The NightLife study - the clinical and cost-effectiveness of thrice-weekly, extended, in-centre nocturnal haemodialysis versus daytime haemodialysis using a mixed methods approach: study protocol for a randomised controlled trial.

BACKGROUND: In-centre nocturnal haemodialysis (INHD) offers extended-hours haemodialysis, 6 to 8 h thrice-weekly overnight, with the support of dialysis specialist nurses. There is increasing observational data demonstrating potential benefits of INHD on health-related quality of life (HRQoL). There is a lack of randomised controlled trial (RCT) data to confirm these benefits and assess safety. METHODS: The NightLife study is a pragmatic, two-arm, multicentre RCT comparing the impact of 6 months INHD to conventional haemodialysis (thrice-weekly daytime in-centre haemodialysis, 3.5-5 h per session). The primary outcome is the total score from the Kidney Disease Quality of Life tool at 6 months. Secondary outcomes include sleep and cognitive function, measures of safety, adherence to dialysis and impact on clinical parameters. There is an embedded Process Evaluation to assess implementation, health economic modelling and a QuinteT Recruitment Intervention to understand factors that influence recruitment and retention. Adults (≥ 18 years old) who have been established on haemodialysis for > 3 months are eligible to participate. DISCUSSION: There are 68,000 adults in the UK that need kidney replacement therapy (KRT), with in-centre haemodialysis the treatment modality for over a third of cases. HRQoL is an independent predictor of hospitalisation and mortality in individuals on maintenance dialysis. Haemodialysis is associated with poor HRQoL in comparison to the general population. INHD has the potential to improve HRQoL. Vigorous RCT evidence of effectiveness is lacking. The NightLife study is an essential step in the understanding of dialysis therapies and will guide patient-centred decisions regarding KRT in the future. TRIAL REGISTRATION: Trial registration number: ISRCTN87042063. Registered: 14/07/2020.

Cost Effectiveness of Difelikefalin Compared to Standard Care for Treating Chronic Kidney Disease Associated Pruritus (CKD-aP) in People with Kidney Failure Receiving Haemodialysis.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP) is associated with an increased risk of depression, poor sleep and reduced health-related quality of life. Two phase III studies (KALM-1 and KALM-2) of difelikefalin showed reduced CKD-aP severity and improved itch-related health-related quality of life in patients with moderate and severe CKD-aP receiving haemodialysis for kidney failure. OBJECTIVE: We aimed to estimate the cost effectiveness of difelikefalin for patients with CKD-aP receiving haemodialysis for kidney failure compared to standard care from a UK National Health Service perspective. METHODS: A cohort model was developed with four health states representing levels of pruritus intensity over time, based on the KALM trials augmented with longer term CKD-aP severity data from another haemodialysis trial (SHAREHD) for standard care. Utilities were estimated from a mapping study of 5-D Itch to EQ-5D-5L in 487 patients receiving haemodialysis, costs were estimated based on resource use alongside the SHAREHD and 2018 unit costs, and inflated to 2021 costs. Costs and quality-adjusted life-years were discounted at 3.5% per annum. A de novo economic model was developed in Microsoft Excel with scenario analyses performed using a range of assumptions. RESULTS: In the base-case analysis over a time horizon of 64 weeks, using a placeholder cost of £75 per 28-days for difelikefalin, the incremental cost-effectiveness ratio of difelikefalin compared with standard care was £19,558/quality-adjusted life-year (QALY). Scenario analyses resulted in incremental cost-effectiveness ratios that ranged from £10,154/QALY (severe only) to £16,957/QALY (5-year horizon) for difelikefalin compared to standard care. Probabilistic sensitivity analyses suggested difelikefalin has a 48.6% probability of being cost effective at a threshold of £20,000/QALY and a 57.2% probability of being cost effective at a threshold of £30,000/QALY. CONCLUSIONS: The cost effectiveness of difelikefalin in a range of scenarios could make it an important pharmacotherapy to address the high burden of disease and unmet need for treatments associated with CKD-aP in the UK.

Intervening to eliminate the centre-effect variation in home dialysis use: protocol for Inter-CEPt-a sequential mixed-methods study designing an intervention bundle.

INTRODUCTION: Use of home dialysis by centres in the UK varies considerably and is decreasing despite attempts to encourage greater use. Knowing what drives this unwarranted variation requires in-depth understanding of centre cultural and organisational factors and how these relate to quantifiable centre performance, accounting for competing treatment options. This knowledge will be used to identify components of a practical and feasible intervention bundle ensuring this is realistic and cost-effective. METHODS AND ANALYSIS: Underpinned by the non-adoption, abandonment, scale-up, spread and sustainability framework, our research will use an exploratory sequential mixed-methods approach. Insights from multisited focused team ethnographic and qualitative research at four case study sites will inform development of a national survey of 52 centres. Survey results, linked to patient-level data from the UK Renal Registry, will populate a causal graph describing patient and centre-level factors, leading to uptake of home dialysis and multistate models incorporating patient-level treatment modality history and mortality. This will inform a contemporary economic evaluation of modality cost-effectiveness that will quantify how modification of factors facilitating home dialysis, identified from the ethnography and survey, might yield the greatest improvements in costs, quality of life and numbers on home therapies. Selected from these factors, using the capability, opportunity and motivation for behaviour change framework (COM-B) for intervention design, the optimal intervention bundle will be developed through workshops with patients and healthcare professionals to ensure acceptability and feasibility. Patient and public engagement and involvement is embedded throughout the project. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Health Research Authority reference 20-WA-0249. The intervention bundle will comprise components for all stake holder groups: commissioners, provider units, recipients of dialysis, their caregivers and families. To reache all these groups, a variety of knowledge exchange methods will be used: short guides, infographics, case studies, National Institute for Health and Care Excellence guidelines, patient conferences, 'Getting it Right First Time' initiative, Clinical Reference Group (dialysis).

The Cost-Effectiveness of Belimumab and Voclosporin for Patients with Lupus Nephritis in the United States.

BACKGROUND AND OBJECTIVES: Despite existing therapies, people with lupus nephritis progress to kidney failure and have reduced life expectancy. Belimumab and voclosporin are two new disease-modifying therapies recently approved for the treatment of lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A de novo economic model was developed to estimate the cost-effectiveness of these therapies, including the following health states: "complete response," "partial response," and "active disease" defined by eGFR and proteinuria changes, kidney failure, and death. Short-term data and mean cohort characteristics were sourced from pivotal clinical trials of belimumab (the Belimumab International Study in Lupus Nephritis) and voclosporin (the Aurinia Urinary Protection Reduction Active-Lupus with Voclosporin trial and Aurinia Renal Response in Active Lupus With Voclosporin). Risk of mortality and kidney failure were on the basis of survival modeling using published Kaplan-Meier data. Each drug was compared with the standard of care as represented by the comparator arm in its respective pivotal trial(s) using US health care sector perspective, with a societal perspective also explored. RESULTS: In the health care perspective probabilistic analysis, the incremental cost-effectiveness ratio for belimumab compared with its control arm was estimated to be approximately $95,000 per quality-adjusted life year. The corresponding incremental ratio for voclosporin compared with its control arm was approximately $150,000 per quality-adjusted life year. Compared with their respective standard care arms, the probabilities of belimumab and voclosporin being cost effective at a threshold of $150,000 per quality-adjusted life year were 69% and 49%, respectively. Cost-effectiveness was dependent on assumptions made regarding survival in response states, costs and utilities in active disease, and the utilities in response states. In the analysis from a societal perspective, the incremental ratio for belimumab was estimated to be approximately $66,000 per quality-adjusted life year, and the incremental ratio for voclosporin was estimated to be approximately $133,000 per quality-adjusted life year. CONCLUSIONS: Compared with their respective standard care arms, belimumab but not voclosporin met willingness-to-pay thresholds of $100,000 per quality-adjusted life year. Despite potential clinical superiority in the informing trials, there remains high uncertainty around the cost-effectiveness of voclosporin.

The effectiveness and value of belimumab and voclosporin for lupus nephritis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Pearson is employed by ICER. Through their affiliated institutions, Tice, Mandrik, Thokala, and Fotheringham received funding from ICER for the work described in this summary.

A breakthrough series collaborative to increase patient participation with hemodialysis tasks: A stepped wedge cluster randomised controlled trial.

BACKGROUND: Compared to in-centre, home hemodialysis is associated with superior outcomes. The impact on patient experience and clinical outcomes of consistently providing the choice and training to undertake hemodialysis-related treatment tasks in the in-centre setting is unknown. METHODS: A stepped-wedge cluster randomised trial in 12 UK renal centres recruited prevalent in-centre hemodialysis patients with sites randomised into early and late participation in a 12-month breakthrough series collaborative that included data collection, learning events, Plan-Study-Do-Act cycles, and teleconferences repeated every 6 weeks, underpinned by a faculty, co-production, materials and a nursing course. The primary outcome was the proportion of patients undertaking five or more hemodialysis-related tasks or home hemodialysis. Secondary outcomes included independent hemodialysis, quality of life, symptoms, patient activation and hospitalisation. ISRCTN Registration Number 93999549. RESULTS: 586 hemodialysis patients were recruited. The proportion performing 5 or more tasks or home hemodialysis increased from 45.6% to 52.3% (205 to 244/449, difference 6.2%, 95% CI 1.4 to 11%), however after analysis by step the adjusted odds ratio for the intervention was 1.63 (95% CI 0.94 to 2.81, P = 0.08). 28.3% of patients doing less than 5 tasks at baseline performed 5 or more at the end of the study (69/244, 95% CI 22.2-34.3%, adjusted odds ratio 3.71, 95% CI 1.66-8.31). Independent or home hemodialysis increased from 7.5% to 11.6% (32 to 49/423, difference 4.0%, 95% CI 1.0-7.0), but the remaining secondary endpoints were unaffected. CONCLUSIONS: Our intervention did not increase dialysis related tasks being performed by a prevalent population of centre based patients, but there was an increase in home hemodialysis as well as an increase in tasks among patients who were doing fewer than 5 at baseline. Further studies are required that examine interventions to engage people who dialyse at centres in their own care.

Statistical Methods for Adjusting Estimates of Treatment Effectiveness for Patient Nonadherence in the Context of Time-to-Event Outcomes and Health Technology Assessment: A Systematic Review of Methodological Papers.

Introduction. Medication nonadherence can have a significant negative impact on treatment effectiveness. Standard intention-to-treat analyses conducted alongside clinical trials do not make adjustments for nonadherence. Several methods have been developed that attempt to estimate what treatment effectiveness would have been in the absence of nonadherence. However, health technology assessment (HTA) needs to consider effectiveness under real-world conditions, where nonadherence levels typically differ from those observed in trials. With this analytical requirement in mind, we conducted a review to identify methods for adjusting estimates of treatment effectiveness in the presence of patient nonadherence to assess their suitability for use in HTA. Methods. A "Comprehensive Pearl Growing" technique, with citation searching and reference checking, was applied across 7 electronic databases to identify methodological papers for adjusting time-to-event outcomes for nonadherence using individual patient data. A narrative synthesis of identified methods was conducted. Methods were assessed in terms of their ability to reestimate effectiveness based on alternative, suboptimal adherence levels. Results. Twenty relevant methodological papers covering 12 methods and 8 extensions to those methods were identified. Methods are broadly classified into 4 groups: 1) simple methods, 2) principal stratification methods, 3) generalized methods (g-methods), and 4) pharmacometrics-based methods using pharmacokinetics and pharmacodynamics (PKPD) analysis. Each method makes specific assumptions and has associated limitations. Five of the 12 methods are capable of adjusting for real-world nonadherence, with only g-methods and PKPD considered appropriate for HTA. Conclusion. A range of statistical methods is available for adjusting estimates of treatment effectiveness for nonadherence, but most are not suitable for use in HTA. G-methods and PKPD appear to be more appropriate to estimate effectiveness in the presence of real-world adherence.

Impact of socioeconomic status on survival following ST-elevation myocardial infarction in a universal healthcare system.

BACKGROUND: Lower socioeconomic status (SES) has been associated with worse outcomes after acute myocardial infarction. Data for survival after ST-elevation myocardial infarction (STEMI) by SES in the current era of primary percutaneous coronary intervention (PCI) is more limited. METHODS: Data was collected for all patients with acute STEMI undergoing primary PCI at The South Yorkshire Cardiothoracic Centre, UK between 2009 and 2014. A Cox regression analysis was used to assess differences in survival by SES quartile (using an area-level measure). RESULTS: Of the 3126 STEMI patients, 2655 (84.9%) were first presentations of STEMI. Lower SES groups generally had a less favourable baseline cardiovascular risk factor profile, with higher rates of smoking (p = 0.001), diabetes (p = 0.007) and previous coronary heart disease (p = 0.025). With the exception of beta-blockers, the use of secondary preventative medications was similar between SES quartiles. Adjusting for age and gender, the most disadvantaged SES quartile trended to a non-significant increased mortality at 30 days (hazard ratio 1.35 (0.79-2.33)), 1 year (1.12 (0.76-1.65)), or 3 years (1.22 (0.88-1.70)) compared to the least disadvantaged SES quartile, but this was attenuated by adjusting for additional cardiovascular risk factors and medication use on discharge. CONCLUSIONS: In this large study of unselected STEMI patients managed by primary PCI, we did not find any significant differences in survival by SES at 30 days, 1 year, or 3 years.

United Kingdom Catheter Study - Protocol Synopsis.

BACKGROUND: High-quality peritoneal dialysis (PD) catheter insertion pathways are essential for optimal access to the therapy. Dialysis outcomes are influenced by a range of patient and center-related factors, and there is a need to better understand these so that catheter insertion pathways can be better matched to individual circumstances. OBJECTIVES: To examine how patient- and center-related factors influence the choice of catheter insertion pathways for a PD patient, and the impact of such factors and pathways on patient outcomes, and specifically, to compare the occurrence of and recovery from PD catheter-related adverse events and mortality in individuals who had surgical catheter insertion with those who had medical catheter insertion, and evaluate health economics. STUDY DESIGN: A prospective multi-center cohort study of incident PD patients at catheter insertion. This is an ancillary study nested within the International Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS). METHODS: Patients will be recruited during a 30-month recruitment period at 45 United Kingdom (UK) renal facilities, with a minimum 12-month follow-up. A graphical Markov model will be fitted to describe the associations between patient demographics, comorbidities, and catheter insertion pathways that are not explained by center practices and their impact on the occurrence of catheter-related adverse events, and patient-reported outcomes. The model will also explore the extent to which the catheter insertion pathway is determined by the center practice patterns, accounting for patient mix. Multi-state models will compare the rate of occurrence of a PD catheter-related adverse event, recovery from this, and mortality in individuals who had surgical catheter insertion compared with those who had medical catheter insertion, accounting for competing events, and adjusting for patient and center factors. A health economics evaluation will establish which, if any, catheter insertion pathway is superior in terms of cost effectiveness. DISCUSSION: The study will provide information on which catheter insertion pathways are better according to individual characteristics and whether it is acceptable for dialysis units to rely on a single catheter insertion technique or whether they should invest in developing flexible pathways that incorporate both medical and surgical PD catheter insertion techniques.

Predicting hospital costs for patients receiving renal replacement therapy to inform an economic evaluation.

OBJECTIVE: To develop a model to predict annual hospital costs for patients with established renal failure, taking into account the effect of patient and treatment characteristics of potential relevance for conducting an economic evaluation, such as age, comorbidities and time on treatment. The analysis focuses on factors leading to variations in inpatient and outpatient costs and excludes fixed costs associated with dialysis, transplant surgery and high cost drugs. METHODS: Annual costs of inpatient and outpatient hospital episodes for patients starting renal replacement therapy in England were obtained from a large retrospective dataset. Multiple imputation was performed to estimate missing costs due to administrative censoring. Two-part models were developed using logistic regression to first predict the probability of incurring any hospital costs before fitting generalised linear models to estimate the level of cost in patients with positive costs. Separate models were developed to predict inpatient and outpatient costs for each treatment modality. RESULTS: Data on hospital costs were available for 15,869 incident dialysis patients and 4511 incident transplant patients. The two-part models showed a decreasing trend in costs with increasing number of years on treatment, with the exception of dialysis outpatient costs. Age did not have a consistent effect on hospital costs; however, comorbidities such as diabetes and peripheral vascular disease were strong predictors of higher hospital costs in all four models. CONCLUSION: Analysis of patient-level data can result in a deeper understanding of factors associated with variations in hospital costs and can improve the accuracy with which costs are estimated in the context of economic evaluations.

Understanding cost of care for patients on renal replacement therapy: looking beyond fixed tariffs.

BACKGROUND: In a number of countries, reimbursement to hospitals providing renal dialysis services is set according to a fixed tariff. While the cost of maintenance dialysis and transplant surgery are amenable to a system of fixed tariffs, patients with established renal failure commonly present with comorbid conditions that can lead to variations in the need for hospitalization beyond the provision of renal replacement therapy. METHODS: Patient-level cost data for incident renal replacement therapy patients in England were obtained as a result of linkage of the Hospital Episodes Statistics dataset to UK Renal Registry data. Regression models were developed to explore variations in hospital costs in relation to treatment modality, number of years on treatment and factors such as age and comorbidities. The final models were then used to predict annual costs for patients with different sets of characteristics. RESULTS: Excluding the cost of renal replacement therapy itself, inpatient costs generally decreased with number of years on treatment for haemodialysis and transplant patients, whereas costs for patients receiving peritoneal dialysis remained constant. Diabetes was associated with higher mean annual costs for all patients irrespective of treatment modality and hospital setting. Age did not have a consistent effect on costs. CONCLUSIONS: Combining predicted hospital costs with the fixed costs of renal replacement therapy showed that the total cost differential for a patient continuing on dialysis rather than receiving a transplant is considerable following the first year of renal replacement therapy, thus reinforcing the longer-term economic advantage of transplantation over dialysis for the health service.

The body composition and excretory burden of lean, obese, and severely obese individuals has implications for the assessment of chronic kidney disease.

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m(2) or more versus the normal of 18.5-25 kg/m(2)) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m(2), height 1.76 m, and BMI 22 or 45 kg/m(2) had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research.

Differential scaling of glomerular filtration rate and ingested metabolic burden: implications for gender differences in chronic kidney disease outcomes.

BACKGROUND: Men commence dialysis with a higher estimated glomerular filtration rate (eGFR) than women and are more likely to transition from chronic kidney disease (CKD) to end-stage renal disease. We hypothesized that for a given estimated body surface area (BSA) men have a greater metabolic burden, and that consequently, the practice of indexing GFR to BSA results in gender differences in the degree of biochemical uraemia. METHODS: Metabolic burden was assessed as estimated dietary protein, calorie, phosphorus, sodium and potassium intakes and urinary urea nitrogen excretion in the Chronic Renal Insufficiency Cohort, Modification of Diet in Renal Disease study, and National Health and Nutrition Examinations Surveys (NHANES) 1999-2010. Uraemia was characterized by serum biochemistry. RESULTS: Per m(2) BSA, men had greater urea nitrogen excretion and intakes of all dietary parameters (P < 0.001 for all). For a given BSA-indexed iothalamate GFR or eGFR, male gender was associated with a 10-15% greater serum urea nitrogen (P < 0.001), giving men with a BSA-indexed GFR of 70-75 mL/min/1.73 m(2) the same serum urea nitrogen concentration as women with a GFR of 60 mL/min/1.73 m(2). However, indexing metabolic burden and GFR to alternative body size measures (estimated total body water, lean body mass or resting energy expenditure) abolished/reversed the gender associations. In NHANES, BSA-indexed eGFR distribution was very similar for men and women, so that adjusting for eGFR had little effect on the gender difference in serum urea. CONCLUSIONS: Indexing GFR to BSA across genders may approximate nature's indexing approach, but gives men a greater ingested burden of protein, calories, sodium, phosphorus and potassium per mL/min GFR. This has implications for gender differences in CKD outcomes.

Did hospital mortality in England change from 2005 to 2010? A retrospective cohort analysis.

BACKGROUND: There is some evidence that hospital performance in England measured by the Dr Foster Hospital Standardised Mortality Ratio (HSMR) has improved substantially over the last 10 years. This study explores mortality in-hospital and up to 30 days post-discharge over a five year period to determine whether there have been improvements in case-mix adjusted mortality, to examine if any changes are due to changes in case-mix adjustment variables such as age, sex, method of admission and comorbidity, and to compare changes between hospital trusts. METHODS: Using Hospital Episode Statistics linked to mortality data from the Office for National Statistics the Summary Hospital-Level Mortality Index (SHMI) was calculated for all patients who were discharged or died in general acute hospital trusts in England for the period 01/04/2005 to 30/09/2010. RESULTS: During this five year period the number of admissions rose by 8% but deaths fell by 5%. The SHMI fell by 24% from 112 to 85 over the period, partly due to fewer deaths but partly due to increasing numbers predicted by the SHMI model. Excluding comorbidities from the model the SHMI fell by 18% from 108 to 89 over this period. The reduction was similar in emergency and elective admissions and in all other sub-groups examined. The average quarterly change in SHMI varied considerably between trusts (range: -4.4 to -0.2). CONCLUSIONS: As measured by the SHMI there has been a 24% improvement in mortality in acute general trusts in England over a period of five and a half years. Part of this improvement is an artificial effect caused by changes in the depth of coding of comorbidities and other effects due to change in case-mix or non-constant risk.