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Background and Purpose: Low blood pressure (BP) is associated with higher stroke mortality, although the factors underlying this association have not been fully explored. We investigated prestroke BP and long-term mortality after ischemic stroke in a national sample of US veterans. Methods: Using a retrospective cohort study design of veterans hospitalized between 2002 and 2007 with a first ischemic stroke and with ≥1 outpatient BP measurements 1 to 18 months before admission, we defined 6 categories each of average prestroke systolic BP (SBP) and diastolic BP, and 7 categories of pulse pressure. Patients were followed-up to 12 years for primary outcomes of all-cause and cardiovascular mortality. We used Cox models to relate prestroke BP indices to mortality and stratified analyses by the presence of preexisting comorbidities (smoking, myocardial infarction, heart failure, atrial fibrillation/flutter, cancer, and dementia), race and ethnicity. Results: Of 29 690 eligible veterans with stroke (mean±SD age 67±12 years, 98% men, 67% White), 2989 (10%) had average prestroke SBP Conclusions: Compared with normotension, low prestroke BP was associated with mortality after stroke, particularly among patients with at least one comorbidity.

Aims: This study aims to develop the first race‐specific and sex‐specific risk prediction models for heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods and results: We created a cohort of 1.8 million individuals who had an outpatient clinic visit between 2002 and 2007 within the Veterans Affairs (VA) Healthcare System and obtained information on HFpEF, HFrEF, and several risk factors from electronic health records (EHR). Variables were selected for the risk prediction models in a ‘derivation cohort’ that consisted of individuals with baseline date in 2002, 2003, or 2004 using a forward stepwise selection based on a change in C‐index threshold. Discrimination and calibration were assessed in the remaining participants (internal ‘validation cohort’). A total of 66 831 individuals developed HFpEF, and 92 233 developed HFrEF (52 679 and 71 463 in the derivation cohort) over a median of 11.1 years of follow‐up. The HFpEF risk prediction model included age, diabetes, BMI, COPD, previous MI, antihypertensive treatment, SBP, smoking status, atrial fibrillation, and estimated glomerular filtration rate (eGFR), while the HFrEF model additionally included previous CAD. For the HFpEF model, C‐indices were 0.74 (SE = 0.002) for white men, 0.76 (0.005) for black men, 0.79 (0.015) for white women, and 0.77 (0.026) for black women, compared with 0.72 (0.002), 0.72 (0.004), 0.77 (0.017), and 0.75 (0.028), respectively, for the HFrEF model. These risk prediction models were generally well calibrated in each race‐specific and sex‐specific stratum of the validation cohort. Conclusions: Our race‐specific and sex‐specific risk prediction models, which used easily obtainable clinical variables, can be a useful tool to implement preventive strategies or subtype‐specific prevention trials in the nine million users of the VA healthcare system and the general population after external validation.

Introduction: Worsening renal function (WRF) predicts poor prognosis in patients with left ventricular systolic dysfunction. The effect of WRF in heart failure with preserved ejection fraction (HFpEF) is unclear. Objective: The objective of this study was to determine whether WRF during index hospitalization for HFpEF is associated with increased death or readmission for heart failure. Methods: National Veterans Affairs electronic medical data recorded between January 1, 2002, and December 31, 2014, were screened to identify index hospitalizations for HFpEF using an iterative algorithm. Patients were divided into 3 groups based on changes in serum Cr (sCr) during this admission. WRF was defined as a rise in sCr ≥0.3 mg/dL. Group 1 had no evidence of WRF, group 2 had transient WRF, and group 3 had persistent WRF at the time of discharge. Results: A total of 10,902 patients with index hospitalizations for HFpEF were identified (mean age 72, 97% male). Twenty-nine percent had WRF during this hospital admission, with 48% showing recovery of sCr and 52% with no recovery at discharge. The mortality rate over a mean follow-up duration of 3.26 years was 72%. Compared to group 1, groups 2 and 3 showed no significant difference in risk of death from any cause (hazard ratio [HR] = 0.95 [95% confidence interval [CI]: 0.87, 1.03] and 1.02 [95% CI: 0.93, 1.11], respectively), days hospitalized for any cause (incidence density ratio [IDR] = 1.01 [95% CI: 0.92, 1.11] and 1.01 [95% CI: 0.93, 1.11], respectively), or days hospitalized for heart failure (IDR = 0.94 [95% CI: 0.80, 1.10] and 0.94 [95% CI: 0.81, 1.09], respectively) in analyses adjusted for covariates affecting renal function and outcomes. Conclusions: While there is a high incidence of WRF during index hospitalizations for HFpEF, WRF is not associated with an increased risk of death or hospitalization. This suggests that WRF alone should not influence decisions regarding heart failure management.

Background In a real-world setting, the effect of pulse rate measured at the time of diagnosis and serially during follow-up and management, on outcomes in heart failure with reduced ejection fraction (HFrEF), has not been well-studied. Furthermore, how beta-blockade use in a real-world situation modifies this relation between pulse rate and outcomes in HFrEF is not well-known. Hence, we identified a large, national, real-world cohort of HFrEF to examine the association of pulse rate and outcomes. Methods Using Veterans Affairs (VA) national electronic health records we identified incident HFrEF cases between 2006 and 2012. We examined the associations of both baseline and serially measured pulse rates, with mortality and days hospitalized per year for heart failure and for any cause, using crude and multivariable Cox proportional hazards and Poisson or negative binomial models, respectively. The exposure was examined as continuous, dichotomous, and categorical. Post-hoc analyses addressed the interaction of pulse rate and beta-blocker target dose. Results We identified 51,194 incident HFrEF cases (67 ± 12 years, 98% male, 77% white. A significant positive, near linear relationship was observed for both baseline and serially measured pulse rates with all-cause mortality, all-cause hospitalization and heart failure hospitalization after adjusting for covariates including beta-blocker use. Patients who had a pulse rate ≥ 70 bpm in the past 6 months had 36% (95% CI: 31–42%), 25% (95% CI: 19–32%), and 51% (95% CI: 33–72%) increased rates of mortality, all-cause hospitalization, and heart failure hospitalization, respectively, compared to patients with pulse rates Conclusions High pulse rate, both at the time of diagnosis and during follow-up, is strongly associated with increased risk of adverse outcomes in HFrEF patients, independent of the use of beta-blockers. In a real-world setting, the majority of HFrEF patients do not achieve target dose of beta-blockade; greater use of strategies to reduce heart rate may improve outcomes in HFrEF.

BACKGROUND AND AIMS: Observational and clinical trial evidence suggests an inverse association of omega-3 polyunsaturated fatty acid with coronary artery disease (CAD) mortality, although relationships with non-fatal CAD and stroke are less clear. We investigated whether omega-3 fatty acid supplement use and fish intake were associated with incident non-fatal CAD and ischemic stroke among US Veterans. METHODS: The Million Veteran Program (MVP) is an ongoing nation-wide longitudinal cohort study of US Veterans with self-reported survey, biospecimen, and electronic health record data. Regular use of omega-3 supplements (yes/no) and frequency of fish intake within the past year were assessed using a food frequency questionnaire. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of omega-3 supplement use and fish intake with incident non-fatal CAD and ischemic stroke, defined from electronic health records using validated algorithms. Multivariable models included demographics, body mass index, education, smoking status, alcohol intake, and exercise frequency. RESULTS: Among 197,761 participants with food frequency data (mean age: 66 ± 12 years, 92% men), 21% regularly took omega-3 supplements and median fish intake was 1 (3–5 ounce) serving/week. Over a median follow-up of 2.9 years for non-fatal CAD and 3.3 years for non-fatal ischemic stroke, we observed 6,265 and 4,042 incident cases of non-fatal CAD and non-fatal ischemic stroke, respectively. Omega-3 fatty acid supplement use was independently associated with a lower risk of non-fatal ischemic stroke [HR (95% CI): 0.88 (0.81, 0.95)] but not non-fatal CAD [0.99 (0.93, 1.06)]. Fish intake was not independently associated with non-fatal CAD [1.01 (0.94, 1.09) for 1–3 servings/month, 1.03 (0.98, 1.11) for 1 serving/week, 1.02 (0.93, 1.11) for 2–4 servings/week, and 1.15 (0.98, 1.35) for ≥5 servings/week, reference =

Background Early convalescent plasma transfusion may reduce mortality in patients with nonsevere coronavirus disease 2019 (COVID-19). Methods This study emulates a (hypothetical) target trial using observational data from a cohort of US veterans admitted to a Department of Veterans Affairs (VA) facility between 1 May and 17 November 2020 with nonsevere COVID-19. The intervention was convalescent plasma initiated within 2 days of eligibility. Thirty-day mortality was compared using cumulative incidence curves, risk differences, and hazard ratios estimated from pooled logistic models with inverse probability weighting to adjust for confounding. Results Of 11 269 eligible person-trials contributed by 4755 patients, 402 trials were assigned to the convalescent plasma group. Forty and 671 deaths occurred within the plasma and nonplasma groups, respectively. The estimated 30-day mortality risk was 6.5% (95% confidence interval [CI], 4.0%–9.7%) in the plasma group and 6.2% (95% CI, 5.6%–7.0%) in the nonplasma group. The associated risk difference was 0.30% (95% CI, −2.30% to 3.60%) and the hazard ratio was 1.04 (95% CI, .64–1.62). Conclusions Our target trial emulation estimated no meaningful differences in 30-day mortality between nonsevere COVID-19 patients treated and untreated with convalescent plasma. Clinical Trials Registration. NCT04545047., This study used electronic health record data to emulate a target trial of early COVID-19 convalescent plasma and 30-day mortality risk. No differences in mortality risk were found between patients with nonsevere COVID-19 who were treated and untreated with plasma.

Background The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death. Methods and results We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30–0.76) and 0.59 (0.31–1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32–1.77) and 1.63 (1.32–2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20–24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality. Conclusions Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted.

We thank May et al for their comments, expanding the number of reported cases of suspected and confirmed heparin‐induced thrombocytopenia (HIT) associated with COVID‐19, and reemphasizing the complexity of the prothrombotic state observed (1). We agree that false‐positive enzyme immunoassay (EIA) detection of anti‐platelet factor 4 (PF4)/heparin antibodies could explain the results we observed in patients #2 and #3 (2), and this has been the conventional interpretation when functional testing (such as the serotonin‐release assay [SRA]) returns negative. We suggested that a false negative SRA result could have explained our findings, as opposed to the contention by May et al that we concluded they were falsely positive, to broaden our discussion about SRA‐negative HIT, a relatively new and evolving clinical condition (3‐6).

Early reports of coronavirus disease 2019 (COVID‐19) clinical features describe a hypercoagulable state, and recent guidelines recommend prophylactic anticoagulation for patients with COVID‐19 with low‐molecular‐weight heparin, but this would be contraindicated in the presence of heparin‐induced thrombocytopenia (HIT). We address the key clinical question whether HIT is also present during COVID‐19. We report 3 cases of thrombocytopenia with antiplatelet factor 4 antibodies among 16 intubated patients with COVID‐19 with adult respiratory distress syndrome, a higher‐than‐expected incidence of 19%. Each patient had evidence of thrombosis (pulmonary embolism, upper extremity venous thromboses, and skin necrosis, respectively). The serotonin release assay confirmed HIT in 1 case, and 2 cases were negative. We believe this is the first reported case of HIT during the COVID‐19 pandemic. Recognition that the thrombocytopenia represented HIT in the confirmed case was delayed. We recommend clinicians monitor platelet counts closely during heparin therapy, with a low threshold to evaluate for HIT.

Potato consumption is highly prevalent around the world. Previous studies have reported a positive association of potato intake with hypertension and type 2 diabetes. However, data are scarce on potato consumption and risk of coronary artery disease (CAD).We hypothesized that potato consumption is positively associated with the incidence of CAD among US veterans.We prospectively studied 148,671 participants from Million Veteran Program (MVP). We used a semi-quantitative 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 hazard ratios (HR) and 95% confidence intervals (95% CI) for CAD events across categories of potato intake.The average age of participants was 64 years at the time of potato assessment. A total of 6309 new cases of CAD occurred during a 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 category of potato consumption was 14.5, 15.0, 15.2, 16.1, and 18.9 per 1000 person-years, respectively. Hazard ratios (95% CI) of CAD were 1.00 (reference), 1.02 (0.93-1.11), 1.02 (0.93-1.12), 1.04 (0.95-1.15), and 1.21 (1.07-1.37) for potato intake of1 cup/month, 1-3 cups/month, 1 cup/week, 2-4 cups/week, and 5+ cups/week respectively, adjusting for age, gender, race, body mass index (BMI), alcohol consumption, exercise, smoking, DASH (Dietary Approaches to Stop Hypertension) score, and education. The observed relation of potato consumption with CAD was not modified by age, BMI, gender, and ethnicity in a secondary analysis. In a sensitivity analysis, exclusion of CAD events occurred during the first year of follow up did not alter the findings.Frequent (5+ cups/week) but not infrequent potato consumption was associated with a higher risk of CAD among MVP participants.

Amantadine and modafinil are neurostimulants that may improve cognitive and functional recovery post-stroke, but the existing study results vary, and no comprehensive review has been published. This systematic review describes amantadine and modafinil administration practices post-stroke, evaluates timing and impact on clinical effectiveness measures, and identifies the incidence of potential adverse drug effects. A librarian-assisted search of the MEDLINE (PubMed) and EMBASE databases identified all English-language publications with “amantadine” or “modafinil” in the title or abstract from inception through February 1, 2020. Publications meeting predefined Patient, Intervention, Comparator, Outcome (PICO) criteria were included: Patients (≥ 18 years of age post-stroke); Intervention (amantadine or modafinil administration); Comparison (pretreatment baseline or control group); Outcomes (cognitive or functional outcome). Amantadine and modafinil administration practices, cognitive and functional outcomes, and incidence of potential adverse drug effects were collected following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance. Quantitative analyses were not performed due to heterogeneity in the clinical effectiveness measures; descriptive data are presented as number (percent) or median (interquartile range). Of 12,620 publications initially identified, 10 amantadine publications (n = 121 patients) and 12 modafinil publications (n = 120 patients) were included. Amantadine was initiated 39 (16, 385) days post-stroke, with most common initial doses of 100 mg once or twice daily (range 100–200 mg/day), and final daily dose of 200 (188, 200) mg/day. Modafinil was initiated 170 (17, 496) days post-stroke, with initial and final daily doses of 100 (100, 350) mg/day and 200 (100, 350) mg/day, respectively. The most common indication was consciousness disorders for amantadine (n = 3/10 publications; 30%) and fatigue for modafinil (n = 5/12; 42%). Forty unique clinical effectiveness measures (1.8 per study) with 141 domains (6.4 per study) were described across all studies. A positive response in at least one clinical effectiveness measure was reported in 70% of amantadine publications and 83% of modafinil publications. Only one publication each for amantadine (10%; n = 5 patients) and modafinil (8%; n = 21 patients) studied acutely hospitalized or ICU patients; both were randomized studies showing improvements in neurocognitive function for amantadine and fatigue for modafinil. Potential adverse drug effects were reported in approximately 50% of publications, most commonly visual hallucinations with amantadine (2% of patients) and dizziness (5% of patients) and dry eyes or mouth (5% of patients). Amantadine and modafinil may improve cognitive and functional recovery post-stroke, but higher-quality data are needed to confirm this conclusion, especially in the acute care setting.

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: 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.

Saphenous vein grafts (SVGs) remain the most often used conduits for coronary bypass grafting (CABG). Progressive intimal hyperplasia contributes to vein-graft disease and vein-graft failure (VGF). We compared the impact of intraoperative preservation of SVGs in a storage solution (DuraGraft®) versus heparinized saline on VGF-related outcomes after CABG.From 1996 to 2004, 2436 patients underwent isolated CABG with ≥ 1 SVG. SVGs were consecutively treated with DuraGraft in 1036 patients (2001-2004) and heparinized saline in 1400 patients (1996-1999). Short- ( 30 days) and long-term (≥ 1000 days) outcomes were assessed using repeat revascularization (primary end point), and major adverse cardiac events (MACE) consisting of the composite of death, nonfatal myocardial infarction, or repeat revascularization.Mean follow-up in the DuraGraft group was 8.5 ± 4.2 years and 9.9 ± 5.6 years in controls. Short-term event rates were low and generally did not differ between groups. DuraGraft was associated with a 45% lower occurrence of nonfatal myocardial infarction after 1000 days (hazard ratio 0.55, 95% CI 0.41-0.74; P 0.0001). There was 35% and 19% lower long-term risk for revascularization (HR 0.65, 95% CI 0.44-0.97; P = 0.037) and MACE (HR 0.81, 95% CI 0.70-0.94; P = 0.0051), respectively, after DuraGraft. Mortality was comparable between both groups at 1, 5, and 10 years. There was no statistically significant association between DuraGraft exposure and time to death starting at 30 or 1000 days (HR 0.91, 95% CI 0.76-1.09; P = 0.29).In this study, intraoperative treatment of SVGs with DuraGraft was associated with a lower risk of long-term adverse events suggesting that efficient intraoperative SVG treatment may reduce VGF-related complications post-CABG. These data warrant randomized clinical trials to validate these findings.

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Background Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood–brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions. Methods A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting. Results Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis. Conclusions Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.

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

STUDY DESIGN Observational study. OBJECTIVE Assess associations between vitamin D levels and other risk factors on future chest illness in a chronic spinal cord injury (SCI) cohort. SETTING Veterans Affairs Boston and the Boston, MA community. METHODS Between August 2009 and August 2017, 253 participants with chronic SCI were followed over a median of 3.2 years (up to 7.4 years) with two to four visits a median of 1.7 years apart. At each visit, plasma 25-hydroxyvitamin D level was obtained, spirometry performed, and a respiratory questionnaire assessing chest illnesses since last visit was completed. Repeated measures negative binomial regression was used to assess chest illness risk longitudinally. RESULTS At entry, 25% had deficient vitamin D levels (

Background Technology-based physical activity (PA) interventions have been shown to improve daily step counts and health-related quality of life, but their effect on long-term clinical outcomes like acute exacerbations (AEs) is unknown in persons with COPD. Methods U.S. Veterans with stable COPD were randomized (1:1) to either pedometer alone (control) or pedometer plus a website with feedback, goal-setting, disease education, and a community forum (intervention) for 3 months. AEs were assessed every 3 months over a follow-up period of approximately 15 months. Pedometer-assessed daily step counts, health-related quality-of-life (HRQL), and self-efficacy were assessed at baseline, end-of-intervention at 3 months, and during follow-up approximately 6 and 12 months after enrollment. Zero-inflated Poisson models assessed the effect of the intervention on risk for AEs, compared to controls. Generalized linear mixed-effects models for repeated measures examined between-group and within-group changes in daily step count, HRQL, and self-efficacy. Results There were no significant differences in age, FEV1% predicted, baseline daily step count, AEs the year prior to enrollment, or duration of follow-up between the intervention (n = 57) and control (n = 52) groups. The intervention group had a significantly reduced risk of AEs (rate ratio = 0.51, [95%CI 0.31–0.85]), compared to the control group. There were no significant between-group differences in change in average daily step count, HRQL, or self-efficacy at 6 and 12 months after enrollment. Conclusions A 3-month internet-mediated, pedometer-based PA intervention was associated with reduced risk for AEs of COPD over 12–15 months of follow-up. ClinicalTrials.gov identifier: NCT01772082.

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.

OBJECTIVE Guidelines for hypertension treatment in patients with diabetes diverge regarding the systolic blood pressure (SBP) threshold at which treatment should be initiated and treatment goal. We examined associations of early SBP treatment with atherosclerotic cardiovascular disease (ASCVD) events in U.S. adults with diabetes. RESEARCH DESIGN AND METHODS We studied 43,986 patients with diabetes who newly initiated antihypertensive therapy between 2002 and 2007. Patients were classified into categories based on SBP at treatment initiation (130–139 or ≥140 mmHg) and after 2 years of treatment (100–119, 120–129, 130–139, 140–159, and ≥160 mmHg). The primary outcome was composite ASCVD events (fatal and nonfatal myocardial infarction and stroke), estimated using inverse probability of treatment-weighted Poisson regression and multivariable Cox proportional hazards regression. RESULTS Relative to individuals who initiated treatment when SBP was 130–139 mmHg, those with pretreatment SBP ≥140 mmHg had higher ASCVD risk (hazard ratio 1.10 [95% CI 1.02, 1.19]). Relative to those with pretreatment SBP of 130–139 mmHg and on-treatment SBP of 120–129 mmHg (reference group), ASCVD incidence was higher in those with pretreatment SBP ≥140 mmHg and on-treatment SBP 120–129 mmHg (adjusted incidence rate difference [IRD] 1.0 [−0.2 to 2.1] events/1,000 person-years) and in those who achieved on-treatment SBP 130–139 mmHg (IRD 1.9 [0.6, 3.2] and 1.1 [0.04, 2.2] events/1,000 person-years for those with pretreatment SBP 130–139 mmHg and ≥140 mmHg, respectively). CONCLUSIONS In this observational study, patients with diabetes initiating antihypertensive therapy when SBP was 130–139 mmHg and those achieving on-treatment SBP

Estimating ASCVD risk in patients with diabetes could guide intensity of risk factor treatment, but existing risk calculators (2013 ACC/AHA ASCVD pooled cohort equations [PCE] and RECODe risk equations [RECODe]) have not been evaluated in a contemporary American population with diabetes. Using validated phenotyping algorithms, we evaluated prediction models for the development of a composite “hard” ASCVD outcome (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) over 5 years in 184,823 diabetic U.S. Veterans without baseline ASCVD receiving primary care in the VA 2002-2007 (2.4% women, 19.5% black, mean age 61 years, 9851 ASCVD events). We compared discrimination using the C-statistic and calibration using the Greenwood-Nam-D’Agostino test (GND) of the PCE variables (sex, age, race, cholesterol, blood pressure [BP], smoking status, BP medications, statin treatment, and aspirin), RECODe, and a series of models using PCE variables with VA sample-specific coefficients. Models with PCE variables and VA-specific coefficients had better discrimination (C=0.642) than the PCE (C=0.582) or RECODe (C=0.633). Successive addition of hemoglobin A1c, estimated glomerular filtration rate, diabetes medications, and statin therapy improved the model (full model, C=0.669), with only minimal enhancement by semisupervised variable selection using LASSO (C=0.672). The C-statistic of the full model was similar in those Conclusion: Health system-specific tailoring of prediction equations provides improved discrimination and calibration compared to existing models. This risk predictor could be embedded in the electronic health record and used to guide intensification of treatment aimed to improve ASCVD outcomes. Disclosure S. Raghavan: None. Y. Ho: None. D. Posner: None. J.L. Vassy: None. D.R. Gagnon: None. L.S. Phillips: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AbbVie Inc., GlaxoSmithKline plc., Kowa Pharmaceutical Europe Co. Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc. Stock/Shareholder; Self; Diasyst Inc. Other Relationship; Self; Diasyst Inc., Janssen Pharmaceuticals, Inc. P.W. Wilson: None. Funding U.S. Department of Veterans Affairs; American Heart Association

Use of insulin or sulfonylureas (SU) carries a risk of hypoglycemia, but the risk with different diabetes therapies, such as premixed insulin, is not well known. We conducted a case-control analysis of 297,263 patients with DIAB and 487,226 NONDIAB in the national VA database who had ≥4 primary care visits, ≥1 A1c, and ≥3 outpatient random plasma glucoses (RPG) in 2002-2003, and examined hypoglycemia by diabetic medication use and other risk factors, through 2012. Hypoglycemia was defined as severe (Emergency Department visit with hypoglycemia [EDHypo]) and by outpatient lab (RPGHypo = RPG Conclusions: Clinically significant hypoglycemia, including both outpatient RPG Disclosure S.C. Markley Webster: Stock/Shareholder; Self; Dexcom, Inc. K.E. Kurgansky: None. L.S. Phillips: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AbbVie Inc., GlaxoSmithKline plc., Kowa Pharmaceutical Europe Co. Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc. Stock/Shareholder; Self; Diasyst Inc. Other Relationship; Self; Diasyst Inc., Janssen Pharmaceuticals, Inc. D.R. Gagnon: None. P.W. Wilson: None. M.K. Rhee: None. Funding Million Veteran Program

Objective The purpose of our study is to examine whether serial measurements of serum sodium values after diagnosis identify a higher-risk subset of patients with heart failure with preserved ejection fraction. Methods We identified 50,932 subjects with HFpEF with 759,577 recorded sNa measurements (mean age 72 ± 11 years) using a validated algorithm in the VA national database from 2002 to 2012. We examined the association of repeated measures of sNa with mortality using a multivariable Cox proportional hazards model. Results After a median follow-up of 2.9 years (IQR: 1.2–5.4), 19,011 deaths occurred. After adjusting for age, sex, race, BMI, glomerular filtration rate, potassium, coronary artery disease, hypertension, hyperlipidemia, atrial fibrillation, pulmonary disease, diabetes, anemia, and medications, we found J-shaped associations of serum sodium with mortality. HRs for all-cause mortality were 2.48 (95% CI: 2.38–2.60) for the sNA 115.00–133.99 category; and 1.40 (95% CI: 1.35–1.46) for the sNA 143.00–175.00 category compared to the 137.01–140.99 category (ref). We used generalized estimating equation-based negative binomial regression to compute the incidence density ratios (IDR) to examine days hospitalized for heart failure and for all causes. There were a total of 1,275,614 days of all-cause hospitalization and 104,006 days of heart-failure hospitalization. The IDRs for the lowest sNA group were 2.03 (95% CI: 1.90–2.18) for all-cause hospitalization and 1.73 (95% CI: 1.39–2.16) for heart-failure hospitalization. Conclusions Our findings suggest that monitoring of serum sodium values during longitudinal follow-up can identify HFpEF patients at risk of adverse outcomes.

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: 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.

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.

AIMS: While some but not all trial data have suggested an elevated risk of type 2 diabetes with statin use, limited data are available on the relation of statin treatment with glycaemia and risk of type 2 diabetes among Veterans. We examined whether statin use was associated with a higher incidence of type 2 diabetes and secondarily, if statin use was associated with high plasma glucose. METHODS: Prospective analysis based on electronic health records of 3,390,799 US Veterans from 2000 to 2012. We used the Veteran Administration Corporate Data Warehouse to obtain information on random plasma glucose. Statin use was captured using the pharmacy database. type 2 diabetes was defined as having at least one inpatient diagnosis or at least two outpatient diagnoses of type 2 diabetes using International Classification of Disease version 9 codes 250.xx, or the use of hypoglycemic agents. We used multi-level derived propensity score and inverse probability weighting to address confounding by indication and Cox regression to estimate relative risk of type 2 diabetes. RESULTS: The mean age was 62±11.9 years; 93.3% were men and 82.7% were white. During a median follow-up of 3.0 years, 443,104 new cases of type 2 diabetes occurred. Compared to no statin use, multivariable adjusted hazard ratio (95% CI) for type 2 diabetes was 1.21 (1.19–1.24) for low statin potency, 1.22 (1.21–1.23) for medium statin potency, and 1.34 (1.32–1.36) for high statin potency (p linear trend

Background Diabetes mellitus is a risk factor for cardiovascular disease (CVD) and has been associated with 2‐ to 4‐fold higher mortality. Diabetes mellitus–related mortality has not been reassessed in individuals receiving routine care in the United States in the contemporary era of CVD risk reduction. Methods and Results We retrospectively studied 963 648 adults receiving care in the US Veterans Affairs Healthcare System from 2002 to 2014; mean follow‐up was 8 years. We estimated associations of diabetes mellitus status and hemoglobin A1c (HbA1c) with all‐cause and CVD mortality using covariate‐adjusted incidence rates and multivariable Cox proportional hazards regression. Of participants, 34% had diabetes mellitus. Compared with nondiabetic individuals, patients with diabetes mellitus had 7.0 (95% CI, 6.7–7.4) and 3.5 (95% CI, 3.3–3.7) deaths/1000‐person‐years higher all‐cause and CVD mortality, respectively. The age‐, sex‐, race‐, and ethnicity‐adjusted hazard ratio for diabetes mellitus–related mortality was 1.29 (95% CI, 1.28–1.31), and declined with adjustment for CVD risk factors (hazard ratio, 1.18 [95% CI, 1.16–1.19]) and glycemia (hazard ratio, 1.03 [95% CI, 1.02–1.05]). Among individuals with diabetes mellitus, CVD mortality increased as HbA1c exceeded 7% (hazard ratios, 1.11 [95% CI, 1.08–1.14], 1.25 [95% CI, 1.22–1.29], and 1.52 [95% CI, 1.48–1.56] for HbA1c 7%–7.9%, 8%–8.9%, and ≥9%, respectively, relative to HbA1c 6%–6.9%). HbA1c 6% to 6.9% was associated with the lowest mortality risk irrespective of CVD history or age. Conclusions Diabetes mellitus remains significantly associated with all‐cause and CVD mortality, although diabetes mellitus–related excess mortality is lower in the contemporary era than previously. We observed a gradient of mortality risk with increasing HbA1c >6% to 6.9%, suggesting HbA1c remains an informative predictor of outcomes even if causality cannot be inferred., See Editorial by Aguilar

Objectives To assess the impact of stent type on the risk of death or myocardial infarction (MI) related to dual antiplatelet therapy (DAPT) more than 12 months (prolonged DAPT) versus 12 or less months after PCI for an acute coronary syndrome (ACS). Background The recent DAPT study reported lower recurrent ischemic events from prolonged DAPT in patients treated with PCI for an ACS, but was underpowered to determine the impact of stent type. Methods We determined clinical outcomes after PCI for an ACS (median follow-up: DES = 26 months, BMS = 46 months) in 18,484 patients in the Veterans Affairs system treated with first generation drug-eluting stents (DES) or bare-metal stents (BMS). We used landmark analyses starting 1 year after the index PCI to assess the risk of prolonged DAPT on the primary endpoint of death or MI. Multivariable and propensity models adjusted for confounding. Results There was a significant interaction between stent type and prolonged DAPT for death and MI (P = 0.0036), death (P = 0.054), and major bleeding (P = 0.0013). Patients treated with prolonged DAPT had lower risks of death or MI (HR = 0.71, 95% CI = 0.61, 0.82) and death (HR = 0.74, 95%CI = 0.62, 0.89) with DES, but not BMS, and higher risks of major bleeding, particularly with BMS (HR = 1.67, P

Key Points Question Are current risk prediction models accurate at estimating risk of initial atherosclerotic cardiovascular (ASCVD) events in veterans? Findings In this cohort study of 1 672 336 veterans with an outpatient visit between 2002 and 2007, the 2013 American College of Cardiology/American Heart Association model overestimated absolute risk of ASCVD during 5 years of follow-up. Statin use was associated with 7% lower relative risk of ASCVD and 25% lower relative risk of ASCVD mortality. Meaning The findings of this study suggest that reestimation and the inclusion of statin use in ASCVD prediction models might be needed for their appropriate use in a health care system., This cohort study examines the performance of the Pooled Cohort Equations (PCE) for 5-year atherosclerotic cardiovascular disease risk estimation in a contemporary cohort and tests the hypothesis that inclusion of statin therapy improves model performance., Importance Current guidelines recommend statin therapy for millions of US residents for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). It is unclear whether traditional prediction models that do not account for current widespread statin use are sufficient for risk assessment. Objectives To examine the performance of the Pooled Cohort Equations (PCE) for 5-year ASCVD risk estimation in a contemporary cohort and to test the hypothesis that inclusion of statin therapy improves model performance. Design, Setting, and Participants This cohort study included adult patients in the Veterans Affairs health care system without baseline ASCVD. Using national electronic health record data, 3 Cox proportional hazards models were developed to estimate 5-year ASCVD risk, as follows: the variables and published β coefficients from the PCE (model 1), the PCE variables with cohort-derived β coefficients (model 2), and model 2 plus baseline statin use (model 3). Data were collected from January 2002 to December 2012 and analyzed from June 2016 to March 2020. Exposures Traditional ASCVD risk factors from the PCE plus baseline statin use. Main Outcomes and Measures Incident ASCVD and ASCVD mortality. Results Of 1 672 336 patients in the cohort (mean [SD] baseline age 58.0 [13.8] years, 1 575 163 [94.2%] men, 1 383 993 [82.8%] white), 312 155 (18.7%) were receiving statin therapy at baseline. During 5 years of follow-up, 66 605 (4.0%) experienced an ASCVD event, and 31 878 (1.9%) experienced ASCVD death. Compared with the original PCE, the cohort-derived model did not improve model discrimination in any of the 4 age-sex strata but did improve model calibration. The PCE overestimated ASCVD risk compared with the cohort-derived model; 211 237 of 1 136 161 white men (18.6%), 29 634 of 218 463 black men (13.6%), 1741 of 44 399 white women (3.9%), and 836 of 16 034 black women (5.2%) would be potentially eligible for statin therapy under the PCE but not the cohort-derived model. When added to the cohort-derived model, baseline statin therapy was associated with a 7% (95% CI, 5%-9%) lower relative risk of ASCVD and a 25% (95% CI, 23%-28%) lower relative risk for ASCVD death. Conclusions and Relevance In this study, lower than expected rates of incident ASCVD events in a contemporary national cohort were observed. The PCE overestimated ASCVD risk, and more than 15% of patients would be potentially eligible for statin therapy based on the PCE but not on a cohort-derived model. In the statin era, health care professionals and systems should base ASCVD risk assessment on models calibrated to their patient populations.

Aims/hypothesisEarly recognition of those at high risk for diabetes as well as diabetes itself can permit preventive management, but many Americans with diabetes are undiagnosed. We sought to determine whether routinely available outpatient random plasma glucose (RPG) would be useful to facilitate the diagnosis of diabetes.MethodsRetrospective cohort study of 942,446 U.S. Veterans without diagnosed diabetes, ≥3 RPG in a baseline year, and ≥1 primary care visit/year during 5-year follow-up. The primary outcome was incident diabetes (defined by diagnostic codes and outpatient prescription of a diabetes drug).ResultsOver 5 years, 94,599 were diagnosed with diabetes [DIAB] while 847,847 were not [NONDIAB]. Baseline demographics of DIAB and NONDIAB were clinically similar, except DIAB had higher BMI (32 vs. 28 kg/m2) and RPG (150 vs. 107 mg/dl), and were more likely to have Black race (18% vs. 15%), all pConclusionsRPG levels below the diabetes "diagnostic" range (≥200 mg/dl) provide good discrimination for follow-up diagnosis. Use of such levels-obtained opportunistically, during outpatient visits-could signal the need for further testing, allow preventive intervention in high risk individuals before onset of disease, and lead to earlier identification of diabetes.

Revascularization is recommended for patients with ischemic cardiomyopathy. However, the magnitude of revascularization-associated ejection fraction (EF) change and its relations to subsequent outcomes are unclear. In 16,490 veterans who underwent a 1st percutaneous coronary intervention (PCI) or

IMPORTANCE: Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene–drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade. OBJECTIVE: To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center. EXPOSURES: IL6R SNPs (rs2228145; rs4129267). MAIN OUTCOMES AND MEASURES: Phenotypes defined by International Classification of Diseases, Ninth Revision codes. RESULTS: Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank. CONCLUSIONS AND RELEVANCE: In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

Better diabetes control generally reduces development of complications, but those with HbA1c Conclusion: Hypoglycemia-associated CVD mortality occurs in general clinical practice-especially with outpatient glucose Disclosure M. Rhee: None. K.E. Kurgansky: None. Y. Ho: None. D.R. Gagnon: None. S. Raghavan: None. J.L. Vassy: None. K. Cho: None. A. Gonzalez: None. F.N. Khan: None. L.R. Staimez: None. C.N. Ford: None. P.W. Wilson: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..

Recent clinical trials have led to revised hypertension guidelines, but the relationship between blood pressure (BP) control and mortality in diabetes patients receiving routine care has not been described in a contemporary national U.S. cohort. We studied 130,192 primary care patients in the Veterans Health Administration with diabetes (ICD-9 codes 250.xx + outpatient diabetes prescription), newly started on a BP medication in 2003-2005, and with a mean systolic BP (SBP) >130 mmHg in the year prior to BP drug initiation. Mean on-treatment outpatient SBP in the 2nd year after BP drug initiation was the primary exposure. All-cause and cardiovascular (CV) mortality through 2014 were the primary outcomes; mean follow-up was 9 years. We estimated associations between SBP and mortality using multivariable Cox proportional hazards regression, adjusting for age, sex, race, comorbidities, HbA1c, number of BP drugs, and CV risk factors. Relative to SBP 121-130 mmHg, all-cause and CV mortality were significantly higher in those with an SBP of 100-120 mmHg or >160 mmHg on treatment. All-cause mortality was lowest in those with an SBP of 131-140 mmHg; CV mortality did not differ significantly between those with an SBP between 121 and 160 mmHg. Conclusions: There was only minor variation in mortality rates for BPs from 121 to 160 mmHg in patients with diabetes and hypertension in routine clinical care, but mortality was higher in those with treated BP 160 mmHg. Disclosure S. Raghavan: None. Y. Ho: None. M. Rhee: None. J.L. Vassy: None. D.R. Gagnon: None. K. Cho: None. P.W. Wilson: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..

Background Heart failure (HF) with preserved ejection fraction (HFpEF) comprises nearly half of prevalent HF, yet is challenging to curate in a large database of electronic medical records (EMR) since it requires both accurate HF diagnosis and left ventricular ejection fraction (EF) values to be consistently ≥50%. Methods We used the national Veterans Affairs EMR to curate a cohort of HFpEF patients from 2002 to 2014. EF values were extracted from clinical documents utilizing natural language processing and an iterative approach was used to refine the algorithm for verification of clinical HFpEF. The final algorithm utilized the following inclusion criteria: any International Classification of Diseases-9 (ICD-9) code of HF (428.xx); all recorded EF ≥50%; and either B-type natriuretic peptide (BNP) or aminoterminal pro-BNP (NT-proBNP) values recorded OR diuretic use within one month of diagnosis of HF. Validation of the algorithm was performed by 3 independent reviewers doing manual chart review of 100 HFpEF cases and 100 controls. Results We established a HFpEF cohort of 80,248 patients (out of a total 1,155,376 patients with the ICD-9 diagnosis of HF). Mean age was 72 years; 96% were males and 12% were African-Americans. Validation analysis of the HFpEF algorithm had a sensitivity of 88%, specificity of 96%, positive predictive value of 96%, and a negative predictive value of 87% to identify HFpEF cases. Conclusion We developed a sensitive, highly specific algorithm for detecting HFpEF in a large national database. This approach may be applicable to other large EMR databases to identify HFpEF patients.

Background The purpose of this study was to evaluate the relationship between serum sodium at the time of diagnosis and long term clinical outcomes in a large national cohort of patients with heart failure with preserved ejection fraction. Methods and Results We studied 25 440 patients with heart failure with preserved ejection fraction treated at Veterans Affairs medical centers across the United States between 2002 and 2012. Serum sodium at the time of heart failure diagnosis was analyzed as a continuous variable and in categories as follows: low (115.00–134.99 mmol/L), low‐normal (135.00–137.99 mmol/L), referent group (138.00–140.99 mmol/L), high normal (141.00–143.99 mmol/L), and high (144.00–160.00 mmol/L). Multivariable Cox regression and negative binomial regression were performed to estimate hazard ratios (95% confidence interval [CI]) and incidence density ratios (95% CI ) for the associations of serum sodium with mortality and hospitalizations (heart failure and all‐cause), respectively. The average age of patients was 70.8 years, 96.2% were male, and 14% were black. Compared with the referent group, low, low‐normal, and high sodium values were associated with 36% (95% CI , 28%–44%), 6% (95% CI, 1%–12%), and 9% (95% CI, 1%–17%) higher risk of all‐cause mortality, respectively. Low and low‐normal serum sodium were associated with 48% (95% CI , 10%–100%) and 38% (95% CI, 8%–77%) higher risk of number of days of heart failure hospitalizations per year, and with 44% (95% CI , 32%–56%) and 18% (95% CI, 10%–27%) higher risk of number of days of all‐cause hospitalizations per year, respectively. Conclusions Both elevated and reduced serum sodium, including values currently considered within normal range, are associated with adverse outcomes in patients with heart failure with preserved ejection fraction.

Background While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. Methods and Results We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow‐up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow‐up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person‐years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84–0.99), 0.87 (0.80–0.95), 0.86 (0.79–0.94), and 0.80 (0.73–0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use ( P linear trend, Conclusions Our data are consistent with an inverse association between Dietary Approach to Stop Hypertension diet score and incidence of CAD among US veterans.

No data exist on the prevalence of ideal cardiovascular health metrics in a national sample of U.S. veterans. We assessed the prevalence of ideal Life's Simple Seven (LSS) metrics in a cross-sectional study of 554,855 U.S. veterans enrolled in the Million Veteran Program (MVP) from 2011 to 2017. We used the American Heart Association's established criteria to categorize each LSS metric as either poor, intermediate, or ideal for a veteran at time of MVP enrollment. Information on adiposity/body mass index, smoking status, diet, and physical activity was obtained from self-reported survey data, and clinical measurements for total cholesterol, blood pressure, and plasma glucose were obtained from electronic health records. Complete data on all LSS health factors were available for 201,745 veterans. The prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal cardiovascular health metrics was 29.2%, 34.6%, 22.6%, 10.0%, 3.0%, 0.6%

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: The association between posttraumatic stress disorder (PTSD) and mortality in patients undergoing implantable cardioverter‐defibrillator (ICD) placement has not been evaluated in US veterans. HYPOTHESIS: PTSD in veterans with ICD is associated with increased mortality. METHODS: We studied a retrospective cohort of 25 678 veterans who underwent ICD implantation between September 30, 2002, and December 31, 2011. Of these subjects, 3280 carried the diagnosis of PTSD prior to ICD implantation. Primary outcome was all‐cause mortality between date of ICD implantation and end of follow‐up (September 30, 2013). We used Cox proportional hazard models to compute multivariable adjusted hazard ratios with corresponding 95% confidence intervals for the relation between PTSD diagnosis and death following ICD placement. RESULTS: During a mean follow‐up of 4.21 ± 2.62 years, 11 015 deaths were reported. The crude incidence rate of death was 87.8 and 103.9/1000 person‐years for people with and without PTSD, respectively. We did not find an association between presence of PTSD before or after ICD implantation and incident death when adjusted for multiple risk factors (hazard ratio: 1.003, 95% confidence interval: 0.948–1.061). In secondary analysis, no statistically significant association was found. CONCLUSIONS: In this retrospective cohort study among more than 25 000 veterans undergoing ICD implantation, almost 13% had a diagnosis of PTSD. Subjects with PTSD were significantly younger, yet they had a higher incidence of coronary heart disease, major cardiac comorbidities, cancer, and mental health conditions. We found no association between presence of PTSD before or after ICD implantation and incident death when adjusting for all covariates.

Article, see p 1193 The article by Pagidipati et al1 in this issue of Circulation reports the implications of inadequate risk factor treatment and control in adults with type 2 diabetes mellitus (T2DM) enrolled in a large multinational clinical trial that evaluated the cardiovascular disease (CVD) safety of an oral dipeptidyl peptidase-4 inhibitor medication that lowers blood glucose. In this post hoc analysis, the authors assessed at baseline the risk factor control for aspirin use, smoking, blood pressure

OBJECTIVE Rigorous evidence is lacking whether online games can improve patients’ longer-term health outcomes. We investigated whether an online team-based game delivering diabetes self-management education (DSME) to patients via e-mail or mobile application (app) can generate longer-term improvements in hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS Patients (n = 456) on oral diabetes medications with HbA1c ≥58 mmol/mol were randomly assigned between a DSME game (with a civics booklet) and a civics game (with a DSME booklet). The 6-month games sent two questions twice weekly via e-mail or mobile app. Participants accrued points based on performance, with scores posted on leaderboards. Winning teams and individuals received modest financial rewards. Our primary outcome measure was HbA1c change over 12 months. RESULTS DSME game patients had significantly greater HbA1c reductions over 12 months than civics game patients (−8 mmol/mol [95% CI −10 to −7] and −5 mmol/mol [95% CI −7 to −3], respectively; P = 0.048). HbA1c reductions were greater among patients with baseline HbA1c >75 mmol/mol: −16 mmol/mol [95% CI −21 to −12] and −9 mmol/mol [95% CI −14 to −5] for DSME and civics game patients, respectively; P = 0.031. CONCLUSIONS Patients with diabetes who were randomized to an online game delivering DSME demonstrated sustained and meaningful HbA1c improvements. Among patients with poorly controlled diabetes, the DSME game reduced HbA1c by a magnitude comparable to starting a new diabetes medication. Online games may be a scalable approach to improve outcomes among geographically dispersed patients with diabetes and other chronic diseases.

tudy Objective The free fraction of valproate (the pharmacologically active moiety, normally 5–10%) may vary significantly in critically ill patients, but this topic is understudied, with only four prior intensive care unit (ICU) case reports. The objective of this study was to evaluate the range of valproate plasma protein binding in ICU patients. Design Observational study of consecutive ICU patients. Setting Neurocritical and medical critical care services in a nonuniversity academic medical center. Patients Consecutive ICU patients treated with valproate with serum albumin less than 4 g/dl. Measurements and Main Results Simultaneous total and free trough serum valproate concentrations were measured as were serum creatinine, blood urea nitrogen, albumin, platelets, and transaminase values. The reference concentration range was 50–125 mg/L (total) and 5–17 mg/L (free). Valproate concentrations were categorized as within reference range, low, or high, and as concordant if both concentrations were in the same category. Data are reported as median (interquartile range). Fifteen patients (nine men) were evaluated. The median age was 63 (34–70) years. The valproate dose was 3 g/day (35 mg/kg/day). No patient had a valproate free fraction of 5–10%; the median was 48%, and the range was 15–89%. Total and free concentrations showed poor correlation (0.43) and were concordant in only two patients (both in the reference range). Free valproate concentration was poorly predicted by an equation correcting for albumin (r = 0.45). Suspected adverse drug events occurred in 10 patients: hyperammonemia in 7 of 12 tested (58%), elevated transaminases in 2 of 15 (13%), and thrombocytopenia in 5 of 15 (33%). Conclusions Protein binding of valproate was highly inconsistent in this cohort of ICU patients, and total valproate concentrations did not predict free concentrations, even when correcting for albumin. Additional research to define best practice for dosing and monitoring valproate and the relationship between free valproate concentrations and clinical or adverse effects in ICU patients is needed.

Introduction To examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. Methods Retrospective cohort of 3,499,378 mostly male US veterans aged ≥65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. Results Survivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. Discussion Survivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD.

Background Physical activity is an important clinical marker of disease status in COPD. COPD is also characterized by low-grade systemic inflammation. However, the relationship between physical activity and systemic inflammation in COPD is unclear. Methods We monitored daily step count, a directly measured physical activity, using the StepWatch Activity Monitor, an ankle-worn accelerometer, in 171 people with stable COPD. Exercise capacity was assessed with the 6-min walk test (6MWT). We measured plasma C-reactive protein (CRP) and IL-6 levels. Linear regression models examined the cross-sectional associations of daily step count and 6MWT distance with CRP and IL-6 levels. Results Subjects had a mean age 72 ± 8 years and mean FEV 1 1.5 ± 0.57 L (54 ± 20% predicted). Median daily step count was 5,203 (interquartile range [IQR], 3,627-7,024], CRP level was 2.4 mg/L (IQR, 1.2-5.0), and IL-6 level was 2.9 pg/mL (IQR, 2.0-5.1). Each 1,000-step increase in daily step count was associated with a 0.94 mg/L and 0.96 pg/mL decrease in CRP ( P = .020) and IL-6 ( P = .044) levels, respectively, adjusting for age, FEV 1 % predicted, pack-years smoked, cardiac disease, current statin use, history of acute exacerbations, and season. There was a significant linear trend of increasing daily step count by quartiles and decreasing CRP ( P = .0007) and IL-6 ( P = .023) levels. Higher 6MWT distance was also significantly associated with lower CRP and IL-6 values. Conclusion People with COPD who walked the most had the lowest plasma CRP and IL-6 levels. These results provide the conceptual basis to study whether an intervention to promote walking will reduce systemic inflammation in people with COPD.

Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.

We identified a protective bone effect at the knee with lipophilic statin use in individuals with chronic spinal cord injury. Lipophilic statin users gained bone at the knee compared to non-users and wheelchair users lost bone compared to walkers. Ambulation and or statins may be effective osteogenic interventions in chronic spinal cord injury (SCI). SCI increases the risk of osteoporosis and low-impact fractures, particularly at the knee. However, during the chronic phase of SCI, the natural history and factors associated with longitudinal change in bone density remain poorly characterized. In this study, we prospectively assessed factors associated with change in bone density over a mean of 21 months in 152 men and women with chronic SCI. A mixed model procedure with repeated measures was used to assess predictors of change in bone mineral density (PROC MIXED) at the distal femur and proximal tibia. Factors with a p value of