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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. [ABSTRACT FROM AUTHOR]

Background--Hereditary thrombophilia is associated with a slightly increased risk of arterial thromboembolism (ATE). Whether hereditary thrombophilia interacts with traditional cardiovascular risk factors on the risk of ATE has yet to be established. Methods and Results--A total of 1891 individuals belonging to 4 family cohorts from the Netherlands were included in the analyses. Five hereditary thrombophilic defects, including factor V Leiden, prothrombin G20210A defect, and deficiencies of the natural anticoagulants (ie, antithrombin, protein C, and protein S), were assessed, and data on risk factors and previous ATE were collected. Thrombophilia was associated with elevated risk of ATE (hazard ratio =1.74, 95% confidence interval, 1.18-2.58; P=0.005). Overall, the association of thrombophilia with ATE tended to be stronger in the presence of traditional cardiovascular risk factors, especially the synergistic effect of thrombophilia with diabetes mellitus was striking (hazard ratio of thrombophilia-ATE association was 1.41 in nondiabetics versus 8.11 in diabetics). Moreover, the association of thrombophilia with ATE tended to be stronger in females and before the age of 55 years as compared with males and individuals >55 years of age, respectively. Conclusions--Thrombophilia is associated with ATE. This association may be stronger in the presence of traditional cardiovascular risk factors in particular in individuals with diabetes mellitus. Future studies on thrombophilia-ATE risk should focus on high-risk populations with high prevalence of traditional cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

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 m², 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 m2. 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 m² 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. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype–guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y12 inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19 *2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19 *17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel–treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. Results: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19 *17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45–2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48–1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56–0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68–1.90]). Conclusions: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19 *17 polymorphism. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/; Unique identifier: NL2872. [ABSTRACT FROM AUTHOR]

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]; I 2 =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.

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk., Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD., Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09)., Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: Whether hereditary protein S, protein C, or antithrombin deficiency is associated with arterial thromboembolism (ATE) and whether history of venous thromboembolism in these subjects predisposes them to subsequent ATE have yet to be determined., Methods and Results: On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46+/-17 years), belonging to 84 different kindreds, in this retrospective family cohort study. Detailed information on previous episodes of venous thromboembolism, ATE, anticoagulant use, and atherosclerosis risk factors was collected. Primary study outcome was objectively verified symptomatic ATE. Of 552 subjects, 308 had protein S (35%), protein C (39%), or antithrombin (26%) deficiency. Overall, annual incidences of ATE were 0.34% (95% confidence interval [CI], 0.23 to 0.49) in deficient versus 0.17% (95% CI, 0.09 to 0.28) in nondeficient subjects; the hazard ratio was 2.3 (95% CI, 1.2 to 4.5). Because the risk hazards varied over lifetime, we performed a time-dependent analysis. After adjusting for atherosclerosis risk factors and clustering within families, we found that deficient subjects had a 4.7-fold (95% CI, 1.5 to 14.2; P=0.007) higher risk for ATE before 55 years of age versus 1.1 (95% CI, 0.5 to 2.6) thereafter compared with nondeficient family members. For separate deficiencies, the risks were 4.6- (95% CI, 1.1 to 18.3), 6.9- (95% CI, 2.1 to 22.2), and 1.1- (95% CI, 0.1 to 10.9) fold higher in protein S-, protein C-, and antithrombin-deficient subjects, respectively, before 55 years of age. History of venous thromboembolism was not related to subsequent ATE (hazard ratio, 1.1; 95% CI, 0.5 to 2.2)., Conclusions: Compared with nondeficient family members, subjects with protein S or protein C deficiency but not antithrombin deficiency have a higher risk for ATE before 55 years of age that is independent of prior venous thromboembolism.

Background: No data are available on the absolute risk of either venous thromboembolism (VTE) or arterial thromboembolism (ATE) in patients with nephrotic syndrome. Reported risks are based on multiple case reports and small studies with mostly short-term follow-up. We assessed the absolute risk of VTE and ATE in a large, single-center, retrospective cohort study and attempted to identify predictive factors in these patients., Methods and Results: A total of 298 consecutive patients with nephrotic syndrome (59% men; mean age, 42+/-18 years) were enrolled. Mean follow-up was 10+/-9 years. Nephrotic syndrome was defined by proteinuria > or =3.5 g/d, and patients were classified according to underlying histological lesions accounting for nephrotic syndrome. Objectively verified symptomatic thromboembolic events were the primary study outcome. Annual incidences of VTE and ATE were 1.02% (95% confidence interval, 0.68 to 1.46) and 1.48% (95% confidence interval, 1.07 to 1.99), respectively. Over the first 6 months of follow-up, these rates were 9.85% and 5.52%, respectively. Proteinuria and serum albumin levels tended to be related to VTE; however, only the predictive value of the ratio of proteinuria to serum albumin was significant (hazard ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P=0.03). In contrast, neither the degree of proteinuria nor serum albumin levels were related to ATE. Sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate predicted ATE (P< or =0.02)., Conclusions: This study verifies high absolute risks of symptomatic VTE and ATE that were remarkably elevated within the first 6 months. Whereas the ratio of proteinuria to serum albumin predicted VTE, estimated glomerular filtration rate and multiple classic risk factors for atherosclerosis were predictors of ATE.