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Venous thromboembolism (VTE) affects 1.2 million people per year in the United States. With several clinical changes in diagnosis and treatment approaches in the past decade, we evaluated contemporary post-VTE mortality risk profiles and trends. Incident VTE cases were identified from the 2011-2019 Medicare 20% Sample, which is representative of nearly all Americans aged 65 and older. The social deprivation index was linked from public data; race/ethnicity and sex were self-reported. The all-cause mortality risk 30 days and 1 year after incident VTE was calculated in demographic subgroups and by prevalent cancer diagnosis status using model-based standardization. Risks for major cancer types, risk differences by age, sex, race/ethnicity, and socio-economic status (SES), and trends over time are also reported. The all-cause mortality risk among older US adults following incident VTE was 3.1% (95% CI 3.0-3.2) at 30 days and 19.6% (95% CI 19.2-20.1) at 1 year. For cancer-related VTE events, the age-sex-race-standardized risk was 6.0% at 30 days and 34.7% at 1 year. The standardized 30-day and 1-year risks were higher among non-White beneficiaries and among those with low SES. One-year mortality risk decreased 0.28 percentage points per year (95% CI 0.16-0.40) on average across the study period, with no trend observed for 30-day mortality risk. In sum, all-cause mortality risk following incident VTE has decreased slightly in the last decade, but racial and socio-economic disparities persist. Understanding patterns of mortality among demographic subgroups and in cancer-associated events is important for targeting efforts to improve VTE management., (© 2023 Wiley Periodicals LLC.)

Venous thromboembolism, that consists of the interrelated conditions deep-vein thrombosis and pulmonary embolism, is an under-appreciated vascular disease. In Western regions, approximately 1 in 12 individuals will be diagnosed with venous thromboembolism in their lifetime. Rates of venous thromboembolism are lower in Asia, but data from other regions are sparse. Numerous risk factors for venous thromboembolism have been identified, which can be classified as acute or subacute triggers (provoking factors that increase the risk of venous thromboembolism) and basal or acquired risk factors (which can be modifiable or static). Approximately 20% of individuals who have a venous thromboembolism event die within 1 year (although often from the provoking condition), and complications are common among survivors. Fortunately, opportunities exist for primordial prevention (prevention of the development of underlying risk factors), primary prevention (management of risk factors among individuals at high risk of the condition) and secondary prevention (prevention of recurrent events) of venous thromboembolism. In this Review, we describe the epidemiology of venous thromboembolism, including the incidence, risk factors, outcomes and opportunities for prevention. Meaningful health disparities exist in both the incidence and outcomes of venous thromboembolism. We also discuss these disparities as well as opportunities to reduce them., (© 2022. Springer Nature Limited.)

Background: Obesity leads to adipocyte hypertrophy and adipokine dysregulation and is an independent risk factor for venous thromboembolism (VTE). However, the association between adipokines and VTE is not well established., Objectives: To examine whether adipokines are associated with increased risk of incident VTE., Methods: We studied 1888 participants of the Multi-Ethnic Study of Atherosclerosis cohort who were initially free of VTE and had adipokine (adiponectin, leptin, and resistin) levels measured at either examination 2 or 3 (2002-2004 or 2004-2005, respectively). During follow-ups, VTE was ascertained through hospitalization records and death certificates by using ICD-9 and 10 codes. We used multivariable Cox proportional hazards regression to assess the association between 1 standard deviation (SD) log-transformed increments in adipokines and incident VTE., Results: The mean ± SD age was 64.7 ± 9.6 years, and 49.8% of participants were women. Medians (interquartile range) of adiponectin, leptin, and resistin were 17.3 (11.8-26.2) mcg/mL, 13.5 (5.6-28.2) ng/mL, and 15.0 (11.9-19.0) ng/mL, respectively. There were 78 incident cases of VTE after a median of 9.7 (5.0-12.4) years of follow-up. After adjusting for sociodemographics, smoking, and physical activity, the hazard ratios (95% CIs) per 1 SD increment of adiponectin, leptin, and resistin were 1.14 (0.90-1.44), 1.29 (1.00-1.66), and 1.38 (1.09-1.74), respectively. The association for resistin persisted after further adjustments for body mass index and computed tomography-derived total visceral adipose tissue area., Conclusion: Higher resistin levels were independently associated with greater risk of incident VTE. Larger prospective cohort studies are warranted to confirm this association., Competing Interests: Declaration of competing interests Dr Michos is on the advisory boards for Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Esperion, Novartis, Novo Nordisk, and Pfizer. None of the authors report any conflict of interest., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources., Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations., Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis., Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Background Pulmonary hypertension (PH) is a devastating potential complication of pulmonary embolism, a manifestation of venous thromboembolism (VTE). The incidence of and risk factors for PH in those with prior VTE are poorly characterized. Methods and Results International Classification of Diseases ( ICD ) codes from inpatient and outpatient medical claims from MarketScan administrative databases for years 2011 to 2018 were used to identify cases of VTE, comorbidities before the VTE event, and PH occurring subsequent to the VTE event. Cumulative incidence and hazard ratios (HR), and their 95% CI, were calculated. The 170 021 VTE cases included in the analysis were on average (±SD) 57.5±15.8 years old and 50.5% were female. A total of 5943 PH cases accrued over an average follow-up of 1.94 years. Two years after incident VTE, the cumulative incidence (95% CI) of PH was 3.5% (3.4%-3.7%) overall. It was higher among older individuals, among women (3.9% [3.8%-4.1%]) than men (3.2% [3.0%-3.3%]), and among patients presenting with pulmonary embolism (6.2% [6.0%-6.5%]) than those presenting with deep vein thrombosis only (1.1% [1.0%-1.2%]). Adjusting for age and sex, risk of PH was higher among patients with VTE with underlying comorbidities. Using the Charlson comorbidity index, there was a dose-response relationship, whereby greater scores were associated with increased PH risk (score ≥5 versus 0: HR, (2.50 [2.30-2.71])). When evaluating individual comorbidities, the strongest associations were observed with concomitant heart failure (HR, 2.17 [2.04-2.31]), chronic pulmonary disease (2.01 [1.90-2.14]), and alcohol abuse (1.66 [1.29-2.13]). Conclusions In this large, real-world population of insured people with VTE, 3.5% developed PH in the 2 years following their initial VTE event. Risk was higher among women, with increasing age, and in those with additional comorbidities at the time of the VTE event. These data provide insights into the burden of PH and risk factors for PH among patients with VTE.

Background: Thirty to seventy percent of all venous thromboembolism (VTE) events are associated with hospitalization. The absolute and relative risks during and after hospitalization are poorly characterized., Objectives: Quantify the absolute rate and relative risk of VTE during and up to 3 months after medical and surgical hospitalizations., Patients/methods: We conducted an observational cohort study between 2010 and 2016 of patients cared for by the University of Vermont (UVM) Health Network's primary care population. Cox proportional hazard models with hospitalization modeled as a time-varying covariate were used to estimate VTE risk., Results: Over 4.3 years of follow-up, 55 220 hospitalizations (156 per 1000 person-years) and 713 first venous thromboembolism events (2.0 per 1000 person-years) occurred. Among individuals not recently hospitalized, the rate of venous thromboembolism was 1.4 per 1000 person-years and 71.8 per 1000 person-years during hospitalization. During the first, second, and third months after discharge, the rates of venous thromboembolism were 35.1, 11.3, and 5.2 per 1000 person-years, respectively. Relative to those not recently hospitalized, the age- and sex-adjusted HRs of venous thromboembolism were 38.0 (95% CI 28.0, 51.5) during hospitalization, and 18.4 (95% CI 15.0, 22.6), 6.3 (95% CI 4.3, 9.0), and 3.0 (95% CI 1.7, 5.4) during the first, second, and third months after discharge, respectively. Stratified by medical versus surgical services the rates were similar., Conclusion: Hospitalization and up to 3 months after discharge were strongly associated with increased venous thromboembolism risk. These data quantify this risk for use in future studies., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases ( ICD ) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]). Conclusions Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.

Background Current scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data. Methods and Results We selected patients with incident VTE initiating oral anticoagulation in the 2011 to 2017 MarketScan databases. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use before oral anticoagulation initiation as potential predictors of bleeding using stepwise selection of variables in Cox models run on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165 434 patients with VTE and initiating oral anticoagulation, of whom 2294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% CI, 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95% CI, 0.67-0.69). For comparison, the c-statistic of the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly (>65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score in this population was 0.62 (95% CI, 0.61-0.63). Conclusions We have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.

Background: Several hemostatic factors and inflammatory markers are associated with the risk of incident venous thromboembolism (VTE), however, most existing data are from case-control studies in Caucasian populations., Objectives: We aimed to prospectively confirm previous findings and explore less studied biomarkers in relation to VTE risk in a multi-racial/multi-ethnic cohort., Methods: Circulating levels of factor VIII, fibrinogen, D-dimer, plasmin-antiplasmin complex (PAP), C-reactive protein (CRP), and interleukin-6 (IL-6) were measured at baseline (2000-2002) in 6706 participants of the Multi-Ethnic Study of Atherosclerosis. Incident VTE was identified using hospitalization discharge codes from baseline to December 31, 2015. Hazard ratios (HRs) of VTE were estimated in Cox regression models., Results: There were 227 events during a median of 14 years of follow-up. Compared with participants in the lowest quartile, the HRs for those above the 95th percentile and p for trend across categories were 3.50 (95% confidence interval [CI] 1.98-6.19; p < .001) for D-dimer, 1.49 (95% CI 0.84-2.63; p = .02) for factor VIII, 1.32 (95% CI 0.76-2.28; p = .99) for fibrinogen, 1.92 (95% CI 1.08-3.42; p = .15) for PAP, 1.68 (95% CI 0.81-3.48; p = .08) for CRP, and 2.55 (95% CI 1.15-5.66; p = .07) for IL-6, after adjustment for demographics and body mass index. For CRP and IL-6, follow-up was restricted to 10 years because of violations of the proportional hazards assumption. No significant interactions by age/ethnicity were observed., Conclusions: We demonstrated a fairly novel association between PAP and risk of incident VTE, and contributed further prospective confirmation regarding the associations of D-dimer, factor VIII, and IL-6 with VTE., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Published studies are inconsistent about whether differences in diet are associated with risk of venous thromboembolism. We studied the association between dietary patterns and incident venous thromboembolism in a large US cohort., Methods: The Atherosclerosis Risk in Communities study followed 14,818 middle-aged males and females for incident venous thromboembolism over an average of 22 years between 1987 and 2015. Trained interviewers assessed dietary intake at visits 1 and 3, using a food frequency questionnaire. We derived 2 dietary pattern scores using principal component analysis and ascertained and verified hospitalized venous thromboembolism. In separate proportional hazards regression analyses, we examined associations of quintiles of the prudent and the Western dietary pattern scores with risk of developing non-cancer-related and total venous thromboembolism, adjusting for demographic characteristics, lifestyle factors, body mass index, and diabetes., Results: With 860 total incident venous thromboembolism events, the hazard ratios (95% confidence intervals) of incident non-cancer-related venous thromboembolism (n = 631) across quintiles of the prudent dietary pattern score were 1 (reference), 1.04 (0.81-1.32), 0.84 (0.65-1.08), 0.70 (0.53-0.91), and 0.88 (0.67-1.15), P trend  = .04. Across quintiles of the Western dietary pattern score, hazard ratios of non-cancer-related venous thromboembolism were 1 (reference), 1.13 (0.87-1.45), 1.20 (0.92-1.56), 1.03 (0.77-1.39), and 1.58 (1.13-2.21), P trend  = .04. Associations were similar for total venous thromboembolism., Conclusions: In this community-based cohort, a prudent dietary pattern was associated with a lower risk of future venous thromboembolism, whereas a Western dietary pattern was associated with a higher risk., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Little is known about the impact of oral anticoagulation (OAC) choice on healthcare encounters during venous thromboembolism (VTE) primary treatment. Among anticoagulant-naïve patients with VTE, we tested the hypotheses that healthcare utilization would be lower among users of direct OACs (DOACs; rivaroxaban or apixaban) than among users of warfarin. MarketScan databases for years 2016 and 2017 were used; healthcare utilization was identified in the first 6 months after initial VTE diagnoses. The 23,864 patients with VTE had on average 0.2 ± 0.5 hospitalizations, spent 1.3 ± 5.2 days in the hospital, had 5.7 ± 5.1 outpatient encounters, and visited an emergency department 0.4 ± 1.1 times. As compared to warfarin, rivaroxaban and apixaban were associated with fewer hospitalizations, days hospitalized, outpatient office visits, and emergency department visits after accounting for age, sex, comorbidities, and medications. Hospitalization rates were 24% lower (incidence rate ratio (IRR): 0.76; 95% CI: 0.69, 0.83) with rivaroxaban and 22% lower (IRR: 0.78; 95% CI: 0.71, 0.87) with apixaban, as compared to warfarin (IRR: 1.00 (reference)). Healthcare utilization was similar between apixaban and rivaroxaban users. Patients with VTE prescribed rivaroxaban and apixaban had lower healthcare utilization than those prescribed warfarin, while there was no difference when comparing apixaban to rivaroxaban. These findings complement existing literature supporting the use of DOACs over warfarin.

Background/objectives: Weight gain increases risk of cardiovascular disease, but has not been examined extensively in relationship to venous thromboembolism (VTE). The association between weight change over 9 years and subsequent VTE among participants in the Atherosclerosis Risk in Communities (ARIC) study was examined, with a hypothesis that excess weight gain is a risk factor for VTE, relative to no weight change., Subjects/methods: Quintiles of 9-year weight change were calculated (visit 4 1996-1998 weight minus visit 1 1987-1989 weight in kg: Quintile 1: ≥-1.81 kg; Quintile 2: <-1.81 to ≤1.36 kg; Quintile 3: >1.36 to ≤4.08 kg; Quintile 4: >4.08 to ≤7.71 kg; Quintile 5: >7.71 kg). Incident VTEs from visit 4 (1996-1998) through 2015 were identified and adjudicated using medical records. Hazard ratios (HRs) were calculated using Cox models., Results: 529 incident VTEs were identified during an average of 19 years of follow up. Compared to Quintile 2, participants in Quintile 5 of weight change had 1.46 times the rate of incident VTE (HR = 1.46 (95% CI 1.09, 1.95), adjusted for age, race, sex, income, physical activity, smoking, and prevalent CVD). The HR for Quintile 5 was modestly attenuated to 1.38 (95% CI 1.03, 1.84) when visit 1 BMI was included in the model. When examined separately, results were significant for unprovoked VTE, but not for provoked VTE. Among those obese at visit 1, both weight gain (HR 1.86 95% CI 1.27, 2.71) and weight loss (HR 2.11 95% CI 1.39, 3.19) were associated with incident VTE, compared with normal-weight participants with no weight change., Conclusions: Weight gain later life was associated with increased risk for unprovoked VTE. Among those with obesity, both weight gain and weight loss were associated with increased risk for VTE.

Objective: Venous thromboembolism (VTE) is a common disease that has a genetic basis. Lifestyle factors contribute to risk, but it is unknown whether healthy lifestyle can mitigate the genetic risk. We studied whether greater adherence to the American Heart Association's cardiovascular health metric, Life's Simple 7 (LS7), is associated with lower incidence of VTE in individuals across categories of a genetic risk score (GRS) for VTE. Approach AND RESULTS: We followed 9026 White participants from the ARIC (Atherosclerosis Risk in Communities) Study, a prospective cohort enrolled in 1987 to 1989 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories. There were 466 incident VTE events over 22.8 years. Participants with an optimal LS7 score had a lower incidence of VTE (3.9%) than those with inadequate LS7 (5.7%). Compared with the high GRS and inadequate LS7 group (hazard ratio=1), those with high GRS and optimal LS7 indeed had a reduced hazard ratio of VTE: 0.65 (95% CI, 0.48-0.89). The group with low GRS and optimal LS7 had the lowest hazard ratio of VTE (0.39 [95% CI, 0.25-0.61]). Of the LS7 components, in all GRS groups, the factor most strongly protective for VTE was normal weight., Conclusions: Among people at low or high genetic risk for VTE, healthier lifestyle factors, particularly normal weight, were associated with a lower incidence of VTE. Further studies should determine the impact of lifestyle changes among patients at high genetic risk of VTE, such as in thrombophilic families.

Background Relatively little is known about the long-term consequences of venous thromboembolism (VTE) on physical functioning. We compared long-term frailty status, physical function, and quality of life among survivors of VTE with survivors of coronary heart disease (CHD) and stroke, and with those without these diseases. Methods and Results Cases of VTE, CHD, and stroke were continuously identified since ARIC (Atherosclerosis Risk in Communities Study) recruitment during 1987 to 1989. Functional measures were objectively captured at ARIC clinic visits 5 (2011-2013) and 6 (2016-2017); quality of life was self-reported. The 6161 participants at visit 5 were, on average, 75.7 (range, 66-90) years of age. By visit 5, 3.2% had had a VTE, 6.9% CHD, and 3.4% stroke. Compared with those without any of these conditions, VTE survivors were more likely to be frail (odds ratio [OR], 3.11; 95% CI, 1.80-5.36) and have low (<10) versus good scores on the Short Physical Performance Battery (OR, 3.59; 95% CI, 2.36-5.47). They also had slower gait speed, less endurance, and lower physical quality of life. VTE survivors were similar to coronary heart disease and stroke survivors on categorical frailty and outcomes on Short Physical Performance Battery assessment. When score on the Short Physical Performance Battery instrument was modeled continuously, VTE survivors performed better than stroke survivors but worse than CHD survivors. Conclusions VTE survivors had triple the odds of frailty and poorer physical function than those without the vascular diseases considered. Their function was somewhat worse than that of CHD survivors, but better than stroke survivors. These findings suggest that VTE patients may benefit from additional efforts to improve postevent physical functioning.

Objective: Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Resting heart rate (RHR), which may be modifiable through lifestyle changes, has been shown to be associated with cardiovascular disease risk and with inflammatory markers that have been predictive of VTE incidence., Methods: We examined whether RHR is also associated with VTE incidence independent of these risk factors. We studied 6479 Multi-Ethnic Study of Atherosclerosis participants free from clinical VTE at baseline who had baseline RHR ascertained by 12-lead ECG. VTE events were recorded from hospital records and death certificates using International Classification of Diseases (ICD)-9 and ICD-10 codes. We categorised RHR as <60, 60-69, 70-79 and ≥80 bpm. We used Cox hazard models to determine the association of incident VTE by RHR., Results: Participants had mean (SD) age of 62 (10) years and RHR of 63 (10) bpm. RHR was cross-sectionally correlated with multiple inflammatory and coagulation factors. There were 236 VTE cases after a median follow-up of 14 years. Compared with those with RHR<60 bpm, the HR (95% CI) for incident VTE for RHR≥80 bpm was 2.08 (1.31 to 3.30), after adjusting for demographics, physical activity, smoking, diabetes and use of atrioventricular (AV)-nodal blockers, aspirin and anticoagulants, and remained significant after further adjustment for inflammatory markers (2.05 (1.29 to 3.26)). Results were similar after excluding those taking AV-nodal blocker medications. There was no effect modification of these associations by sex or age., Conclusion: Elevated RHR was positively associated with VTE incidence after a median of 14 years; this association was independent of several traditional VTE and inflammatory markers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Importance: Testosterone therapy is increasingly prescribed in patients without a diagnosis of hypogonadism. This therapy may be associated with increased risk of venous thromboembolism (VTE) through several mechanisms, including elevated hematocrit levels, which increase blood viscosity., Objective: To assess whether short-term testosterone therapy exposure is associated with increased short-term risk of VTE in men with and without evidence of hypogonadism., Design, Setting, and Participants: This case-crossover study analyzed data on 39 622 men from the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database from January 1, 2011, to December 31, 2017, with 12 months of follow-up. Men with VTE cases who were free of cancer at baseline and had 12 months of continuous enrollment before the VTE event were identified by International Classification of Diseases codes. Men in the case period were matched with themselves in the control period. Case periods of 6 months, 3 months, and 1 month before the VTE events were defined, with equivalent control periods (6 months, 3 months, and 1 month) in the 6 months before the case period., Exposures: National drug codes were used to identify billed testosterone therapy prescriptions in the case period (0-6 months before the VTE) and the control period (6-12 months before the VTE)., Main Outcomes and Measures: The main outcome in this case-only experiment was first VTE event stratified by the presence or absence of hypogonadism., Results: A total of 39 622 men (mean [SD] age, 57.4 [14.2] years) were enrolled in the study, and 3110 men (7.8%) had evidence of hypogonadism. In age-adjusted models, testosterone therapy use in all case periods was associated with a higher risk of VTE in men with (odds ratio [OR], 2.32; 95% CI, 1.97-2.74) and without (OR, 2.02; 95% CI, 1.47-2.77) hypogonadism. Among men without hypogonadism, the point estimate for testosterone therapy and VTE risk in the 3-month case period was higher for men younger than 65 years (OR, 2.99; 95% CI, 1.91-4.68) than for older men (OR, 1.68; 95% CI, 0.90-3.14), although this interaction was not statistically significant (P = .14)., Conclusions and Relevance: Testosterone therapy was associated with an increase in short-term risk for VTE among men with and without hypogonadism, with some evidence that the association was more pronounced among younger men. These findings suggest that caution should be used when prescribing testosterone therapy.

Background: Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown., Objectives: In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed., Methods: During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE., Results: Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE., Conclusions: In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Venous thromboembolism incidence rates are 30%-100% higher in US blacks than whites. We examined the degree to which differences in the frequencies of socioeconomic, lifestyle, medical risk factors, and genetic variants explain the excess venous thromboembolism risk in blacks and whether some risk factors are more strongly associated with venous thromboembolism in blacks compared with whites., Methods: We measured venous thromboembolism risk factors in black and white participants of the Atherosclerosis Risk in Communities study in 1987-1989 and followed them prospectively through 2015 for venous thromboembolism incidence., Results: Over a mean of 22 years, we identified 332 venous thromboembolisms in blacks and 578 in whites, yielding 65% higher crude incidence rates per 1000 person-years in blacks. The age and sex-adjusted hazard ratio (95% confidence interval) of venous thromboembolism for blacks compared with whites was 2.04 (1.76, 2.37) for follow-up >10 years and was attenuated to 1.14 (0.89, 1.46) when adjusted for baseline confounders or mediators of the race association, which tended to be more common in blacks. For example, adjustment for just baseline weight, family income, and concentration of plasma factor VIII reduced the regression coefficient for race by 75%. There were no significant (P <0.05) 2-way multiplicative interactions of race with any risk factor, except with a 5-single nucleotide polymorphism (5-SNP) genetic risk score (a weaker venous thromboembolism risk factor in blacks) and with hospitalization for heart failure (a stronger venous thromboembolism risk factor in blacks)., Conclusion: The higher incidence rate of venous thromboembolism in blacks than whites was mostly explained by blacks having higher frequencies of venous thromboembolism risk factors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Understanding of the comparative bleeding risks of oral anticoagulant (OAC) therapies for the primary treatment of venous thromboembolism (VTE) is limited. Therefore, among anticoagulant-naïve VTE patients, we conducted comparisons of apixaban, rivaroxaban and warfarin on the rate of hospitalised bleeding within 180 days of OAC initation. MarketScan databases for the time-period from 2011 to 2016 were used and, for each OAC comparison, new users were matched with up to five initiators of a different OAC. The final analysis included 83 985 VTE patients, who experienced 1944 hospitalised bleeding events. In multivariable-adjusted Cox regression models, rate of hospitalised bleeding was lower among new users of apixaban when compared to new users of rivaroxaban [hazard ratio (95% confidence interval) 0·58 (0·41-0·80)] or warfarin [0·68 (0·50-0·92)]. Overall, the hospitalised bleeding rate was similar when comparing new users of rivaroxaban to new users of warfarin [0·98 (0·68-1·11)], though there was some suggestion that rivaroxaban was associated with lower bleeding risk among younger individuals. Findings from this large real-world population concur with results from the randomised trial which found lower bleeding risk with apixaban versus warfarin and, for the first time, reveal a lower risk of bleeding in a comparison of apixaban versus rivaroxaban., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: Oral anticoagulation (OAC) prescribed to AF patients for the prevention of cardioembolic complications likely has the added benefit of preventing venous thromboembolism (VTE). This study evaluated, among AF patients who are anticoagulated, whether type of OAC was associated with subsequent VTE risk., Methods: Non-valvular AF patients prescribed OACs between 2010 and September 2015 were identified via the MarketScan administrative claims databases. OACs included warfarin and direct OACs (DOACs: dabigatran, rivaroxaban, and apixaban). Incident VTE was defined by ICD-9-CM codes. Patients were matched on age, sex, CHA 2 DS 2 -VASc, and high-dimensional propensity scores. The final analysis included 117,912 AF patients., Results: In total, 1357 VTE events accrued over a mean follow-up of 484 days. In multivariable-adjusted, propensity score-matched Cox models, relative to new users of warfarin, risk of incident VTE was lower among new users of dabigatran [hazard ratio (95% confidence interval) = 0.55 (0.47-0.66)] and apixaban [0.51 (0.39-0.68)], but similar among new users of rivaroxaban [1.01 (0.87-1.19)]. In head-to-head DOAC comparisons, VTE risk was lower among users of dabigatran [0.48 (0.36-0.64)] and apixaban [0.61 (0.47-0.78)] vs rivaroxaban. Findings were mostly similar across patient sub-groups., Conclusions: In this large practice-based population of AF patients prescribed OACs for primary prevention of stroke and systemic embolization, subsequent risk of VTE was lowest among those prescribed apixaban and dabigatran, while risk was similar with prescriptions for warfarin and rivaroxaban. Among AF patients prescribed OACs, lowering the risk of VTE may be an additional benefit of apixaban and dabigatran, beyond the reduced bleeding risk observed in randomized clinical trials.

Aim: Periodontal disease is a cardiovascular disease (CVD) risk factor but few studies have considered the relationship between periodontal disease and venous thromboembolism (VTE). We hypothesized that periodontal disease is independently associated with increased risk of incident VTE., Materials and Methods: We used data from 8,092 participants of the Atherosclerosis Risk in Communities (ARIC) study to examine periodontal disease in 1996-1998 and incident VTE through 2011. Periodontal disease was determined using self-reported tooth loss due to gum disease and dental examinations. Cox proportional hazards regression models were used to estimate hazard ratios for VTE and 95% confidence intervals adjusted for relevant confounders., Results and Conclusions: Participants were on average 62.7 years old at baseline and 13.9% self-reported tooth loss from gum disease. Over a mean of 12.9 years of follow-up, there were 313 incident VTE events. Self-reported tooth loss due to gum disease was associated with 30% higher VTE risk (HR = 1.29 (0.96, 1.73) after adjusting demographic factors, SES, periodontal risk factors, oral hygiene, and access to dental care variables. No statistically significant associations between clinical measures of periodontitis and VTE were observed after adjustment. Further research is needed to elucidate whether a relationship between periodontal disease and VTE exists., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oral anticoagulants used for the primary treatment of venous thromboembolism (VTE) include warfarin and the more recently introduced direct oral anticoagulants (DOACs), including rivaroxaban, apixaban, dabigatran and edoxaban. Information on the comparative safety of these medications in routine clinical practice is lacking. We identified patients with diagnoses for VTE and prescriptions for oral anticoagulants using claims data from a large U.S. insurance database from 2012 to 2017. Marginal structural logistic models were used to examine associations between type of oral anticoagulant and risk of all-cause mortality. Of 62,431 enrolees in this analysis, 51% were female and the mean age was 61.9 years. Initial oral anticoagulant prescriptions were for warfarin ( n  = 35,704), rivaroxaban ( n  = 21,064) and apixaban ( n  = 5,663). A total of 1,791 deaths occurred within 6 months of the initial oral anticoagulant prescription. Risk of all-cause mortality was not associated with having a prescription for warfarin versus any DOAC or between any head-to-head DOAC comparisons. Also, associations generally did not vary when stratified by VTE type, sex, age, co-morbidities (including renal disease) or anti-platelet medication use. In this observational study, the associations with all-cause mortality comparing DOACs versus warfarin agree with results from previous clinical trials and observational studies, while the associations for head-to-head DOAC comparisons provide new information on the comparative safety of DOACs. Our findings suggest that other criteria such as patient preference, cost, recurrent VTE risk or bleeding risk should be used when determining the choice of anticoagulant for the primary treatment of VTE., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Warfarin and direct oral anticoagulants (DOACs) are used for the initial treatment and secondary prevention of venous thromboembolism (VTE), and have similar efficacy. Patient concerns and preferences are important considerations when selecting an anticoagulant, yet these are not well studied., Methods: VTE patients ( n  = 519) were surveyed from online sources (clotconnect.org, stoptheclot.org and National Blood Clot Alliance Facebook followers [ n  = 495]) and a haematology clinic in Vermont ( n  = 24)., Results: Patients were 83% females and on average (±standard deviation [SD]) 45.7 ± 13.1 years; 65% self-reported warfarin as their initial VTE treatment and 35% a DOAC. Proportions reporting being extremely concerned about the following outcomes were as follows: recurrent VTE 33%, major bleeding 21%, moderate bleeding 16% and all-cause death 29%. When asked about oral anticoagulant characteristics, patients strongly preferred anticoagulants that are reversible (53%), and for which blood drug levels can be monitored (30%). Lower proportions agreed with statements that regular blood testing is inconvenient (18%), that they are comfortable using the newest drug versus an established drug (15%) and that it is difficult to change their diet to accommodate their anticoagulant (17%). In multivariable-adjusted models, patients tended to have had as their initial treatment, and to currently be taking, the oral anticoagulant option they personally preferred., Discussion: Patients held the greatest concern for recurrent VTE and mortality, regardless of which treatment they were prescribed. Potential weaknesses of warfarin (e.g., dietary restrictions, regular monitoring) were generally not considered onerous, while warfarin's advantages (e.g., ability to monitor) were viewed favourably., Competing Interests: Dr. Stephan Moll has consulted for Janssen (manufacturers Xarelto/rivaroxaban), Boehringer-Ingelheim (Pradaxa/dabigatran etexilate and Praxbind/idarucizumab) and Portola (betrixaban and andexanet). The commercial entities had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. No other authors have any conflicts of interest to disclose., (Schattauer GmbH Stuttgart.)

Background and Objectives: Acute triggers for VTE, which may include infection, are understudied, as is the timing and duration of VTE risk after infection. We hypothesized that there is an association between hospitalization with infection and short-term VTE risk that exceeds the known association between hospitalization and VTE., Methods: VTE cases and infections were identified in the Atherosclerosis Risk in Communities (ARIC) cohort. A case-crossover design and conditional logistic regression were used to compare hospitalized infections among VTE cases (14, 30, 42, and 90days before VTE) with corresponding control periods 1year and 2years prior. Since hospitalization is a known VTE trigger, study design and analytical techniques were used to isolate the impact of infection., Results: There were 845 adjudicated incident VTE cases. Hospitalization with infection was more common in all case periods compared to equivalent control periods: 14day OR (95% CI)=1.7 (0.5, 5.8), 30day OR (95% CI)=2.7 (1.1, 6.4), 42day OR (95% CI)=2.2 (1.1, 4.7), and 90day OR (95% CI)=1.2 (0.7, 2.0). The association was generally strongest in exposure periods closest to the VTE event and decreased as the time window before VTE increased., Conclusions: These results support the hypothesis that hospitalized infection is a trigger of VTE. VTE preventive measures may prevent VTE events if used in the peri-infection period but clinical trials are needed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE)., Methods: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis., Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively., Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE., Competing Interests: Disclosures: None declared. All authors submitted the ICMJE form on Disclosure of Potential Conflicts of Interest. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services., (© 2016 American Heart Association, Inc.)

Background: Although venous stasis is a risk factor for venous thromboembolism (VTE) and orthostatic hypotension (OH) can cause venous stasis, to our knowledge no study has examined the relationship between OH and VTE risk. We sought to quantify the association between OH and VTE (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that OH was positively associated with incident VTE., Methods: We measured OH-defined as a drop in systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing-in participants aged 45-64 years in ARIC (n = 12,480) and ≥65 years in CHS (n = 5,027) at baseline visits (1987-1989 in ARIC; 1989-1990 and 1992-1993 in CHS), and followed participants for incident VTE (n = 568 in ARIC through 2011 and n = 148 in CHS through 2001). We calculated adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for incident VTE in relation to OH status., Results: In CHS, there was a positive association between OH status and incident VTE (HR for VTE = 1.74 (95% CI: 1.20-2.51)). In contrast, there was no association between OH and VTE in the ARIC study (HR for VTE = 0.97 (95% CI: 0.70-1.33))., Conclusions: Community-dwelling older adults with OH had a moderately increased risk of VTE. These results were not seen in a population-based middle-aged cohort., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Greater public awareness of venous thromboembolism may be an important next step for optimizing venous thromboembolism prevention and treatment. "Lifetime risk" is an easily interpretable way of presenting risk information. Therefore, we sought to calculate the lifetime risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study., Methods: We followed participants aged 45-64 years in ARIC (n = 14,185) and ≥65 in CHS (n = 5414) at baseline visits (1987-1989 in ARIC, 1989-1990 and 1992-1993 in CHS) for incident venous thromboembolism (n = 728 in ARIC through 2011 and n = 172 in CHS through 2001). We estimated lifetime risks and 95% confidence intervals of incident venous thromboembolism using a modified Kaplan-Meier method, accounting for the competing risk of death from other causes., Results: At age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7). High-risk groups were African Americans (11.5% lifetime risk), those with obesity (10.9%), heterozygous for the factor V Leiden (17.1%), or with sickle cell trait or disease (18.2%). Lifetime risk estimates differed by cohort; these differences were explained by differences in time period of venous thromboembolism ascertainment., Conclusions: At least 1 in 12 middle-aged adults will develop venous thromboembolism in their remaining lifetime. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Diabetes mellitus (DM) may be a risk factor for venous thromboembolism (VTE) but results are inconsistent., Aim: We conducted a systematic review and meta-analysis of epidemiologic studies to quantify the association between DM and VTE., Methods and Results: We included studies identified in PubMed, Web of Science, and CINAHL through 07/31/2014. We identified 19 studies that met our selection criteria. We pooled RRs using a random-effects model: the pooled RR for the association of DM with VTE was 1.10 (95% CI: 0.94-1.29). Between-study heterogeneity was explored with a forest plot, funnel plot, meta-regression, and a stratified analysis. Between-study heterogeneity was observed and not explained by study design, method of DM assessment, or degree of adjustment for confounding. Sensitivity analyses omitted one study at a time to assess the influence of any single study on the pooled estimate. These analyses indicated that one large study was highly influential; when this study was excluded, the pooled estimate increased and just reached statistical significance: 1.16 (95% CI: 1.01-1.34)., Conclusions: This meta-analysis suggests either no association or a modest positive one between DM and VTE in the general population. DM is unlikely to play a major role in VTE development., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Approximately 10% of the general population has elevated blood concentrations of hepatic enzymes, which are linked to increased coagulation markers. We tested whether elevated hepatic enzymes are associated with increased risk of venous thromboembolism (VTE)., Methods: We followed 12,604 adults with measurements of alanine transaminase, aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) prospectively for VTE occurrence., Results: AST and GGT above the laboratory normal values were associated over two decades of follow-up with increased risk of total (n = 532) and provoked VTE (n = 332), but with not unprovoked VTE (n = 200). In a model adjusted for age, race, sex, hormone replacement, alcohol intake, diabetes, body mass index, estimated glomerular filtration rate, and C-reactive protein, the hazard ratios (HR) (95% confidence interval) for high versus normal AST were 1.46 (1.00-2.11) for total VTE and 1.83 (1.21-2.79) for provoked VTE. For high GGT, the HR were 1.34 (1.06-1.69) for total VTE and 1.43 (1.07-1.91) for provoked VTE. When follow-up was limited to the first 10 years, associations were even stronger (HR ≈ 1.7 for total VTE)., Conclusions: Elevated concentrations of two hepatic enzymes (AST and GGT) in this general middle-aged population are associated with a modestly increased risk of VTE., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites. However, prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope., Methods and Results: We ascertained VTE from 3 prospective studies: the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Reasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438 090 person-years, 916 incident VTE events (302 in blacks) occurred in 51 149 individuals (17 318 blacks) who were followed up. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in the CHS (hazard ratio, 1.81; 95% confidence interval, 1.20-2.73) but not ARIC (hazard ratio, 1.21; 95% confidence interval, 0.96-1.54). In REGARDS, there was a significant region-by-race interaction (P=0.01): Blacks in the Southeast had a significantly higher rate of VTE than blacks in the rest of the United States (hazard ratio, 1.63; 95% confidence interval, 1.08-2.48) that was not seen in whites (hazard ratio, 0.83; 95% confidence interval, 0.61-1.14)., Conclusions: The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies or different regional rates of VTE. Further studies of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.

Increased levels of plasma troponins and natriuretic peptides are markers of cardiac dysfunction associated with increased risk of cardiovascular disease. Little information exists on cardiac dysfunction and occurrence of venous thromboembolism (VTE). In two prospective epidemiological cohorts, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with VTE occurrence. The Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS) measured plasma TnT and NT-proBNP in 13,719 men or women with no history of venous thrombosis, coronary heart disease, or heart failure and followed them for approximately 10 years for VTE occurrence (n = 348 VTEs). In both ARIC and CHS, TnT was associated positively with incidence of total VTE and provoked VTE, but not with unprovoked VTE: age, race, and sex-adjusted hazard ratios for total VTE in the pooled analysis were 1.00, 0.85, 1.36, 1.51, and 1.98 (p-trend <0.0001) across five categories of TnT. In contrast, the association of NT-proBNP with VTE was positive in ARIC (hazard ratios approximately 2.5-fold for the highest versus lowest NT-proBNP quintiles), but non-existent in CHS.

Diabetes has been inconsistently associated with increased risk of venous thromboembolism (VTE) and there is little direct evidence on the associations of glycemia levels with VTE. We used data from the Atherosclerosis Risk in Communities study to test the hypothesis that glycemia, as measured by hemoglobin A1c (A1c), is positively associated with VTE. Participants aged 45-64 years (n = 12,298) had A1c measured in 1990 and were followed for incident VTE (n = 345) through 2005. Because A1c is affected by diabetes treatment, analyses were stratified by history of diagnosed diabetes. Owing to evidence of non-linearity, we categorized A1c according to clinical cut-points: <5.7, 5.7-6.4, and ≥ 6.5% in those with no diagnosed diabetes; <7.0 and ≥ 7.0% in those with diagnosed diabetes. After adjustment for potential confounders, the hazard ratios (95% CIs) for VTE across increasing A1c categories were 1 (referent), 1.02 (0.77, 1.35) and 0.72 (0.41, 1.29) for those without diagnosed diabetes, and 1.30 (0.77, 2.17) and 1.41 (0.95, 2.09) for those with diagnosed diabetes. To explore the relation, we employed various models to adjust for potential confounding variables and modeled A1c as tertiles. We consistently found elevated hazard ratios in those with diagnosed diabetes, though the association was not statistically significant in every model. Hazard ratios in those without diagnosed diabetes were close to 1. In conclusion, our results are mildly suggestive that diagnosed diabetes and high levels of glucose, per se, may increase the risk of VTE. Elevated glucose was not related to VTE in those without diagnosed diabetes.

Introduction: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied., Methods: We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3 years (from 1996-98 through 2005) for VTE occurrence (n=226)., Results: There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥130 mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14)., Conclusion: Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Recent findings suggest that chronic kidney disease (CKD) may be associated with an increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted., Methods and Results: We pooled individual participant data from 5 community-based cohorts from Europe (second Nord-Trøndelag Health Study [HUNT2], Prevention of Renal and Vascular End-stage Disease [PREVEND], and the Tromsø study) and the United States (Atherosclerosis Risks in Communities [ARIC] and Cardiovascular Health Study [CHS]) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria, and CKD with objectively verified VTE. To estimate adjusted hazard ratios for VTE, categorical and continuous spline models were fit by using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1178 VTE events occurred over 599 453 person-years follow-up. Relative to eGFR 100 mL/min per 1.73 m(2), hazard ratios for VTE were 1.29 (95% confidence interval, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for eGFR 60, 1.82 (1.27-2.60) for eGFR 45, and 1.95 (1.26-3.01) for eGFR 30 mL/min per 1.73 m(2). In comparison with an albumin-to-creatinine ratio (ACR) of 5.0 mg/g, the hazard ratios for VTE were 1.34 (1.04-1.72) for ACR 30 mg/g, 1.60 (1.08-2.36) for ACR 300 mg/g, and 1.92 (1.19-3.09) for ACR 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted hazard ratio for CKD, defined as eGFR <60 mL/min per 1.73 m(2) or albuminuria ≥30 mg/g, (versus no CKD) was 1.54 (95% confidence interval, 1.15-2.06). Associations were consistent in subgroups according to age, sex, and comorbidities, and for unprovoked versus provoked VTE, as well., Conclusions: Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.

Apart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12-1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m² had a HR for VTE of 3.09 (95%CI: 2.26-4.23) compared to those with normal BMI (<25 kg/m²). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.

Venous thromboembolism (VTE) recurs frequently. Greater height is associated with increased risk of incident VTE, but it is unclear whether height is related to risk of VTE recurrence. Recurrent VTE is associated with substantial morbidity and mortality, thus identifying individuals at greatest risk of experiencing a recurrent event, who may benefit from extended anticoagulant therapy, is vitally important. Using data from the Iowa Women,s Health Study, we explored whether greater height was associated with increased risk of VTE recurrence.Among 1,691 women who experienced an initial VTE event, 286(16.9%) experienced a recurrent event. Risk of recurrence was 76%(95% CI: 16% -186%) higher among women >66 inches [168 cm] tall relative to those ≤62 inches [158 cm] tall, after adjustment for age and waist circumference. Future research should evaluate whether body height improves clinical prediction of VTE recurrence risk.

Recently, there has been interest in determining whether diet is associated with the risk of venous thromboembolism. The article by Varraso et al. (Am J Epidemiol. 2012;175(2):114-126) published in this issue of the Journal is an important contribution to this literature. In this commentary, the author discusses the findings of Varraso et al. within the context of the existing literature and posits epidemiologic explanations for why investigators might have failed to identify strong associations between diet and venous thromboembolism.

Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesised that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus torso length. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height, we standardised leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 years. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modelled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.

Background: The incidence of venous thromboembolism (VTE) is increased with severe kidney disease, but whether less-severe chronic kidney disease (CKD) increases the risk of VTE is less certain., Methods: We studied this in a prospective cohort of 10 700 whites and African Americans, aged 53-75 years, attending Visit 4 (1996-98) of the Atherosclerosis Risk in Communities Study. Estimated glomerular filtration rate (eGFR) values were estimated from prediction equations based on serum creatinine (eGFR(creat)) or cystatin C (eGFR(cys)). Normal kidney function was defined as eGFR ≥90 ml/min/1.73 m(2), mildly decreased kidney function as eGFR between 60 and 89 ml/min/1.73 m(2) and Stage 3 to 4 CKD as eGFR between 15 and 59 ml/min/1.73 m(2). VTE occurrence (n = 228) was ascertained over a median of 8.3 years., Results: For eGFR(cys), the age-, race- and sex-adjusted hazard ratios of total VTE were 1.0, 1.40 and 1.94 (P trend = 0.003) for normal kidney function, mildly impaired kidney function and Stage 3 to 4 CKD, respectively. These respective hazard ratios were moderately attenuated to 1.0, 1.26 and 1.60 (P trend = 0.04) with adjustment for hormone replacement therapy, diabetes and body mass index. Associations between CKD based on eGFR(cys) and VTE were slightly stronger for idiopathic VTE than for secondary VTE. In contrast, CKD based on eGFR(creat) was not associated with total VTE occurrence., Conclusions: Stage 3 to 4 CKD, based on eGFR(cys) but not eGFR(creat), was associated with an approximately 1.6-fold increased risk of VTE.

Tissue factor pathway inhibitor (TFPI) inhibits tissue factor, a potent coagulation initiator. Limited evidence suggests that low TFPI levels are associated with increased risk of venous thromboembolism (VTE). We measured total TFPI in a nested case-control study in the Longitudinal Investigation of Thromboembolism Etiology. Control subjects were frequency matched 2:1 to cases on age, sex, race, and cohort. Odds ratios (ORs) for VTE by TFPI levels were computed using logistic regression models adjusting for age, race, sex, coagulation factors (factors VII, VIII, IX, XI, D-dimer), and body mass index (BMI). To evaluate for greater than additive interactions, we calculated the percent relative excess risk due to interaction between TFPI and other VTE risk factors. A total of 534 cases of VTE occurred and matched to 1,091 controls. Mean baseline TFPI in ng/ml (standard deviation) in those who developed VTE and controls was 36.4 (12.8) and 35.0 (11.1), respectively. Higher TFPI was associated with male sex, age, BMI, factors VII, VIII, IX, XI, and D-dimer. TFPI level did not differ by ethnicity, factor V Leiden, or prothrombin G20210A. Compared with those in the upper 95%, the bottom 5% of TFPI had an age-, sex-, race-, and study-adjusted OR (95% CI) of 1.35 (0.86, 2.12) for VTE. Adjusting for factors VII, VIII, IX, and XI the OR was 1.93 (1.05, 3.53). Further addition of D-dimer and BMI to this model decreased the OR to 1.70 (0.98, 2.93). Low TFPI did not demonstrate greater than additive interaction with other VTE risk factors.

Objectives: We sought to document incidence, case-fatality, and recurrence rates of venous thromboembolism (VTE) in women and to explore the relationship of demographic, lifestyle, and anthropometric factors to VTE incidence., Methods: Data from participants aged 55 to 69 years in the Iowa Women's Health Study were linked to Medicare data for 1986 through 2004 (n = 40 377) to identify hospitalized VTE patients., Results: A total of 2137 women developed VTE, yielding an incidence rate of 4.04 per 1000 person-years. The 28-day case-fatality rate was 7.7%, and the 1-year recurrence rate was 3.4%. Educational attainment, physical activity, and age at menopause were inversely associated with VTE. Risk of secondary (particularly cancer-related) VTE was higher among smokers than among those who had never smoked. Body mass index, waist circumference, waist-to-hip ratio, height, and diabetes were positively associated with VTE risk. Hormone replacement therapy use was associated with increased risk of idiopathic VTE., Conclusions: VTE is a significant source of morbidity and mortality in older women. Risk was elevated among women who were smokers, physically inactive, overweight, and diabetic, indicating that lifestyle contributes to VTE risk.

The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.

The role of inflammation in the causation of venous thromboembolism (VTE) is uncertain. In 10,505 participants of the Atherosclerosis Risk in Communities (ARIC) Study, we assessed the association of the systemic inflammation marker, elevated C-reactive protein (CRP), with incidence of VTE (n=221) over a median of 8.3 years of follow-up. Adjusted for age, race, and sex, the hazard ratios of VTE across quintiles of CRP were 1.0, 1.61, 1.16, 1.56, and 2.31 (p for trend p<0.0007). For CRP above the upper 10 percentile (> or = 8.55 mg/L), compared with the lowest 90% of CRP values, the hazard ratio of VTE was 2.07 (95% CI 1.47, 2.94). Further adjustment for baseline hormone replacement therapy, diabetes, and body mass index attenuated the hazard ratios only slightly. For example, the adjusted hazard ratio of VTE was 1.76 (95% CI 1.23, 2.52) for CRP above versus below the 90(th) percentile. In conclusion, this prospective, population-based study suggests elevated CRP is independently associated with increased risk of VTE.

Background: Little is known about the role of diet in the development of venous thromboembolism (VTE). We explored the prospective relation of dietary patterns, food groups, and nutrients to incident VTE in older women., Methods: In 1986, Iowa women aged 55 to 69 years completed a mailed survey, including a 127-item food frequency questionnaire. These data were linked to Medicare data from 1986 to 2004, and International Classification of Diseases discharge codes were used to identify hospitalized VTE cases. Cox regression analyses evaluated relations of 2 principal components-derived dietary patterns, 11 food groups, and 6 nutrients to VTE, adjusted for age, education, smoking status, physical activity, and energy intake., Results: Over 19 years of follow-up, 1,950 of the 37,393 women developed VTE. Women consuming alcohol daily were at 26% (95% CI 11%-38%) lower risk of VTE as compared to nonconsumers. All alcoholic beverages types were in the direction of lower risk; however, only beer and liquor were statistically significant. After basic adjustments, coffee was inversely related to VTE, and diet soda and fish positively related. However, these associations were confounded and became nonsignificant after adjustment for body mass index and diabetes. No associations were observed with consumption of 'Western' or 'Prudent' dietary patterns, fruit, vegetables, dairy, meat, refined grains, whole grains, regular soda, vitamins E, vitamin B6, vitamin B12, folate, omega-3 fatty acids, or saturated fat., Conclusions: In this cohort of older women, greater intake of alcohol was associated with a lower risk of incident VTE. No other independent associations were seen between diet and VTE.

Objectives: Previous studies on a potential association between endodontic infection (EI) and cardiovascular disease (CVD) produced mixed results. Endodontic treatment (ET) may also be linked to cardiovascular risk, as a marker for prior chronic dental infection and subclinical EI in other teeth. We tested the hypothesis that ET is associated with elevated risk of coronary heart disease (CHD), ischemic stroke (IS), heart failure (HF), or venous thromboembolism (VTE).Methods: ARIC participants who completed the dental ancillary study exam 4 (1996-1998; n = 6,638) were included in the analyses. Participants were followed through 2013 for CHD, stroke, and HF and 2011 for VTE. Cox-proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CHD, IS, HF, and VTE across ET classifications adjusting for age, sex, race/center, education, income, smoking, alcohol consumption, BMI, statin use, family history of CHD, physical activity, diet quality, insurance status, last dental visit, dental visit frequency, having a current dentist, and tooth loss due to gum disease.Results: Among participants, 21.0% reported a single ET, while 28.5% reported multiple ETs. Over a median of 15.8 years of follow-up, there were 506 incident CHD events, 311 IS events, 739 HF events, and 219 VTE events. There were no significant associations between self-reported history of ET and any of our outcomes (HR (95%CI): CHD = 1.16 (0.87,1.44), IS = 0.77 (0.55,1.09), HF = 1.00 (0.81,1.24), VTE = 0.98 (0.67,1.43)) after adjustment.Conclusions: Our results do not support an independent association between ET and development of CHD, IS, HF, or VTE. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied. Methods: We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3years (from 1996-98 through 2005) for VTE occurrence (n =226). Results: There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥130mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14). Conclusion: Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk. [Copyright &y& Elsevier]