Abstract
Aims
Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce.
Methods and results
Systematic phenotyping of ...CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40–80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% 95% confidence interval (CI), 35.6–37.4%, 13.3% 12.6–13.9%, and 40.8% 39.9–41.7%, respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication hazard ratio (HR) 1.46 (95% CI 1.19–1.79), P = 0. 0003. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort HR 1.51 (95% CI 1.11–2.05), P = 0.009.
Conclusion
Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.
Graphical Abstract
Chronic venous insufficiency is highly prevalent in the general population and associated with arterial cardiovascular disease and an increased risk of all-cause mortality.
Endogenous arginine derivatives homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethyarginine (SDMA) are independent mortality predictors in atherosclerotic cardiovascular disease ...(CVD). Our study reports the first analysis, whether homoarginine, ADMA and SDMA predict venous thromboembolism (VTE) recurrence and overall mortality in patients with suspected acute VTE. We assessed serum levels of homoarginine, ADMA and SDMA by LC-MS/MS in 865 individuals from a prospective consecutive cohort of patients with clinical suspicion of VTE. The median follow-up time for mortality was 1196 days. VTE was confirmed by imaging in 418 patients and excluded in 447 patients. Low levels of homoarginine and high levels of ADMA or SDMA independently predicted all-cause mortality after adjustment for sex, age, oral anticoagulants, body mass index, arterial hypertension, diabetes mellitus, smoking, dyslipidemia, chronic heart failure, history of stroke, creatinine and cancer both in patients with VTE and without VTE. Interestingly, none of those parameters was predictive for VTE recurrence. We provide the first report that low circulating levels of homoarginine and high circulating levels of ADMA and SDMA independently predict all-cause mortality in patients with suspected VTE. These parameters might serve as markers of "frailty" and should be considered for future risk stratification approaches in this clinical population. Taking into account that homoarginine supplementation is protective in animal models of CVD and safe in healthy human volunteers, our study provides the basis for future homoarginine supplementation studies in patients with suspected VTE to investigate possible direct protective effects of homoarginine in this population.
Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered ...by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked 'missForest' and the recently published 'GSimp' method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the cost-saving of a specialized, eHealth-based management service (CS) in comparison to regular medical care (RMC) for the management of patients receiving oral anticoagulation (OAC) ...therapy. Costs of hospitalization were derived via diagnosis-related groups which comprise diagnoses (ICD-10) and operation and procedure classification system (OPS), which resulted in OAC-related (i.e. bleeding/ thromboembolic events) and non-OAC-related costs for both cohorts. Cost for anticoagulation management comprised INR-testing, personnel, and technical support. In total, 705 patients were managed by CS and 1490 patients received RMC. The number of hospital stays was significantly lower in the CS cohort compared to RMC (CS: 23.4/100 py; RMC: 68.7/100 py); with the most pronounced difference in OAC-related admissions (CS: 2.8/100 py; RMC: 13.3/100 py). Total costs for anticoagulation management amounted to 101 EUR/py in RMC and 311 EUR/py in CS, whereas hospitalization costs were 3261 IQR 2857-3689 EUR/py in RMC and 683 504-874 EUR/py in CS. This resulted in an overall cost saving 2368 EUR/py favoring the CS. The lower frequency of adverse events in anticoagulated patients managed by the telemedicine-based CS compared to RMC translated into a substantial cost-saving, despite higher costs for the specialized management of patients.Trial registration: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.
Previous reports have investigated the impact of age on D-Dimer testing in elderly individuals with suspected deep vein thrombosis (DVT), but data on the age-related diagnostic value of D-dimer in a ...sample covering a broad age range are limited. The present study determined age-specifically the diagnostic accuracy of D-dimer and compared it to C-reactive protein (CRP), a marker of inflammation, in 500 patients with suspected DVT from the VTEval project (NCT02156401). Sensitivity of D-dimer was lower in patients < 60 years in comparison to patients ≥ 60 years (∆-16.8%), whereas specificity was 27.9% higher. Lowest levels of sensitivity were detected for female sex, unprovoked DVT, low thrombotic burden, and distal DVT. A fixed D-dimer threshold of 0.25 mg/L FEU resulted in elevated sensitivity for patients < 60 with a reduction of false negatives by 40.0% for proximal DVT and by 50.0% for distal DVT. In patients < 60 years, D-dimer and CRP demonstrated comparable diagnostic performance for both proximal and distal DVT (p > 0.05). In conclusion, these data outline a clinically-relevant limitation of D-dimer testing among younger patients with suspected DVT indicating a necessity for age-adapted cut-off values. Further research is required to decrypt the role of inflammation in the pathophysiology and diagnosis of venous thrombosis.
Background Preclinical data have indicated a link between use of vitamin K antagonists ( VKA ) and detrimental effects on vascular structure and function. The objective of the present study was to ...determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population. Methods and Results Clinical and laboratory data, as well as medical-technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5-hour visit at the study center of the population-based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; 0.41/4.66; P=0.019), ankle-brachial index (β=-0.03; -0.04/-0.01; P<0.0001), intima-media thickness (β=+0.03 mm 0.01/0.05; P=0.0098), left ventricular ejection fraction (β=-4.02% -4.70/-3.33; P<0.0001), E/E' (β=+0.04 0.01/0.08; P=0.014) left ventricular mass (β=+5.34 g/m
4.26/6.44; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro-atrial natriuretic peptide: β=+0.58 pmol/L 0.50/0.65; P<0.0001; midregional pro-adrenomedullin: β=+0.18 nmol/L 0.14/0.22; P<0.0001; N-terminal pro B-type natriuretic peptide: β=+1.90 pg/mL 1.63/2.17; P<0.0001; fibrinogen: β=+143 mg/dL 132/153; P<0.0001; C-reactive protein: β=+0.31 mg/L 0.20/0.43; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP 2C9, CYP 4F2, and VKORC 1 were modulating effects of VKA on subclinical markers of cardiovascular disease. Conclusions These data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long-term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.
Venous thromboembolism (VTE) is a life-threatening disease with risk of recurrence. Oral anticoagulation (OAC) with vitamin K antagonists (VKA) is effective to prevent thromboembolic recurrence. We ...aimed to investigate the quality of OAC of VTE patients in regular medical care (RMC) compared to a telemedicine-based coagulation service (CS). The thrombEVAL study (NCT01809015) is a prospective, multi-center study to investigate OAC treatment (recruitment: January 2011–March 2013). Patients were evaluated using clinical visits, computer-assisted personal interviews, self-reported data and laboratory measurements according to standard operating procedures. Overall, 360 patients with VTE from RMC and 254 from CS were included. Time in therapeutic range (TTR) was higher in CS compared to RMC (76.9% (interquartile range IQR 63.2–87.1%) vs. 69.5% (52.3–85.6%), p < 0.001). Crude rate of thromboembolic events (rate ratio RR 11.33 (95% confidence interval CI 1.85–465.26), p = 0.0015), clinically relevant bleeding (RR 6.80 (2.52–25.76), p < 0.001), hospitalizations (RR 2.54 (1.94–3.39), p < 0.001) and mortality under OAC (RR 5.89 (2.40–18.75), p < 0.001) were consistently higher in RMC compared with CS. Patients in RMC had higher risk for primary outcome (clinically relevant bleedings, thromboembolic events and mortality, hazard ratio HR 5.39 (95%CI 2.81–10.33), p < 0.0001), mortality (HR 5.54 (2.22–13.84), p = 0.00025), thromboembolic events (HR 6.41 (1.51–27.24), p = 0.012), clinically relevant bleeding (HR 5.31 (1.89–14.89), p = 0.0015) and hospitalization (HR 1.84 (1.34–2.55), p = 0.0002). Benefits of CS care were still observed after adjusting for comorbidities and TTR. In conclusion, anticoagulation quality and outcome of VTE patients undergoing VKA treatment was significantly better in CS than in RMC. Patients treated in CS had lower rates of adverse events, hospitalizations and lower mortality. CS was prognostically relevant, beyond providing advantages of improved international ratio (INR) monitoring.
Oral anticoagulation (OAC) is effective at preventing and treating thromboses and thromboembolism in patients with normal renal function. We aimed to research the impact of severe renal failure (RF) ...on patient outcome and to determine the potential benefit of caring for these patients in a specialized coagulation service (CS). A total of 1516 usual medical care patients and 756 CS-managed patients of the thrombEVAL multicenter (21 centers), prospective, cohort study (NCT01809015) were analyzed in a 3-year follow-up. Patients with RF (serum creatinine >3 mg/dL, no renal replacement therapy) were compared to patients without RF in usual care and a CS. The fluctuations in the international normalized ratios were significantly lower in CS-managed patients, and regardless of treatment in usual care or a CS, the time in therapeutic range was significantly lower in RF patients. Cox regression-adjusted hazard ratios for long-term outcome (1.5, 95% CI: 1.22-1.83,
< 0.001), death (1.62, CI: 1.27-2.08,
< 0.001), and hospitalization (1.21, CI: 1.02-1.44,
= 0.032) were significantly higher in RF patients in usual care. Furthermore, there was a trend of more bleeding events in RF patients. CS-treated patients had significantly lower adjusted hazard ratios for death (0.24, CI: 0.14-0.39,
< 0.001), hospitalizations (0.41, CI: 0.34-0.5,
< 0.001), clinically relevant bleeding (0.29, CI: 0.18-0.47,
< 0.001), and major bleeding (0.33, CI: 0.18-0.59,
< 0.001). Thus, patients who required oral anticoagulation therapy benefitted significantly from being managed in a specialized coagulation service, regardless of their renal function.
To investigate the impact of lockdown policies on the recruitment of an ongoing cohort study.
We performed descriptive analyses of recruitment, dropout, and baseline characteristics over time. Oxford ...Stringency Index was used to assess the impact of regional constraints on recruitment.
Drop in recruitment clearly reflected the Stringency Index within the first months of the pandemic. Unexpectedly, drop-out rates declined in 2020/2021. Baseline characteristics were comparable, yet younger women were recruited more frequently during the pandemic.
There was no strong evidence of recruitment bias due to the pandemic.
The COVID-19 pandemic is a potential source of bias for ongoing studies and its influence on the study conduct (e.g., recruitment, drop-out) should be thoroughly evaluated to ensure that study results are not biased in this regard. The Oxford's Government Stringency Index can be used to identify pandemic-affected time periods.
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