Dataset Information

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D).

ABSTRACT:

Introduction

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10-15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment.

Methods

ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored.

Results

Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214).

Conclusion

This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

SUBMITTER: Macdougall IC

PROVIDER: S-EPMC10210075 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D).

Macdougall Iain C IC Meadowcroft Amy M AM Blackorby Allison A Cizman Borut B Cobitz Alexander R AR Godoy Sergio S Jha Vivekanand V Johansen Kirsten L KL McMahon Gearoid G Obrador Gregorio T GT Wong Muh Geot MG Singh Ajay K AK

American journal of nephrology 20230207 1-2

<h4>Introduction</h4>Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10-15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment.<h4>Methods</h4>ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA ...[more]

PMID: 36739866

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Project description:BackgroundThe prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305).MethodsASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study).ResultsIn ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined.ConclusionsPrespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat.Trial registrationThe ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

Project description:Rationale & objectiveSince the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences.Study designRetrospective observational cohort study.Setting & participantsUS Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014.PredictorsErythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic.OutcomesAssociations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups.Analytical approachBaseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model.ResultsOf 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days.LimitationsOnly US Medicare patients were included and different hyporesponder definitions may have influenced the results.ConclusionsThis study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Project description:IntroductionHyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in patients with anaemia of chronic kidney disease may lead to increased ESA doses to achieve target haemoglobin levels; however, elevated doses may be associated with increased mortality. Furthermore, patients with hyporesponsiveness to ESAs have poorer clinical outcomes than those who respond well to ESAs. Incidence and clinical characteristics of patients with ESA hyporesponsiveness were explored in a real-world setting.MethodsThis was a retrospective study of electronic medical records of adults with stage 5 chronic kidney disease receiving renal replacement therapy and ESA treatment, from 1 January 2015 to 31 December 2021. The primary objective was ESA hyporesponsiveness rate/1000 days, with a hyporesponsive event defined as ESA use at an elevated dose, according to National Institute for Health and Care Excellence (NICE) criteria. Other hyporesponsiveness definitions applied were erythropoietin resistance index-defined ESA hyporesponsiveness (ERI) Kidney Disease Improving Global Outcomes (KDIGO) and a clinical practicality algorithm.ResultsIn total, 85,259 patients were included in the analysis; 59.9% were male, median (interquartile range) ESA starting dose was 733.3 (400.0, 1200.0) IU/week and follow-up duration was 2.2 (1.0, 4.2) years. Incidence of ESA hyporesponsiveness varied when applying different definitions; NICE 0.05/1000 days (5.2% of patients), ERI 0.40/1000 days (40.7%), KDIGO 0.15/1000 days (15.4%), and clinical practicality algorithm 0.48/1000 days (47.9%). ESA doses remained higher in hyporesponsive versus responsive patients, yet haemoglobin levels were similar between groups.ConclusionThe results from this study, which applied multiple hyporesponsiveness definitions to a large, geographically diverse population of patients with anaemia of CKD, showed variation in ESA hyporesponsiveness incidence rates depending on definitions used and higher ESA doses in hyporesponsive versus responsive patients. These results underscore the need for individualised clinical assessment and thorough evaluation when considering ESA dose adjustments to reach haemoglobin targets. Graphical abstract available for this article.Trial registrationNCT05530291.

Project description:BackgroundEvidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice.MethodsDuring the years 2009-2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out.ResultsIn general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0-1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2-2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1-2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2-0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3-0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness.ConclusionsThe study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients' quality of life.

Dataset Information

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D).

Introduction

Methods

Results

Conclusion

Publications

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D).

Similar Datasets

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