Association of Mild to Moderate Chronic Kidney Disease With Venous Thromboembolism Pooled Analysis of Five Prospective General Population Cohorts

BACKGROUND: Recent findings suggest that chronic kidney disease (CKD) may be associated with 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 five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m(2), HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m(2). Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m(2) or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE. 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

Cardiovascular Risk Factors Associated With Venous Thromboembolism.

IMPORTANCE: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. DESIGN, SETTING, AND PARTICIPANTS: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. EXPOSURES: A panel of several established cardiovascular risk factors. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). RESULTS: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. CONCLUSIONS AND RELEVANCE: Older age, smoking, and adiposity were consistently associated with higher VTE risk.This research has been conducted using the UK Biobank resource under Application Number 26865. This work was supported by underpinning grants from the UK Medical Research Council (grant G0800270), the British Heart Foundation (grant SP/09/002), the British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (grant 268834), the European Commission Framework Programme 7 (grant HEALTH-F2-2012-279233), and Health Data Research UK. Dr Danesh holds a British Heart Foundation Personal Chair and a National Institute for Health Research Senior Investigator Award

Association of Factor V Leiden with Subsequent Atherothrombotic Events:A GENIUS-CHD Study of Individual Participant Data

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population