemic, many states have enacted policies limiting opioid prescriptions. There is a paucity of evidence of the impact of opioid prescribing interventions in primary care populations, including whether unintended consequences arise from limiting the availability of prescribed opioids. OBJECTIVE: Our aim was to compare changes in opioid overdose and related adverse effects rate among primary care patients following the implementation of state-level prescribing policies. DESIGN: A cohort of primary care patients within an interrupted time series model. PARTICIPANTS: Electronic medical record data for 62,776 adult (18+ years) primary care patients from a major medical center in Vermont from January 1, 2016, to June 30, 2018. INTERVENTIONS: State-level opioid prescription policy changes limiting dose and duration. MAIN MEASURES: Changes in (1) opioid overdose rate and (2) opioid-related adverse effects rate per 100,000 person-months following the July 1, 2017, prescription policy change. KEY RESULTS: Among primary care patients, there was no change in opioid overdose rate following implementation of the prescribing policy (incidence rate ratio; IRR: 0.64, 95% confidence interval; CI: 0.22-1.88). There was a 78% decrease in the opioid-related adverse effects rate following the prescribing policy (IRR: 0.22, 95%CI: 0.09-0.51). This association was moderated by opioid prescription history, with decreases observed among opioid-naïve patients (IRR: 0.18, 95%CI: 0.06-0.59) and among patients receiving chronic opioid prescriptions (IRR: 0.17, 95%CI: 0.03-0.99), but not among those with intermittent opioid prescriptions (IRR: 0.51, 95%CI: 0.09-2.82). CONCLUSIONS: Limiting prescription opioids did not change the opioid overdose rate among primary care patients, but it reduced the rate of opioid-related adverse effects in the year following the state-level policy change, particularly among patients with chronic opioid prescription history and opioid-naïve patients. Limiting the quantity and duration of opioid prescriptions may have beneficial effects among primary care patients.

Liver Fibrosis is Associated with Ischemic Stroke Risk in Women but not Men: The REGARDS Study.

BACKGROUND: Nonalcoholic fatty liver disease is inconsistently associated with ischemic stroke, with one study suggesting an association in women and not men. The relative importance of liver fibrosis, as opposed to fatty liver, for cardiovascular risk is increasingly appreciated. We hypothesized that advanced liver fibrosis is associated with incident ischemic stroke risk, and especially in women. METHODS: We performed a case-cohort study in the REasons for Geographic and Racial Differences in Stroke cohort. Black and white individuals aged 45 and older were recruited between 2003 and 2007 and followed for ischemic stroke. The Fibrosis-4 (FIB-4) score and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) were calculated using baseline data for stroke cases and a cohort random sample; advanced liver fibrosis was classified using validated cutoffs. Cox proportional hazards models were used to estimate hazard ratios (HR) of stroke after adjusting for potential confounders. Sex differences were assessed. RESULTS: There were 572 incident ischemic strokes (285 in women) over 5.4 (SD, 2.2) years. Advanced liver fibrosis was not significantly associated with ischemic stroke overall using the FIB-4 (HR 1.44; 95% CI 0.49-4.28) or NFS (HR 1.76; 95% CI 0.67-4.61). However, liver fibrosis was associated with stroke in women (HR 3.51; 95% CI 1.00-12.34) but not men (HR 0.70, 95% CI 0.16-3.16) (P = 0.098 for interaction) when using FIB-4. A similar but non-significant sex difference was seen for NFS. CONCLUSION: Advanced liver fibrosis may be associated with a higher risk of ischemic stroke in women but not men.

Hemoglobin levels and coronary heart disease risk by age, race, and sex in the reasons for geographic and racial differences in stroke study (REGARDS).

Higher and lower hemoglobin concentrations are associated with coronary heart disease (CHD), but whether this risk is consistent across age, sex, and race is unclear. The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study is an observational cohort study of 30 239 black, and white, adults aged 45 and older recruited 2003-7. Participants were included if they had hemoglobin measures, were CHD-free at baseline, and had all baseline variables. The primary outcome was incident CHD. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for incident CHD by hemoglobin concentration. This was expressed as a continuous variable and divided into age-, sex-, and race-specific quintiles. The 16 332 participants were included, contributing 114 362 person-years of follow-up and 915 incident CHD events. The mean age was 63 years, 35% were male, 41% were black, and the mean baseline hemoglobin was 13.6 g/dL (SD 1.4). A significant non-linear association between hemoglobin and CHD was identified (P < .001). This association differed significantly by race (P = .025) but not by sex or age. In whites, the risk for incident CHD was higher in the lowest (HR 2.28, 95% CI 1.61, 3.33) and highest (HR 1.94, 95% CI 1.35, 2.79) hemoglobin quintiles relative to the third quintile. For blacks, only those in the lowest hemoglobin quintile had an increased risk for incident CHD events (HR 1.70, 95% CI 1.20, 2.41). Hemoglobin is an independent risk factor for CHD in whites and blacks but with different hemoglobin concentrations conferring different risks.

Effects of human demand on conservation planning for biodiversity and ecosystem services.

Safeguarding ecosystem services and biodiversity is critical to achieving sustainable development. To date, ecosystem services quantification has focused on the biophysical supply of services with less emphasis on human beneficiaries (i.e., demand). Only when both occur do ecosystems benefit people, but demand may shift ecosystem service priorities toward human-dominated landscapes that support less biodiversity. We quantified how accounting for demand affects the efficiency of conservation in capturing both human benefits and biodiversity by comparing conservation priorities identified with and without accounting for demand. We mapped supply and benefit for 3 ecosystem services (flood mitigation, crop pollination, and nature-based recreation) by adapting existing ecosystem service models to include and exclude factors representing human demand. We then identified conservation priorities for each with the conservation planning program Marxan. Particularly for flood mitigation and crop pollination, supply served as a poor proxy for benefit because demand changed the spatial distribution of ecosystem service provision. Including demand when jointly targeting biodiversity and ecosystem service increased the efficiency of conservation efforts targeting ecosystem services without reducing biodiversity outcomes. Our results highlight the importance of incorporating demand when quantifying ecosystem services for conservation planning.

Efectos de la Demanda Humana sobre la Planeación de la Conservación para la Biodiversidad y los Servicios Ambientales Resumen La salvaguardia de los servicios ambientales y de la biodiversidad es muy importante para lograr el desarrollo sustentable. A la fecha, la cuantificación de los servicios ambientales se ha enfocado en el suministro biofísico de servicios con un menor énfasis en los beneficiarios humanos (es decir, la demanda). Es sólo cuando se considera a ambos que los ecosistemas benefician a las personas, pero la demanda puede cambiar las prioridades de los servicios ambientales hacia los paisajes dominados por humanos, los cuales mantienen una menor biodiversidad. Cuantificamos cómo afecta la consideración de la demanda a la eficiencia de la conservación en la captura de los beneficios humanos y de la biodiversidad al comparar las prioridades de conservación con y sin la consideración de la demanda. Mapeamos el suministro y el beneficio para tres servicios ambientales (mitigación de inundaciones, polinización de cultivos y actividades recreativas basadas en la naturaleza) al adaptar los modelos de servicios ambientales existentes para que incluyeran y excluyeran los factores que representan la demanda humana. Después identificamos las prioridades de conservación para cada uno con el programa de planeación de la conservación Marxan. En el caso particular de la mitigación de inundaciones y la polinización de cultivos, el suministro fue un sustituto pobre para el beneficio debido a que la demanda cambió la distribución espacial de la provisión de servicios ambientales. La inclusión de la demanda cuando nos enfocamos en la biodiversidad y en los servicios ambientales como conjunto incrementó la eficiencia de los esfuerzos de conservación enfocados en los servicios ambientales sin reducir los resultados para la biodiversidad. Nuestros resultados resaltan la importancia de la incorporación de la demanda cuando se cuantifican los servicios ambientales para la planeación de la conservación.

Modeling the status, trends, and impacts of wild bee abundance in the United States.

Wild bees are highly valuable pollinators. Along with managed honey bees, they provide a critical ecosystem service by ensuring stable pollination to agriculture and wild plant communities. Increasing concern about the welfare of both wild and managed pollinators, however, has prompted recent calls for national evaluation and action. Here, for the first time to our knowledge, we assess the status and trends of wild bees and their potential impacts on pollination services across the coterminous United States. We use a spatial habitat model, national land-cover data, and carefully quantified expert knowledge to estimate wild bee abundance and associated uncertainty. Between 2008 and 2013, modeled bee abundance declined across 23% of US land area. This decline was generally associated with conversion of natural habitats to row crops. We identify 139 counties where low bee abundances correspond to large areas of pollinator-dependent crops. These areas of mismatch between supply (wild bee abundance) and demand (cultivated area) for pollination comprise 39% of the pollinator-dependent crop area in the United States. Further, we find that the crops most highly dependent on pollinators tend to experience more severe mismatches between declining supply and increasing demand. These trends, should they continue, may increase costs for US farmers and may even destabilize crop production over time. National assessments such as this can help focus both scientific and political efforts to understand and sustain wild bees. As new information becomes available, repeated assessments can update findings, revise priorities, and track progress toward sustainable management of our nation's pollinators.

Hepatocyte growth factor and risk of incident stroke in Black and White Americans in the Reasons for Geographic and Racial Differences in Stroke study.

Background: Hepatocyte growth factor (HGF) is a cytokine produced in response to endothelial damage. Higher levels correlate with cardiovascular risk factors, including hypertension and diabetes. Objectives: We hypothesized that HGF is associated with stroke. Methods: The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White Americans aged ≥45 years from 2003 to 2007. In this case-cohort study, after 5.5 years of follow-up, circulating baseline HGF was measured in 557 participants with incident ischemic stroke and in a cohort random sample of 964 participants. Hazard ratios (HRs) per SD log-transformed HGF and by HGF quintile were calculated using Cox proportional hazards models adjusting for stroke risk factors and other correlates of HGF. Differences by race and sex were tested using interaction terms. Results: Median HGF was 295 (IQR, 209-402) pg/mL. HGF was higher with older age, male sex, prevalent cardiovascular disease, smoking, and warfarin use, but did not differ by race. The adjusted HR of incident ischemic stroke per SD higher baseline HGF (145 pg/mL) was 1.30 (CI, 1.00-1.70), with no difference by sex or race. HGF in the highest (>434 pg/mL) vs lowest quintile (<135 pg/mL) was associated with an adjusted HR of incident stroke of 2.12 (CI, 1.31-3.41). Conclusion: In the REGARDS study, higher HGF was associated with increased risk of incident ischemic stroke in Black and White adults, with a doubling in risk of HGF in the top quintile compared with the lowest quintile after adjusting for other stroke risk factors.

Development and validation of a risk model for hospital-acquired venous thrombosis: the Medical Inpatients Thrombosis and Hemostasis study.

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race. CONCLUSION: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

Graph and circuit theory connectivity models of conservation biological control agents.

The control of agricultural pests is an important ecosystem service provided by predacious insects. In Midwestern USA, areas of remnant tallgrass prairie and prairie restorations may serve as relatively undisturbed sources of natural predators, and smaller areas of non-crop habitats such as seminatural areas and conservation plantings (CP) may serve as stepping stones across landscapes dominated by intensive agriculture. However, little is known about the flow of beneficial insects across large habitat networks. We measured abundance of soybean aphids and predators in 15 CP and adjacent soybean fields. We tested two hypotheses: (1) landscape connectivity enhances the flow of beneficial insects; and (2) prairies act as a source of sustaining populations of beneficial insects in well-connected habitats, by using adaptations of graph and circuit theory, respectively. For graph connectivity, incoming fluxes to the 15 CP from connected habitats were measured using an area- and distance-weighted flux metric with a range of negative exponential dispersal kernels. Distance was weighted by the percentage of seminatural area within ellipse-shaped landscapes, the shape of which was determined with correlated random walks. For circuit connectivity, effective conductance from the prairie to the individual 15 CP was measured by regarding the flux as conductance in a circuit. We used these two connectivity measures to predict the abundance of natural enemies in the selected sites. The most abundant predators were Anthocoridae, followed by exotic Coccinellidae, and native Coccinellidae. Predator abundances were explained well by aphid abundance. However, only native Coccinellidae were influenced by the flux and conductance. Interestingly, exotic Coccinellidae were negatively related to the flux, and native Coccinellidae were highly influenced by the interaction between exotic Coccinellidae and aphids. Our area- and distance-weighted flux and the conductance variables showed better fit to field data than area-weighted flux or Euclidean distance from the prairie. These results indicate that the network of seminatural areas has greater influence on the flow of native predators than that of exotic predators, and that the prairie acts as a source for native Coccinellidae. Managers can enhance conservation biocontrol and sustain the diversity of natural enemies by optimizing habitat networks.

Association between peripheral blood cytopenia and cancer mortality: A race-specific risk factor for cancer death.

BACKGROUND: Cytopenia is associated with cancer through mechanisms including clonal hematopoiesis and chronic inflammation. Cytopenia is more prevalent in Black people but its relationship with racial disparities in cancer mortality is unknown. METHODS: Cytopenia was defined in 19,028 Black and White participants recruited between 2003 and 2007 for the REasons for Geographic and Racial Differences in Stroke cohort, based on age-, sex-, and race-adjusted ranges for blood counts. Cancer death was ascertained from Social Security Death and National Death Indexes. Multivariable Cox models estimated the risk of cancer mortality associated with cytopenia, adjusting for demographics (model1), anemia and cancer risk factors (model2), and socioeconomics (model3). Racial differences in the cytopenia-cancer death association were tested by cross-product interaction terms. RESULTS: Cytopenia was identified in 383 (2%) participants, 250 (65%) White, and 113 (35%) Black people. With median follow-up 11.3 years, 1,224 (6.4%) cancer deaths occurred. Cytopenia was associated with increased risk of cancer mortality in model1 (HR = 1.57, 95%CI 1.15-2.24), model2 (HR = 1.67, 95%CI 1.22-2.30), and model3 (HR = 1.59, 95%CI 1.17-2.17). Participants with cytopenia had twofold increased cumulative incidence of cancer death (13% vs. 6.5%, p < 0.01). Race by cytopenia interaction terms showed higher HR for cancer death in Black compared to White participants: 2.01 versus 1.41 (pinteraction  = 0.016, model1), 2.12 versus 1.45 (pinteraction  = 0.009, model2), and 1.82 versus 1.44 (pinteraction  = 0.04, model3). CONCLUSION: In this large, observational biracial prospective study, cytopenia was a risk factor for cancer death, with stronger association in Black than White people. Though race impacted the association of cytopenia with cancer mortality, cytopenia was not a mediator of the racial disparity in cancer mortality.

The relative risk of bleeding after medical hospitalization: the medical inpatient thrombosis and hemorrhage study.

BACKGROUND: Clinically relevant bleeding risk in discharged medical patients is underestimated and leads to rehospitalization, morbidity, and mortality. Studies assessing this risk are lacking. OBJECTIVE: The aim of this study was to develop and validate a computable phenotype for clinically relevant bleeding using electronic health record (EHR) data and quantify the relative and absolute risks of this bleeding after medical hospitalization. METHODS: We conducted an observational cohort study of people receiving their primary care at sites affiliated with an academic medical center in northwest Vermont, United States. We developed a computable phenotype using EHR data (diagnosis codes, procedure codes, laboratory, and transfusion data) and validated it by manual chart review. Cox proportional hazard models with hospitalization modeled as a time-varying covariate were used to estimate clinically relevant bleeding risk. RESULTS: The computable phenotype had a positive predictive value of 80% and a negative predictive value of 99%. The bleeding rate in individuals with no medical hospitalizations in the past 3 months was 2.9 per 1000 person-years versus 98.9 per 1000 person-years in those who were discharged in the past 3 months. This translates into a hazard ratio (95% CI) of clinically relevant bleeding of 22.9 (18.9, 27.7), 13.0 (10.0, 16.9), and 6.8 (4.7, 9.8) over the first, second, and third months after discharge, respectively. CONCLUSION: We developed and validated a computable phenotype for clinically relevant bleeding and determined its relative and absolute risk in the 3 months after medical hospitalization discharge. The high rates of bleeding observed underscore the clinical importance of capturing and further studying bleeding after medical discharge.

Development of a computable phenotype using electronic health records for venous thromboembolism in medical inpatients: the Medical Inpatient Thrombosis and Hemostasis study.

Background: Accurate and efficient methods to identify venous thromboembolism (VTE) events in hospitalized people are needed to support large-scale studies. Validated computable phenotypes using a specific combination of discrete, searchable elements in electronic health records to identify VTE and distinguish between hospital-acquired (HA)-VTE and present-on-admission (POA)-VTE would greatly facilitate the study of VTE, obviating the need for chart review. Objectives: To develop and validate computable phenotypes for POA- and HA-VTE in adults hospitalized for medical reasons. Methods: The population included admissions to medical services from 2010 to 2019 at an academic medical center. POA-VTE was defined as VTE diagnosed within 24 hours of admission, and HA-VTE as VTE identified more than 24 hours after admission. Using discharge diagnosis codes, present-on-admission flags, imaging procedures, and medication administration records, we iteratively developed computable phenotypes for POA-VTE and HA-VTE. We assessed the performance of the phenotypes using manual chart review and survey methodology. Results: Among 62,468 admissions, 2693 had any VTE diagnosis code. Using survey methodology, 230 records were reviewed to validate the computable phenotypes. Based on the computable phenotypes, the incidence of POA-VTE was 29.4 per 1000 admissions and that of HA-VTE was 3.6 per 1000 admissions. The POA-VTE computable phenotype had positive predictive value and sensitivity of 88.8% (95% CI, 79.8%-94.0%) and 99.1% (95% CI, 94.0%- 99.8%), respectively. Corresponding values for the HA-VTE computable phenotype were 84.2% (95% CI, 60.8%-94.8%) and 72.3% (95% CI, 40.9%-90.8%). Conclusion: We developed computable phenotypes for HA-VTE and POA-VTE with adequate positive predictive value and sensitivity. This phenotype can be used in electronic health record data-based research.

Race-Dependent Association of High-Density Lipoprotein Cholesterol Levels With Incident Coronary Artery Disease.

BACKGROUND: Plasma lipids are risk factors for coronary heart disease (CHD) in part because of race-specific associations of lipids with CHD. OBJECTIVES: The purpose of this study was to understand why CHD risk equations underperform in Black adults. METHODS: Between 2003 and 2007, the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort recruited 30,239 Black and White individuals aged ≥45 years from the contiguous United States. We used Cox regression models adjusted for clinical and behavioral risk factors to estimate the race-specific hazard of plasma lipid levels with incident CHD (myocardial infarction or CHD death). RESULTS: Among 23,901 CHD-free participants (57.8% White and 58.4% women, mean age 64 ± 9 years) over a median 10 years of follow-up, 664 and 951 CHD events occurred among Black and White adults, respectively. Low-density lipoprotein cholesterol and triglycerides were associated with increased risk of CHD in both races (P interaction by race >0.10). For sex-specific clinical HDL-C categories: low HDL-C was associated with increased CHD risk in White (HR: 1.22; 95% CI: 1.05-1.43) but not in Black (HR: 0.94; 95% CI: 0.78-1.14) adults (P interaction by race = 0.08); high HDL-C was not associated with decreased CHD events in either race (HR: 0.96; 95% CI: 0.79-1.16 for White participants and HR: 0.91; 95% CI: 0.74-1.12 for Black adults). CONCLUSIONS: Low-density lipoprotein cholesterol and triglycerides modestly predicted CHD risk in Black and White adults. Low HDL-C was associated with increased CHD risk in White but not Black adults, and high HDL-C was not protective in either group. Current high-density lipoprotein cholesterol-based risk calculations could lead to inaccurate risk assessment in Black adults.

Venous thrombosis risk during and after medical and surgical hospitalizations: The medical inpatient thrombosis and hemostasis (MITH) study.

BACKGROUND: Thirty to seventy percent of all venous thromboembolism (VTE) events are associated with hospitalization. The absolute and relative risks during and after hospitalization are poorly characterized. OBJECTIVES: Quantify the absolute rate and relative risk of VTE during and up to 3 months after medical and surgical hospitalizations. PATIENTS/METHODS: We conducted an observational cohort study between 2010 and 2016 of patients cared for by the University of Vermont (UVM) Health Network's primary care population. Cox proportional hazard models with hospitalization modeled as a time-varying covariate were used to estimate VTE risk. RESULTS: Over 4.3 years of follow-up, 55 220 hospitalizations (156 per 1000 person-years) and 713 first venous thromboembolism events (2.0 per 1000 person-years) occurred. Among individuals not recently hospitalized, the rate of venous thromboembolism was 1.4 per 1000 person-years and 71.8 per 1000 person-years during hospitalization. During the first, second, and third months after discharge, the rates of venous thromboembolism were 35.1, 11.3, and 5.2 per 1000 person-years, respectively. Relative to those not recently hospitalized, the age- and sex-adjusted HRs of venous thromboembolism were 38.0 (95% CI 28.0, 51.5) during hospitalization, and 18.4 (95% CI 15.0, 22.6), 6.3 (95% CI 4.3, 9.0), and 3.0 (95% CI 1.7, 5.4) during the first, second, and third months after discharge, respectively. Stratified by medical versus surgical services the rates were similar. CONCLUSION: Hospitalization and up to 3 months after discharge were strongly associated with increased venous thromboembolism risk. These data quantify this risk for use in future studies.

Biomarkers as MEDiators of racial disparities in risk factors (BioMedioR): Rationale, study design, and statistical considerations.

PURPOSE: Relative to White adults, Black adults have a substantially higher prevalence of hypertension and diabetes, both key risk factors for stroke, cardiovascular disease, cognitive impairment, and dementia. Blood biomarkers have shown promise in identifying contributors to racial disparities in many chronic diseases. METHODS: We outline the study design and related statistical considerations for a nested cohort study, the Biomarker Mediators of Racial Disparities in Risk Factors (BioMedioR) study, within the 30,239-person biracial REasons for Geographic And Racial Differences in Stroke (REGARDS) study (2003-present). Selected biomarkers will be assessed for contributions to racial disparities in risk factor development over median 9.4 years of follow-up, with initial focus on hypertension, and diabetes. Here we outline study design decisions and statistical considerations for the sampling of 4,400 BioMedioR participants. RESULTS: The population for biomarker assessment was selected using a random sample study design balanced across race and sex to provide the optimal opportunity to describe association of biomarkers with the development of hypertension and diabetes. Descriptive characteristics of the BioMedioR sample and analytic plans are provided for this nested cohort study. CONCLUSIONS: This nested biomarker study will examine pathways with the target to help explain racial differences in hypertension and diabetes incidence.

Venous thrombosis recurrence risk according to warfarin versus direct oral anticoagulants for the secondary prevention of venous thrombosis.

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.

Television viewing, physical activity and venous thromboembolism risk: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

INTRODUCTION: Television (TV) viewing may be associated with increased venous thromboembolism (VTE) risk independent of VTE risk factors including physical activity. This association was assessed in a large biracial US cohort of Black and White adults. METHODS: Between 2003 and 2007 The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited 30,239 participants aged ≥45 years, who were surveyed for baseline TV viewing and followed for VTE events. TV viewing was categorized as <2 hours (light), 2 to 4 hours (moderate), and ≥4 hours (heavy) per day. Physical activity was classified as poor, intermediate, or ideal based on reported weekly activity. Hazard ratios of TV viewing and physical activity were calculated adjusting for VTE risk factors. Multiple imputation for missingness was used as a sensitivity analysis. RESULTS: Over 96,813 person-years (median: 5.06 years) of follow-up there were 214 VTE events. Heavy TV viewing was not associated with VTE risk in the unadjusted and fully adjusted model (adjusted hazard ratio [aHR]: 0.92 [95% confidence interval (CI): 0.62, 1.36]). Ideal physical activity trended toward a reduced VTE risk (HR: 0.71 [95%CI: 0.51, 1.01]). There was no evidence of an interaction between TV viewing, physical activity, and risk of VTE. CONCLUSIONS: In this contemporary racially and geographically diverse US cohort, there was no association between TV viewing and VTE risk, before and after accounting for physical activity. The high burden of traditional VTE risk factors in REGARDS may mask any association of TV viewing with VTE, or TV viewing may have only a modest association with VTE risk.

Thrombo-inflammatory biomarkers and D-dimer in a biracial cohort study.

BACKGROUND: Higher D-dimer is a risk factor for cardiovascular diseases and venous thromboembolism. In the general population, D-dimer and other thrombo-inflammatory biomarkers are higher among Black individuals, who also have higher risk of these conditions compared to White people. OBJECTIVE: To assess whether Black individuals have an exaggerated correlation between D-dimer and thrombo-inflammatory biomarkers characteristic of cardiovascular diseases. METHODS: Linear regression was used to assess correlations of 11 thrombo-inflammatory biomarkers with D-dimer in a cross-sectional study of 1068 participants of the biracial Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. RESULTS: Adverse levels of most biomarkers, especially fibrinogen, factor VIII, C-reactive protein, N-terminal pro-B-type natriuretic peptide, and interleukin (IL)-6, were associated with higher D-dimer. Several associations with D-dimer differed significantly by race. For example, the association of factor VIII with D-dimer was more than twice as large in Black compared to White participants. Specifically, D-dimer was 26% higher per standard deviation (SD) higher factor VIII in Black adults and was only 11% higher per SD higher factor VIII in White adults. In Black but not White adults, higher IL-10 and soluble CD14 were associated with higher D-dimer. CONCLUSIONS: Findings suggest that D-dimer might relate to Black/White differences in cardiovascular diseases and venous thromboembolism because it is a marker of amplified thrombo-inflammatory response in Black people. Better understanding of contributors to higher D-dimer in the general population is needed.

Peripheral Blood Cytopenia and Risk of Cardiovascular Disease and Mortality.

Background Individual blood cell count abnormalities have been associated with cardiovascular disease and increased mortality. In this study, we defined a "cytopenia phenotype," reflecting bone marrow hypoproliferation, to determine if peripheral blood cytopenia is associated with increased cardiovascular disease and mortality risk. Methods and Results Study participants were derived from a biracial observational cohort study, REGARDS (Reasons for Geographic and Racial Differences in Stroke), that enrolled 30 239 Black and White participants aged ≥45 years between 2003 and 2007. Median follow up was ≈9 years. The current study included 19 864 participants from REGARDS study (37.9% men, 40% Black participants) who have complete blood count available at study enrollment. We defined a cytopenia phenotype based on age-, sex-, and race-adjusted lowest fifth percentile of blood counts. Multivariable Cox proportional hazards models estimated the hazard ratios (HR) and 95% CI of cytopenia for mortality and incident cardiovascular disease in adjusted models. Mean age of the study participants was 64 years (SD:9.7). The prevalence of cytopenia was 1.9% (n=378). Cytopenia was associated with increased risk of all-cause mortality (HR, 1.73; 95% CI, 1.34-2.22) and cardiovascular disease mortality (HR, 1.56; 95% CI, 1.11-2.29). Cytopenia was associated with stroke risk in Black but not White participants (HR, 1.96 versus 0.86; P-interaction for race=0.08) and was not associated with coronary heart disease risk. Conclusions We defined a cytopenia phenotype with clinical implications for mortality and stroke risk in a large biracial and geographically diverse population. Whether generated through somatic mutations or decreased organ function, cytopenia was associated with mortality risk and was a race-specific risk factor for stroke.

Soluble CD14, Ischemic Stroke, and Coronary Heart Disease Risk in a Prospective Study: The REGARDS Cohort.

Background Soluble CD14 (sCD14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case-cohort study, sCD14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease (CHD), and a cohort random sample (n=1039). Cox models estimated hazards ratios (HR) of incident ischemic stroke or CHD per 1 SD higher sCD14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD14 was 1.42 (95% CI: 1.12, 1.80), with no association among whites (HR 1.02 [95% CI: 0.82, 1.27]). Higher sCD14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD14 among blacks at age 45 years was 2.30 (95% CI: 1.45, 3.65) compared with 1.56 (95% CI: 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI: 1.20, 1.91) among blacks and 1.02 (95% CI: 0.80, 1.31) among whites. Conclusions sCD14 may be a race-specific stroke and CHD risk marker.

Life's Simple 7 and Incident Hypertension: The REGARDS Study.

Background The Life's Simple 7 (LS7) metric incorporates health behaviors (body mass index, diet, smoking, physical activity) and health factors (blood pressure, cholesterol, glucose) to estimate an individual's level of cardiovascular health. The association between cardiovascular health and incident hypertension is unresolved. Hypertension's threshold was recently lowered and it is unclear if better cardiovascular health is associated with lower risk of incident hypertension with the updated threshold or in a multirace cohort. We sought to assess the association between better LS7 score and risk of incident hypertension among Black and White adults using a 130/80 mm Hg hypertension threshold. Methods and Results We determined the association between LS7 metric and incident hypertension in the REGARDS (Reasons for Geographic and Racial Disparities in Stroke) study, including participants free of baseline hypertension (2003-2007) who completed a second visit between 2013 and 2016. Hypertension was defined as systolic/diastolic blood pressure ≥130/80 mm Hg or antihypertensive medication use. Each LS7 component was assigned 0 (poor), 1 (intermediate), or 2 (ideal) points. We generated a 14-point score by summing points. Among 2930 normotensive participants (20% Black, 80% White), the median (25th-75th percentiles) LS7 total score was 9 (8-10) points. Over a median follow-up of 9 years, 42% developed hypertension. In the fully adjusted model, each 1-point higher LS7 score had a 6% lower risk of incident hypertension (risk ratio, 0.94 per 1 point; 95% CI, 0.92-0.96). Conclusions Better cardiovascular health was associated with lower risk of incident hypertension using a 130/80 mm Hg hypertension threshold among Black and White adults.