Publications by authors named "Lisa Eggebrecht"

18 Publications

  • Page 1 of 1

Homoarginine and methylarginines independently predict long-term outcome in patients presenting with suspicion of venous thromboembolism.

Sci Rep 2021 May 5;11(1):9569. Epub 2021 May 5.

Department of Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

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.
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http://dx.doi.org/10.1038/s41598-021-88986-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100302PMC
May 2021

Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism.

Blood 2021 May;137(19):2681-2693

Preventive Cardiology and Preventive Medicine, Center for Cardiology.

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 Project, a multicenter 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 5 proteins: interferon-γ, glial cell line-derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) 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 noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.
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http://dx.doi.org/10.1182/blood.2019004571DOI Listing
May 2021

Cost saving analysis of specialized, eHealth-based management of patients receiving oral anticoagulation therapy: Results from the thrombEVAL study.

Sci Rep 2021 Jan 28;11(1):2577. Epub 2021 Jan 28.

Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz, 55131, Germany.

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.
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http://dx.doi.org/10.1038/s41598-021-82076-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844022PMC
January 2021

Missing value imputation in proximity extension assay-based targeted proteomics data.

PLoS One 2020 14;15(12):e0243487. Epub 2020 Dec 14.

Institute of Organismic and Molecular Evolution, Johannes Gutenberg University Mainz, Mainz, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243487PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735586PMC
January 2021

Telemedicine-Based Specialized Care Improves the Outcome of Anticoagulated Individuals with Venous Thromboembolism-Results from the thrombEVAL Study.

J Clin Med 2020 Oct 13;9(10). Epub 2020 Oct 13.

Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

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%), < 0.001). Crude rate of thromboembolic events (rate ratio [RR] 11.33 (95% confidence interval [CI] 1.85-465.26), = 0.0015), clinically relevant bleeding (RR 6.80 (2.52-25.76), < 0.001), hospitalizations (RR 2.54 (1.94-3.39), < 0.001) and mortality under OAC (RR 5.89 (2.40-18.75), < 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), < 0.0001), mortality (HR 5.54 (2.22-13.84), = 0.00025), thromboembolic events (HR 6.41 (1.51-27.24), = 0.012), clinically relevant bleeding (HR 5.31 (1.89-14.89), = 0.0015) and hospitalization (HR 1.84 (1.34-2.55), = 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.
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http://dx.doi.org/10.3390/jcm9103281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602093PMC
October 2020

Isolated Pulmonary Embolism Is Associated With a High Risk of Arterial Thrombotic Disease: Results From the VTEval Study.

Chest 2020 07 23;158(1):341-349. Epub 2020 Mar 23.

Department of Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. Electronic address:

Background: Isolated PE is associated with a higher burden of atherosclerotic disease than other manifestations of VTE.

Research Question: We hypothesized that the presence of isolated PE may signal a chronically elevated risk of arterial thrombotic disease.

Study Design And Methods: Data from the VTEval Study, a prospective cohort study enrolling individuals with clinical suspicion and imaging-based diagnosis or exclusion of VTE, were analyzed. Patients with PE received whole-leg ultrasonography to assess presence of DVT. Regularized logistic regression identified features that discriminate between isolated PE and other VTE phenotypes at clinical presentation. Survival analyses were performed to evaluate the crude and adjusted 3-year risks of arterial thrombotic disease, recurrent VTE, and death.

Results: The sample comprised 510 patients. Isolated PE patients (n = 63) had a distinct clinical profile from patients with other VTE phenotypes (n = 447). COPD, peripheral artery disease, atrial fibrillation, and coronary artery disease were significantly more prevalent among patients with isolated PE. Isolated PE patients had significantly higher risk (incidence rate ratio vs DVT-associated PE, 3.7 (95% CI, 1.3-10.8, P = .009); vs isolated DVT, 4.8 (1.7-14.3, P = .001) of arterial thrombotic events (ie, myocardial infarction, stroke/transient ischemic attack). After adjustment for clinical profile and medication intake, the risk of arterial thrombotic events for patients with isolated PE remained quadruple that of other VTE phenotypes (hazard ratio [HR], 3.8 [1.3-10.9], P = .01).

Interpretation: Patients with isolated PE are at higher risk for arterial thrombosis and may require screening for arterial disease and development of novel therapeutic strategies.

Clinical Trial Registration: NCT02156401.
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http://dx.doi.org/10.1016/j.chest.2020.01.055DOI Listing
July 2020

Specialized Management of Oral Anticoagulation Therapy Improves Outcome in Patients with Chronic Renal Insufficiency.

J Clin Med 2020 Feb 28;9(3). Epub 2020 Feb 28.

Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

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.
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http://dx.doi.org/10.3390/jcm9030645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141283PMC
February 2020

The relevance of depressive symptoms for the outcome of patients receiving vitamin K-antagonists: Results from the thrombEVAL cohort study.

Eur Heart J Cardiovasc Pharmacother 2020 Jan 10. Epub 2020 Jan 10.

DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.

Aims: Although depressive symptoms are highly prevalent in patients receiving oral anticoagulation (OAC), the relevance of depression for the outcome of anticoagulated individuals is unknown.

Methods And Results: We analyzed data from the multi-center cohort study thrombEVAL (NCT01809015), investigating the efficacy of OAC with vitamin K-antagonists. There was an independent study monitoring, and an independent review panel assessed the endpoints. Out of n = 1,558 participants, information about depressive symptoms, as measured by the two-item screener PHQ-2, was available in n = 1,405 individuals. The mean follow-up period was 28.04 months, with a standard deviation of 11.52 months. In multivariable Cox regression analysis, baseline PHQ-2 sum score was a strong and robust predictor of clinically-relevant bleeding (hazard ratio (HR) 1.13, 95% confidence interval 1.03-1.24; p = 0.011) and all-cause mortality (HR 1.18, 1.08-1.28; p = 0.001) independent of age, sex, high school graduation, partnership, clinical profile, intake of SSRI, and quality of OAC therapy. Individuals with clinically significant depressive symptoms (PHQ-2 ≥3) had a 57% increased risk for clinically relevant bleeding (fully adjusted HR 1.57, 1.08-2.28) and 54% greater risk for death (fully adjusted HR 1.54, 1.09-2.17). There was no association of depressive symptoms with thromboembolic events. For hospitalization, individuals with depressive symptoms (PHQ-2 ≥3) did not experience an elevated risk in the fully adjusted model (HR 1.08, 0.86, 1.35; p = 0.52).

Conclusions: Assessment of depression by the PHQ-2 provided independent long-term prognostic information beyond common biomedical risk factors. These findings highlight the need for targeting depressive symptoms in the management of patients receiving OAC therapy.
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http://dx.doi.org/10.1093/ehjcvp/pvz085DOI Listing
January 2020

Subtherapeutic Anticoagulation Control under Treatment with Vitamin K-Antagonists-Data from a Specialized Coagulation Service.

Thromb Haemost 2019 Aug 10;119(8):1347-1357. Epub 2019 Jun 10.

Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.

In contrast to overanticoagulation, evidence on risk factors and outcome of subtherapeutic oral anticoagulation (OAC) with vitamin K-antagonists (VKAs) under optimum care is limited. We investigated the clinical phenotype, anticoagulation control, and clinical outcome of 760 VKA patients who received OAC therapy by a specialized coagulation service in the thrombEVAL study (NCT01809015). During 281,934 treatment days, 278 patients experience ≥ 1 episode of subtherapeutic anticoagulation control and had lower quality of OAC therapy compared to 482 patients without subtherapeutic international normalized ratio: 67.6%, interquartile range (IQR) 54.9%/76.8% versus 81.0%, IQR 68.5%/90.4%;  < 0.001. In Cox regression analysis with adjustment for age, sex, cardiovascular risk factors, comorbidities, and treatment characteristics, female sex (hazard ratio [HR], 1.4, 95% confidence interval [CI], 1.0/1.9;  = 0.03), diabetes (HR, 1.4, 95% CI, 1.0/2.0;  = 0.03), and living alone (HR, 1.5, 95% CI, 1.1/2.1;  = 0.009) were independent risk factors of subtherapeutic anticoagulation control, whereas atrial fibrillation (HR, 0.6, 95% CI, 0.4/0.9;  = 0.02) and self-management of OAC therapy (HR, 0.2, 95% CI, 0.1/0.6;  = 0.001) were protective. In addition, active smoking (HR, 1.7, 95% CI, 0.9/3.0;  = 0.086) and living in a nursing home (HR, 1.6, 95% CI, 0.8/3.2;  = 0.15) indicated an elevated risk at the borderline of statistical significance. For the prediction of recurrent subtherapeutic anticoagulation, living alone was the only independent risk factor (HR, 1.7, 95% CI, 1.1/2.5;  = 0.013). The present study suggests that women, diabetics, and patients living alone experience an increased risk of low-quality VKA therapy and might potentially benefit from treatment with direct-acting anticoagulants.
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http://dx.doi.org/10.1055/s-0039-1692175DOI Listing
August 2019

Potential of Multidimensional, Large-scale Biodatabases to Elucidate Coagulation and Platelet Pathways as an Approach towards Precision Medicine in Thrombotic Disease.

Hamostaseologie 2019 Jun 5;39(2):152-163. Epub 2019 Feb 5.

Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Cardiovascular and especially thrombotic diseases remain a major cause of morbidity and mortality worldwide. In past years, significant improvements in understanding disease processes, risk assessment, and prediction of clinical outcome in the field of thrombosis and haemostasis have been made by using large-scale biodatabases. These important research resources enable a comprehensive research approach by integrating clinical, environmental, genomic, and molecular information. Cutting edge, high throughput technologies open new data dimensions for clinical large-scale investigations. Joining multiple information levels from several pathophysiological pathways in contrast to a single marker approach might better model the complexity of disease pathogenesis. This review focuses on the possibilities that ultimately allow conducting wide-scale analyses for unravelling the multifaceted interplay between coagulation and cellular (e.g., platelets) elements in the development of thrombotic disease. It further provides examples for the use of biodatabases in the field of venous thromboembolism, explores the links between venous and arterial thrombotic diseases, and finally informs on the current use of platelet biomarkers in the thrombosis and haemostasis field.
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http://dx.doi.org/10.1055/s-0038-1677520DOI Listing
June 2019

Direct oral anticoagulants and vitamin K antagonists are linked to differential profiles of cardiac function and lipid metabolism.

Clin Res Cardiol 2019 Jul 2;108(7):787-796. Epub 2019 Jan 2.

Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

Background: Experimental data indicate that direct acting oral anticoagulants (DOAC) and vitamin K antagonists (VKA) may exert differential effects on cardiovascular disease.

Methods: Data from the prospective, observational, single-center MyoVasc Study were used to examine associations of DOAC as compared to VKA with subclinical markers of cardiovascular disease, cardiac function, and humoral biomarkers in heart failure (HF).

Results: Multivariable analysis adjusted for age, sex, traditional cardiovascular risk factors, comorbidities, and medications with correction for multiple testing demonstrated that DOAC therapy was among all investigated parameters an independent significant predictor of better diastolic function (E/E': β - 0.24 [- 0.36/- 0.12]; P < 0.0001) and higher levels of ApoA1 (β + 0.11 g/L [0.036/0.18]; P = 0.0038) compared to VKA therapy. In propensity score-weighted analyses, the most pronounced differences between DOAC and VKA-based therapy were also observed for E/E' (∆ - 2.36) and ApoA1 (∆ + 0.06 g/L). Sensitivity analyses in more homogeneous subsamples of (i) individuals with AF and (ii) individuals with asymptomatic HF confirmed the consistency and robustness of these findings. In the comparison of factor IIa and Xa-directed oral anticoagulation, no differences were observed regarding cardiac function (E/E' ratio: β - 0.22 [- 0.36/- 0.08] vs. β - 0.24 [- 0.37/- 0.11]) and lipid metabolism (ApoA1: β 0.10 [0.01/0.18] vs. β 0.12 [0.04/0.20]) compared to VKA therapy.

Conclusion: This study provides the first evidence for differential, non-conventional associations of oral anticoagulants on cardiac function and lipid metabolism in humans. The potentially beneficial effect of DOACs in the highly vulnerable population of HF individuals needs to be further elucidated and may have implications for individually tailored anticoagulation therapy.
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http://dx.doi.org/10.1007/s00392-018-1408-yDOI Listing
July 2019

Relevance of Polypharmacy for Clinical Outcome in Patients Receiving Vitamin K Antagonists.

J Am Geriatr Soc 2019 03 11;67(3):463-470. Epub 2018 Dec 11.

Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

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] = 1.62; 95% confidence interval [CI] = 1.04-2.52; p = .033); hospitalization (HR = 1.60; 95% CI = 1.26-2.03; p < .001; and all-cause mortality (HR = 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.
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http://dx.doi.org/10.1111/jgs.15712DOI Listing
March 2019

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population-Based Gutenberg Health Study.

J Am Heart Assoc 2018 09;7(17):e008650

1 Preventive Cardiology and Preventive Medicine Center for Cardiology University Medical Center Mainz Mainz Germany.

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.
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http://dx.doi.org/10.1161/JAHA.118.008650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201416PMC
September 2018

Management of Oral Anti-Coagulation in Patients with Heart Failure-Insights from the ThrombEVAL Study.

Thromb Haemost 2018 Nov 24;118(11):1930-1939. Epub 2018 Oct 24.

German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany.

Patients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care ( = 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outcome, results were compared with data from individuals receiving specialized care for anti-coagulation ( = 760). Overall, the sample comprised of 813 individuals with HF and 1,160 subjects without HF in the regular care cohort. Quality of OAC assessed by time in therapeutic range (TTR) was 66.1% (47.8%/82.8%) for patients with HF and 70.6% (52.1%/85.9%) for those without HF ( = 0.0046). Stratification for New York Heart Classification (NYHA)-class demonstrated a lower TTR with higher NYHA classes: TTR 69.6% (49.4%/85.6%), TTR 66.5% (50.1%/82.9%) and TTR 61.8% (43.1%/79.9%). This translated into a worse net clinical benefit outcome for HF (hazard ratio [HR] 1.63 [1.31/2.02];  < 0.0001) and an increased risk of bleeding (HR 1.40 [1.04/1.89];  = 0.028). Management in a specialized coagulation service resulted in an improvement of all, TTR (∆+12.5% points), anti-coagulation-specific and non-specific outcome of HF individuals. In conclusion, HF is an independent risk factor for low quality of OAC therapy translating into an increased risk for adverse events, which can be mitigated by specialized care.
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http://dx.doi.org/10.1055/s-0038-1673380DOI Listing
November 2018

Sustained atrial fibrillation increases the risk of anticoagulation-related bleeding in heart failure.

Clin Res Cardiol 2018 Dec 9;107(12):1170-1179. Epub 2018 Jun 9.

Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

Background: Oral anticoagulation therapy in individuals with atrial fibrillation (AF) reduces the risk of thromboembolic events at cost of an increased bleeding risk. Whether anticoagulation-related outcomes differ between patients with paroxysmal and sustained AF receiving anticoagulation is controversially discussed.

Methods: In the present analysis of the prospective multi-center cohort study thrombEVAL, the incidence of anticoagulation-related adverse events was analyzed according to the AF phenotype. Information on outcome was centrally recorded over 3 years, validated via medical records and adjudicated by an independent review panel. Study monitoring was provided by an independent institution.

Results: Overall, the sample comprised 1089 AF individuals, of whom n = 398 had paroxysmal AF and n = 691 experienced sustained AF. In Cox regression analysis with adjustment for potential confounders, sustained AF indicated an independently elevated risk of clinically relevant bleeding compared to paroxysmal AF [hazard ratio (HR) 1.40 (1.02; 1.93); P = 0.038]. For clinically relevant bleeding, a significant interaction of the pattern of AF type with concomitant heart failure (HF) was detected: HR 2.45 (1.51, 3.98) vs. HR 0.85 (0.55, 1.34); P = 0.003. In HF patients, sustained AF indicated also an elevated risk of major bleeding [HR 2.25 (1.26, 4.20); P = 0.006]. A simplified HAS-BLED score incorporating only information on age (> 65 years), bleeding history, and HF with sustained AF demonstrated better discriminative performance for clinically relevant bleeding than the original version: AUC: 0.583 vs. AUC: 0.642 (P = 0.004).

Conclusions: In HF patients receiving oral anticoagulation, sustained AF indicates a substantially elevated risk of bleeding.

Clinical Trial Registration: https://clinicaltrials.gov , identifier: NCT01809015.
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http://dx.doi.org/10.1007/s00392-018-1293-4DOI Listing
December 2018

[Physicians' Opinion on Health Care in Oral Anticoagulation].

Dtsch Med Wochenschr 2018 May 19;143(9):e76-e84. Epub 2017 Dec 19.

Präventive Kardiologie und Medizinische Prävention, Zentrum für Kardiologie, Universitätsmedizin Mainz, Mainz.

Background:  The introduction of direct oral anticoagulants (DOAC) in addition to the established Vitamin K antagonist (VKA) has increased the complexity of antithrombotic therapy leading to numerous treatment options. Studies of the medical evaluation of the current treatment situation by health care providers, which are of great importance for the development of treatment strategies in addition to studies on pharmacovigilance, are limited in the literature.

Methods:  11 700 physicians (Rhineland-Palatinate, Germany) were contacted to participate in the web-based survey on health care with oral anticoagulation (OAC). After detailed quality control, the study was analysed in synopsis with routine care data of VKA patients of the thrombEVAL study programme (N = 2.011).

Results:  In total, 512 physicians (mean age: 48.0 ± 9.6 years; 74.0 % male) participated in the study. In general, quality of OAC therapy was rated as "average/satisfactory" (2.9 ± 0.9). Comparison of physicians' perception with data from routine care highlighted marked differences regarding time in therapeutic range (+ 6.4 % [95 %-CI 2.7 %; 9.5 %]), duration of control intervals (- 35.0 % [28.0 %; 41.4 %]) and rate of OAC-related complications (+ 61.8 [37.8 %; 83.3 %], which differed additionally and statistically-significant between physician groups. The willingness to use DOAC was approximately 50 % lower in general physicians as compared to specialists (36.6 % [25.4 %; 47.8 %] vs. 72.4 % [66.0 %; 78.9 %]; p < 0.0001). Regarding management of OAC therapy, 73.8 % [69.7 %; 77.9 %] advocated the establishment of a service hotline and 67.3 % [62,9 %; 71.6 %] a specialized coagulation service.

Discussion:  The present survey among physicians reveals a need for optimization of OAC therapy in daily practice. Specialized care models might facilitate optimized OAC therapy with both VKAs and DOACs.
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http://dx.doi.org/10.1055/s-0043-123041DOI Listing
May 2018

Age-related diagnostic value of D-dimer testing and the role of inflammation in patients with suspected deep vein thrombosis.

Sci Rep 2017 07 4;7(1):4591. Epub 2017 Jul 4.

Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, 55131, Mainz, Germany.

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.
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http://dx.doi.org/10.1038/s41598-017-04843-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496875PMC
July 2017