Randomized studies have demonstrated that high-volume hemodiafiltration results in reduced mortality compared to conventional hemodialysis treatment. However, eligibility criteria in these trials may limit generalizability to routine clinical practice. Some of these trials reported a limited number of events, underscoring the need to further evaluate the effect of hemodiafiltration on mortality. We will conduct a target trial emulation study using data from routine clinical practice. The primary aim of this study is to evaluate whether high-volume hemodiafiltration reduces all-cause mortality. The secondary aim is to assess cause-specific mortality. Other aims include assessing all-cause and cause-specific hospitalizations, as well as cumulative length of hospital stay and the dose–response relationship between convection volume in hemodiafiltration and the outcomes. Data will be obtained from the second version of ApolloDialDb (Apollo), an anonymized dialysis dataset capturing over 1000 variables from patients from all over the world. For this study, we will include adult patients from European countries with kidney failure who initiated with at least one treatment of high-flux hemodialysis or hemodiafiltration between 01 January 2018 and 30 June 2024, and who were prescribed a thrice-weekly dialysis schedule at the start. Patients starting with home dialysis will be excluded. We will use a target trial emulation approach with a clone-censor-weight design and marginal structural models, controlling for selection bias, survivor bias, and competing risk bias. Sub-analyses will be performed to investigate the effect of high-volume hemodiafiltration (≥ 23 L of convection volume). Inverse probability weighting will be applied to adjust for predefined confounders including sociodemographic, clinical, and anthropometric factors, as well as comorbidities to achieve balance between treatment groups. In addition to randomized studies, prior large observational studies have indicated a survival benefit for hemodiafiltration, as well as a possible reduction of hospitalizations. The target trial emulation study outlined in this protocol will expand this knowledge and provide generalizable insights on the effects of hemodiafiltration on outcomes by using real-world data representative of routine clinical practice while appropriately addressing sources of bias. This protocol outlines a study in which we will examine the effects of hemodiafiltration (HDF) compared with high flux hemodialysis (HD) using data from standard day-to-day dialysis care, collected from across Europe. Clinical trials have previously shown that HDF provides benefits for survival and quality of life. However, it remains uncertain whether these benefits apply to all patients or only in healthier patients, who meet the eligibility criteria to participate in a clinical trial. We will use advanced statistical methods, specifically target trial emulation, to closely mimic a randomized clinical trial using real-world data and thereby reduce bias. The study will evaluate overall 5-year survival, causes of death, hospitalizations, and the impact of higher HDF convection volumes to help guide future dialysis care decisions.

Management of asymptomatic severe mitral regurgitation (MR) is challenging. Both early mitral valve repair surgery and active surveillance with facilitated surgery are possible strategies. The DutchAMR registry compares clinical outcomes between these two strategies. Patients were included between 2013–2019. Primary endpoints were cerebrovascular accidents (CVA), reoperations, and mortality. Facilitated surgery was defined as mitral valve repair surgery performed after developing a surgical indication during active surveillance. Ninety-nine patients were enrolled; 71 in active surveillance and 28 in early surgery. Over a median follow-up time of 5.1 years, 51

INTRODUCTION:Cardiovascular risk assessment and management in the paediatric population is a relatively uncharted territory. However, atherogenesis starts during childhood, making childhood and adolescence an important window of opportunity to prevent atherosclerotic cardiovascular disease (ASCVD) later in life. An emerging group at risk for early ASCVD are children with chronic conditions. This paper describes the rationale, design and methods for the Secondary Manifestations of ARTerial diseases in the Young with a chronic condition (SMART-Youth) study. This study aims to identify disease-associated and lifestyle-associated cardiovascular risk factors for preclinical atherosclerosis in children with a chronic condition. The results of this study may fuel development of tailored cardiovascular risk assessment and management strategies in children at-risk. METHODS AND ANALYSIS:This is a prospective longitudinal cohort study including children aged 8-18 years with various chronic conditions (cystic fibrosis, juvenile idiopathic arthritis, systemic autoimmune disease, chronic kidney disease, primary immunodeficiency, autoinflammatory conditions, inflammatory bowel disease, congenital heart disease, premature birth, fetal growth restriction and children with persistent somatic symptoms) at the Wilhelmina Children's Hospital of the University Medical Center Utrecht in The Netherlands. Assessment of cardiovascular risk factors includes blood pressure, body mass index, visceral and subcutaneous abdominal adipose tissue, nutrition, physical activity, stress, circulating lipids, HbA1c and C-reactive protein measurements. Preclinical atherosclerosis is measured by carotid intima-media thickness, carotid distension and carotid-femoral pulse wave velocity. These assessments are performed at baseline, 2-year follow-up and 17-18 years of age. Enrollment runs from August 2024 onwards, with a minimal study duration of 15 years and an estimated final sample of more than 2000 children. State-of-the-art regression-based methods will be used to examine the association of cardiovascular risk factors and preclinical atherosclerosis. Longitudinal data analysis methods will be used to model these associations over time. ETHICS AND DISSEMINATION:Ethical approval was granted by the Medical Ethics Review Board of the University Medical Center Utrecht (NL84874.041.23). Written informed consent by participants and their parents is required for participation. Collected data will be made available to researchers upon reasonable request to the Steering Committee. Study findings will be disseminated through peer-reviewed publications, presentations at scientific meetings and meetings with patient organisations.

BackgroundPatient-reported outcome (PRO) measures are increasingly used in clinical trials and clinical care to assess symptoms, functioning, and health-related quality of life (HRQoL). In dialysis research, instrument-driven approaches that rely on legacy measures may not fully capture outcomes that matter most to patients or treatment-related experiences such as dialysis-specific fatigue and recovery. Therefore, a patient-informed, domain-guided PRO toolbox for adults with end-stage kidney disease (ESKD) receiving maintenance dialysis was developed and applied in the CONVINCE trial.MethodsA multi-method, triangulation approach was used, comprising: 1) a targeted literature review of PROMs and symptom concepts used in maintenance dialysis research, 2) review of international core outcome initiatives relevant to kidney disease and haemodialysis, 3) semi-structured interviews and focus groups with patients (n = 13) and health care professionals (n = 4). Concepts identified across sources were compiled, compared, and prioritized based on recurrence across evidence sources, salience to patients, anticipated sensitivity to dialysis modality, and feasibility of repeated assessment within the CONVINCE trial.ResultsThe literature review identified 97 PROMs. Domains and symptom content were extracted from these instruments and mapped against concepts covered by international core outcome initiatives and qualitative data. Triangulation resulted in an ESKD PRO toolbox comprising nine prioritized health domains: general health/health perception, fatigue, physical function, social roles, depression, anxiety, pain, sleep, and cognitive function. Most of these domains could be assessed within the PROMIS® health domain framework. To complement these generic domain measures, a dialysis-specific symptom list and additional items to assess dialysis-related fatigue, treatment-related recovery time were included.ConclusionThe ESKD PRO toolbox provides a patient-informed, domain-guided framework for repeated longitudinal assessment of outcomes relevant to patients receiving maintenance dialysis. Its application in CONVINCE illustrates how PROMIS® -based domain assessment can be combined with dialysis-specific symptom and fatigue measures to capture treatment-related patient experiences.

There is increasing evidence of an inverse relationship between air pollution and cognitive functioning. Yet, the biological mechanisms underlying this relationship remain underexplored in healthy and vulnerable populations. This study examined cross-sectional and longitudinal associations between air pollution and global cognitive functioning in individuals without or with heart failure, carotid occlusive disease, or vascular cognitive impairment. We also assessed whether the cross-sectional associations were mediated by white matter hyperintensities (WMH), total brain volume (TBV), and cerebral blood flow (CBF). The cross-sectional and longitudinal analyses included data from 341 and 180 Heart-Brain Study participants, respectively. Cognitive functioning was measured using neuropsychological tests at baseline and two-year follow-up. Brain Magnetic Resonance Imaging provided WMH and TBV in mL, and CBF in mL/100g/min. WMH and TBV were divided by total intracranial volume. Annual average outdoor concentrations of particulate matter with diameters <2.5 µm and <10.0 µm, and nitrogen dioxide in µg/m3 in residential six-digit postal code areas were linked to participants at baseline. Adjusted multi-level regression analyses showed no significant cross-sectional or longitudinal associations between air pollution and global cognitive functioning. The associations between air pollutants and global cognitive functioning were not significantly mediated by WMH, TBV, and CBF. In this study, air pollution was not associated with global cognitive functioning or brain health indicators in healthy individuals and those with cardiovascular disorders along the heart-brain axis. Larger studies with longer follow-up periods are warranted to extend the present findings and to further elucidate potential associations between air pollution, cognition, and the underlying biological mechanisms.

INTRODUCTION:Carotid endarterectomy (CEA) is performed to lower the long-term risk of stroke in patients with carotid stenosis. Data evaluating long-term outcomes after CEA are scarce, but crucial for accurately determining long-term benefits. We aimed to estimate the long-term risk of major adverse cardiovascular and cerebrovascular events (MACE) after CEA. PATIENTS AND METHODS:A data linkage study was performed using patients from the Athero-Express biobank study who underwent CEA in two Dutch tertiary referral hospitals between 2002 and 2020. Data were linked to the Cause of Death Register, Population Register from Statistics Netherlands and the Hospital Discharge Register. The primary outcome was the occurrence of MACE at any time during follow-up and in the postprocedural (beyond 30 days) period. RESULTS:CEA was performed in 2123 unique patients; linkage was possible for 1876. Median age was 70 years, 70% was male, and 87% had a symptomatic stenosis. MACE occurred in 455 patients (24.3%) during 9.2 years median follow-up. Five and 10-year cumulative incidence of MACE was 14.3% and 26.4%, respectively. Vascular death was the predominant contributor to MACE with 246 events (54.1%). Older age, current smoking, lower estimated glomerular filtration rate, diabetes mellitus and coronary artery disease (CAD) were associated with an increased risk of MACE. Preoperative antiplatelet use was associated with decreased risk of MACE. Patients with ischaemic stroke as qualifying event were at higher risk of MACE (P = .018). The incidence rate of MACE did not change over time (P = .9). DISCUSSION:Patients remain at high risk of MACE after CEA, especially of vascular death and in older patients, current smokers and patients with diabetes or CAD. CONCLUSION:These findings underscore the need to enhance cardiovascular preventive strategies following CEA, in order to optimise long-term benefit.

Abstract Background High blood pressure (BP) is an often treatable cause of cardiovascular disease. We developed an intervention, featuring a cardiovascular expert team and a toolbox, to support healthcare professionals (HCPs) in hypertension management and enhance patient self-management. Aim This study evaluates the adoption and feasibility of this intervention. Design and Setting A mixed-methods study in general practices in the Netherlands. Methods HCPs could consult a cardiovascular expert team and use a self-management toolbox for their patients as preferred. We interviewed HCPs guided by the Consolidated Framework of Implementation Research (CFIR), and HCPs completed the Determinants of Implementation Behaviour Questionnaire (DIBQ). Using CFIR-ERIC matching tool, we matched implementation strategies to identified barriers. Adults with elevated BP, who were prescribed at least two blood pressure lowering medications were eligible to participate. Patient and disease characteristics were extracted from the electronical medical record. Results Of 591 eligible patients at thirteen general practices, 176 participated. The cardiovascular expert team was well-received, with 33 unique consultations, although nurse practitioners (NPs) might need the expertise of the expert team more frequently than general practitioners (GP) (adoption). The toolbox was perceived as challenging to use (feasibility). We subsequently identified three key strategies to improve implementation. Mean systolic and diastolic BP were 158/87 mmHg at baseline and 148/85 mmHg after 12 months, although this change cannot be conclusively linked to the intervention. Conclusions Structured implementation strategies may be helpful in hypertension management. The cardiovascular expert team was considered valuable, but might be better targeted to NPs rather than GPs.

BACKGROUND:Left ventricular diastolic dysfunction is frequently observed in patients with chronic kidney disease. Nevertheless, the relationship between chronic kidney disease and left ventricular diastolic dysfunction over time is poorly understood. This study aims to assess whether the association between chronic kidney disease and left ventricular diastolic dysfunction varies over time. METHODS:We included outpatients from the Utrecht Patient-Oriented Database, who underwent at least 2 echocardiographic assessments and had a measurement of kidney function. Linear mixed-effects models were used to estimate the associations of estimated glomerular filtration rate (eGFR) and echocardiographic parameters. RESULTS:A total of 1812 patients were included and stratified into 3 groups on the basis of eGFR: >90 (491), 60-90 (923), and <60 (398). The mean age was 66.7 years, with 62.3% being men. At baseline, patients with lower eGFR exhibited a higher prevalence of hypertension (62.3% versus 55.2%) and diabetes (19.6% versus 11.6%). Linear mixed-effects models showed that declining eGFR was significantly associated with increased E/e' ratio, left atrial volume index, tricuspid regurgitation velocity, and left ventricular mass index, with respective estimates of -0.03 (P<0.001), -0.04 (P=0.005), -0.00 (P<0.001), and -0.16 (P<0.001). The interaction between time and eGFR was not statistically significant (P>0.20). CONCLUSIONS:This study shows that lower kidney function was consistently associated with a more adverse diastolic echocardiographic phenotype, characterized by higher filling pressures, greater structural remodeling, and increased hemodynamic burden. This phenotype was already established at initial clinical assessment and did not show measurable further divergence on serial routine echocardiograms.

Key PointsCoverage of patient characteristics in existing trials of hemodiafiltration versus hemodialysis seems to be broad but incomplete.Randomized trials of hemodiafiltration versus hemodialysis have been primarily limited to Europe.Inconsistencies between trials and registries support further studies using real-world data to explore applicability of existing evidence.BackgroundSelection criteria in randomized trials (randomized controlled trials [RCTs]) can lead to differences in key characteristics between trial participants and real-life populations. We evaluated reporting of population characteristics in existing RCTs of hemodiafiltration (HDF) and in real-life populations included in kidney registries to descriptively identify key differences.MethodsWe used systematic review methodology to identify existing RCTs of HDF versus hemodialysis (1966 to May 2024). We also searched the Fresenius Quantitative Market Analysis team registry database (2024 update) for existing registries from Europe, the Asia-Pacific region, and America including populations on HDF. Patient characteristics from RCTs and registries were extracted, summarized, and compared descriptively.ResultsEleven RCTs (N=5108) and eight registries (N=1,147,167) were identified. There were no RCTs in the United States and only two small RCTs from Australia (N=124) and Brazil (N=195). Most trials were from Europe. Key characteristics consistently reported in both RCTs and registries were only age, sex, diabetes, cardiovascular disease, vascular access type, and dialysis vintage. There was moderate to high heterogeneity for these patient characteristics in RCTs, indicating enrollment of a broad array of people. The proportion of people with diabetes was 26% in RCTs and 43% in registries. The prevalence of arteriovenous fistulas/graft was 90% in RCTs and 70% in registries.ConclusionsThere was a broad but incomplete array of patient characteristics in existing RCTs and real-world registries of HDF versus hemodialysis. Data were primarily limited to Europe and only a core set of demographic and clinical variables. Apart for age, sex, diabetes, cardiovascular disease, vascular access type, and dialysis vintage, other patient and treatment relevant characteristics were erratically or not at all reported in RCTs as well as in real-world registries. With potential differences in patient populations, we support the need for studies examining HDF in real-world settings, e.g., with target emulation trials.

Cognitive impairment is common in patients with heart failure, but to which extent cognitive complaints are evaluated and listed in clinical practice is unknown. Therefore, this study aims to identify whether cognitive complaints are listed in clinical notes of patients with heart failure, consistent with listed complaints in clinical notes of patients attending memory clinics, by using natural language processing (NLP) techniques. Patients with heart failure and patients attending a memory outpatient clinic were identified by using echocardiography reports and presence of memory outpatient clinic codes stored in the Utrecht Individual-Oriented Database (UPOD) from 2011 to 2023. Named Entity Detection and Linking (NER+L) strategies MedCAT and MedCATTrainer were used to extract listed complaints in clinical notes by patient group, and it was assessed whether cognitive complaints were listed in clinical notes of patients with heart failure. Among 5803 patients with heart failure, dyspnea (57.1%), chest pain (48.4%), and oedema (43.6%) were the most listed complaints. In 967 patients attending memory clinics, memory problem (80.9%), getting lost (24.1%), and being morose (22.5%) were the most listed complaints. Notably, in patients with heart failure, the reporting of memory problems was low at 2.6%. This study shows a low reporting frequency of cognitive complaints in clinical notes of patients with heart failure, even though both conditions often co-occur according to cross-sectional studies. This points towards a potential underrecognition of cognitive complaints in patients with heart failure during clinical practice. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is part of the Heart-Brain Connection crossroads (HBCx) consortium of the Dutch CardioVascular Alliance (DCVA). HBCx has received funding from the Dutch Heart Foundation under grant agreements 201828 and CVON 201206. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics of our study was reviewed by the Medical Ethics Committee NedMec (METC NedMec). METC NedMec is a recognized Medical Research Ethics Committee in the Netherlands, formed through a collaboration between UMC Utrecht, Prinses Máxima Centrum for pediatric oncology, and the Antoni van Leeuwenhoek institute. As our research involves retrospective analysis of electronic health records (EHR) and does not fall under the scope of the Dutch Medical Research Involving Human Subjects Act (WMO), the committee determined that formal ethical approval was not required (waived). Furthermore, in line with GDPR Article 14(5)(b), individual patient consent was not required due to the disproportionate effort involved in contacting all individuals. Data management specialists from an ISO 9001 certified database (Utrecht Patient-Oriented Database) extracted, pseudonymized and securely stored the data. As we worked with electronic health records collected with an IRB waiver for informed consent from NedMec, under the disproportionate effort clause, I will not be able to share data with others. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes s we worked with electronic health records collected with an IRB waiver for informed consent from NedMec, under the disproportionate effort clause, I will not be able to share data with others.

OBJECTIVE:To investigate sex differences in the pharmacological treatment of hypertension in primary care. DESIGN:Cross-sectional study among 14,384 patients with hypertension from the Julius General Practitioners' Network, without cardiovascular disease or diabetes, treated with antihypertensive medications. METHODS:We compared men and women in the number and type of prescribed antihypertensives and their blood pressure. RESULTS:Women (n=8596) and men (n=5788) were prescribed the same number of antihypertensive agents on average (1.8). Women received lower dosages, more often beta-blockers (35% vs. 26%, p<0.001) and diuretics (54% vs. 51%, p<0.001), but less often ACE inhibitors (35% vs. 46%, p<0.001) and calcium channel blockers (29% vs. 36%, p<0.001). Blood pressure control was more often achieved in women than in men (50% vs. 46%, p<0.001). CONCLUSION:Although current guidelines do not distinguish between sexes, differences exist in the type and dosage of antihypertensives prescribed, and in the rate of blood pressure control.

High-flux hemodialysis (HD) and high-dose hemodiafiltration (HDF) are established treatments for patients with kidney failure. Since HDF has been associated with improved survival rates compared to HD, we evaluated the cost-effectiveness of HDF compared to HD. Cost-utility analyses were performed from a societal perspective alongside the multinational randomized controlled CONVINCE trial. A Markov cohort model was used to extrapolate results to a lifetime time horizon. Costs of dialysis sessions were based on published data, with two scenarios reflecting different estimates for costs of dialysis staff. Other healthcare resource use, productivity losses and quality of life were collected in the electronic case report form or by country-adapted, self-reported questionnaires. Scenario and probabilistic sensitivity analyses were performed. In the two-year trial-based analysis, HDF was associated with higher quality-adjusted life years (QALYs) and higher costs, with incremental costs per QALY (ICER) of €31,898 and €37,344, depending on dialysis staff costs. The lifetime Markov cohort model resulted in ICERs of €27,068 and €36,751. Compared to HD, HDF resulted in an additional year in perfect health at increased costs. Sensitivity analyses of the lifetime analyses showed the probability of cost-effectiveness was more than 90% at willingness-to-pay threshold of €50,000/QALY. The ICER was €13,231 when excluding all costs in additional life years. The probability of cost-effectiveness was mainly driven by costs due to additional dialysis sessions in life years gained, and not due to additional costs per dialysis session. As costs may differ between countries and centers, we recommend translating our results to local settings.

BackgroundTreatment targets for cardiovascular risk management (CVRM) make no distinction between women and men.AimTo explore sex differences in achieving treatment targets in patients who participated in a nurse-led, integrated CVRM care programme in primary care between 2013 and 2019.Design & settingWe conducted a dynamic cohort study in the Eindhoven region, which is the south-eastern part of the Netherlands.MethodWe assessed outcomes of three biological risk factors (systolic blood pressure [SBP], low-density lipoprotein [LDL] cholesterol, and estimated glomerular filtration rate [eGFR]) and four lifestyle factors (smoking, physical activity, alcohol intake, and body mass index [BMI]). Points (1 = on target; 0 = not on target) were assigned for biological risk factors, lifestyle factors, and an overall score. Using the annual results, we applied multivariable regression models to study trends over time and differences in trends between women and men.ResultsThe number of participants increased from 24,889 to 38,067, mean age increased from 67.3 years to 71.5 years, with around 52 % women each year. The average of seven risk factors on target increased significantly from 4.6 to 4.9 in women, and from 4.7 to 5.0 in men, with no statistical difference between women and men. Differences between women and men in 2013 in the number of both biological and lifestyle factors on target did not materially change over time.ConclusionIntegrated cardiovascular management care led to improvements in cardiovascular risk factors on target, equally well in women than in men. Differences in risk factors on target between women and men in 2013 were still present in 2019.

Clinically apparent resistant hypertension (CARH) is common and a major health problem because it increases the risk of cardiovascular events. We aim to assess whether a stepwise work-up management strategy for patients with CARH in primary care would result in better blood pressure control compared to usual care. A pragmatic, cluster-randomised controlled trial (cRCT). General practitioners (GPs) from 22 practices (10 intervention arm; 12 usual care) recruited 106 patients aged 18–80 years who had an office blood pressure (BP) > 140/90 mmHg and were prescribed three or more antihypertensive drugs from different therapeutic classes for three or more months in an adequate dose. This study was conducted between October 2018 and June 2021. The intervention was a stepwise approach comprising of (i) 24-hour blood pressure measurements, (ii) dedicated attention on intake of blood pressure raising compounds, (iii) on lifestyle and on compliance to and (iv) optimalisation of medication, and (v) referral to specialist care, when appropriate. The control group received usual care. Primary outcome was the difference in 24-hours systolic BP between intervention and usual care measured at 8 months after baseline. Neither 24-hour nor office systolic BP 8 months after baseline significantly differed between intervention and usual care arm: 136.9 mmHg versus 132.6 mmHg (p = 0.15) and 146.1 mmHg versus 147.6 mmHg (p = 0.51), respectively. No significant differences across groups were seen in number of prescribed BP lowering medication: 2.98 versus 3.11, or controlled hypertension after 8 months: 22

BACKGROUND:Frequent hemodialysis provided more than three times per week may lower mortality and improve health-related quality of life. Yet, the evidence is inconclusive. We evaluated the benefits and harms of frequent hemodialysis in people with kidney failure compared with standard hemodialysis. METHODS:We performed a systematic review of randomized controlled trials including adults on hemodialysis with highly sensitive searching in MEDLINE, Embase, CENTRAL, and Google Scholar on 3 January 2024. Data were pooled using random-effects meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. We adjudicated evidence certainty using GRADE. RESULTS:From 11,142 unique citations, only seven studies involving 518 participants proved eligible. The effects of frequent hemodialysis on physical and mental health were imprecise due to few data. Frequent hemodialysis probably had uncertain effect on death from all cause compared with standard hemodialysis (relative risk 0.79, 95% confidence interval 0.33-1.91, low certainty evidence). Data were not reported for death from cardiovascular causes, major cardiovascular events, fatigue or vascular access. CONCLUSION:The evidentiary basis for frequent hemodialysis is incomplete due to clinical trials with few or no events reported for mortality and cardiovascular outcome measures and few participants in which patient-reported outcomes including health-related quality of life and symptoms were reported.

The CONVINCE randomized trial found a slower decline in self-reported health status in people receiving hemodiafiltration versus hemodialysis for renal replacement therapy, particular improvements were seen in physical and cognitive function, pain interference and social participation. There is clinical interest in whether these benefits of hemodiafiltration are modified by age, sex, time on dialysis, diabetes and cardiovascular disease, and type of vascular access. The CONVINCE trial data was used to perform prespecified subgroup analyses looking at the comparative effects of hemodiafiltration versus hemodialysis on self-reported health status (Physical Function, Fatigue, Pain Interference, Sleep Disturbance, Anxiety, Cognitive Function, Depression, Ability to Participate in Social Roles and Activities) by the following subgroups: age (>65, 50–65, <50 years), sex (male/female), time on dialysis (>5, 2–5, <2 years), diabetes (yes/no) and cardiovascular disease (yes/no), and type of vascular access (catheter/graft vs arteriovenous fistula). Self-reported health status data was available every 3 months over the course of the trial. We tested subgroup interaction in a longitudinal linear mixed model. Of 1360 patients randomized in CONVINCE, health status data were available for 1211 patients (89%). The effect of hemodiafiltration on sleep disturbance was significantly better in people with arteriovenous fistula as compared to those with catheters/grafts (p = 0.026). People who had been on dialysis for more than 5 years had better physical function when randomized to hemodiafiltration (p = 0.028). Being on hemodiafiltration had a stronger effect on pain interference in people who were <50 years (p = 0.044) and the effects on cognitive function were better in people who had no history of cardiovascular disease (p = 0.048) (see Fig. 1). The CONVINCE study found significant effects of high-dose hemodiafiltration on some domains of health status compared to high flux hemodialysis. These benefits appear to differ slightly between patient subgroups, which could be simply the results of multiple statistical comparisons and underpowered sample, but also of relevance to be further explored in pooled analyses of randomized trials in view of clinicians’ interest on the question.

Abstract Background and Aims Haemodiafiltration (HDF) with an appropriate dosing reduces death from any cause based on an individual participant data meta-analysis and aggregated data meta-analyses of available randomized trials. No differences in treatment effect are reported for specific patient populations when defined on a single characteristic in subgroup analyses. Yet, it is unclear to what extent individual patients, characterized by a combination of clinical characteristics, may benefit from HDF. This study aimed to develop and internally validate a treatment effect prediction model to determine which individual patients would benefit most from well dosed HDF, compared with haemodialysis (HD), in terms of survival. Method Individual participant data from five randomized controlled trials (CONTRAST, ESHOL, Turkish HDF study, French HDF study, CONVINCE) comparing HDF with HD on all-cause mortality were used to derive a Royston-Parmar model for exploring the prediction of absolute treatment effect of HDF based on pre-specified patient and disease characteristics, notably age, sex, body mass index, diabetes mellitus, history of cardiovascular disease, creatinine levels, and c-reactive protein levels. Internal validation of the model was performed using internal-external cross validation. Results Among 4153 participants, with a median follow-up of 30 months (Q1-Q3: 24-36), death from any cause occurred in 558 patients (27.2%). The median predicted survival benefit of HDF compared with HD was 6.9 (Q1–Q3: 5.6–9.0) months, with a range of 2 to 42 months. Patients who were predicted to benefit most from HDF were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine levels. Internal-external cross validation showed adequate discrimination and calibration. Conclusion All-cause mortality is reduced by HDF compared with HD in ESKD patients. Yet, the absolute survival benefit seems to considerably differ between individual patients. Our results suggest that the effects of HDF on absolute survival can be predicted accurately using a combination of readily available patient and disease characteristics. This prediction model approach exemplifies the potential of prediction algorithms in supporting clinical decision-making for the choice of treatment options. Validation and potential updates to the presented algorithm are necessary, along with a preferable randomized evaluation of its clinical impact before widespread implementation.