Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients.

BACKGROUND: Abiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown. MATERIALS AND METHODS: We retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index. RESULTS: A total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). CONCLUSIONS: To our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk.

Impact of anticoagulant choice on hospitalized bleeding risk when treating cancer-associated venous thromboembolism.

Essentials Bleeding risk by anticoagulant choice for cancer-associated venous thrombosis (CA-VTE) is unknown. 26 894 people with CA-VTE were followed for bleeding in a claims database in the United States. Hospitalized bleeding risk was similar with direct acting oral anticoagulants vs. warfarin. Relative hospitalized bleeding risk varied by cancer type and anticoagulant choice. SUMMARY: Background Direct acting oral anticoagulants (DOACs) are associated with less bleeding than traditional venous thromboembolism (VTE) treatments in the general population but are little studied in cancer-associated VTE (CA-VTE). Objective To determine whether different anticoagulation strategies for CA-VTE have different hospitalized bleeding rates. Patients/Methods We conducted a retrospective study of patients with CA-VTE, diagnosed between 2011 and 2015, in a large administrative database. Using validated algorithms, we identified 26 894 CA-VTE patients treated with anticoagulants and followed them for hospitalized severe bleeding. Cox models were used to assess bleeding risk, adjusted for age, sex, high dimensional propensity score and frailty. Results Over 27 281 person-years of follow-up (median 0.6 years), 1204 bleeding events occurred, for a bleeding rate of 4.4% per patient-year. Bleeding rates varied by cancer type, with the highest rate for upper gastrointestinal cancers (8.6%) and the lowest for breast cancer (2.9%). In Cox models (hazard ratio [HR]; 95% confidence interval [CI]), compared with warfarin, DOACS and low-molecular-weight heparin (LMWH) had similar hazards of bleeding (HR, 0.88; 95% CI, 0.69-1.11 and 0.98; 0.85-1.13). Compared with LMWH, there was no difference in hazard of bleeding with DOACs (0.86; 0.66-1.12). There was heterogeneity in bleeding risk with DOACs by cancer type, with a higher risk of bleeding in upper gastrointestinal cancers and lower risk of bleeding in prostate cancer and hematologic cancers. Conclusions In this practice-based sample of CA-VTE patients, DOACs were associated with similar bleeding risks to warfarin and LMWH. These findings suggest a complex association of bleeding risk with anticoagulant choice in cancer patients.

Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism.

Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N-terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY: Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996-1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to ≥ 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT-proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the Atherosclerosis Risk in Communities Study.

Essentials Atrial fibrillation (AF) may increase risk of venous thromboembolism (VTE), and vice versa. Bidirectionality was assessed prospectively via data from 15 129 black and white individuals. AF was associated with greater risk of developing VTE, and VTE with greater risk of AF. Associations were strongest among blacks and in the first 6 months after initial diagnosis. SUMMARY: Background Atrial fibrillation (AF) and venous thromboembolism (VTE) frequently co-occur. These conditions have shared risk factors and are accompanied by coagulation abnormalities. Furthermore, mechanistic pathways may directly link the disorders. Objectives To test the hypothesis that individuals with incident AF are at greater risk of developing VTE, and those with VTE are at elevated risk of AF. We also tested whether associations were stronger in the first 6 months after the initial diagnosis, and explored race differences. Patients/Methods A total of 15 129 ARIC study participants (45-64 years, 55% female, 26% Black) were followed from 1987 to 2011 for incident AF and VTE (median follow-up 19.8 years). Multivariable-adjusted Cox regression was used, with AF and VTE modeled as time-dependent exposures. Results Incident AF was associated with greater risk of subsequent incident VTE (hazard ratio [95% CI], 1.71 [1.32-2.22]); the association was stronger in Black people (2.30 [1.48-3.58]) and during the first 6 months after AF diagnosis (5.08 [3.08-8.38]). Similarly, incident VTE was associated with increased risk of incident AF (1.73 [1.34-2.24]), especially in Black people (2.40 [1.55-3.74]) and in the first 6 months after VTE diagnosis (4.50 [2.61-7.77]). Conclusions The occurrence of AF was associated with increased risk of incident VTE, and occurrence of VTE was associated with greater risk of incident AF. Associations were particularly strong among Black people and during the first 6 months after the initial diagnosis, although they remained elevated even after 6 months. These findings highlight patient populations that may be at increased risk of AF and VTE, and perhaps should be targeted with preventive strategies.

Vitamin D Status and Prevalent Early Age-Related Macular Degeneration in African Americans and Caucasians: The Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVES: Vitamin D status has been hypothesized to protect against development of early age-related macular degeneration (AMD) via its anti-inflammatory properties and its possible beneficial influence on blood pressure control. We investigated the association between vitamin D status and prevalent early AMD in a community-based cohort. DESIGN: This was a cross-sectional study. SETTING: This was a secondary data analysis of already existing data from the Atherosclerosis Risk in Communities Study (ARIC) cohort collected from 1990 to 1995. PARTICIPANTS: There were 9,734 (7,779 Caucasians, 1,955 African American) ARIC participants (aged 46 to 70 at visit 2 [1990-1992]) with 25(OH)D data available at visit 2, AMD assessment at visit 3 (1993-1995), and complete covariate data. MEASUREMENTS: Vitamin D status was assessed with serum 25-hydroxyvitamin D (25(OH)D) concentrations from bloods drawn at visit 2. Prevalent, early AMD (n=511) was assessed at visit 3 (1993-95) with nonmydriatic retinal photographs of one randomly chosen eye. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD by categories of 25(OH)D in nmol/L (deficient <30, inadequate 30-<50, and two categories of adequate status: 50-<75 and ≥75). Linear trend was estimated using continuous 25(OH)D concentrations. ORs were adjusted for age, race, and smoking status. We further adjusted for hypertension status to examine if vitamin D status influenced early AMD via its effects on blood pressure. Exploratory analyses of effect modification by age, sex, race and high risk genotypes [Y402H complement factor H (CFH) rs1061170 and the A69S age-related maculopathy susceptibility 2 (ARMS2) rs10490924 polymorphisms] were conducted. RESULTS: The prevalence of early AMD was 5%, and 5% of participants were vitamin D deficient. The adjusted OR (95% CIs) for early AMD among those with adequate (≥75 nmol/L) compared to deficient (<30 nmol/L) vitamin D status was 0.94 (0.59-1.50), p-trend=0.86. Further adjustment for hypertension status did not influence results (OR [95% CI]=0.95 [0.59-1.52], p-trend=0.84). Results did not vary significantly by age, race, sex, early AMD subtype (soft drusen or retinal pigment epithelium depigmentation), or ARMS2 genotype. Results did not vary significantly by CFH genotype in African Americans. The p for multiplicative interaction between 25(OH)D and CFH genotype was 0.06 in Caucasians, but OR [95% CIs] for AMD by vitamin D status were similar in each CFH genotype and not statistically significant. CONCLUSIONS: Vitamin D status was not associated with early AMD in this cohort sample.

Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis.

Essentials Observational data suggest taller people have a higher risk of venous thromboembolism (VTE). We used Mendelian randomization techniques to further explore this association in three studies. Risk of VTE increased by 30-40% for each 10 cm increment in height. Height was more strongly associated with deep vein thrombosis than with pulmonary embolism. SUMMARY: Background Taller height is associated with a greater risk of venous thromboembolism (VTE). Objectives To use instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship. Methods Participants of European ancestry were included from two cohort studies (Atherosclerosis Risk in Communities [ARIC] study and Cardiovascular Health Study [CHS]) and one case-control study (Mayo Clinic VTE Study [Mayo]). We created two weighted genetic risk scores (GRSs) for height; the full GRS included 668 single-nucleotide polymorphisms (SNPs) from a previously published meta-analysis, and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10-cm increment in height. ORs were pooled across the three studies by the use of inverse variance-weighted random effects meta-analysis. Results Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% confidence interval [CI] 1.11-1.46), 1.34 (95% CI 1.04-1.73) and 1.45 (95% CI 1.04-2.01) per 10-cm greater height, respectively. Conclusions Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including taller people having a greater venous surface area, a higher number of venous valves, or greater hydrostatic pressure, need to be explored further.

Parathyroid hormone is associated with incident diabetes in white, but not black adults: The Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: Accumulating evidence has linked elevated parathyroid hormone (PTH) with insulin resistance, beta cell dysfunction and dysglycaemia, however, its role in the development of diabetes is largely unclear, particularly among non-whites. We sought to examine the association of PTH with the incidence of diabetes. METHODS: We studied 8066 white and 2034 black adults aged 46-70 years at baseline (1990-92) from the ARIC Study with follow-up for incident diabetes ascertained during study visits conducted in 1993-95 and 1996-98. Hazard ratios (HR) and their 95% CIs for diabetes adjusted for demographics, lifestyle, and 25-hydroxyvitamin D were estimated according to PTH measured at baseline. RESULTS: PTH was higher among blacks than whites (median [IQR], 43.8 [35.0-55.8] vs. 37.9 [30.4-47.3] pg/mL; P<0.001). During a median follow-up of 6 years, 498 white and 167 black participants developed diabetes. The association of PTH with diabetes varied significantly by race (P-interaction 0.02). PTH was not associated with risk for diabetes among black adults. Among whites, HRs according to quintiles of PTH were 1 (referent), 0.95 (0.71, 1.29), 0.95 (0.70, 1.28), 1.12 (0.84, 1.51), and 1.31 (0.98, 1.76) (P-trend 0.03). When a clinical cut-point for PTH was applied (≥65pg/mL; 5.7% of whites), the HR for diabetes among whites was 1.38 (1.01, 1.88). Results were similar when restricted to participants with normal baseline kidney function. CONCLUSION: In this large, population-based study, elevated PTH was independently associated with risk for diabetes among white, but not black adults. Further studies are needed to elucidate the mechanisms that may underlie this differential association of PTH with diabetes across race groups.

Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Low vitamin D levels, measured by serum 25-hydroxyvitamin D [25(OH)D], are associated with increased stroke risk. Less is known about whether this association differs by race or D binding protein (DBP) single nucleotide polymorphism (SNP) status. Our objective was to characterize the associations of and interactions between 25(OH)D levels and DBP SNPs with incident stroke. It was hypothesized that associations of low 25(OH)D with stroke risk would be stronger amongst persons with genotypes associated with higher DBP levels. METHODS: 25(OH)D was measured by mass spectroscopy in 12 158 participants in the Atherosclerosis Risk in Communities (ARIC) study (baseline 1990-1992, mean age 57 years, 57% female, 23% black) and they were followed through 2011 for adjudicated stroke events. Two DBP SNPs (rs7041, rs4588) were genotyped. Cox models were adjusted for demographic/behavioral/socioeconomic factors. RESULTS: During a median of 20 years follow-up, 804 incident strokes occurred. The lowest quintile of 25(OH)D (<17.2 ng/ml) was associated with higher stroke risk [hazard ratio (HR) 1.34 (1.06-1.71) versus highest quintile]; this association was similar by race (P interaction 0.60). There was weak evidence of increased risk of stroke amongst those with 25(OH)D < 17.2 ng/ml and either rs7041 TG/GG [HR = 1.29 (1.00-1.67)] versus TT genotype [HR = 1.19 (0.94-1.52)] (P interaction 0.28) or rs4588 CA/AA [HR = 1.37 (1.07-1.74)] versus CC genotype [HR = 1.14 (0.91-1.41)] (P interaction 0.11). CONCLUSIONS: Low 25(OH)D is a risk factor for stroke. Persons with low 25(OH)D who are genetically predisposed to high DBP (rs7041 G, rs4588 A alleles), who therefore have lower predicted bioavailable 25(OH)D, may be at greater risk for stroke, although our results were not conclusive and should be interpreted as hypothesis generating.

Prospective study of sickle cell trait and venous thromboembolism incidence.

BACKGROUND: Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established. OBJECTIVES: We sought to determine the association of sickle cell trait with deep vein thrombosis and pulmonary embolism. METHODS: Middle-aged African Americans participating in a prospective, population-based cohort investigation, the Atherosclerosis Risk in Communities Study, were followed from 1987 through 2011 for incident hospitalized pulmonary embolism (n = 111) or isolated deep vein thrombosis (n = 138), verified by physician review of medical records. Sickle cell trait (heterozygosity for hemoglobin S, n = 268) was compared with no sickle cell trait (n = 3748). RESULTS: Over a median of 22 years of follow-up, 249 participants had an incident venous thromboembolism. The hazard ratio of venous thromboembolism was 1.50 (95% confidence interval [CI] 0.96-2.36) for participants with vs. without sickle cell trait, after adjustment for age, sex, ancestry, hormone replacement therapy (women), body mass index, diabetes, and estimated glomerular filtration rate. This hazard ratio was 2.05 (95% CI 1.12-3.76) for pulmonary embolism and 1.15 (95% CI 0.58-2.27) for deep vein thrombosis without pulmonary embolism. CONCLUSIONS: Sickle cell trait in African Americans carries a 2-fold increased risk of pulmonary embolism but does not elevate deep vein thrombosis risk. Because neonatal screening for sickle hemoglobin is being conducted in the United States, consideration should be paid to the increased pulmonary embolism risk of individuals with sickle cell trait.

Inflammation markers and incident venous thromboembolism: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Inflammation biomarkers are associated with the venous thromboembolism (VTE) risk factors obesity and age; however, the relationships of inflammation with VTE risk remain controversial. OBJECTIVES: To examine associations of four inflammation biomarkers, i.e. C-reactive protein (CRP), serum albumin, white blood cell (WBC) count, and platelet count (PLTC), with incident VTE, and to determine whether they mediate the association of age or obesity with VTE. PATIENTS/METHODS: Hazards models adjusted for VTE risk factors were used to calculate the prospective association of each biomarker with incident VTE in 30,239 participants of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Mediation of the associations of obesity and age with VTE were examined by bootstrapping. Over a period of 4.6 years, there were 268 incident VTE events. After adjustment for VTE risk factors, the hazard ratios (HRs) were 1.25 (95% confidence interval [CI] 1.09-1.43) per standard deviation (SD) higher log-CRP and 1.25 (95% CI 1.06-1.48) per SD lower albumin; there were no associations for WBC count or PLTC. The association of body mass index (BMI), but not age, with VTE was partially mediated by CRP and albumin. In risk factor-adjusted models, the percentage attenuations of the BMI HR for VTE after introduction of CRP or albumin into the models were 15.4% (95% CI 7.7-33.3%) and 41.0% (95% CI 12.8-79.5%), respectively. CONCLUSION: Higher CRP levels and lower serum albumin levels were associated with increased VTE risk, and statistically mediated part of the association of BMI with VTE. These data suggest that inflammation may be a potential mechanism underlying the relationship between obesity and VTE risk.

Serum 25-hydroxyvitamin D and risk of venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Some evidence suggests that an inadequate vitamin D level may increase the risk for atherosclerotic cardiovascular disease. Whether a low vitamin D level plays a role in venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, is largely unexplored. OBJECTIVES: We tested prospectively, in the Atherosclerosis Risk in Communities (ARIC) cohort, whether the serum level of 25-hydroxyvitamin D (25[OH]D) is inversely associated with VTE incidence, and whether it partly explains the African American excess of VTE in the ARIC Study. PATIENTS AND METHODS: We measured 25(OH)D by using mass spectroscopy in stored samples of 12 752 ARIC Study participants, and followed them over a median of 19.7 years (1990-1992 to 2011) for the incidence of VTE (n = 537). RESULTS: The seasonally adjusted 25(OH)D level was not associated with VTE incidence. In a model adjusted for age, race, sex, hormone replacement therapy, and body mass index, the hazard ratios of VTE across 25(OH)D quintiles 5 (high) to 1 (low) were: 1 (ref.), 0.84 (95% confidence interval [CI] 0.65-1.08), 0.88 (95% CI 0.68-1.13), 1.04 (95% CI 0.78-1.38), and 0.90 (95% CI 0.64-1.27). The lowest 25(OH)D quintile contained 59% African Americans, whereas the highest quintile contained 7% African Americans. However, lower 25(OH)D levels explained little of the 63% greater VTE risk of African Americans over whites in this cohort. CONCLUSIONS: A low 25(OH)D level was not a risk factor for VTE in this prospective study. However, the totality of the literature (three studies) suggests that a low 25(OH)D level might modestly increase VTE risk in whites, but this needs further confirmation.

Vitamin D and cognitive function and dementia risk in a biracial cohort: the ARIC Brain MRI Study.

BACKGROUND AND PURPOSE: Some recent studies in older, largely white populations suggest that vitamin D, measured by 25-hydroxyvitamin D [25(OH)D], is important for cognition, but such results may be affected by reverse causation. Measuring 25(OH)D in late middle age before poor cognition affects behavior may provide clearer results. METHODS: This was a prospective cohort analysis of 1652 participants (52% white, 48% black) in the Atherosclerosis Risk in Communities (ARIC) Brain MRI Study. 25(OH)D was measured from serum collected in 1993-1995. Cognition was measured by the delayed word recall test (DWRT), the digit symbol substitution test (DSST) and the word fluency test (WFT). Dementia hospitalization was defined by ICD-9 codes. Adjusted linear, logistic and Cox proportional hazards models were used. RESULTS: Mean age of participants was 62 years and 60% were female. Mean 25(OH)D was higher in whites than blacks (25.5 vs. 17.3 ng/ml, P < 0.001). Lower 25(OH)D was not associated with lower baseline scores or with greater DWRT, DSST or WFT decline over a median of 3 or 10 years of follow-up (P > 0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. Although not statistically significant, lower levels of 25(OH)D were suggestive of an association with increased dementia risk [hazard ratio for lowest versus highest race-specific tertile: whites 1.32 (95% confidence interval 0.69, 2.55); blacks 1.53 (95% confidence interval 0.84, 2.79)]. CONCLUSIONS: In contrast to prior studies performed in older white populations, our study of late middle age white and black participants did not find significant associations between lower levels of 25(OH)D with lower cognitive test scores at baseline, change in scores over time or dementia risk.

Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: HMG-CoA reductase inhibitors (statins) reduce the risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers; however, the mechanism for the reduction in VTE risk is unknown. AIM: In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk. METHODS: Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women aged 45-84 years, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race and sex-adjusted mean hemostatic factor levels were compared between statin users and non-users, and multivariable linear regression models were used to assess associations of statin use with hemostatic factors, adjusted for age, race/ethnicity, education, income, aspirin use, hormone replacement therapy (in women), and major cardiovascular risk factors. RESULTS: Participants using statins had lower adjusted levels of D-dimer (- 9%), C-reactive protein (- 21%) and factor VIII (- 3%) than non-users (P < 0.05). Homocysteine and von Willebrand factor levels were non-significantly lower with statin use. Higher fibrinogen (2%) and plasminogen activator inhibitor-1 (22%) levels were observed among statin users than among non-users (P < 0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors with statin use. CONCLUSIONS: Findings of lower D-dimer, FVIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and non-users is warranted.

Age at menarche and risk of type 2 diabetes among African-American and white women in the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: We examined race differences in the association between age at menarche and type 2 diabetes before and after adjustment for adiposity. METHODS: We analysed baseline and 9-year follow-up data from 8,491 women (n = 2,505 African-American, mean age 53.3 years; n = 5,986 white, mean age 54.0 years) in the Atherosclerosis Risk in Communities (ARIC) study. Stratifying by race, we used logistic regression to estimate the OR for prevalent diabetes at baseline, and Cox proportional hazard models to estimate the HR for incident diabetes over follow-up according to age at menarche category (8-11, 12, 13, 14 and 15-18 years). RESULTS: Adjusting for age and centre, we found that early age at menarche (8-11 vs 13 years) was associated with diabetes for white, but not African-American women in both the prevalent (white OR 1.72, 95% CI 1.32, 2.25; African-American OR 1.13, 95% CI 0.84, 1.51; interaction p = 0.043) and incident models (white HR 1.43, 95% CI 1.08, 1.89; African-American HR 1.20, 95% CI 0.87, 1.67; interaction p = 0.527). Adjustment for adiposity and lifestyle confounders attenuated associations for prevalent (white OR 1.41, 95% CI 1.05, 1.89; African-American OR 0.94, 95% CI 0.68, 1.30; interaction p = 0.093) and incident diabetes (white HR 1.22, 95% CI 0.92, 1.63; African-American HR 1.11, 95% CI 0.80, 1.56; interaction p = 0.554). CONCLUSIONS/INTERPRETATION: Early menarche was associated with type 2 diabetes in white women, and adulthood adiposity attenuated the relationship. We did not find a similar association in African-American women. Our findings suggest that there may be race/ethnic differences in the influence of developmental factors in the aetiology of type 2 diabetes, which merit further investigation.

Genetic admixture is associated with plasma hemostatic factor levels in self-identified African Americans and Hispanics: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Epidemiologic studies report that self-identified African Americans typically have higher hemostatic factor levels than do self-identified Caucasians or Hispanics. OBJECTIVE: To enhance understanding of phenotypic variation in hemostatic factor levels by race/ethnicity, we evaluated the relationship between genetic ancestry and hemostatic factor levels among Multi-Ethnic Study of Atherosclerosis (MESA) study participants. PATIENTS/METHODS: Our sample included 712 African American and 701 Hispanic men and women aged 45 to 84 years. Individual global ancestry was estimated from 199 genetic markers using STRUCTURE. Linear regression models were used to evaluate the relationship between ancestry and hemostatic factor levels, adjusting for age, gender, education, income and study site. RESULTS: Among African Americans, mean ± standard deviation (SD) ancestry was estimated as 79.9% ± 15.9% African and 20.1% ± 15.9% European. Each SD (16%) greater African ancestry was associated with 2.1% higher fibrinogen levels (P = 0.007) and 3.5% higher plasmin-antiplasmin (PAP) levels (P = 0.02). Ancestry among African Americans was not related to levels of factor (F)VIII or D-dimer. Mean ± SD estimated ancestry among Hispanics was 48.3% ± 23.8% Native American, 38.8% ± 21.9% European, and 13.0% ± 8.9% African. In Hispanics, each SD (19%) greater African ancestry was associated with 2.7% higher fibrinogen levels (P = 0.009) and 7.9% higher FVIII levels (P = 0.0002). In Hispanics, there was no relation between African ancestry and D-dimer or PAP levels, or between European ancestry and hemostatic factor levels. CONCLUSIONS: Greater African ancestry among African Americans and Hispanics was associated with higher levels of several hemostatic factors, notably fibrinogen. These results suggest that genetic heterogeneity contributes, albeit modestly, to racial/ethnic differences in hemostatic factor levels.

Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study.

BACKGROUND: Thrombin is an enzyme that is essential for the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin. OBJECTIVES: We evaluated the relationship of basal peak thrombin generation with the risk of future venous thromboembolism (VTE), and determined whether associations were independent of other coagulation markers. METHODS: The Longitudinal Investigation of Thromboembolism Etiology (LITE) study investigated VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases and 1004 controls). Logistic regression was used to estimate the relationship of peak thrombin generation with VTE, adjusted for age, sex, race, center, and body mass index. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer. RESULTS: Relative to the first quartile of peak thrombin generation, the odds ratio (OR) of VTE for those above the median was 1.74 [95% confidence interval (CI) 1.28-2.37]. The association was modestly attenuated by adjustment for FVIII and D-dimer (OR 1.47, 95% CI 1.05-2.05). Associations appeared to be stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with FV Leiden or low activated partial thromboplastin time. CONCLUSIONS: In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independently of established VTE risk factors.

Serological evidence of infections and Type 2 diabetes: the MultiEthnic Study of Atherosclerosis.

AIMS: Prospective studies have identified chronic inflammation as a risk factor for Type 2 diabetes. However, it is not known whether infection by specific pathogens or having a greater 'pathogen burden' is associated with diabetes. The aim of this study was to examine the cross-sectional relation of seropositivity to five pathogens (Chlamydia pneumoniae, cytomegalovirus, Helicobacter pylori, hepatitis A virus, herpes simplex virus) and prevalent diabetes. METHODS: Baseline data from a random sample of MultiEthnic Study of Atherosclerosis (MESA) participants (n = 1000; age 45-84 years) were used. Diabetes was defined by American Diabetes Association 2003 criteria, and 'pathogen burden' by the number of pathogens (0-5) for which an individual was seropositive. Logistic regression was used to test differences in diabetes prevalence by seropositivity. Linear regression was used to explore associations between pathogen seropositivity and the inflammation markers C-reactive protein, interleukin-6 and fibrinogen. RESULTS: Diabetes prevalence was 12.7%, whereas seropositivity for C. pnuemoniae was 76%, cytomegalovirus 77%, H. pylori 45%, hepatitis A 58% and herpes simplex virus 85%. Seventy-two percent were seropositive for three or more pathogens. In crude analyses, the prevalence of diabetes was higher among those with a pathogen burden of three or more, and with seropositivity to cytomegalovirus, H. pylori, hepatitis A and herpes simplex virus. After adjustment for demographic covariates (particularly race), all associations became non-significant. Pathogen seropositivity was also not related to inflammation marker levels. CONCLUSIONS: Following demographic adjustments, no associations were observed between infection by several pathogens and diabetes status, suggesting no aetiological role for them in the occurrence of diabetes.

Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study.

BACKGROUND: Hemostatic factors and endothelial markers may play some role in racial/ethnic differences in cardiovascular disease (CVD) rates. However, little information exists on hemostatic factors and endothelial markers across racial/ethnic groups. OBJECTIVES: To describe, in four American racial/ethnic groups (Caucasian, Black, Hispanic, and Chinese), mean levels of selected hemostatic factors and endothelial markers. PATIENTS AND METHODS: Multi-ethnic Study of Atherosclerosis baseline data were used (participant age: 45-84 years). Sex-specific analysis of covariance models, and t-tests for pairwise comparisons, were used to compare means of factors and markers. Adjustments were made for demographics and traditional CVD risk factors. Differences were significant at P < 0.05. RESULTS: Blacks had the highest levels of factor VIII, D-Dimer, plasmin-antiplasmin (PAP), and von Willebrand factor, among the highest levels of fibrinogen and E-selectin (women only), but among the lowest levels of intercellular adhesion molecule 1 (ICAM-1), and, in men, the lowest levels of plasminogen activator inhibitor-1 (PAI-1). Whites and Hispanics tended to have intermediate levels of factors and markers, although they had the highest levels of ICAM-1, and Hispanics had the highest mean levels of fibrinogen and E-selectin (women only). Chinese participants had among the highest levels of PAI-1, but the lowest, or among the lowest, of all other factors and markers. No soluble thrombomodulin differences were observed. CONCLUSIONS: In this large cohort, hemostatic factor and endothelial marker mean levels varied by race/ethnicity, even after adjustment for traditional CVD risk factors.