Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

PURPOSE: Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. METHODS: This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. RESULTS: Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of the patients, adherence to vericiguat was high as indicated by a medication possession ratio of  ≥ 80%, and 67% of the patients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. CONCLUSION: In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice.

PURPOSE: REASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy. METHODS: Radium-223 was administered in routine clinical practice. Interim safety analysis was planned after enrolment of the first 600 patients. Patient characteristics and safety data by previous administration of chemotherapy (docetaxel and/or cabazitaxel) were investigated. RESULTS: This interim analysis included 583 patients. Median duration of observation was 7 months (range, 0-20). Nineteen patients treated with concomitant chemotherapy were excluded, 564 (97%) were eligible for exploratory analysis according to prior use of chemotherapy; 190 (34%) had previously received and completed chemotherapy, and 374 (66%) had not. In the prior versus no prior chemotherapy group, a higher proportion of patients had an Eastern Cooperative Oncology Group performance status of ≥2 (22% vs 11%) and > 20 metastatic lesions (26% vs 15%), median alkaline phosphatase (162.0 vs 115.0 U/L) and prostate-specific antigen (132.0 vs 40.2 ng/mL) levels were higher, and a lower proportion completed 6 radium-223 injections (45% vs 63%). Drug-related treatment-emergent adverse events (TEAEs) occurred in 63 and 48%, and haematological drug-related TEAEs in 21 and 9% of patients who had or had not previously received chemotherapy. Four drug-related deaths were reported, all in the prior chemotherapy group. CONCLUSIONS: The short-term safety profile of radium-223 in routine clinical practice was comparable to other clinical studies, irrespective of prior chemotherapy use. Haematological TEAEs occurred more frequently in the prior chemotherapy group, presumably due to decreased bone marrow function as a consequence of more advanced disease and prior exposure to cytotoxic therapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, and a lower proportion discontinued radium-223 treatment.

Dynamics of the erythropoiesis stimulating agent resistance index in incident hemodiafiltration and high-flux hemodialysis patients.

Hyporesponsiveness to erythropoiesis-stimulating agent therapy in dialysis patients is poorly understood. Some studies report an improvement in the erythropoiesis-stimulating agent resistance index (ERI) with hemodiafiltration (HDF) versus high-flux hemodialysis (HD). We explored ERI dynamics in 38,340 incident HDF and HD patients treated in 22 countries over a 7-year period. Groups were matched by propensity score at baseline (6 months after dialysis initiation). The follow-up period (mean of 1.31 years) was stratified into 1 month intervals with delta analyses performed for key ERI-related parameters. Dialysis modality, time interval, and polycystic kidney disease were included in a linear mixed model with the outcome ERI. Baseline ERI was nonsignificantly higher in HDF versus HD treatment. ERI decreased significantly faster in HDF-treated patients than in HD-treated patients, was decreased in both HD and HDF when patients were treated with intravenous darbepoetin alfa, but only in HDF when treated with intravenous recombinant human erythropoietin (rHuEPO). A clear difference between HD- and HDF-treated patients could only be found for patients with high baseline ERI and assigned to intravenous rHuEPO treatment. A significant advantage in terms of lower ERI for patients treated by HDF was found. Sensitivity analysis limited this advantage for HDF to those patients treated with intravenous rHuEPO (not darbepoetin alfa or subcutaneous rHuEPO) and to patients with a high baseline ERI. Thus, our results allow more accurate planning for future clinical trials addressing anemia management in dialysis patients.

Longitudinal Changes in Body Composition in Patients After Initiation of Hemodialysis Therapy: Results From an International Cohort.

OBJECTIVE: In patients with advanced kidney disease, metabolic and nutritional derangements induced by uremia interact and reinforce each other in a deleterious vicious circle. Literature addressing the effect of dialysis initiation on changes in body composition (BC) is limited and contradictory. The aim of this study was to evaluate changes in BC in a large international cohort of incident hemodialysis patients. METHODS: A total of 8,227 incident adult end-stage renal disease patients with BC evaluation within the initial first 6 months of baseline, defined as 6 months after renal replacement therapy initiation, were considered. BC, including fat tissue index (FTI) and lean tissue index (LTI), were evaluated by Body Composition Monitor (BCM, Fresenius Medical Care, Bad Homburg, Germany). Exclusion criteria at baseline were lack of a BCM measurement before or after baseline, body mass index (BMI) < 18.5 kg/m(2), presence of metastatic solid tumors, treatment with a catheter, and prescription of less or more than 3 treatments per week. Maximum follow-up was 2 years. Descriptive analysis was performed comparing current values with the baseline in each interval (delta analysis). Linear mixed models considering the correlation structure of the repeated measurements were used to evaluate factors associated with different trends in FTI and LTI. RESULTS: BMI increased about 0.6 kg/m(2) over 24 months from baseline. This was associated with increase in FTI of about 0.95 kg/m(2) and a decrease in LTI of about 0.4 kg/m(2). Female gender, diabetic status, and low baseline FTI were associated with a significant greater increase of FTI. Age > 67 years, diabetes, male gender, high baseline LTI, and low baseline FTI were associated with a significant greater decrease of LTI. CONCLUSIONS: With the transition to hemodialysis, end-stage renal disease patients presented with distinctive changes in BC. These were mainly associated with gender, older age, presence of diabetes, low baseline FTI, and high baseline LTI. BMI increases did not fully represent the changes in BC.

Season affects body composition and estimation of fluid overload in haemodialysis patients: variations in body composition; a survey from the European MONDO database.

BACKGROUND: Seasonal variations in blood pressure (BP) and inter-dialytic weight gain (IDWG) are well established in dialysis patients. However, no study has assessed changes in body composition (BC) in this population. METHODS: In this survey, seasonal variations in fat mass (FM), lean tissue mass (LTM), extracellular water (ECW) and fluid overload (FO) were assessed in 42 099 dialysis patients (mean age 61.2 years, 58% males) from the Fresenius Medical Care Europe database, as part of the MONitoring Dialysis Outcomes (MONDO) consortium, in relation to other nutritional parameters, IDWG and BP. BC was assessed by a body composition monitor (BCM®, Fresenius Medical Care, Bad Homburg, Germany). RESULTS: FM was highest in winter and lowest in summer (▵FM -1.17 kg; P < 0.001), whereas LTM was lowest during winter and highest in summer (▵LTM 0.86 kg; P < 0.0001). ECW and FO were lowest in winter, and highest in spring (▵ECW: 0.13 L; P < 0.0001, ▵FO: 0.31 L; P < 0.0001) and summer (▵ECW: 0.15 L; P < 0.0001 and ▵FO: 0.2 L; P < 0.0001), despite a higher systolic blood pressure (SBP; 136.7 ± 17.4 mmHg) and IDWG (3.0 ± 1.1 kg) during winter. C-reactive protein (CRP), serum sodium and haemoglobin levels were highest in winter, whereas serum albumin was lowest in fall. Normalized protein catabolic rate (nPCR) was lowest in winter and matched variations in BC only to a minor degree. CONCLUSIONS: BC and hydration state, assessed by bio-impedance spectroscopy, follows a seasonal pattern which may be of relevance for the estimation of target weight, and for the interpretation of longitudinal studies including estimates of BC. Whether these changes should lead to therapeutic interventions could be the focus of future studies.

Interdialytic weight gain, systolic blood pressure, serum albumin, and C-reactive protein levels change in chronic dialysis patients prior to death.

Reports from a United States cohort of chronic hemodialysis patients suggested that weight loss, a decline in pre-dialysis systolic blood pressure, and decreased serum albumin may precede death. However, no comparative studies have been reported in such patients from other countries. Here we analyzed dynamic changes in these parameters in hemodialysis patients and included 3593 individuals from 5 Asian countries; 35,146 from 18 European countries; 8649 from Argentina; and 4742 from the United States. In surviving prevalent patients, these variables appeared to have notably different dynamics than in patients who died. While in all populations the interdialytic weight gain, systolic blood pressure, and serum albumin levels were stable in surviving patients, these indicators declined starting more than a year ahead in those who died with the dynamics similar irrespective of gender and geographic region. In European patients, C-reactive protein levels were available on a routine basis and indicated that levels of this acute-phase protein were low and stable in surviving patients but rose sharply before death. Thus, relevant fundamental biological processes start many months before death in the majority of chronic hemodialysis patients. Longitudinal monitoring of these dynamics may help to identify patients at risk and aid the development of an alert system to initiate timely interventions to improve outcomes.

Type of vascular access and survival among very elderly hemodialysis patients.

The use of central venous catheters (CVC) for hemodialysis (HD) is associated with higher mortality compared to arteriovenous access (AV). However, studies analyzing the influence of the type of vascular access on the survival of very elderly patients (≥75 years) initiating HD are few and involve only a limited number of patients. We studied a cohort of 5,466 incident patients who started HD; of these, 1,841 were aged ≥75. Types of vascular access for HD were classified as either CVC, which included both tunneled and non-tunneled catheters, or AV, which included AV fistula and grafts. The outcome of the study was all-cause mortality during the follow-up period. In the whole cohort, AV use was associated with a survival advantage over CVC use (88 and 63% at 2 and 5 years, respectively, in patients with an AV as compared to 75 and 48% in patients with a CVC) (p < 0.0001). Among patients ≥75, CVC use was associated with a higher number of deaths compared to AV use. Patients ≥75 with an AV showed a greater survival as compared to patients ≥75 with a CVC (80 and 53% at 2 and 5 years, respectively, vs. 68 and 43%; p < 0.0001). Multivariate analysis revealed that CVC use and the presence of arrhythmia were independent risk factors of death in patients ≥75, whereas obesity was associated with greater survival. In conclusion, the type of vascular access has a significant influence on the survival of very elderly patients (≥75) initiating HD. CVC use was associated with poorer survival compared to AV access.

Monitoring dialysis outcomes across the world--the MONDO Global Database Consortium.

BACKGROUND/AIMS: Dialysis providers frequently collect detailed longitudinal and standardized patient data, providing valuable registries of routine care. However, even large organizations are restricted to certain regions, limiting their ability to separate effects of local practice from the pathophysiology shared by most dialysis patients. To overcome this limitation, the MONDO (MONitoring Dialysis Outcomes) research consortium has created a platform for the joint analysis of data from almost 200,000 dialysis patients worldwide. METHODS: We examined design and operation of MONDO as well as its methodology with respect to patient inclusion, descriptive data and other study parameters. RESULTS: MONDO partners contribute primary databases of anonymized patient data and collaboratively analyze populations across national and regional boundaries. To that end, datasets from different electronic health record systems are converted into a uniform structure. Patients are enrolled without systematic exclusions into open cohorts representing the diversity of patients. A large number of patient level treatment and outcome data is recorded frequently and can be analyzed with little delay. Detailed variable definitions are used to determine if a parameter can be studied in a subset or all databases. CONCLUSION: MONDO has created a large repository of validated dialysis data, expanding the opportunities for outcome studies in dialysis patients. The density of longitudinal information facilitates in particular trend analysis. Limitations include the paucity of uniform definitions and standards regarding descriptive information (e.g. comorbidities), which limits the identification of patient subsets. Through its global outreach, depth, breadth and size, MONDO advances the observational study of dialysis patients and care.

Converting to a capitation system for dialysis payment--the Portuguese experience.

Due to the challenge of operating within an economically strained healthcare budget, Portuguese health authorities convened with dialysis providers and agreed on a framework to change from a fee-for-service reimbursement modality to a capitation payment system for hemodialysis. This article reviews the components of the agreed capitation package implemented in 2008 as well as the necessary preparatory work undertaken by a for-profit 34-unit dialysis network (approx. 4,200 patients) to cope with the introduction of this system. Furthermore, trends in clinical quality indicators and in resource management are reviewed for 3 years immediately following capitation introduction. Here, improvements were observed over time for the specified clinical targets. Simultaneously, costs controllable by the physician could be reduced. As more countries convert to a capitation or bundled payment system for hemodialysis services, this article offers insight into the scope of the necessary preparatory work and the possible consequences in terms of costs and treatment quality.

Lung Infection by Human Bocavirus Induces the Release of Profibrotic Mediator Cytokines In Vivo and In Vitro.

Human Bocavirus subtype 1 (HBoV1) is associated with respiratory diseases and may contribute to chronic lung diseases by persisting in the infected host. Here the question was addressed if HBoV infections could contribute to fibrogenesis processes as suggested by previously published clinical observations. Cytokine profiles induced by HBoV infection in CuFi-8 air-liquid interphase cell cultures and in bronchoalveolar lavage fluid (BALF) of 20 HBoV-positive and 12 HBoV-negative patients were analysed by semi-quantitative Western spot blot analyses. Although lots of cytokines were regulated independently of HBoV status, several cytokines associated with lung fibrosis and tumour development, e.g., EGF, VEGF, TARC (CCL17), TNF-α, TNF-ß, TIMP-1, were clearly upregulated in the HBoV-positive cohort. These findings suggest that the development of lung fibrosis might be triggered by HBoV induced cytokine expression.

Improved survival of incident patients with high-volume haemodiafiltration: a propensity-matched cohort study with inverse probability of censoring weighting.

BACKGROUND: Haemodiafiltration (HDF) is the preferred dialysis modality in many countries. The aim of the study was to compare the survival of incident patients on high-volume HDF (HV-HDF) with high-flux haemodialysis (HD) in a large-scale European dialysis population. METHODS: The study population was extracted from 47,979 patients in 369 NephroCare centres throughout 12 countries. Baseline was six months after dialysis initiation; maximum follow-up was 5 years. Patients were either on HV-HDF (defined as with ≥21 litres substitution fluid volume per session) or on HD if on that treatment for ≥75% of the 3 months before baseline. The main predictor was treatment modality. Other parameters included country, age, gender, BMI, haemoglobin, albumin and Charlson comorbidity index. Propensity score matching and Inverse Probability of Censoring Weighting (IPCW) were applied to reduce bias by indication and consider modality crossover, respectively. RESULTS: After propensity score matching, 1,590 incident patients remained. Kaplan-Meier and proportional Cox regression analyses revealed no significant survival advantage of HV-HDF. Results were biased by modality crossover: during the 5-year study period, 7% of HV-HDF patients switched to HD, and 55% of HD patients switched to HV-HDF. IPCW uncovered a statistically significant survival advantage of HV-HDF (OR 0.501; CI 0.366-0.684; p < 0.001). A higher benefit of HV-HDF for some subgroups was revealed, for example, non-diabetics, patients 65-74 years, patients with obesity or high blood pressure. CONCLUSIONS: This large-scale study supports the generalizability of previous RCT findings regarding the survival benefit of HV-HDF. Sub-group analysis showed that some sub-cohorts appear to benefit more from HV-HDF than others.

Modifiable factors associated with achievement of high-volume post-dilution hemodiafiltration: results from an international study.

BACKGROUND: The aim was to investigate factors associated with the successful achievement of ≥21 l/session of substitution fluid volume in patients on post-dilution hemodiafiltration. METHODS: 3315 patients treated in 6 European countries with the Fresenius 5008 CorDiax machine including the AutoSub Plus feature were considered. Variables that showed a relationship with convection volume were entered in a multivariable logistic regression model. RESULTS: Mean blood flow was 379 ± 68 ml/min. Median substitution volume was 24.7 L (IQR 22.0-27.4 L). Mean filtration fraction was 28.3 ± 4.1%. 81.5% of sessions qualified as high-volume HDF (substitution volumes ≥21 L). Higher age, dialyzer surface area, blood flow and treatment time were positively associated with the achievement of ≥21 L substitution volume; higher body mass index, male gender, higher hematocrit, graft or catheter vs. fistula, and start of week vs. mid-week were negatively associated. CONCLUSIONS: Dialysis center policy in terms of blood flow, treatment time, filter size, and perhaps even hemoglobin targets plays a key role in achieving high-volume HDF. All of these are modifiable factors that can help in prescribing an optimal combination of dialyzer size, achievable blood flows, and treatment times.

Body composition and survival in dialysis patients: results from an international cohort study.

BACKGROUND AND OBJECTIVES: High body mass index appears protective in hemodialysis patients, but uncertainty prevails regarding which components of body composition, fat or lean body mass, are primarily associated with survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data between April 2006 and December 2012 were extracted from the Fresenius Medical Care Europe subset of the international MONitoring Dialysis Outcomes initiative. Fresenius Medical Care Europe archives a unique repository of predialysis body composition measurements determined by multifrequency bioimpedance (BCM Body Composition Monitor). The BCM Body Composition Monitor reports lean tissue indices (LTIs) and fat tissue indices (FTIs), which are the respective tissue masses normalized to height squared, relative to an age- and sex-matched healthy population. The relationship between LTI and FTI and all-cause mortality was studied by Kaplan-Meier analysis, multivariate Cox regression, and smoothing spline ANOVA logistic regression. RESULTS: In 37,345 hemodialysis patients, median (25th-75th percentile) LTI and FTI were 12.2 (10.3-14.5) and 9.8 (6.6-12.4) kg/m(2), respectively. Median (25th-75th percentile) follow-up time was 266 (132-379) days; 3458 (9.2%) patients died during follow-up. Mortality was lowest with both LTI and FTI in the 10th-90th percentile (reference group) and significantly higher at the lower LTI and FTI extreme (hazard ratio [HR], 3.37; 95% confidence interval [95% CI], 2.94 to 3.87; P<0.001). Survival was best with LTI between 15 and 20 kg/m(2) and FTI between 4 and 15 kg/m(2) (probability of death during follow-up: <5%). When taking the relation between both compartments into account, the interaction was significant (P=0.01). Higher FTI appeared protective in patients with low LTI (HR, 3.37; 95% CI, 2.94 to 3.87; P<0.001 at low LTI-low FTI, decreasing to HR, 1.79; 95% CI, 1.47 to 2.17; P<0.001 at low LTI-high FTI). CONCLUSIONS: This large international study indicates best survival in patients with both LTI and FTI in the 10th-90th percentiles of a healthy population. In analyses of body composition, both lean tissue and fat tissue compartments and also their relationship should be considered.

Relationship of Neutrophil-to-Lymphocyte Ratio and Serum Albumin Levels with C-Reactive Protein in Hemodialysis Patients: Results from 2 International Cohort Studies.

BACKGROUND/AIM: The neutrophil-to-lymphocyte ratio (NLR), defined as the neutrophil count divided by lymphocyte count, is an inexpensive and readily available parameter, which may serve as a surrogate for inflammation markers, such as C-reactive protein (CRP). The aim of this study was to determine the utility of NLR in the prediction of elevated CRP levels in hemodialysis (HD) patients. METHODS: We analyzed 43,272 HD patients from 2 distinct cohorts within the Monitoring Dialysis Outcomes research collaboration in whom contemporaneous measurements of neutrophil and lymphocyte counts, serum albumin and CRP levels were available. Logistic regression was used to determine the relationship of trichotomized NLR (<2.5, 2.5-5 and >5.0) and albumin levels (<3.1, 3.1-4.0 and >4.0 g/dl) with elevated CRP levels (>10.0, >20.0 and >30.0 mg/l). Congruence of the prediction models was examined by comparing the regression parameters and by cross-validating each regression equation within the other cohort. RESULTS: We found that NLR >5.0 vs. <2.5 (cohort 1: OR 2.3; p < 0.0001 and cohort 2: OR 2.0; p < 0.0001) was associated with CRP levels >10.0 mg/l. Stepwise increase in odds ratio for CRP >10.0 mg/l was observed with the combination of high NLR and low albumin levels (NLR >5.0 and albumin <3.1) (cohort 1: OR 7.6; p < 0.0001 and cohort 2: OR 11.9; p < 0.0001). Cross-validation of the 2 regression models revealed a predictive accuracy of 0.68 and 0.69 in the respective cohorts. CONCLUSION: This study suggests that NLR could serve as a potential surrogate marker for CRP. Our results may add to diagnostic abilities in settings where CRP is not measured routinely in HD patients. NLR is easy to integrate into daily practice and may be used as a marker of systemic inflammation.

Survival of incident patients on high-volume online hemodiafiltration compared to low-volume online hemodiafiltration and high-flux hemodialysis.

BACKGROUND: Hemodiafiltration is becoming a preferred treatment modality for dialysis patients in many countries. The volume of substitution fluid delivered has been indicated as an independent mortality risk factor. The aim of this study is to compare patient survival on three different treatment modalities: high-flux hemodialysis, low-volume online HDF (oHDF) and high-volume oHDF. METHODS: Incident hemodialysis and oHDF patients treated in 13 NephroCare centers in Bosnia and Herzegovina, Serbia and Slovenia between January 1, 2007, and December 31, 2011, were included in this epidemiological cohort study. High-volume oHDF was defined as substitution volume higher than the median substitution volume infused, otherwise low-volume. Main predictor was treatment modality at baseline and in time-dependent model. Other predictors were age, gender, diabetes mellitus, cerebrovascular accident, arrhythmia, hemoglobin and C-reactive protein. RESULTS: Four hundred and forty-two patients were included in the study. Median substitution fluid volume was 20.4 L. Mean difference between the oHDF groups in substitution fluid volume was 8.3 ± 5.2 L [95 % confidence intervals (95 % CI) 7.1-9.5, p < 0.0001]. The unadjusted hazard ratios (HR) with 95 % CI compared to high-flux HD were 0.87 (0.5-1.5) for low-volume oHDF and 0.29 (0.13-0.63) for high-volume oHDF. After the adjustment for covariates, the HR for patients on low-volume oHDF remained statistically insignificant compared to high-flux HD (0.84; 95 % CI 0.46-1.53), while patients on high-volume oHDF showed a marked and significantly lower HR (0.29; 95 % CI 0.13-0.68) than patients on high-flux HD in baseline model. While this effect failed to reach significance in the time-dependent model (HR 0.477; 95 % CI 0.196-1.161), possibly due to an inadequate sample size here, the consistency of results in both models supports the robustness of the findings. After switching from high-flux hemodialysis to oHDF, mean hemoglobin and albumin levels did not change significantly. Mean erythropoietin resistance index (ERI) and erythropoiesis stimulating agents (ESA) consumption decreased significantly (p = 0.02, p = 0.03, respectively). CONCLUSIONS: The median substitution volume used in these three countries for post-dilutional oHDF is 20.4 L. oHDF is associated with significant reductions in ERI and ESA consumption. Only high-volume oHDF is associated with improved survival compared to high-flux hemodialysis.