BACKGROUND Although polypharmacy is associated with a negative clinical outcome in various settings and commonly observed in patients receiving oral anticoagulation therapy, evidence on the relevance for the clinical outcome of anticoagulated patients is currently limited. The aim of the study was to investigate the effect of polypharmacy on the clinical outcomes among patients taking phenprocoumon. DESIGN Prospective cohort study. SETTING Regular medical care. PARTICIPANTS Information on 2011 individuals receiving vitamin K antagonists was available for analysis from the prospective multicenter thrombEVAL study. MEASUREMENTS Data were obtained from clinical visits, computer‐assisted interviews, and laboratory measurements. Information on clinical outcome was obtained during a 3‐year follow‐up period and subsequently validated via medical records. RESULTS The prevalence of polypharmacy (five drugs or more) was 84.1% (n = 1691). Quality of anticoagulation therapy assessed by time in therapeutic range was lower in individuals on five to eight drugs and nine drugs or more (70.7% and 64.7%, respectively) compared with subjects without polypharmacy (73.4%). In addition, a significantly higher variability of international normalized ratio measurements was found in the presence of polypharmacy. The cumulative incidence of bleeding, hospitalization, and all‐cause mortality, but not for thromboembolic events, increased across groups of medication. In adjusted Cox regression analysis, polypharmacy is an independent risk factor for bleeding (hazard ratio [HR]≥ 9 drugs vs 1‐4 drugs = 1.62; 95% confidence interval [CI] = 1.04‐2.52; p = .033); hospitalization (HR≥ 9 drugs vs 1‐4 drugs = 1.60; 95% CI = 1.26‐2.03; p < .001; and all‐cause mortality (HR≥ 9 drugs vs 1‐4 drugs = 2.16; 95% CI = 1.43‐3.27; p < .001) in a dose‐dependent relationship. Per additional drug, bleeding risk was increased by 4%. CONCLUSIONS Polypharmacy influences the quality of anticoagulation therapy and translates into an elevated risk of adverse events in anticoagulated patients. This suggests that additional medication intake in such patients should be critically reviewed by physicians, and it highlights the importance of initiating investigations aimed at reducing multiple medication intake. J Am Geriatr Soc 67:463–470, 2019.
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.
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.
Renal impairment, a source of chronic hypercoagulability 1 and inflammation, 2 is known to reduce the specificity of the D-dimer test in the diagnosis of venous thromboembolism (VTE). 3 This leads to many false positives in such patients and consequently to additional costs, as well as the unnecessary exposure of patients with renal impairment to contrast dye used in computed tomographic pulmonary angiography. 3 To address this issue, researchers have attempted to develop renal function-based thresholds for the D-dimer test. 4-6 The thresholds presented so far have varied greatly, which we surmised might have been due to unmeasured confounding factors. We therefore studied whether a renal function-adjusted D-dimer test could improve diagnostic performance for individuals with suspected VTE, and how the relationship between D-dimer levels and estimated glomerular filtration rates (eGFR) is affect
Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism (GMP-VTE) Project, a multi-center prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n=96) against those of patients with DVT-associated PE (n=276) or isolated DVT (n=160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of five proteins: interferon-γ (IFNG), glial cell line-derived neurotrophic growth factor (GDNF), polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), peptidyl arginine deiminase type-2 (PADI2) and interleukin-15 receptor subunit α (IL-15Rα). These proteins were orthogonally validated using cis protein quantitative trait loci (cis pQTLs). External replication in an independent population-based cohort (n=5,778) further validated the proteomic results, and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years, interquartile range: 1.6 - 4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate non-canonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.
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