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Introduction: Cardiovascular disease (CVD) is the leading cause of mortality and disability in the United States. Spatiotemporal modeling of disease incidence may guide prevention efforts toward regions most at risk in the future. Methods: We examined spatiotemporal trends in composite CVD events, defined as myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, coronary artery disease, or cardiovascular death, using electronic health records from 9,718,107 U.S. Veterans who used VA healthcare facilities from 2003-2018. Age-standardized annual incidence by state was modeled using the Bernardinelli model, a Bayesian Poisson regression with linear temporal trends for the US and individual states. Results: There were 626,271 CVD events over 16 years of follow up and annual incidence fell gradually from 11.5% in 2003 to 6.6% in 2018. Incidence among all US veterans decreased an estimated 3.1% [95% CI: -3.3%, -2.9%] per year (RR year = 0.969). State-level incidences also decreased monotonically over the follow-up period (Figure panel A ), ranging from an absolute decrease 5.0% (RI) to 1.7% (OR). Estimated incidence for the five states most above (RI, FL, NC, MT, LA) and most below (OR, NV, CT, OK, MI) the national trend are plotted against the US average in Figure panel B . These outlying states differed significantly from the overall trend (posterior probabilities ≥ 99.7%), and the magnitude of trend was loosely correlated with initial incidence rate (in 2003). Notably, four states crossed the national average over the study period: CT and OK started below average in 2003 but ended above in 2018, whereas RI and NC started with high incidence and ended with below average incidence in 2018. Conclusions: Among US veterans, there was significant geographic variation in the rate of decline of incident CVD from 2003-2018. Future research will investigate the mechanisms underpinning the observed trends, particularly prevalence and control of risk factors.

Background Recent guidelines on dual antiplatelet therapy (DAPT) duration after percutaneous coronary intervention (PCI) balance the subsequent risks of major bleeding with ischemic events. Although generally favoring shorter DAPT duration with second‐generation drug‐eluting stents, the effects on long‐term outcomes in the wider population are uncertain. Methods and Results We tracked all patients having PCI with second‐generation drug‐eluting stents in the Veterans Affairs Healthcare System between 2006 and 2016 for death, myocardial infarction, stroke, and major bleeding up to 13 years. We compared these outcomes with 4 DAPT durations of 1 to 5, 6 to 9, 10 to 12, and 13 to 18 months after the index PCI using hazard ratios (HRs) and 95% CIs from Cox proportional hazards models adjusted by inverse probability weighting. A total of 40 882 subjects with PCI were followed up for a median of 4.3 (25%–75%: 2.4–6.5) years. DAPT discontinuation was rare early after PCI (5.8% at 1–5 months and 6.3% at 6–9 months) but increased (19% and 44%) >9 months. The risk of cardiovascular and noncardiovascular death was higher (HR, 2.03–3.41) with DAPT discontinuation Conclusions Stopping DAPT after 9 months is associated with lower long‐term risks of adverse ischemic and bleeding events and supports recent guidelines of shorter duration DAPT after PCI with second‐generation drug‐eluting stents.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

The prediction of myocardial infarction (MI), acute ischemic stroke (AIS), cardiovascular (CVD) death, and 3-point MACE (MI, AIS, or CVD death) in Million Veteran Program (MVP) participants over 8 years of follow up was evaluated using environmental/traditional risk factors (“E”), polygenic risk scores (“G”), and a combination of both approaches (“GxE”). Individuals free of atherosclerotic cardiovascular disease (ASCVD) at baseline were included. Risk factor levels for the participants close to the time of MVP enrollment for age, sex, systolic blood pressure, cholesterol, HDL cholesterol, smoking status, and diabetes status were analyzed. Outcomes were determined from VA electronic record data, Medicare/Medicaid data, and the National Death Index. Analyses were undertaken separately for non-Hispanic European (EUR), African American (AFR), and Hispanic (HIS) participants. There were 157,941 veterans at risk with 8,157 MI events, 2,024 AIS events, 1,778 CVD deaths, and 9,350 3-pt MACE events over 8 years of follow-up. The overall results showed good performance with the environmental model for all three racial-ethnic groups, with C-statistics ranging from 0.69 to 0.77. The G models showed very modest prediction capabilities and similarly modest improvement in the combined GxE models. In conclusion, traditional risk factor modeling has been shown to be highly effective and, in the MVP experience, the additional impact of genetic or genetic interaction information was small.

Introduction: The majority of population-based studies of myocardial infarction (MI) rely on billing codes for classification. Classification algorithms employing machine learning (ML) increasingly used for phenotyping using electronic health record (EHR) data. Hypothesis: ML algorithms integrating billing and information from narrative notes extracted using natural language processing (NLP) can improve classification of MI compared to billing code algorithms. Improved classification will improve power to compare risk factors across population subgroups. Methods: Retrospective cohort study of nationwide Veterans Affairs (VA) EHR data. MI classified using 2 approaches: (1) published billing code algorithm, (2) published phenotyping pipeline incorporating NLP and ML. Results compared against gold standard chart review of MI outcomes in 308 Veterans. We also tested known association between high density lipoprotein cholesterol (HDL-C) and MI outcomes classified using the 2 approaches among Black and White Veterans, stratified by sex and race; prior study showed HDL-C less protective for Black compared to White individuals. Results: We studied 17,176,658 million Veterans, mean age 69 years, 94% male, 12% self-report Black, 71% White. The billing code algorithm classified MI at positive predictive value (PPV) 0.64 compared to the published ML approach, PPV 0.90; the latter classified a modestly higher percentage of non-White Veterans. Using ML algorithm for MI, we replicated a reduced protective effect of HDL-C in Black vs White male and female Veterans (Table); with the billing code algorithm no association was observed between low density lipoprotein cholesterol (LDL-C) or HDL-C with MI among Black female Veterans. Conclusions: Using nationwide VA data, application of an ML approach improved classification of MI particularly among non-White Veterans, resulting in improved power to study differences in association for MI risk factors among Black and White Veterans.

Introduction: Frailty has been associated with an increased risk of all-cause mortality and CV events. There are limited data from the modern era of CV prevention to examine the relationship between frailty and CV mortality. We hypothesized that frailty would be associated with with increased risk of CV mortality. Methods: All Veterans ≥65 who were regular users of VA care from 2002–2014 were included. Index date was the last visit date in the year of cohort entry. Data were queried biennially, with frailty & outcomes queried each period. Frailty was defined using a 31-item previously validated frailty index, ranging from 0-1. Degrees of frailty were defined as: not frail (FI 0.1-≤0.2), mild frailty (FI >0.2-≤0.3), moderate frailty (FI >0.3-≤0.4), and severe frailty (FI >0.4). Variables were extracted from national VA administrative data linked to Medicare and Medicaid. The primary outcome was CV mortality. Survival analysis was performed. Models were adjusted for age, sex, race/ethnicity, geographic region, smoking status, hyperlipidemia, statin use, and blood-pressure medication use. Results: There were 2,837,152 Veterans included in the analysis. In 2002 mean age was 74+/- 5.8 years and in 2012 was 76+/- 8.1 years, 98% were male, 88.8% were white. In 2002, the median frailty score was 0.16 (IQR= 0.13). This increased and then stabilized to 0.19 for 2006 to 2012 (IQR= ranging 0.19 to 0.23). Overall frailty became more prevalent over time (prevalence increased from 31.9% in 2002 to 46.5% in 2012). The presence of frailty was associated with increased risk of CVD mortality at every degree of frailty and year, as shown in the Table. Discussion: Frailty is highly prevalent in the VA population, and both the presence and severity of frailty are tightly correlated with CV death. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished.

Objective: This is a large prospective study aimed to develop risk prediction models of CVD and all-cause mortality in patients who survived MI. Methods: Using 2002-2012 national electronic health record data from the Veterans Health Administration, sex-specific risk prediction models for CVD and all-cause death were developed from the 5-year follow-up data of 100,601 first MI survivors aged >30 years. Model performance was evaluated using a 5-fold cross-validation approach. Results: We followed 98,657 male and 1,944 female MI survivors up to 5 years (407,199 person-years). There were 31,622 deaths (men 31,147, women 475) and 12,901 CVD deaths (men 12,752, women 149) observed during follow up. Among men, greater age, current smoking, diabetes, atrial fibrillation, heart failure, peripheral artery disease, geographic region, and lower BMI (2 ) were associated with increased risk of subsequent CVD and all-cause-mortality, while statin treatment, hypertension medication, beta-blocker, eGFR level, and high BMI (≥25 kg/m 2 ) were significantly associated with reduced risk of CVD and all-cause-mortality. Similar associations were generally observed among women. We observed U-shaped relations between total cholesterol and outcomes, and HDL cholesterol and outcomes. The prediction models demonstrated good discrimination and calibration. The estimated Harrell’s C-statistics of the final models versus the cross-validation estimates were similar, ranging from 0.75 to 0.81. The predicted risk of death was well-calibrated compared to observed risk. Conclusions: We developed and validated risk prediction models of 5-year risk for CVD and all-cause death for patients following MI. Traditional risk factors, co-morbidity, lack of blood pressure or lipid treatment, and geographic region were all associated with greater risk of CVD and all-cause mortality.

Introduction: Obesity and metabolic dysfunction, individually, are known risk factors of stroke, coronary artery disease (CAD), and mortality. However, few studies have examined the long-term risk for CAD among non-obese people with metabolic dysfunction, and no studies have been conducted for Veterans of the United States. Hypothesis: Veterans who are metabolically obese normal weight (MONW) at baseline have an increased risk of developing CAD compared to metabolically healthy normal weight (MHNW) veterans enrolled in the Million Veteran Program (MVP). Methods: We included MVP participants who had a stable normal body mass index (18.5-25kg/m 2 ) five years prior to enrollment. Metabolic obesity was defined as having three or more of the Adult Treatment Panel III criteria [diabetes, hypertension, low HDL-C (≤40 mg/dl for men, ≤50 mg/dl for women), and high triglycerides (≥150 mg/dl)] at enrollment. CAD was defined as non-fatal myocardial infarction, ischemic heart disease or angina pectoris. Participants with prevalent CAD, major cancers and incomplete lifestyle information were excluded. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CAD incidence. In secondary analyses, we stratified by sex and race to evaluate possible effect modification. Results: Of the 16,764 people identified as normal weight with complete data, 15% were MONW, 84.5% were male, 84.4% were White and the mean age was 63.1 ± 14.2. Over a median follow up of 3.6 (IQR 1.8-5.2) years, there were 847 incident CAD events observed. MONW individuals had a 64% (95% CI: 40 -91%) higher risk of CAD compared to normal weight individuals, controlling for age, race, sex, education, smoking status, physical activity, alcohol use and diet. In secondary analyses, we observed a nominally higher risk among women who were MONW [HR (95% CI): 2.74 (1.30-5.77) for women vs. 1.60 (1.37-1.88) for men], however the interaction of MONW and sex was not statistically significant (interaction p=0.19). Similarly, the interaction of MONW and race was not statistically significant [1.62 (1.37-1.92) for White, 1.55 (0.97-2.48) for Black, and 2.26 (1.03-4.95) for other, interaction p=0.83)]. Conclusions: MONW Veterans had a higher risk of CAD compared to MHNW Veterans. This risk was magnified in female Veterans and attenuated in White and Black Veterans compared to other races (Asian, Pacific Islander, Native American, other). These findings will need to be validated in future studies.

Background: Dietary habits are a major determinant of cardiovascular disease (CVD) and mortality risk. However, data on the role of dairy intake on the risk of CVD and death has been inconsistent. Objective: The primary objective is to assess whether total consumption of dairy products is associated with a lower risk of CVD and/or total mortality among US Veterans. Methods: In a prospective cohort study of US Veterans from the Million Veteran Program (MVP), dairy intake was collected through a self-reported food frequency questionnaire at baseline. Incidence of composite CVD (including MI, stroke, and cardiovascular death) and total mortality were measured via electronic health records and the National Death Index database. Cox Proportional hazard models were used to compute the multivariable adjusted hazard ratio of CVD and total mortality. Results: A total of 188,833 Veterans were studied with a mean age of 63.3 ± 12.3 years. After a mean follow-up of 3.2 years for CVD and 3.3 years for total mortality, 9,898 cases of CVD and 6,826 deaths occurred. Median dairy consumption was 1.2 servings/day. In a multivariable Cox regression adjusted for age, gender, race, body mass index (BMI), smoking, alcohol use, exercise, diet quality, diabetes mellitus, and level of education; hazard ratios (95% CI) for CVD were 1.00 (0.89-1.14) for dairy intake of 1-2 servings/week, 1.05 (0.92-1.20) for 2-3 servings/week, 1.01 (0.90-1.12) for 3-5 servings/week, 0.97 (0.87-1.08) for 5-7 servings/week, 0.96 (0.87-1.05) for 1-2 servings/day, 1.02 (0.91-1.13) for 2-3 servings/day, 1.02 (0.90-1.15) for 3-4 servings/day, and 1.11 (0.98-1.26) for 4+ servings/day as compared to Conclusion: Dairy intake was not associated with composite CVD. However, there was suggestive evidence for J-shaped relation of dairy intake with total mortality.

Background: Atherosclerotic cardiovascular disease (ASCVD) incidence is greater in Hispanic population. Traditional 2013 Pooled Cohort Equation (PCE) models tend to over-predict risks among Veterans by two-fold. Assessment of ASCVD risk with statin therapy has not been extensively investigated in Hispanic Veterans. Objective: We compared 5-year ASCVD incidence of White Hispanic vs White Non-Hispanic Veterans, 18-79 years at baseline in a cohort during 2002-2014. Methods: Ethnicity was determined from census and electronic health data where a Veteran’s last name has a 0.76 positive predictive value for Hispanic ethnicity. We used sex and ethnicity specific Cox models to predict 5-year ASCVD morbidity and mortality. The analyses included PCE variables (age, cholesterol, HDL-C, systolic pressure, blood pressure treatment, smoking, diabetes) plus statin use. Results: A total of 1,383,993 Veterans were in our study with 69,055 (4.9%) females and 81,773 (5.9%) Hispanics. Mean age, cholesterol and HDL-C levels were similar for Hispanics and Non-Hispanics. Smoking, BP therapy, and statin use were less common in Hispanics. Over 5 years of follow-up, 3.9% of Hispanic and 4% of Non-Hispanics developed ASCVD, and 1.3% of Hispanics and 2% of Non-Hispanics experienced ASCVD death. Discrimination of ASCVD events was improved by retraining prediction models using traditional ASCVD risk factors and statin use, with the following concordance statistics: Male Hispanic (0.73), Male Non-Hispanic (0.66), Female Hispanic (0.80), Female Non-Hispanic (0.79). Statin use was associated with a 17% lower ASCVD risk in Hispanics of both sexes and 9% lower ASCVD risk for Non-Hispanics of both sexes. Conclusions and Relevance: Traditional variables plus statin use are efficient predictors of ASCVD morbidity and mortality in a contemporary cohort of Hispanic U.S. Veterans. Baseline statin use was associated with lower risk of ASCVD events in Hispanics compared to Non-Hispanics.

OBJECTIVES:. Quantify scholarly activity by pharmacists who are Fellows within the American College of Critical Care Medicine and to develop a potential publication benchmark for fellowship application. DESIGN:. Review of the Scopus and PubMed online citation databases. SETTING:. None. PATIENTS:. None. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Pharmacists designated Fellow of Critical Care Medicine (FCCM) were identified in January 2021 by the Society of Critical Care Medicine. Pharmacists designated Master of Critical Care Medicine (MCCM), without an active license, or were not identified in either online citation database were excluded. Practice setting characteristics were obtained from the American Hospital Association including country, state, geographic region, number of staffed beds, and hospital designation. Two online citation databases (Scopus and PubMed) were queried in February 2021, and year of first publication, total publications, citations, and Hirsch index were recorded. Of the 152 pharmacists designated FCCM, 138 (91%) were evaluable. Reasons for exclusion included MCCM designation (n = 7; 5%), lack of data in either online citation database (n = 4; 3%), and no active pharmacist license (n = 3; 2%). Most pharmacists were practicing in the Southern geographic region of the United States (n = 62; 45%) and at an academic medical center (n = 116; 84%). The median year of FCCM convocation was 2016 (2012–2019) and of the first publication was 2007 (2002–2011). After removing duplicates, 4,488 unique publications were identified. The median number of publications per individual pharmacist was 20 (9–43) with 10 (5–19) between the year of their first publication and FCCM convocation. Most scholarly activity was in the form of original research (n = 3,173; 71%) or reviews (n = 795; 18%). Individual pharmacists have 244 (99–661) citations and an h-index of 8 (5–13). CONCLUSIONS:. Pharmacists designated FCCM have maintained a high level of scholarly activity. Pharmacists pursuing fellowship may use these data as a benchmark for fulfilling aspects of the core area of scholarly activities related to critical care medicine prior to application.

Objective:To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas.Methods:This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia.Results:We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61–0.73) and 0.78 (95% CI 0.72–0.83) for those Conclusions:After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans

Introduction: Electroencephalographic suppression ratio (SR) measured six hours after resuscitation from cardiac arrest (SR6) can stratify risk of neurological-etiology death (NED) after cardiac arrest. Confounders of this tool for risk stratification have not been described. Hypothesis: Misclassification of risk of NED by SR6 is explained by characteristics of the patient, arrest, or treatment. Methods: Comatose patients prospectively enrolled in an IRB-approved cardiac arrest database were treated by protocol. Patients with brain death or death after withdrawal of life support measures (WLST) due to poor neurological prognosis were considered NED; neuroprognostication follows European Resuscitation Council guidelines. We analyzed patients misclassified by the SR6; high SR that did not suffer NED, or low SR6 that had NED. We reviewed factors associated with misclassification in bivariate analysis, and performed chart review for potential confounders of SR6. Results: Among 364 patients resuscitated from cardiac arrest and with complete data, SR6 predicted NED with AUC 0.89, and an optimal cutoff value of 55.5%. Forty (11%) patients with high SR6 and 17 (5%) with low SR6 were misclassified. In bivariate analysis, factors associated with high SR misclassification were older age 62.6(±14.9) vs. 56.4 (±16) p=0.02, prior neuropathology [20% vs 9.1%, p=0.049], and longer no-flow time (7 [4-9] vs 5 [2-7] minutes, p=0.01). Those associated with low SR misclassification were heart failure [29.4% vs 11.4%, p=0.045] hypertension [82.4% vs 44.6%, P=0.003], obesity [29.4% vs 10.7%, p=0.04], seizures [47.1% vs 21.5%, p=0.03], and higher BMI 33.9 [26.5-36.1] vs 27.8 [23.7-31.3], p=0.04. In chart review, misclassification was associated with early WLST due to family preference, drug or alcohol overdose, seizures, death due to non-neurological cause, preexisting neurological disease, and “favorable” SR6 trajectory. Conclusion: Age, seizures, drug overdose, and non-neurological causes of death may confound accurate neurological risk stratification using processed EEG very early after cardiac arrest. In addition to these “fixed” confounders, a few patients have dynamic SR that improves after 6 hours, and deserve further study.

Introduction: The frequency of opioid-related cardiac arrest (ORCA) is increasing across several geographic regions in the United States. Understanding how Maine’s urban and rural areas are affected by ORCA is necessary to improving prevention and treatment of this public health threat. Hypothesis: Patient demographics, clinical features, rurality and survival to emergency department (ED) admission vary significantly between ORCA and non-ORCA. Methods: We evaluated the National Emergency Medical Services Information System data from 2016-2017 for all emergency 911 responses in which emergency medical services (EMS) reported non-traumatic out of hospital cardiac arrest (OOHCA). We defined ORCA as EMS suspected opioid overdose as the primary etiology, or an overdose without established etiology and naloxone administered during cardiopulmonary resuscitation (CPR). Rurality was assigned using Rural-Urban Commuting Area Codes (RUCA). Demographics and arrest-specific factors were compared between ORCA and non-ORCA, followed by logistic regression to evaluate how ORCA was associated with survival to ED admission. Results: There were 3131 EMS responses for OOHCA during the study period. One hundred sixty-eight (5%) patients met the definition of ORCA. These patients were younger (35 ± 9 years vs 62 ± 17 years, p Conclusions: Patients in Maine with ORCA are distinctly different from patients with non-ORCA, are more likely to survive to ED admission and are seen more commonly in metropolitan and large rural areas.

Background: Responses to new anti-hypertensive therapy (AHT) can differ. Cluster analysis of longitudinal systolic blood pressure (SBP) data allows identification of individuals with similar trajectories, which enables hypothesis generation to potentially explain the observed patterns. We examined electronic health data from U.S. Veterans initiating AHT from 2002-2009. Methods: SBP was tracked for 1 year before and up to 2 years after AHT initiation. Subjects were clustered using a K-means approach with the mean of the squared Euclidean distances as a distance metric and evaluated for the optimal number of clusters. Thin-plate splines were used to display the smoothed trajectories of each group with predicted SBP measures over time. Results: A total of 45,598 subjects contributed 783,852 SBP measurements. Five clusters of subjects with similar trajectories were produced, providing visualization of SBP [Figure 1] prior to initiation, immediately after starting therapy, and after longer treatment duration. For example, Group 1 had the lowest mean age, lowest HDL-C, lowest LDL-C, highest triglycerides, lowest baseline SBP, lowest insulin use, and highest statin use. Conclusions: Trajectory clustering for SBP identifies distinct response groups that differ in response to therapy, laboratory measures, and medication use. Future analyses can examine anti-hypertensive medication use, compliance and genetic factors to identify potential causes for these trajectories. These cluster analyses can provide new analytical approaches related to risk factor diagnosis and treatment.

Introduction: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity in the U.S. We mapped ACC/AHA ASCVD risk in U.S. Veterans outpatients across U.S. geographic regions. Methods: We computed 10-year ASCVD risk using the 2013 ACC/AHA risk calculator with risk factor values derived from electronic health records and compared the estimates to observed ASCVD rates within Veterans Health Administration (VHA) population. We mapped the standardized differences in the observed and predicted risk at the county level using ArcGIS software. Results: There were 1.48 million VHA users between 2002-2007 aged 40 to 79 with median 10 years of follow-up. Mean age was 60 years, 96% were male, and 80% were white. The average 10-year predicted ASCVD risk after adjustment for true follow-up time at baseline was 13.8%, and the average observed risk was 6.6%, an overestimation of 7.2%. At baseline, 43.1% of patients were taking anti-hypertensive medications and 20.3% were taking statins. After updating risk factor statuses two years following baseline, 75.9% were taking anti-hypertensive medication, 42.6% were takings statins, and average predicted risk was dropped to 12.1%. In sex- and race-specific analyses the 2013 ACC/AHA risk calculator over-estimated 10-year ASCVD risk in white female, non-white female, white male, and non-white male by 2.0%, 2.0%, 8.1% and 4.8%, respectively. The greatest over-predictions in 10-year ASCVD risks were observed in western Arizona, southern California, southern Florida and Pennsylvania. These regions had higher percentages of white male VHA users compared to national averages. Conclusion: The 2013 ACC/AHA risk equation generally over-predicts ASCVD risk in the VHA population, particularly among white male Veterans. Increased anti-hypertensive and statin therapy with continual care at VHA was also associated with lower ASCVD risk. The mapping of these results allowed an overall visualization of the geographic variation across the U.S.

Introduction: Blacks and Hispanics have been shown to have higher stroke mortality than non-Hispanic whites. However, this may be due to higher incidence of strokes in blacks and Hispanics. Fewer studies have investigated health disparities in post-stroke mortality stratified by stroke type. We studied risk of mortality by race/ethnicity after either incident acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) in a national sample of patients from the Veteran’s Health Administration (VHA). Methods: We included patients with a first occurrence of an inpatient AIS or ICH in a VHA hospital between 2002-2007. We categorized patients as non-Hispanic white, non-Hispanic black, or Hispanic. Veterans with any prior stroke-related code were excluded. For each of AIS and ICH, we constructed a piecewise multivariate survival model for post event all-cause mortality. We separated follow-up intervals into 1 year post admission. Results: We identified 36,569 patients with an incident stroke in 2002-2007 (91% AIS, 9% ICH). The proportion of white, black, and Hispanic patients with AIS was 68%, 26%, and 6% respectively; and in ICH was 63%, 27%, and 10%. Compared to whites, blacks had better survival for AIS in the first 30 days, while Hispanics tended to have better survival in the 30-90 day and >1 year intervals. With ICH, blacks had higher mortality in the first 30 days. (Table 1) Conclusion: Blacks experience better 30-day survival after AIS compared to whites, but worse 30-day survival after ICH. This may be driven by higher prevalence of hypertension in blacks leading to small vessel occlusion, which is associated with lower mortality, or poorer control of blood pressure in the setting of ICH, which is associated with higher mortality. Hispanic patients may have better long-term survival after stroke compared to whites, a ‘Hispanic paradox’ that has been shown in other studies. Stroke events should be stratified by ischemic and hemorrhagic type when evaluating for racial disparities in outcomes.

Introduction: Familial hypercholesterolemia (FH) phenotype, defined in part by LDL-Cholesterol (LDL-C) ≥190mg/dL, is a strong risk factor for cardiovascular disease (CVD). The 2013 ACC/AHA cholesterol guidelines recommend high intensity statins for primary prevention irrespective of global risk assessment. We sought to determine predictors of high intensity statin initiation in patients with FH phenotype in the Veteran’s Health Administration (VHA). Methods: Inclusion criteria consisted of VHA care (2002-2014), age ≥21 years, absence of prevalent CVD, baseline maximum LDL-C ≥190 mg/dL, no prior statin use, and statin initiation within 90 days of outpatient LDL-C measurement. Baseline characteristics were obtained from the electronic health record. We defined baseline LDL-C using quartile cutoffs. High intensity statin definitions were based on the 2013 cholesterol guidelines plus high dose simvastatin when it was available. Multivariable logistic regression models were constructed to determine the odds of high intensity statin initiation versus low or moderate intensity. Results: A total of 88,878 Veterans (age=53.7±11.6, men=91%; white race=74%, LDL-C mean=209.5±23.9, Q1=195, median=202, Q3=215) met inclusion criteria. High intensity statin was initiated in 29,533 (33%) of patients. Comorbidities included smoking history (80%), hypertension (39%), diabetes (10%), and chronic kidney disease (3%). Significant predictors were age >40 years, male sex, diabetes, hypertension, black race, smoking, higher baseline LDL-C quartile, and recent calendar year. Veterans with cancer and white race had lower odds of statin initiation. Conclusion: Nearly 1/3 of the Veteran population with the FH phenotype was started on high intensity statins. They were more likely to be older, black, smokers, hypertensive, diabetic, and have a higher baseline LDL-C. The odds of high intensity statin initiation increased in recent years, which may partly reflect practice changes concordant with recent cholesterol guidelines.

There are concerns that 2013 ACC/AHA ASCVD pooled risk prediction models are not accurate predictors in contemporary American patient populations, and that these models do not take into account the highly prevalent use of statin therapy or the effects of statins on vascular disease prevention. Using validated phenotyping algorithms, we evaluated the accuracy of the pooled risk model for the development of Hard ASCVD in 1.42 million Veterans (4.3% women, 16.6% black) with mean age 60 years (range 40-79 years) at baseline VA outpatient clinic evaluations in 2002-2004. There were 93,250 Hard ASCVD events over a mean of 8.4 years of follow up. We estimated Hard ASCVD risk using traditional variables (age, sex, race, total cholesterol, HDL cholesterol, diabetes mellitus, systolic blood pressure, blood pressure treatment, and smoking history) employed in the 2013 ACC/ACC ASCVD risk report. Three analytic approaches were undertaken, using 1) published 2013 ACC/AHA prediction equations, 2) 2013 ACC/AHA variables to fit VA-specific Cox regression models for white men, black men, white women, and black women, and 3) model 2 plus baseline statin use. The Harrell’s c-statistics for the models are shown in the table along with the hazard ratios for statins from model 3. Traditional predictor variables were generally statistically significant in all models, and model 1 over predicted absolute risk of Hard ASCVD in VA by approximately 6%, and statin use was associated with up to an 18% reduction in ASCVD risk. In conclusion, these results demonstrate that the pooled ASCVD prediction model performs relatively well in the VA setting, as shown by relatively good c-statistics. The 2013 ACC/AHA over predicted ASCVD risk and statin therapy at baseline was an important determinant of outcomes.

Background: Potato consumption is highly prevalent all around the world. Previous studies have reported a positive association of potato intake with hypertension and diabetes due to high glycemic load. However, data are scarce on potato consumption and risk of coronary artery disease (CAD). Hypothesis: We hypothesized that potato consumption is positively associated with risk of CAD. Method: We prospectively studied 148,671 participants from Million Veteran Program(MVP). We used a Willett food frequency questionnaire to assess consumption of baked, boiled, and mashed potatoes. The incidence of CAD was assessed through electronic health record. We used Cox Proportional hazard model to compute the hazard ratio and 95% confidence interval (95% CI) for CAD events across categories of potato intake. Results: The average age of men was 64 years ( SD = 12) and 90 % were men. A total of 6,309 new cases of CAD occurred during mean follow up of 2.7 ± 1.4 y. Median potato consumption was 1 cup/week. The crude incidence of CAD from lowest to highest categories of potato consumption was 14.1, 15.0, 15.2, 16.1, and 18.9 per 1000 person-years, respectively. Hazard ratios ( 95% CIs) of CAD were 1.00 ( reference), 1.01 (0.92-1.11), 1.02 ( 0.93-1.11), 1.04 (0.95 - 1.15), and 1.21 (1.07-1.36) for potato intake of Conclusion: Frequent (5+ cups/week) but not infrequent potato consumption was associated with a higher risk of CAD among MVP participants.

Introduction: Improved control of hypertension is largely credited for declines in stroke incidence and mortality. Previous studies have reported worse outcomes after ischemic stroke with lower blood pressures prior to the stroke. We investigated the relationship between pre-stroke systolic blood pressure (SBP) and mortality after ischemic stroke among U.S. Veterans. Methods: This longitudinal analysis assessed mortality risk after incident stroke in a national sample of Veterans Health Administration hospitalizations between 2002 and 2007. We included patients who had admission ICD-9 codes for ischemic stroke (433.x1, 434, and 436, excluding 434.x0) and ≥1 outpatient blood pressure measurements 1 to 18 months prior to stroke. We defined 6 categories of average baseline SBP: Results: There were 29,458 hospitalizations (mean age 67±12 years, 98% male) for incident stroke. During 4.1±3.3 years mean follow-up, there were 15,489 deaths (54%). There were 6,629 vascular deaths (23%). In a fully adjusted model, with high normal pre-stroke SBP (130-139) as the reference, risk of all-cause mortality was increased for patients with very low-to-normal SBP ( Conclusions: In U.S. Veterans hospitalized with first-ever stroke, very low and very high pre-stroke systolic blood pressure levels increased risk of all-cause and vascular mortality. Optimal SBP targets after stroke, particularly in patients with low pre-stroke SBP, merit further investigation.

Background: Individuals with an interleukin 6 receptor (IL6R) genetic variant not on IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. Thus, studying whether the IL6R variant is protective for a phenotype can inform which diseases may benefit from treatment with IL6R blockade. To test this hypothesis, we performed a Phenome-Wide Association Study (PheWAS) to screen for associations between an IL6R variant and a broad range of phenotypes in the electronic health records (EHR). Methods: We studied veteran participants in the Veteran’s Affairs Million Veteran’s Project using genomic data linked to EHR. We extracted all diagnoses codes and mapped them to phenotype groups using published PheWAS methods. Routine laboratory measurements, e.g. liver function tests, were also extracted. A PheWAS was performed by constructing logistic regression models testing associations between the IL6R variant (Asp358Ala, rs2228145) and 1,866 phenotype groups; linear regression models were constructed to screen for associations between IL6R and 26 routine laboratory measurements. All models were adjusted for age, gender, and race. Significance was reported using false discovery rate ≤0.05 and Bonferroni correction. Results: We studied 342,529 participants; the minor allele frequency of the IL6R variant was 35.3%. IL6R was most strongly associated with a reduced risk of aortic aneurysm (OR 0.91-0.92, 95% CI 0.89, 0.94) (Figure 1). We observed the expected association between IL6R and reduced C-reactive protein. We also observed known side effects of IL6R blockade, elevated transaminases, as well as elevated triglycerides, an initially unexpected result in the early clinical trials. Conclusion: In this proof of concept study, we demonstrate the utility of PheWAS to inform drug effects using the largest US-based biobank study. The strong association with aortic aneurysm corresponded with the newest indication for IL6R blockade to prevent aortic aneurysms due to large vessel vasculitis.

Introduction: Severe elevations of LDL-Cholesterol (LDL-C) ≥190mg/dl in adults, representing the familial hypercholesterolemia (FH) phenotype, have been associated with increased risk of cardiovascular disease (CVD). The 2013 AHA/ACC guidelines recommend high intensity statin therapy to reduce LDL-C by ≥50%. We identified patients with FH phenotype in the Veterans Health Administration (VHA) who were statin-naive and determined the degree of LDL-C reduction over one year after statin initiation and the efficacy of statin intensity on ≥50% reduction. Methods: Patients receiving care at the VHA from 2002-2007, ≥21 years of age, with baseline LDL-C measurement of ≥190 mg/dl (LDL-C 0 ), and statin-naïve were included. Statin initiation was required within 90 days of LDL-C 0 , and a follow up level (LDL-C 1 ) had to be collected within one year ± 90 days. All participants were free of clinical CVD at baseline. Baseline characteristics were ascertained from patient charts. LDL-C reduction was defined as the difference between LDL-C 0 and LDL-C 1 . Multivariable logistic regression models, adjusted for age, sex, race, diabetes, kidney disease, hypertension, and hypertension treatment were constructed to determine the odds of goal LDL-C (≥50%) reduction by statin intensity. We defined statin intensity per the 2013 AHA/ACC guidelines. High intensity statins included Simvastatin 80mg, Atorvastatin 40-80mg, and Rosuvastatin 20-40mg. Results: We included 35,894 Veterans (Men: N= 33,049 (92.1%), Age=55±10 years; Women: N=2845 (7.9%), Age=50±11 years). The mean duration between LDL-C 0 and LDL-C 1 was 52±7 weeks. The population was predominantly white (78.1%). Mean LDL-C 0 was 210±22 mg/dl, triglycerides were 175±126 mg/dl. At baseline, 0.3% had kidney disease, 14.1% diabetes, and 52.8% hypertension. Mean absolute LDL-C reduction in the population was 70.2±41.9 mg/dl. A total of 6718 (18.7%) patients achieved an LDL-C reduction of ≥50%. Among these patients, 5.2% were on low, 62.2% were on moderate, and 32.6% were on high intensity statins. In multivariable-adjusted logistic regression models using moderate intensity statins as the comparator, high intensity therapy resulted in 97% higher odds of achieving goal LDL-C reduction (Odds ratio [OR]=1.97; 95% Confidence Interval [CI]=1.85-2.09), and low intensity statins resulted in 42% lower odds of achieving goal LDL-C reduction (OR= 0.58; 95%CI= 0.52-0.65). Conclusions: In a large veteran population with the FH phenotype, though there was a marked reduction in LDL-C with statin therapy, most patients did not achieve goal LDL-C reduction of ≥50%. This may be related to statin intensity, individual response to statin therapy, or lack of adherence to treatment. In multivariable-adjusted logistic regression models, patients on high intensity statins had 2-fold odds of goal LDL-C reduction compared to moderate intensity statins.

Introduction: Prior studies have suggested a link between diet and Coronary Artery Disease (CAD), but there have been mixed findings on the risks and benefits of coffee and tea consumption. We assessed whether there is an association and dose response between coffee and tea intake on CAD incidence among Veterans. Methods: Million Veteran Program (MVP) is a national, representative longitudinal study of Veterans for genomic and non-genomic research that combines data from self-reported surveys, electronic health records, and biospecimens. Using food frequency data collected from 2011-2017 and CAD outcomes obtained from electronic health records, we used cox proportional hazard ratios (HR) to evaluate the association of coffee or tea intake with CAD incidence among Veterans with complete data. Follow-up began at the completion of the food frequency survey. Tea and coffee were evaluated separately, with intake categorized as never or less than one cup/month, 1-3 cups/month, one cup/week, 2-4 cups/week, 5-6 cups/week, one cup/day, 2-3 cups/day, 4-5 cups/day, or 6+ cups/day. For tea, the last two categories were combined to obtain stable estimates. Multivariate models were adjusted for known CAD risk factors (age, smoking status, physical activity, and education) and other caffeine use (e.g. tea for coffee). We plan to use restricted cubic splines to assess dose-response relationships. Results: Among 139,549 participants (90.3% male, mean age 64 ± 12 years), 74.2% consumed 1+ cups of coffee a month and 53.7% consumed 1+ cups of tea a month. During a median follow up of 3.2 years, we observed 4,715 new cases of CAD. Compared to those who drank less than one cup of coffee/month, adjusted HRs (95% CI) for CAD were 1.06 (0.92-1.22) for 1-3 cups/month, 1.09 (0.91-1.29) for one cup/week, 0.96 (0.84-1.10) for 2-4 cups/week, 0.92 (0.81-1.04) for 5-6 cups/week, 0.93 (0.85-1.01) for one cup/day, 0.99 (0.91-1.07) for 2-3 cups/day, 1.05 (0.93-1.19) for 4-5 cups/day, and 1.08 (0.92-1.28) for 6+ cups/day (p-linear trend=0.24). Compared to those who drank less than one cup of caffeinated tea/month, adjusted HRs (95% CI) for CAD were 1.08 (0.99-1.17) for 1-3 cups/month, 1.11 (0.99-1.23) for one cup/week, 1.01 (0.91-1.12) for 2-4 cups/week, 1.03 (0.89-1.17) for 5-6 cups/week, 1.04 (0.93-1.17) for one cup/day, 1.12 (0.98-1.28) for 2-3 cups/day, and 1.27 (1.04-1.58) for 4+ cups/day (p-linear trend=0.14). Conclusion: While coffee intake was not associated with incidence of CAD, there was an elevated risk of CAD restricted to Veterans consuming 4+ cups of caffeinated tea per day.

Introduction: The use of statins after acute myocardial infarction (MI) has been shown to reduce the risk of recurrent MI and mortality. We examined the association between statin therapy and the risk of 1 year mortality after MI hospitalization. Methods: Data from the Veterans Health Administration was used to create a national sample of Veterans hospitalized for their first MI event between 2002 and 2015. Veterans with prevalent heart failure, stroke, or cancer diagnoses at the time of discharge for the index MI and prolonged hospitalization (greater than 30 days) were excluded. The statin therapy group was defined as Veterans having any statin prescription at the time of discharge. The primary outcome was all-cause mortality obtained from the National Death Index. We fitted a Cox regression model adjusted for age, length of hospital stay, peak cardiac troponin I ratio (the ratio of the peak measurement to the reference upper limit of normal for the assay) during hospitalization, statin use before admission, beta blocker prescription at discharge, liver disease, peripheral arterial disease, estimated glomerular filtration rate, high-density lipoprotein and total cholesterol levels. Billing codes were used to define exclusion criteria and co-morbidities. Results: Among 16,263 Veterans hospitalized for MI, mean age was 62 years and 98% were men. During 350 days mean follow up, 966 deaths occurred. In the statin therapy group 709/13,334 (5.3%) of Veterans died compared to 257/2,929 (8.8%) of Veterans without statin therapy. In an age-adjusted model, 1-year mortality was 35% lower (HR 0.65, 95%CI 0.56 - 0.75) for patients that were prescribed a statin at discharge compared to Veterans who did not receive a statin at discharge. In a multivariable model we observed a 27% (HR 0.73, 95% CI 0.63 - 0.85) lower risk of death for users of statin therapy compared to non-users (Figure). Conclusions: Statin therapy prescribed after a first MI event may reduce the 1 year risk of all-cause mortality.

OBJECTIVE Continuous antipsychotic treatment is important in schizophrenia, and studies have shown that rates of discontinuation are high. Some studies suggest that weight gain may lead schizophrenic patients to discontinue treatment, whereas other studies show smaller effects of weight gain on medication discontinuation, and some find weight gain associated with symptom improvement. Our retrospective cohort study investigated the effect of weight change on the continued use for 1 year (persistence) of all antipsychotics, then among users of first-generation antipsychotics and second-generation antipsychotics (SGAs), and lastly subgroups of SGAs. METHODS We identified 2130 patients with schizophrenia starting an antipsychotic that had not used 1 in the prior year. Using multivariable logistic regression adjusted for demographic and clinical variables, we determined the odds of remaining persistent on medication among patients who either gained weight or did not gain weight in the following year. RESULTS For all antipsychotics combined, weight change was not associated with persistence. Among SGAs, weight gain was associated with a 23% increase in the adjusted odds ratio (OR) for persistence (OR, 1.23; 95% confidence interval [CI], 1.00-1.51), whereas there was a nonsignificant decrease in the adjusted odds of persistence among first-generation antipsychotic users (OR, 0.74; 95% CI, 0.43-1.28). When SGAs were divided into subgroups (clozapine/olanzapine, risperidone/quetiapine), both had increases in the likelihood of persistence, but only the association for clozapine/olanzapine was significant at a trend level (adjusted OR, 1.46; 95% CI, 0.99-2.16). CONCLUSIONS These findings are supportive of other research that shows weight gain does not invariably lead to medication discontinuation and may be associated with clinical improvement.

Background: Anemia is increasingly being identified as a poor prognostic factor in patients with heart failure with reduced ejection fraction. However, few studies, and with small sample sizes, have examined the role of anemia in patients with heart failure with preserved ejection fraction (HFpEF). Thus, the purpose of our study is to examine whether anemia is associated with mortality in a large national cohort of patients with HFpEF. Methods: We identified subjects with HFpEF using a validated algorithm in the national Veterans Affairs patient database from 2002 to 2012. The criteria for HFpEF included: all recorded ejection fractions > 50% and symptoms, signs and treatment for heart failure. Anemia was identified using the International Classification of Diseases (ICD-9) code at the index time of HFpEF diagnosis. All-cause mortality was confirmed from medical death records and Center for Medicare Services data. Using a multivariable Cox proportional hazards model, we examined the association of anemia at the time of HFpEF diagnosis with all-cause mortality. Results: In total, 29,022 HFpEF patients met criteria for HFpEF. Mean age of the participants was 71±12 years; 96% were men, 84% were white, 35% had anemia, 88% had hypertension, 65% had hyperlipidemia and 42% had coronary artery disease at baseline. After a median follow-up of 3.6 years (IQR: 1.7-6.4), 17,269 deaths occurred. After adjusting for age, sex, race, body mass index, coronary artery disease, hypertension, hyperlipidemia, atrial fibrillation, chronic obstructive pulmonary disease, diabetes mellitus, serum sodium, renal function, heart rate and ejection fraction, patients with anemia had higher mortality (HR 1.52, 95% CI 1.47-1.57, p < 0.0001) as compared to those without anemia. Conclusion: Our study suggests that prevalent anemia is associated with an increased risk of all-cause mortality among US veterans with HFpEF. Further studies may shed light on its role as a prognosticator and potential therapeutic target in this population.

Introduction: Increased levels of cardiac troponin at the time of myocardial infarction (MI) have been shown to predict mortality. However, troponin is renally cleared and kidney function itself impacts mortality. We tested the hypothesis that baseline kidney function modifies the relationship between peak cardiac troponin I ratio (cTnI-R) and 30 day mortality after MI. Methods: Data from the Veterans Health Administration was used to create a national sample of hospitalized Veterans with a discharge diagnosis of MI between 2002 and 2015. The peak cTnI-R, calculated as the highest cTnI during the hospitalization compared to the upper limit of normal for each assay, was used as a proxy for the date of the MI event. Veterans with a history of cancer or blood vessel surgery 5 days before peak cTnI were excluded. The closest estimated glomerular filtration rate (eGFR) measured within 2 years prior to hospital admission was used as a marker of baseline kidney function. We created quartiles of peak cTnI-R and clinically relevant levels of eGFR (2 ) and fitted Cox regression adjusting for calendar year, age, length of hospital stay, region, diabetes, major mental health conditions and baseline use of diuretics, anti-hypertensives and anti-lipemics. We used subjects in the first quartile of troponin with eGFR of 60+ as common reference. Results: Among 56,073 Veterans hospitalized for MI, mean age was 67 and 98% were men. During 28 days mean follow up, 4,533 deaths occurred. 30 day mortality steadily increased across quartiles of peak cTnI-R; however, the increase in mortality was higher in eGFR below 30, suggesting effect modification of troponin-mortality relation by eGFR (p for interaction between eGFR and troponin 0.03) (Figure). Conclusions: Our data show that the positive relation of troponin with 30 day mortality post MI is modified by kidney function. Veterans with impaired kidney function carry a higher risk of 30 day mortality after MI compared to those with normal eGFR for a given troponin quartile.

Background: More than one-third of US adults are obese and the prevalence has remained stable since 2003. In the largest cohort of 515,912 men and women participating in the Million Veteran Program (MVP), we analyzed trends in baseline weight/obesity across the years of enrollment. Objective: The goal of this study is to examine prevalence and trends in baseline characteristics among US Veterans enrolled in MVP between 2011 and 2016. We highlight the trends in BMI over the enrollment period. Methods: BMI was computed for 479,521 Veterans who enrolled in MVP between 2011 to September 2016. Participants reported weight and height on the baseline survey. Missing survey data was supplemented with patient EMR data taken closest to enrollment date and stratified by year of enrollment. Results: Mean age was 61.2 (SD=13.8), 91.6% (391,124/427,187) were men, 73.8% (353,720/479,520) White, 18.8% (90,020/479,520) Black, and 7.4% (35,593/479,520) Hispanic. Overall, mean BMI was 29.7 [range 11.3 to 78.5]. Prevalence of underweight, normal weight, and overweight was 0.7% (3,164/479,521), 19.4% (93,318/479,521), 38.4% (184,625/479,521), respectively, in this cohort. While the prevalence of obesity increased with consecutive years of enrollment in men and overall, we did not observe such trend for other categories of adiposity (Fig). When stratified by race we did not observe any difference in prevalence of underweight and normal weight among White and Black participants. Prevalence of obesity was higher in Blacks, but the rate of obesity among Whites appears to be growing at a faster rate than in Blacks. Compared to the general VHA (Veterans Health Administration) population, prevalence of obesity and the distributions of race, gender, and ethnicity were similar among participants in MVP. Conclusion: Our data show that the prevalence of overweight/obesity is high among US Veterans. Across consecutive years of enrollment, prevalence of obesity but not overweight appears to increase across each ethnic group.

Background: While some but not all trial data have suggested a slightly elevated risk of type 2 diabetes (T2D), limited data are available on the relation of statin use with glycemia among US veterans. Objective: To test the hypothesis that treatment with a statin is associated with elevated serum glucose and a higher risk of T2D among US veterans. Methods: We studied 549,143 US veterans with electronic health records from 1998 to 2016. We used the VA Corporate Data Warehouse to obtain information on glucose (fasting and non-fasting). Statin use was captured using the pharmacy database. T2D was defined as having at least one inpatient diagnosis or at least 2 outpatient diagnoses of T2D using ICD 9 codes 250.xx, or the use of hypoglycemic agents. We addressed confounding by indication using propensity score (included 444 variables/interactions) for receiving statin and inverse probability weighting in the Cox regression. Results: The mean age was 60±12.8 y; 94.3% were men; 77.1% were white; and 15.4% were black. In this cohort, simvastatin was the most prescribed statin (84%) followed by lovastatin (7%). During a median follow-up of 4.4 years, 130,819 new cases of T2D occurred. Among 418,847 veterans receiving statin, we observed a 2 mg/dl increase in serum glucose when comparing serum glucose measured at the time of statin initiation and short-term Conclusions: Our data show a positive association between statin use and increase in both serum glucose and incidence of T2D among US veterans. If confirmed by others, this suggests closer monitoring of patients at risk of T2D when statin therapy is initiated.

Although well-described for patients who require dialysis, information on transfusion burden related to anemia in the nondialysis patient population with chronic kidney disease (CKD) is lacking.A retrospective study was conducted of patients with CKD and chronic anemia from 2002 through 2007 in the Veterans Administration Healthcare System. Included patients had stage 3 CKD or higher and anemia (one or more hemoglobin [Hb] levels11 g/dl or received anemia therapy [erythropoiesis-stimulating agents [ESAs], iron, or both]). The outcome of interest was transfusion events, which was evaluated in relation to the absolute Hb level and changes in Hb levels overall and according to the type of treatment received (no treatment, iron therapy, ESA therapy, or ESA and iron therapy) concurrent with each Hb measurement.Among 97,636 patients with CKD and anemia, we observed 68,556 transfusion events (61 events per 100 person-years), 86.6% of which occurred in inpatient settings. At all Hb levels, transfusion events were highest during periods of no treatment and increased with declining Hb levels. Between an Hb of 10.0 and 10.9 g/dl, the transfusion rate was 2.0% for those who received an ESA, iron, or both and 22% for those who received no treatment; at an Hb level of 7.0 to 7.9 g/dl, the transfusion rate was 10 to 12% for treated and 58% for untreated patients. Low absolute Hb levels but not Hb changes was most predictive of a transfusion even after adjustment for patient case mix.Transfusions are still used to treat anemia in patients who have CKD and do not require dialysis, although they occur considerably less frequently in patients who receive other available anemia therapies.

Clinicians commonly use nonindicated (or "off-label") medications for the treatment of alcoholism, although there is no clear evidence to support this practice. Quetiapine and trazodone are 2 medications frequently used in this manner, especially to treat sleep disturbance associated with alcohol withdrawal. Using national administrative data from the Department of Veterans Affairs, we compared the differences among these medications in time to rehospitalization after discharge from an index hospitalization for alcohol dependence. Our outcome measure was the difference in time (weeks) to rehospitalization for patients given medications in 1 of 4 groups: quetiapine alone (median, 6.1 weeks); trazodone alone (median, 10.1 weeks); quetiapine combined (median, 7.1 weeks); and trazodone combined (median, 10.3 weeks) with other frequently used psychotropic drugs. Differences between groups were examined with Cox's proportional hazards regression using trazodone in combination with other medications as the reference category. Crude hazard ratios were determined first and then adjusted for covariates. There was no difference in the risk of rehospitalization when patients using quetiapine in combination were compared with the reference category (hazard ratio [HR] = 1.08; confidence interval [CI], 0.99-1.17; P < 0.0936). In contrast, when quetiapine was used alone there was a significantly higher risk of rehospitalization (HR = 1.22; CI = 1.06-1.41; P < 0.005). When trazodone was used alone there was no difference in risk in the unadjusted analysis (HR = 1.05; CI = 0.96-1.14; P < 0.3076); however, the HR increased to a significant level after adjusting for covariates (HR, 1.14; CI = 1.05-1.24; P < 0.0029) and for those with 2+ previous discharges (HR = 1.25; CI = 1.14-1.37; P < 0.0001). These findings suggest the need for additional studies to better understand what symptoms of alcoholism benefit from the use of these medications, at what dose levels, and with what other medication combinations.

Introduction: Clinicians are hesitant to prescribe oral anticoagulants to older adults with atrial fibrillation (AF) due to concerns over bleeding risk. Hypothesis: As many data on bleeding events are from trials of rigorously selected patients, we hypothesized that major bleeding events (requiring hospitalization) would be more common than previously reported. Methods: We created a retrospective cohort of 31,951 Veterans with AF aged ≥75 years who were new referrals to VA anticoagulation clinics (warfarin) from 1/1/02 - 12/31/12. Patients with comorbid conditions requiring warfarin (e.g. pulmonary embolus) were excluded. Data were extracted from the VA electronic medical record and linked with Medicare claims data for subsequent hospitalizations. The primary outcome was any hospitalization for bleeding. We identified bleeding subtypes by source, and compared characteristics of patients with and without bleeding hospitalizations. Results: Mean population age was 81.1 years, 98.1% were male, and 8.4% were nonwhite. Over a median follow-up period of 2.62 years, 7288 patients (22.8%) were hospitalized for bleeding. There were 12,004 total bleeding events; overall, 980 (13.4%) patients experienced multiple events. The most common bleeding sources (first event) were gastrointestinal (50.8%), genitourinary (21.6%), and intracranial (9.4%) (Figure). The median time to first bleeding event was 1.59 years. Patients hospitalized for bleeding were more likely to have coronary disease (48.4% vs. 40.9%, P Conclusions: After initiating warfarin, over one in five older Veterans are hospitalized for bleeding, most commonly from a gastrointestinal source. Comorbidity burden and labile INR place these patients at increased risk.

Objectives— Atherosclerotic coronary artery calcification (CAC) is associated with increased coronary heart disease (CHD) risk. Matrix Gla protein (MGP) is an inhibitor of calcification in vivo. However, little is known regarding the distribution of circulating MGP and its associations with CHD risk factors or with CAC in humans. Methods and Results— Serum MGP concentrations were determined in 2 independent populations of men and women free of clinically apparent cardiovascular disease: study A, n=316, mean age 58 years, and study B, n=452, mean age 68 years. CAC was determined by computed tomography. Mean MGP concentrations were 98.4 and 198 ng/mL in men, and 97.4 and 201 ng/mL in women, in study A and study B, respectively. In both cohorts, MGP levels were higher with increasing age. In age-adjusted analyses, there was an association of circulating MGP with increasing Framingham CHD risk score (in study A, P =0.003 in men and P =0.016 in women, respectively; in study B, a nonsignificant increase in men and P =0.05 in women, respectively). Significant associations of circulating MGP with high-density lipoprotein and other individual CHD risk factors were also noted in both cohorts. There were no consistent associations between MGP and CAC after adjustment for CHD risk score in the 2 cohorts. Conclusions— MGP is associated with individual CHD risk factors and the Framingham CHD risk score in men and women free of clinically apparent CHD. The relation of MGP with CAC deserves further study in larger populations.

Background: Cigarette smoking potentiates the antiplatelet effect of clopidogrel. Guidelines recommend clopidogrel for 12 months after percutaneous coronary intervention (PCI) with bare-metal (BMS) or drug-eluting (DES) stents. Whether smoking affects the risk of ischemic events related to clopidogrel use beyond 12 months after PCI is unknown Methods: We identified all PCIs performed in the Veterans Affairs (VA) health system from 2002-2006 and linked the information with the VA pharmacy database. VA and non-VA clinical outcomes were identified by ICD-9 codes from the VA National Patient Care and CMS/Medicare databases. All patients who were event-free at 12 months were followed for death, myocardial infarction (MI), or target vessel revascularization (TVR) up to 4 years following PCI. Prolonged (i.e., > 12 months) vs. clopidogrel use for < 12 months was assessed for each outcome within each stent type using propensity score adjusted inverse probability of weighting (IPW) Cox-proportional hazards analyses. Results: From 2002-2006, 28,507 patients included in the study underwent PCI and were event free at 12 months. Of these, 42% were smokers (n = 11,989) at the index PCI, 51% received a DES (n = 14, 594) and 45% were treated with prolonged clopidogrel use (n = 12,968). Following a 12-month landmark period, 2,194 deaths, 2,288 death or MIs, and 2,010 TVRs occurred. In smokers, prolonged clopidogrel use was associated with a lower risk of death and death or MI with both stent types (interaction p ≤ 0.10). In non-smokers, prolonged clopidogrel use was associated with a lower risk of death (interaction p = 0.04) and death or MI (interaction p = 0.03) in patients receiving DES only (Table). Conclusions: Prolonging clopidogrel more than 12 months after PCI may lower the risk of death or MI in smokers irrespective of stent type and in non-smokers receiving DES only. This study suggests that the duration of clopidogrel use after PCI may be tailored to smoking status and stent-type.

Introduction: Clopidogrel up to 12 months after an acute coronary syndrome (ACS) lowers the risk of major adverse coronary events. Guidelines recommend clopidogrel for 12 months after coronary intervention (PCI) with bare-metal (BMS) or drug-eluting (DES) stents. The value of prolonging clopidogrel beyond 12 months in PCI patients with ACS is unknown. Hypothesis: We hypothesize that prolonged clopidogrel differentially reduces adverse events in patients receiving DES compared with those receiving BMS for an ACS. Methods: We linked all PCIs in the national Veterans Affairs (VA) health system from 2002-2006 with the VA pharmacy database. VA and non-VA clinical outcomes were identified by ICD9 codes from the VA and CMS/Medicare databases. All patients who were event free at 12 months were followed for death, myocardial infarction (MI), and recurrent target vessel revascularization (TVR). The hazard ratio for prolonged clopidogrel use (more than 12 months) versus clopidogrel for less than or equal to 12 months was assessed for each outcome within each stent type, using Cox proportional hazards models. Multivariable models and propensity models were also used to adjust for confounding related to the propensity for prolonged clopidogrel treatment. Results: After exclusions, 28,507 patients had PCI and were event free at 12 months. Of these, 18,279 (64%) had an ACS at their index PCI including 9,336 (51%) who received a DES and 8,447 (46%) who received prolonged clopidogrel. Events occurring up to 4 years after PCI in these ACS patients included 1358 deaths, 1885 death or MIs, and 1335 TVRs. Prolonged clopidogrel was associated with lower risk of death (interaction p=0.04) and death or MI (interaction p=0.001) only in patients receiving DES (Table). Similar results were seen in multivariable and propensity models. Conclusions: Prolonging clopidogrel more than 12 months after PCI for ACS may lower the risk of death or MI in patients receiving DES but not in patients receiving BMS.

The Large T Antigen (TAg) of polyomaviruses (PyVs) is a helicase required for viral DNA replication and an oncoprotein that stimulates quiescent cells to reenter a proliferative state conducive to viral DNA synthesis. In doing so, TAg engages in multiple protein-protein interactions with host DNA replication and cell-cycle control machineries. To identify which viral-host interaction might be susceptible to competition by a peptidic inhibitor, we scanned the TAg protein with 50-60 amino acid long overlapping peptides for functional dominant-negative inhibitors in our cell-based assay of SV40 DNA replication. This method identified a potent inhibitory peptide derived from the first exon of TAg which bears high sequence homology with the J-domain of the Hsp40/DNAJ co-chaperone family, and is required for viral DNA replication. Studies have found that the J-domain interacts with Hsc70 and stimulates its ATPase/chaperone activity, to release E2F from pRb-containing complexes bound to TAg to promote viral DNA replication and transformation. Characterization of our J-domain inhibitory peptide (aa 2-64) confirmed that it interacts with Hsc70. Mutagenesis of the HPD motif conserved in all known DnaJ homologues, abolished the interaction of the peptide with Hsc70 and its ability to inhibit SV40 DNA replication. Notably, the overexpression of this J-domain peptide could also inhibit viral DNA replication for the clinically relevant human PyVs JCV, BKV and MCV, whose reactivation in immunocompromised patients is associated with the development of progressive multifocal leukencephalopathy, BK-induced nephropathy, and Merkel Cell Carcinoma respectively. Collectively, these results suggest that the J-domain peptide inhibits viral DNA replication by competing with full length TAg for Hsc70 binding. As such, this peptide represents a promising tool to study the function of Hsc70 in PyV DNA replication and to develop therapies for the treatment of PyV-associated diseases including Merkel Cell Carcinoma caused by MCPyV.

BACKGROUND Sinking prebeta lipoprotein is a putative marker for elevated levels of lipoprotein (a). Although prospective data suggest that increased plasma lipoprotein (a) is an independent risk factor for coronary heart disease in men, no prospective studies are available in women. METHODS AND RESULTS From 1968 through 1975, sinking prebeta lipoprotein was determined by paper electrophoresis in 3103 women Framingham Heart Study participants who were free of prevalent cardiovascular disease. A sinking prebeta lipoprotein band was detectable in 434 of the women (14%) studied. The median follow-up interval was approximately 12 years. Incident cardiovascular disease was associated with band presence using a proportional hazards model that included age, smoking, body mass index, systolic blood pressure, glucose intolerance, low- and high-density lipoprotein cholesterol, and ECG left ventricular hypertrophy. Multivariable adjusted relative risk estimates (with 95% confidence intervals) for outcomes in the band present versus absent groups were as follows: myocardial infarction (82 events), 2.37 (1.48 to 3.81); intermittent claudication (62 events), 1.94 (1.07 to 3.50); cerebrovascular disease (83 events), 1.88 (1.12 to 3.15); total coronary heart disease (174 events), 1.61 (1.13 to 2.29); and total cardiovascular disease (305 events), 1.44 (1.09 to 1.91). A subset analysis indicated that band presence was 50.9% sensitive and 95.4% specific for detecting plasma lipoprotein (a) levels of > 30 mg/dL, the threshold value linked to increased cardiovascular disease risk in men. CONCLUSIONS Sinking prebeta lipoprotein was a valid surrogate for elevated lipoprotein (a) levels in Framingham Heart Study women. Band presence and, equivalently, elevated plasma lipoprotein (a), was a strong, independent predictor of myocardial infarction, intermittent claudication, and cerebrovascular disease. Confirmation of these findings in other longitudinal studies of women is needed.

This study sought to determine if individuals with high-normal blood pressure (diastolic blood pressure of 85-89 mm Hg) progress to hypertension more frequently than those with normal blood pressure (diastolic blood pressure less than 85 mm Hg), thus advancing to a higher cardiovascular risk category. Individuals from the Framingham Heart Study were placed in normal and high-normal blood pressure categories and followed for 26 years for the development of hypertension. With hypertension defined as a diastolic blood pressure of 95 mm Hg or greater or the initiation of antihypertensive therapy, 23.6% of men and 36.2% of women with normal blood pressure developed hypertension compared with 54.2% of men and 60.6% of women with high-normal blood pressure. The relative risk for the development of hypertension associated with high-normal blood pressure was 2.25 for men (95% confidence interval [CI], 1.8-2.8; p less than 0.0001) and 1.89 for women (95% CI, 1.5-2.3; p less than 0.0001). The age-adjusted relative risks estimated by the proportional hazards model were 3.36 for men and 3.37 for women (p less than 0.001). Among those risk factors examined, baseline systolic and diastolic blood pressure, Metropolitan relative weight, and change in weight over time were significant predictors of future hypertension in men and women whose initial blood pressure was normal. For men with high-normal blood pressure, systolic blood pressure and change in weight were identified as risk factors for future hypertension. These results indicate that the probability of individuals with blood pressure in the high-normal range developing hypertension is twofold to threefold higher than in those with normal blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)