Bailey, Kent R.

Abstract Background: Recent trends in the incidence of venous thromboembolism (VTE), including idiopathic vs. non-idiopathic VTE, have not been well described. Objective: To estimate the incidence of deep vein thrombosis (DVT) and pulmonary embolism with or without DVT (PE), and describe trends in incidence. Methods: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident DVT and PE over the 35-year period, 1966–2000 (n=3342). For all cases, the complete medical records in the community were reviewed for demographic and baseline characteristics previously identified as risk factors for VTE. Generalized linear models assuming a Poisson error structure, and using a log link function, and a log (population) offset will be used to assess the relationship of crude incidence rates to gender, year of diagnosis and age at diagnosis. Results: The overall average age- and sex-adjusted annual VTE incidence was 122 per 100,000 person-years (DVT, 56 per 100,000; PE, 66 per 100,000), with higher age-adjusted rates among men than women (134 versus 115 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 4 to 1110 per 100,000 for age groups 0–19 to 90–110 years. Compared to the 5-year period, 1981–85 (when non-invasive diagnostic testing became routinely available), the overall VTE incidence through 2000 remains unchanged. However, the DVT incidence and the PE incidence significantly increased and decreased, respectively, adjusting for age and gender (p<0.001 for both). The overall age- and sex-adjusted annual incidence of idiopathic VTE was 11.7 per 100,000 person-years (DVT, 6.6 per 100,000; PE, 5.1 per 100,000), with age-adjusted rates also higher among men than women (15.1 vs. 9.1 per 100,000). Interestingly, again compared to 1981–85, idiopathic VTE incidence decreased for 1991–95 (p=0.001) and 1996–2000 (p=0.32), adjusting for age and gender. Idiopathic DVT incidence decreased for 1991–95 (p=0.09), and idiopathic PE incidence decreased for both 1991–95 (p=0.004) and 1996–2000 (p=0.03). The overall age- and sex-adjusted annual incidence of non-idiopathic VTE was 109.4 per 100,000 (DVT, 48.4 per 100,000; PE, 60.7 per 100,000), again, with age-adjusted rates higher in men than women (115.1 vs. 106.8 per 100,000). Non-idiopathic DVT incidence increased steadily since 1981–85 (p=0.006, p<0.001, and p<0.001 for increasing DVT incidence for 1986–1990–1991–1995–1996–2000, respectively, adjusting for age and gender). Non-idiopathic PE incidence, however, remained unchanged for 1986–2000. Conclusions: VTE remains a major national health problem, especially among the elderly. Despite improved VTE prophylaxis efficacy and utilization, the overall incidence of VTE remains unchanged. However, the decreasing incidence of idiopathic DVT, and particularly idiopathic PE (with its associated poor survival) raises the possibility that the total number of VTE(PE)-related deaths may also be decreasing, albeit slightly. This hypothesis requires formal testing. The increasing or steady incidence of non-idiopathic DVT and PE, respectively, suggests the need for more widespread, effective VTE prophylaxis.

Abstract Abstract 2256 Background: The incidence of venous thromboembolism (VTE) may be increasing due to the obesity epidemic. Objective: To estimate the incidence of VTE and describe trends in incidence adjusted for the population's increase in BMI. Methods: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis (DVT) or pulmonary embolism (PE) over the 13-year period, 1988–2000 (n=1,400). Age and BMI at VTE diagnosis and gender were collected for all cases. Age was categorized into 10 year intervals. Using a model for the population distribution of BMI derived from several (n=6) non-VTE Olmsted County cohorts (n=8,011 individuals), we calculated the probability of falling into each of five BMI categories (<18.5, 18.5–24, 25–29, 30–34, 35+) for each age, gender and calendar year. In Olmsted County in the median age group, the prevalence of BMI >30 kg/m2increased from approximately 15% in 1980 to 36% in 2000. We applied these probabilities to the decennial census data for 1980, 1990, 2000 using linearly interpolated census values for intra-census years to obtain Olmsted County age/sex/calendar year/BMI category denominators. Generalized linear modeling assuming a Poisson error structure, and using a log link function, and a log (population) offset was used to assess the relationship of crude incidence rates to gender, year of diagnosis, age and BMI. Results: The overall average age- and sex-adjusted annual VTE incidence was 120 per 100,000 person-years (DVT: 66 per 100,000; PE: 54 per 100,000), with higher age-adjusted rates among men than women (129 versus 113 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 3 to 1,079 per 100,000 for age groups 0–19 to 90–110 years. Age and sex-adjusted VTE incidence increased by increasing BMI category (88, 112, 106, 150, and 195 per 100,000 person-years, respectively, by increasing BMI category). Unadjusted for BMI, VTE incidence was unchanged from 1988 through 2000 (p=0.70). After adjusting for age, gender and calendar year, VTE incidence increased with increasing BMI (p<0.0001). The calendar year incidence slope estimate decreased numerically from 3% per decade to minus 4% per decade after adjusting for increasing BMI, remaining nonsignificant (p=0.57). Conclusions: VTE remains a major national health problem, especially among the obese. Despite the dramatically increasing population BMI, and the significant association of BMI category with VTE incidence, the overall incidence of VTE remained unchanged over the timeframe, 1988–2000. Disclosures: No relevant conflicts of interest to declare.

Background Neprilysin is a metalloprotease involved in proteolysis of numerous peptides, including natriuretic peptides, and is of prognostic and therapeutic importance in heart failure with reduced ejection fraction. No studies have investigated circulating neprilysin in the community, its clinical correlates, or its relationship to cardiovascular disease in the general population. Methods and Results Plasma neprilysin was measured in 1536 participants from Olmsted County, Minnesota, using a commercially available sandwich ELISA assay. Clinical and echocardiographic correlates and subsequent outcomes were determined. Soluble neprilysin is non‐normally distributed in the community (median: 3.9 ng/mL; interquartile range: 1.0–43.0 ng/mL). There was no relationship between plasma neprilysin and age (Spearman correlation: −0.04, P =0.16); body mass index (Spearman correlation: −0.04, P =0.16); glomerular filtration rate (Spearman correlation: −0.007, P =0.8); or A‐, B‐, or C‐type natriuretic peptides (Spearman correlation: 0.03, P =0.22; −0.001, P =0.96; 0.01, P =0.67, respectively). Among tertiles of neprilysin, the lowest tertile group had the highest prevalence of smokers ( P <0.001), hypertension ( P =0.04), dyslipidemia ( P =0.03), and diastolic dysfunction ( P =0.02). Soluble neprilysin was not prospectively associated with death or heart failure over a median of 10.7 years. Conclusions In a large community‐based cohort, for the first time, we described the distribution of circulating neprilysin in the general community. We observed that neprilysin does not correlate with natriuretic peptide levels and is not independently associated with adverse outcomes. The novel associations observed between low soluble neprilysin levels and an adverse cardiometabolic and smoking profile requires further investigation.

European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.

AbstractBackgroundOur aim is to explain the lack of clarity in the ways in which anxiety and depression, which are common in defecatory disorders (DD), may contribute to the disorder. In this study, we evaluate the effects of mental stress and relaxation on anal pressures and the mechanisms thereof.MethodsIn 38 healthy women and 36 DD patients, rectoanal pressures were assessed at rest and during mental stressors (ie, word‐color conflict [Stroop] and mental arithmetic tests) and mental relaxation, before and after randomization to placebo or the adrenergic α1‐antagonist alfuzosin.Key ResultsDuring the baseline Stroop test, the anal pressure increased by 6 ± 13 mm Hg (mean ± SD, P = 0.004) in healthy women and 9 ± 10 mm Hg (P = 0.0001) in constipated women. During mental arithmetic, the anal pressure increased in healthy (4 ± 8 mm Hg, P = 0.002) and constipated women (5 ± 9 mm Hg, P = 0.004). After relaxation, anal pressure declined (P = 0.0004) by 3 ± 4 mm Hg in DD patients but not in controls. Alfuzosin reduced (P = 0.0001) anal resting pressure (by 31 ± 19 mm Hg) vs placebo (16 ± 18 mm Hg). However, during the postdrug Stroop test, anal pressure increased (P = 0.0001) in participants who received alfuzosin but not placebo.Conclusions & InferencesIn healthy controls and DD patients, mental stressors likely increased anal pressure by contracting the internal anal sphincter; relaxation reduced anal pressure in DD patients. Alfuzosin reduced anal resting pressure but did not block the Stroop‐mediated contractile response, which suggests that this response is not entirely mediated by adrenergic α1 receptors.

Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.

Abstract BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA &lt; 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P &lt; 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.

Background Automated individualized risk prediction tools linked to electronic health records ( EHR s) are not available for management of patients with peripheral arterial disease. The goal of this study was to create a prognostic tool for patients with peripheral arterial disease using data elements automatically extracted from an EHR to enable real‐time and individualized risk prediction at the point of care. Methods and Results A previously validated phenotyping algorithm was deployed to an EHR linked to the Rochester Epidemiology Project to identify peripheral arterial disease cases from Olmsted County, MN, for the years 1998 to 2011. The study cohort was composed of 1676 patients: 593 patients died over 5‐year follow‐up. The c‐statistic for survival in the overall data set was 0.76 (95% confidence interval [CI], 0.74–0.78), and the c‐statistic across 10 cross‐validation data sets was 0.75 (95% CI, 0.73–0.77). Stratification of cases demonstrated increasing mortality risk by subgroup (low: hazard ratio, 0.35 [95% CI, 0.21–0.58]; intermediate‐high: hazard ratio, 2.98 [95% CI, 2.37–3.74]; high: hazard ratio, 8.44 [95% CI, 6.66–10.70], all P <0.0001 versus the reference subgroup). An equation for risk calculation was derived from Cox model parameters and β estimates. Big data infrastructure enabled deployment of the real‐time risk calculator to the point of care via the EHR . Conclusions This study demonstrates that electronic tools can be deployed to EHR s to create automated real‐time risk calculators to predict survival of patients with peripheral arterial disease. Moreover, the prognostic model developed may be translated to patient care as an automated and individualized real‐time risk calculator deployed at the point of care.