key: cord-1034329-blr3c72o
authors: Singh, Ajay K; Blackorby, Allison; Cizman, Borut; Carroll, Kevin; Cobitz, Alexander R; Davies, Rich; Jha, Vivekanand; Johansen, Kirsten L; Lopes, Renato D; Kler, Lata; Macdougall, Iain C; McMurray, John J V; Meadowcroft, Amy M; Obrador, Gregorio T; Perkovic, Vlado; Solomon, Scott; Wanner, Christoph; Waikar, Sushrut S; Wheeler, David C; Wiecek, Andrzej
title: Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial
date: 2021-03-21
journal: Nephrol Dial Transplant
DOI: 10.1093/ndt/gfab065
sha: a3e18e317421f61b6cd111c285a77581adc243f3
doc_id: 1034329
cord_uid: blr3c72o

BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety. METHODS: We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries. RESULTS: The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. CONCLUSIONS: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D. This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807.

• anemia is a common complication in patients with chronic kidney disease (CKD); untreated, it is ubiquitous in patients with CKD who are on dialysis; • treatment of anemia with erythropoiesis-stimulating agents (ESAs) successfully corrects hemoglobin (Hb) levels;

however, ESAs can be associated with adverse cardiovascular (CV) outcomes; and • this large study is needed to evaluate whether daprodustat-a hypoxia-inducible factor prolyl hydroxylase inhibitor-is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: Hb efficacy and CV safety in patients with CKD who are on dialysis.

What this study adds?

• this is one of the largest anemia studies in dialysis patients (n ¼ 2964), being performed in 35 countries across Europe, North America, Latin America and Asia Pacific. Baseline characteristics were similar to patients enrolled in other large CV outcome trials and relevant patient registries, thus supporting the generalizability of this study population; • a high proportion of the study population has a history of CV disease and/or diabetes mellitus; however, on average, control of diabetes and blood pressure were consistent with Kidney Disease: Improving Global Outcomes guidelines or local equivalents; and • standardizing the doses of randomized treatment, along with utilizing the same dose adjustment algorithm, iron management criteria and anemia rescue algorithm allow for a more unbiased comparison between the groups.

What impact this may have on practice or policy?

• this study was designed to determine the efficacy and safety of daprodustat in a way that will help ensure the clinical applicability of the results: the study population is large, diverse and broadly representative of patients with CKD undergoing dialysis; and • if daprodustat is noninferior to ESAs, it may provide an alternative oral dosing regimen to existing treatment options, which may be preferable among certain patients.

Anemia is ubiquitous among patients with chronic kidney disease (CKD) who are on dialysis (CKD G5D) [1] . The introduction of recombinant human erythropoietin (rhEPO) treatment in 1989 was one of the most important advances in the treatment of patients on dialysis and other patients with CKD. In the past, severe anemia was common, diminishing patients' quality of life and resulting in the need for frequent blood transfusions [2] . Treatment with rhEPO and its analogs [erythropoiesis-stimulating agents (ESAs)] to partially correct anemia has improved patients' lives and substantially reduced requirements for blood transfusion. However, several randomized trials have demonstrated either no benefit or even harm in relation to cardiovascular (CV) and other outcomes when treatment with rhEPO and its analogs were used to normalize hemoglobin (Hb) in patients with CKD [3] [4] [5] [6] . Indeed, post hoc analysis have suggested that exposure to high doses of exogenous rhEPO may present a possible increase in CV and mortality risk in these patients [7] [8] [9] . The emergence of newer compounds termed hypoxiainducible factor prolyl hydroxylase inhibitors (HIF-PHIs) to stimulate erythropoiesis through the inhibition of HIF-prolyl hydroxylase (PHD) enzymes PHD1, PHD2 and PHD3 may represent an alternative treatment strategy [10] . Recently approved in China and Japan, these agents are currently in development for the rest of the world [11] [12] [13] . PHD inhibition leads to stabilization of HIF-a transcription factors and expression of HIF-responsive genes involved in adaptation to hypoxia, including EPO and genes that regulate iron uptake, mobilization and transport, as well as resulting in decreased hepcidin production [14, 15] . Given the safety concerns with rhEPO and its analogs and challenges associated with parenteral therapies in some CKD populations, HIF-PHIs such as daprodustat (previously GSK1278863) are being developed to treat anemia of CKD.

In prior clinical trials of up to 52 weeks in Japan, daprodustat increased Hb to target goals in patients with anemia as effectively as darbepoetin alfa [16] . However, unlike rhEPO therapy, daprodustat increased Hb without raising plasma EPO to supraphysiologic levels [17, 18] . Across the trials published to date, daprodustat appears generally well tolerated with the more frequently reported adverse events being common events characteristic of the target populations [16] [17] [18] [19] . As an oral alternative to the parenterally administered rhEPOs, daprodustat may also prove to be more convenient to nondialysis and peritoneal dialysis (PD) patients, as it is more easily delivered, stored and administered.

Here we describe the essential design elements and baseline characteristics of patients randomized in the Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Dialysis (ASCEND-D) trial.

ASCEND-D is a global, randomized, open-label (sponsorblind), parallel-group, active-controlled, event-driven Phase 3 trial comparing the efficacy and safety of daprodustat in patients with CKD G5D being treated with an ESA for anemia (ClinicalTrials.gov: NCT02879305; EudraCT Number: 2016-000541-31). The study was approved by the ethics committee at every participating institution and was conducted according to the recommendations of Good Clinical Practice and the declaration of Helsinki. All patients provided written informed consent.

ASCEND-D consists of four periods: a screening period, a placebo run-in period, a treatment period and a follow-up period ( Figure 1 ). The 4-week screening period permitted eligibility determination based on laboratory assessments to be confirmed, while the 4-week run-in period was used to establish adherence to daprodustat placebo tablets and study procedures. Prior ESAs were continued during the screening and run-in periods. Subjects were randomized to daprodustat or rhEPO control [intravenous (IV) epoetin alfa for hemodialysis (HD) patients and subcutaneous darbepoetin alfa for PD patients]. Thereafter, the treatment period was divided into a stabilization phase from Day 1 to Week 28, and a maintenance phase (MP) from Week 28 to the end of study (EOS) visit, with dose titration to achieve the pre-specified Hb target range (10-11 g/dL). The follow-up period consisted of a visit 4-6 weeks after stopping randomized treatment, only for those patients who continued randomized treatment until the EOS visit.

Patients attended routine follow-up at least every 4 weeks during Year 1 of the study and at least every 12 weeks thereafter. Patients who permanently discontinued randomized treatment prior to the EOS were followed at 12-weekly intervals off-treatment until the EOS visit. Serum and plasma samples were collected at baseline, Week 28 and Week 52 for future analysis of biomarkers and iron metabolism.

Eligibility was determined at Week 8, with select criteria confirmed at Day 1 (randomization). Eligible patients were adults, treated with an approved ESA for !6 weeks before screening, had a screening Hb of 8-12 g/dL, on a consistent mode of dialysis for >90 days before screening, demonstrated adherence to daprodustat placebo tablets during the run-in period, and able to provide informed consent. The key inclusion and exclusion criteria are provided in Table 1 and complete entry criteria are outlined in Supplementary data, Table S1 .

Daprodustat and rhEPO dosing strategies and iron treatment for managing Hb are detailed in Table 2 . A rescue algorithm was in place to minimize the risk of patients having an inadequate Hb response for an extended period and to enable consistency in the application of rescue therapy across the study (Table 3) .

This trial was developed in consultation with the USA and European regulatory agencies. The co-primary noninferiority (NI) objectives of the trial are to compare Hb efficacy and CV safety among patients receiving daprodustat versus those 962 A.K. Singh et al.

receiving rhEPO. The NI Hb efficacy objective will be assessed with the co-primary endpoint of mean change in Hb between baseline and the evaluation period (EP; average over ). An external, independent and blinded endpoints committee (Duke Clinical Research Institute) will adjudicate events used to assess the NI CV safety objective with the co-primary endpoint of time to first adjudicated major adverse CV event [MACE; the composite of all-cause mortality, nonfatal myocardial infarction (MI) and nonfatal stroke]. Principal secondary superiority endpoints, including superiority assessment of MACE, and other secondary endpoints are listed in Table 4 .

Patients were stratified by dialysis type fHD [including hemodiafiltration (HDF) and hemofiltration (HF)] or PDg, by region, and by participation in the ambulatory blood pressure (BP) monitoring sub-study. Following stratification, patients were randomized 1:1 to receive oral daprodustat or rhEPO control. A central randomization approach was used to protect against selection bias due to the open-label design.

A sample size of 3000 was planned for this event-driven trial based on the co-primary CV safety objective and an event target of 945 adjudicated first MACE. This includes on-and off-treatment MACE in the intent-to-treat (ITT) population. This event count provides $90% power to establish NI with a NI margin hazard ratio of 1.20 for daprodustat compared with rhEPO, assuming a true underlying 3% lower relative risk of MACE in favor of daprodustat (i.e. a true underlying hazard ratio of 0.97), and 80% power for NI under the assumption that the true underlying risk of MACE is the same in both groups (i.e. a true underlying hazard ratio of 1.00). The study completed randomization in August 2018. In August 2020, prior to study unblinding and after discussion with the regulatory authorities, as well as approval with the external steering committees (SCs) and the Independent Data Monitoring Committee (IDMC), the MACE NI margin was changed to 1.25, reducing the event target to 664 while maintaining $90% power. The rationale for the NI margin change was to accelerate study closeout in consideration of the coronavirus disease 2019 (COVID- 19) pandemic and to align with the NI margin used in other HIF-PHI clinical studies [20] . There are no identified risks to subject safety or data integrity with these changes.

The planned study size provides >99% power for the Hb NI test with a NI margin of À0.75 g/dL for the (daprodustat -rhEPO) Hb difference. This includes on and off-treatment Hb values in the ITT population. Multiple imputation will be used to impute missing Hb values. The co-primary endpoints will be tested in parallel for NI at the one-sided 2.5% level, and NI will need to be established for both co-primary endpoints to proceed to evaluate the principal secondary endpoints for superiority. Statistical testing for the principal secondary endpoints will be adjusted for multiplicity using the Holm-Bonferroni for multiplicity adjustment [21] .

Descriptive statistics in the form of number and percentage of patients or median and 25th and 75th percentiles (P25 and P75) are provided for baseline variables. Baseline values are presented for the ITT population, overall and by CV disease (CVD) history, defined as having a history of at least one of the following: angina pectoris, MI, stroke, transient ischemic attack (TIA), coronary artery disease, heart failure, atrial fibrillation, cardiac arrest or valvular heart disease.

ASCEND-D was developed in collaboration with the Executive SC (ESC) and SC. The ESC provides academic and scientific leadership and ensures that conduct of this study as well the other the Proactive IV Iron Therapy in HD Patients (PIVOTAL) studies in the ASCEND program conform to protocols. The SC provides scientific, medical and operational advice to the ESC. Members of these committees comprised Hb and iron, standard of care and regional recruitment and retention sub-committees to review in-stream, blinded, aggregate data on an ongoing basis to identify potential issues and to escalate to the SC and ESC as required. An IDMC reviews safety and efficacy data as defined in the protocols and makes recommendations for additions or adjustments, as well as evaluating the co-primary MACE endpoint at a planned interim analysis to assess for futility of achieving NI at study completion. An external, independent and blinded Clinical Events Classification (CEC) group, led by the Duke Clinical Research Institute, in collaboration with George Clinical, was in charge of adjudicating pre-defined events (all-cause mortality, MI, stroke, hospitalization for heart failure and thromboembolic events). Committee members and their respective affiliations, along with the CEC Primary Investigator, are presented in Supplementary data, Table S2 .

To assess generalizability, we compared baseline characteristics of ASCEND-D patients with those enrolled in two other large, randomized, controlled, trials, the INNO 2 VATE prevalent trial [20] and the PIVOTAL trial [22, 23] , which evaluated anemia treatment in maintenance dialysis patients. A comparison of the ASCEND-D population was also made with more contemporaneous registry data sets with sufficient patient information to allow meaningful comparison, i.e. Dialysis Outcomes and Practice Patterns Study (DOPPS), US Renal Data System (USRDS) [24, 25] .

ASCEND-D is being conducted in 431 centers in 35 countries. The country-level patient distribution is listed in Supplementary data, Table S3 . In total, 44% of patients originated in Europe Middle East Africa (EMEA), 29% in North America (NA; predominantly USA), 14% in Latin America (LA) and 13% in the Asia Pacific (APAC) region.

A total of 5408 patients were screened, including patients who were re-screened and 2444 (45%) who did not meet entry criteria and were not randomized. The reasons for screen failure are listed in Supplementary data, Table S4 . A total of 2964 patients were randomized. One additional patient was randomized but had not provided valid informed consent so was removed from the randomized count. 

Baseline characteristics are summarized in Table 5 . The ITT cohort has a median age of 58 years with 43% being female. Eighty-nine percent of patients were treated with HD and 11% with PD.

Forty-five percent of patients reported a history of CVD (Table 5) . A history of stroke was reported by 7% and TIA by 4%. Among patients with CVD, 51% had a history of coronary artery disease, 22% angina pectoris and 19% MI. More patients Iron must be stopped if values of ferritin >800 ng/mL and TSAT >20% or if TSAT >40% are present Investigators are to be guided by local/regional guidelines and may stop administration of iron at a lower ferritin or TSAT level if clinically indicated; the framework for starting and stopping iron is based on a review of global and regional iron guidelines, as well as input from the ASCEND SCs The Hb and Iron sub-committee of the SC is monitoring blinded patient Hb and iron data during the trial Assessment of the quality of clinical care provided to patients was monitored by the Standard of Care sub-committee of the SC. a During the trial, overrides of the dose adjustment algorithm for exceptional circumstances associated with a safety concern are permitted if approved by the sponsor. For patients who have switched from HD to PD who are randomized to rhEPO, the baseline dose for the purposes of the rescue algorithm is the new darbepoetin alfa dose. c For patients who previously were evaluated for rescue and who can continue in the trial, 'post-rescue' dose is the dose of randomized treatment that a subject is receiving at the study visit after initial intervention. d Repeat HemoCue Hb at the same study visit to confirm Hb (using the same sample); take average of two values. PRBC, packed red blood cells.

ASCEND-D trial design and baseline characteristics with CVD had diabetes mellitus than patients without CVD (49% versus 35%, respectively). Likewise, use of beta-blockers, statins, vitamin K antagonists and aspirin was higher among patients with a history of CVD. Patients with and without reported CVD had similar BPs; $46% were taking angiotensinconverting enzyme inhibitors (ACEi) or angiotensin receptor II blockers (ARB).

A functioning arterio-venous fistula (AVF) was present in $69% of patients; 9% had an AV graft (AVG); a tunneled or nontunneled central venous catheter (CVC) was present in 9% and 1%, respectively.

Patients enrolled in ASCEND-D generally had similar demographic characteristics as patients in the other CVOTs ( Table 6 ). The ASCEND-D and the INNO 2 VATE prevalent trials, the latter investigating another HIF-PHI, vadadustat, were of similar trial design utilizing an rhEPO active control, while PIVOTAL investigated high versus low-dose IV iron. Both INNO 2 VATE and ASCEND-D were global trials; however, ASCEND-D included more patients in EMEA and less in NA than INNO 2 VATE; in contrast, PIVOTAL was conducted in the UK. The HIF-PHI patient populations were of similar racial composition, while PIVOTAL overwhelmingly enrolled white patients. There were similar rates for CVD history (utilizing similar definitions) for both the ASCEND-D and the INNO 2 VATE trials [not reported (NR) for PIVOTAL], while diabetes history was similar for all trials. ASCEND-D had higher rates of hypertension than PIVOTAL and INNO 2 VATE and higher rates of heart failure than PIVOTAL (NR for INNO 2 VATE).

Both INNO 2 VATE and PIVOTAL had slightly higher baseline BP measures than ASCEND-D (Table 6 ) but similar Hb levels. Concomitant medications were similar for the HIF-PHI trials; however, PIVOTAL reported lower ACEi/ARB use and higher antiplatelet therapy and lipid-lowering use. Interestingly, prior ESA dose was lower in ASCEND-D than in the other CVOTs, while the proportion of subjects using IV 

To assess generalizability, we compared demographic and clinical characteristics of patients enrolled in the ASCEND-D study with several contemporaneous, real-world, global registry datasets, including DOPPS [24, 26] and USRDS [25] (Table 7) , with DOPPS including patients from the USA and Europe. Other global registries were explored but excluded from comparison due to the sparsity of the pertinent data. Data from DOPPS and USRDS were generally similar to the ASCEND-D population. Notable differences included race where a larger Black population was reported in the USRDS than ASCEND-D, which only comprised 29% patients from the USA. Hb levels were higher in the global DOPPS dataset than ASCEND-D where subjects were dosed to achieve Hb concentrations within the range of 10-11 g/dL; interestingly, higher ESA doses were seen in the US datasets relative to ASCEND-D.

ASCEND-D was designed to include a broad population as representative of the overall dialysis population as possible, with the appropriate measures to enable valid efficacy and safety comparisons across treatment groups. Sites were selected to achieve a balance in recruitment across EMEA, NA and LA, and APAC. Entry criteria were developed to identify a stable, maintenance and adequately treated dialysis population. A placebo run-in period was established to confirm compliance with an oral medication and to minimize withdrawal of consent post-randomization seen in a prior daprodustat HD study [18] . Exclusions ensured events that could impact the safety analysis were not present, including anemia due to causes other than CKD, recent CV events or cancer and uncontrolled hypertension.

The Hb target range of 10-11 g/dL was selected to accommodate the varying anemia guidelines and ESA labeling worldwide. The selection of rhEPO control was based on pragmatic clinical dialysis practice. In earlier daprodustat clinical trials, investigators were responsible for managing rhEPO dosing in the control group, which led to higher Hb values than targeted [27] . Therefore, a decision was made to apply the same dose adjustment algorithm for both treatment groups, as well as to provide the study rhEPO and develop a standard set of dose steps that were aligned with rhEPO labeling. Similarly, iron management criteria and an anemia rescue algorithm have been developed, and used for both treatment groups. For the latter, only IV iron and/or transfusions were allowed, in addition to randomized treatment, as an early intervention to improve Hb before considering a patient to have met the rescue endpoint and to permanently discontinue randomized treatment. Standardizing the doses of randomized treatment, along with utilizing the same dose adjustment algorithm, iron management criteria and anemia rescue algorithm allow for a more unbiased comparison between the groups. The baseline characteristics of dialysis patients recruited in ASCEND-D were similar to that of other large CVOTs of dialysis patients. The most relevant comparison is between ASCEND-D and the INNO 2 VATE prevalent trial, which are both investigating HIF-PHIs; trial design, demographic and clinical characteristics were similar. While INNO 2 VATE had a higher recruitment in the USA, ASCEND-D had a higher recruitment from EMEA. Comparisons with PIVOTAL [22] and other historical CVOTs in dialysis patients also indicate similar baseline characteristics [28] [29] [30] , with the exception of a lower prior ESA dose and higher rate of IV iron usage for ASCEND-D. Utilization of a lower ESA dose in ASCEND-D likely reflects differences in US recruitment (29% ASCEND-D versus 61% INNO 2 VATE). In contrast to INNO 2 VATE, where only 16% of patients had baseline IV iron use, 64% of ASCEND-D patients had baseline IV iron use, comparable with DOPPS data [24] .

Registry data provided an additional way to compare patient characteristics with ASCEND-D to determine generalizability. Because of its global nature, DOPPS is arguably a better comparator than country-based registries. ASCEND-D compares favorably with DOPPS with respect to demographic and clinical characteristics [26] , thus supporting the generalizability of this study population, with the exception of a higher Hb in DOPPS given the practice pattern outside of the USA to treat to higher Hb targets than the pre-specified target in ASCEND-D, which was developed in line with worldwide ESA labeling. Comparisons with US datasets from DOPPS [26] and USRDS [25] demonstrated that baseline characteristics were generally similar, with only a few accountable differences (e.g. race and Hb level). The main limitation of the ASCEND-D trial is the open-label design. Blinding dialysis patients to randomized treatment is challenging because the active comparator is either administered intravenously or subcutaneously, whereas daprodustat is an oral medication and would have introduced a number of complexities and potential limitations to the study, including limiting the generalizability of the study. Importantly, the adjudication of clinical outcomes is blinded to the treatment assignment minimizing the risk of ascertainment bias [31] . Likewise, the sponsor remained blind to treatment assignment throughout the trial. Although the study patient population is younger than the average age of dialysis patients, it is common for trials to recruit younger patients given that older patients are frailer and less likely to participate in trials. Additionally, the selection of rhEPO type, dose steps and frequency of administration were pre-specified in the comparator group and may differ from local ESA protocols. Likewise, a common dose adjustment algorithm across treatment groups was implemented, which may differ from local practice.

These limitations are balanced by other strengths. ASCEND-D is a prospective randomized CVOT with one of the largest numbers of patients recruited worldwide. Patients were recruited not only from academic centers but also from community practices. It is notable that the racial and ethnic composition of ASCEND-D, although similar to other large trials, is more diverse than often seen in trials enrolling dialysis patients. The standard of care for patients on dialysis (e.g. diabetes, BP control and dialysis adequacy) was consistent with Kidney Disease: Improving Global Outcomes guidelines or local equivalent [32] . Overall, the study population, including patients on PD, and prevalence of CVD appears typical of global patients undergoing dialysis, ideal for determining the safety and efficacy of daprodustat.

In conclusion, ASCEND-D enrolled 2964 patients who are broadly representative of patients with anemia of CKD on dialysis. The study will test the hypothesis that daprodustat is noninferior to comparator rhEPO for two co-primary endpoints, Hb efficacy and CV safety. Results from ASCEND-D, expected in late 2021, will inform on an alternative option to treat anemia in dialysis patients.

Supplementary data are available at ndt online.

Editorial support in the form of writing assistance, assembling figures, grammatical editing and referencing was provided by Jonathan Plumb, PhD, of Fishawack Indicia, part of Fishawack Health, and was funded by GlaxoSmithKline.

ASCEND-D is funded by GlaxoSmithKline.

A.K.S. contributed to the design, interpretation of data, supervision and management of the research, writing and critical review of this manuscript. All authors contributed to the design, interpretation of data, management of research, writing and critical review of this manuscript. All authors affirm that authorship is merited based on the International Committee of Medical Journal Editors authorship criteria. A.K.S. was the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

reports consultancy fees from GlaxoSmithKline and stock in Gilead. K.C. reports consultancy fees from GlaxoSmithKline

Servier and Vitae; research funding from Pfizer (supplied drug and seed funding for TESTING trial) and GlaxoSmithKline; honoraria from AbbVie

reports personal fees from Public Health Advocacy Institute, CVS, Roth Capital Partners, Kantum Pharma, Mallinckrodt, Wolters Kluewer, GE Health Care, GlaxoSmithKline, Mass Medical International

are employees of and stockholders in GlaxoSmithKline

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