Visual Abstract
Keywords: hemodialysis, hemoglobin, erythropoietin, anemia, clinical trial, blood pressure, epoetin, randomized controlled trials, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), chronic kidney disease
Abstract
Background and objectives
Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA).
Design, setting, participants, & measurements
Patients on hemodialysis with a baseline hemoglobin of 8–11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly (n=270) or conventional epoetin (n=137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28–52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability.
Results
Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], −0.05; 95% confidence interval, −0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%).
Conclusions
Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated.
Clinical Trial registry name and registration number:
Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033
Introduction
Anemia is a common complication in hemodialysis-dependent patients with CKD (1,2), with >90% of patients in the United States receiving an erythropoiesis-stimulating agent (ESA) such as recombinant human erythropoietin (1). Virtually all patients with CKD undergoing hemodialysis also require some intravenous iron due to continuing blood losses and impaired intestinal iron absorption from elevated serum hepcidin (3–5).
Randomized trials have demonstrated that ESA therapy can increase the risk of cardiovascular events and death, and hyporesponders to ESAs seem to be at highest risk, even in the present era where hemoglobin targets and ESA doses are lower (6–10). Adequate iron availability is essential for optimal erythropoiesis, but markers guiding iron requirements have poor predictive value, frequently resulting in inadequate or excessive iron administration (11).
Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Inhibition of certain prolyl hydroxylase enzymes by HIF-PHIs increases endogenous erythropoietin production (12–14).
HIF-PHIs may also influence overall iron availability for erythropoiesis by directly regulating particular intestinal iron transporters, including ferroportin, and potentially directly lowering serum hepcidin levels or indirectly lowering hepcidin by stimulating enhanced erythropoiesis (13,15,16).
Daprodustat has been administered as a once daily dose in most clinical trials to date, including in patients with CKD undergoing hemodialysis (14,17). However, because standard clinical practice is to administer recombinant human erythropoietin three times weekly during in-center hemodialysis sessions (18) and in-center administration of medications improves adherence and outcomes, this study was designed to assess the efficacy and safety of daprodustat administered three times weekly during hemodialysis treatments. To maintain blinding in this trial, all participants received both an oral medication (daprodustat or placebo) and an intravenous injection (epoetin alfa or saline).
Materials and Methods
Study Design
The Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Three Times Weekly Dosing in Dialysis (ASCEND-TD) study was a randomized, double-blinded, active-controlled, double-dummy, parallel-group, global phase 3 trial comparing the efficacy and safety of daprodustat with epoetin alfa (epoetin) in patients on hemodialysis with anemia of CKD. The study included a 4-week screening period to assess eligibility, a 52-week treatment period, and a 4- to 6-week follow-up period (Supplemental Figure 1). The treatment period included a stabilization period (day 1 to week 28), during which study treatment was dose titrated to achieve and maintain hemoglobin in the target range of 10–11 g/dl, and an evaluation period (weeks 28–52) to assess efficacy and safety (Supplemental Figure 1). Study treatment could be dose titrated during the evaluation period if required.
Randomization was stratified by region, and participants were centrally randomized 2:1 to receive either oral daprodustat three times weekly and intravenous saline or intravenous epoetin once weekly or three times weekly (according to dose level) and placebo tablets using an Interactive Response Technology System (Pharmaceutical Product Development, LLC, Wilmington, NC). The randomization schedule was computer generated using the validated randomization system Prism. The participants, investigators, site staff, and sponsor were blinded to study treatment assignment, except for a limited number of site and sponsor staff responsible for handling unblinded study treatment (i.e., intravenous saline or epoetin) and management of unblinded data. Study treatment dose level was not blinded.
Study Population
Eligible participants were adults with anemia of CKD on ESAs for ≥8 weeks receiving in-center hemodialysis (including hemofiltration or hemodiafiltration) for >90 days and at least three times weekly and had hemoglobin at randomization of 8–11.5 g/dl (Supplemental Table 1).
Key exclusion criteria included planned kidney transplantation within 52 weeks after randomization, ferritin ≤100 ng/ml or transferrin saturation (TSAT) ≤20% at screening, anemia other than anemia of CKD, gastrointestinal bleeding, cardiovascular event within 8 weeks of screening through randomization, and history of malignancy within 2 years of screening through randomization (Supplemental Table 1).
Participants continued study treatment until week 52 unless they developed a protocol-defined criterion for stopping study treatment (Supplemental Table 1).
Study End Points
The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period to compare the effect of daprodustat versus epoetin on hemoglobin response. The principal secondary end point was average monthly on-treatment intravenous iron dose to week 52.
Other secondary end points included (1) hemoglobin change from baseline to week 52; (2) proportion of hemoglobin responders defined as participants with mean hemoglobin within the analysis range (10–11.5 g/dl) during the evaluation period; (3) time to permanently stopping study treatment due to meeting rescue criteria; (4) mean changes from baseline in systolic BP, diastolic BP, and mean arterial pressure at week 52; and (5) number of BP elevation events per 100 person-years. Other end points are listed in Supplemental Table 2.
The safety evaluation included routine laboratory and adverse event (AE) monitoring as well as adjudication of major adverse cardiovascular events (MACEs; a composite of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), although the study was not designed or powered for formal statistical testing.
Study Procedures and Assessments
Blood samples for hemoglobin analysis via HemoCue (HemoCue AB, Angelholm, Sweden) and the central laboratory were collected throughout the trial, as were safety assessments. The time period for MACE follow-up began at randomization and ended at study completion or withdrawal, except that any death reported after this time was included in the analysis (Supplemental Material).
Treatments and Dosage
Starting doses for each participant were determined on the basis of prior ESA dose (Supplemental Table 3). Daprodustat doses of 2–48 mg were administered three times weekly. Epoetin total weekly doses of 1500–60,000 IU were administered either three times weekly or once weekly depending on the dose level (Supplemental Table 4).
A protocol-specified study treatment dose-adjustment algorithm was followed to achieve and maintain hemoglobin within the target range (Supplemental Table 5). An Interactive Response Technology system calculated dose adjustments following the dosing algorithm. A protocol-specified rescue algorithm minimized participants having an inadequate response to treatment for an extended period and enabled consistency in the application of rescue therapy (Supplemental Table 6).
Iron therapy was administered if ferritin was ≤100 ng/ml and/or TSAT was ≤20%, and it was stopped if ferritin was >800 ng/ml and TSAT was >20% or if TSAT was >40%. Iron dose and route of administration were determined by the investigator.
Ethical Considerations
The study was reviewed and approved by the ethics committee or institutional review board at each trial center in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study was conducted at 90 centers in 13 countries, and it was initiated on September 5, 2018 and completed on June 19, 2020. Written informed consent was obtained from each participant.
Statistical Analyses
Approximately 402 participants were planned to be randomized in a 2:1 ratio to daprodustat or epoetin to provide at least 100 participants exposed to daprodustat for 1 year. The expected difference between arms in mean hemoglobin change from baseline and the evaluation period was 0 g/dl, and the anticipated between-patient SD was 1.5 g/dl. With a prespecified noninferiority margin of −0.75 g/dl and the assumption that approximately 10% of participants would have no hemoglobin values measured during the evaluation period, 402 randomized participants would provide >90% power to test the primary hypothesis.
Primary analyses were on the basis of the intent-to-treat population, defined as all randomized participants regardless of whether they took the assigned study treatment. The primary analysis of mean change in hemoglobin from baseline to the average during the evaluation period was performed after multiple imputation using analysis of covariance (ANCOVA) adjusted for treatment, baseline hemoglobin, and region. Hemoglobin during the evaluation period was defined as the mean of all available postrandomization hemoglobin values (on and off treatment) during the evaluation period regardless of discontinuation or interruption of the study treatment and regardless of the receipt of nonrandomized ESA medications for any reason, including rescue or blood transfusions. The primary analysis was designed to test whether daprodustat was noninferior to epoetin using a prespecified noninferiority margin of −0.75 g/dl.
Multiple imputation analysis was performed using all available hemoglobin values (on and off treatment) and was conducted under a set of assumptions about missing hemoglobin values.
Intermittent missing postbaseline scheduled hemoglobin data in both arms through week 52 were imputed using the SAS PROC MI procedure to generate 200 datasets with only monotone missing patterns. Burn-in iterations and maximum iteration were both set to 500. The seed for reproducibility was set to 204,837. The imputations were done by study treatment and region.
For each of the monotone missing datasets (of the 200 imputed as indicated above), the missing scheduled hemoglobin values through week 52 were imputed on the basis of the missing at random (MAR) assumption and were performed using PROC MI by treatment and region. The monotone regression had baseline hemoglobin and prior scheduled (possibly imputed) hemoglobin values (and may include region) as covariates. The seed for reproducibility was set to 204,837.
The low and high cutoffs at hemoglobin values of 6 and 15 g/dl, respectively, were applied to all imputed hemoglobin values.
Evaluation period hemoglobin values were computed and compared across treatment groups using the primary ANCOVA model described above. Rubin rules were used to combine the results of the imputed datasets using the SAS PROC MIANALYZE procedure (19). As a result, a single estimated treatment difference and its standard error were produced, with which a 95% confidence interval (95% CI) was calculated.
The analysis of average monthly intravenous iron dose to week 52 while on treatment was performed in the intent-to-treat population using ANCOVA adjusted for treatment, baseline monthly intravenous iron dose, and region. Conditional on the primary end point achieving noninferiority, the principal secondary end point was tested for superiority using a one-sided 2.5% significance level.
Supplemental Material has a description of statistical analyses used for other end points.
Results
Overall, 407 participants were randomized to the study treatment (n=270 daprodustat; n=137 epoetin), 404 (99%) completed the study, and 289 (71%) completed the study treatment (Figure 1).
Figure 1.
Participant disposition. aParticipants could have more than one reason for screen failure, so the number of reasons for screen failure may sum to more than the participant total. bThe randomized (intent-to-treat) population is defined as all randomized participants. cPrimary reason. Participants may have only one primary reason for study withdrawal/study treatment discontinuation. Participants whose primary reason for study treatment discontinuation was protocol-defined stopping criteria may have also reported an adverse event (AE) leading to permanent discontinuation of study treatment; for example, participants who met the stopping criterion of a cancer event may have also reported a cancer-related AE. dParticipants who completed the study include (1) those who completed the 52-week treatment, (2) those who continued in the study to week 52 after permanently discontinuing the study treatment, and (3) those who died while in the study.
Baseline demographics were largely similar between groups, except that the daprodustat group was older, had a higher percentage of women, and had a higher median prior ESA dose (Table 1).
Table 1.
Baseline characteristics of participants in the ASCEND-TD trial (intent-to-treat population)
| Characteristic | Daprodustat, n=270 | Epoetin, n=137 | Total, n=407 |
|---|---|---|---|
| Age, yr, median (IQR) | 60 (50–69) | 56 (46.5–65.5) | 59 (49–69) |
| Men, n (%) | 149 (55) | 81 (59) | 230 (57) |
| Race, n (%) | |||
| White | 195 (72) | 94 (69) | 289 (71) |
| Black | 49 (18) | 32 (23) | 81 (20) |
| Asian | 20 (7) | 9 (7) | 29 (7) |
| Dialysis modality, n (%) | |||
| Hemodialysis | 237 (88) | 120 (88) | 357 (88) |
| Hemofiltration/hemodiafiltration | 33 (12) | 17 (12) | 50 (12) |
| Dialysis vintage, yr, n (%) | |||
| <2 | 82 (30) | 42 (31) | 124 (30) |
| ≥2 to <5 | 95 (35) | 52 (38) | 147 (36) |
| ≥5 | 93 (34) | 43 (31) | 136 (33) |
| Dialysis access type, n (%) a | |||
| Arteriovenous fistula | 212 (79) | 106 (77) | 318 (78) |
| Arteriovenous graft | 23 (9) | 14 (10) | 37 (9) |
| Central venous catheter | 34 (13) | 16 (12) | 50 (12) |
| Postdialysis weight, kg, median (IQR) | 74.0 (63.0–86.5) | 75.4 (63.9–90.4) | 74.2 (63.3–87.0) |
| Postdialysis BP, mm Hg, median (IQR) | |||
| Systolic BP | 135 (119–150) | 133 (117–153) | 135 (118–150) |
| Diastolic BP | 74 (63–82) | 76 (64–83) | 74 (63–82) |
| Standardized prior ESA dose, U/wk, median IQR | 6297 (4214–11,724) | 5943 (4000–10,208) | 6094 (4143–10,400) |
| ESA hyporesponder, n (%) | 37 (14) | 21 (15) | 58 (14) |
| Iron use, n (%) | |||
| Intravenous iron including alone plus with oral | 174 (64) | 100 (73) | 274 (67) |
| Oral only | 17 (6) | 10 (7) | 27 (7) |
| No iron therapy | 78 (29) | 27 (20) | 105 (26) |
| Hemoglobin, g/dl, median (IQR) | 10.5 (10.0–11.0) | 10.7 (10.2–11.3) | 10.6 (10.0–11.1) |
| Ferritin, ng/ml, median (IQR) | 589 (334–933) | 553 (364–918) | 574 (344–924)b |
| Serum iron, µg/dl, median (IQR) | 73 (56–89) | 73 (61–95) | 73 (56–95)b |
| TIBC, µg/dl, median (IQR) | 212 (195–240) | 212 (193–240) | 212 (195–240)b |
| Transferrin saturation, %, median (IQR) | 32 (27–42) | 35 (29–45) | 33 (27–43)b |
| Hepcidin, ng/ml, median (IQR) | 159 (88–233) | 176 (108–253) | 170 (94–245)b |
| hsCRP, mg/dl, median (IQR) | 0.43 (0.16–0.10) | 0.47 (0.17–0.15) | 0.43 (0.17–0.11)b |
| Cardiovascular risk score for participants on hemodialysis, n (%) c | |||
| Low risk, tertile 1: <11 | 83 (31) | 51 (37) | 134 (33) |
| Medium risk, tertile 2: 11 to <16 | 93 (34) | 34 (25) | 127 (31) |
| High risk, tertile 3: ≥16 | 94 (35) | 52 (38) | 146 (36) |
| Cardiovascular risk score for participants on hemodialysis b,c | |||
| Mean (SD) | 13.2 (5.7) | 13.2 (6.1) | 13.2 (5.8) |
| Median | 13.0 | 13.0 | 13.0 |
| Minimum, maximum | −2, 25 | 0, 30 | −2, 30 |
| History of cardiovascular disease, n (%) d | |||
| No | 160 (59) | 83 (61) | 243 (60) |
| Yes | 110 (41) | 54 (39) | 164 (40) |
| History of stroke, n (%) | |||
| No | 244 (90) | 118 (86) | 362 (89) |
| Yes | 26 (10) | 19 (14) | 45 (11) |
| History of myocardial infarction, n (%) | |||
| No | 239 (89) | 128 (93) | 367 (90) |
| Yes | 31 (11) | 9 (7) | 40 (10) |
| History of heart failure, n (%) | |||
| No | 204 (76) | 104 (76) | 308 (76) |
| Yes | 66 (24) | 33 (24) | 99 (24) |
| History of thromboembolic events, n (%) | |||
| No | 218 (81) | 101 (74) | 319 (78) |
| Yes | 52 (19) | 36 (26) | 88 (22) |
| Left ventricular hypertrophy | 53 (20) | 36 (26) | 89 (22) |
| Arrhythmia | 26 (10) | 20 (15) | 46 (11) |
| Peripheral vascular disease | 28 (10) | 14 (10) | 42 (10) |
| Smoking history, n (%) | |||
| Never smoked | 183 (68) | 80 (58) | 263 (65) |
| Current smoker | 25 (9) | 23 (17) | 48 (12) |
| Former smoker | 62 (23) | 34 (25) | 96 (24) |
| β-blockers use at randomization, n (%) | |||
| No | 142 (53) | 66 (48) | 208 (51) |
| Yes | 128 (47) | 71 (52) | 199 (49) |
| Statin use at randomization, n (%) | |||
| No | 250 (93) | 130 (95) | 380 (93) |
| Yes | 20 (7) | 7 (5) | 27 (7) |
| Aspirin use at randomization, n (%) | |||
| No | 165 (61) | 80 (58) | 245 (60) |
| Yes | 105 (39) | 57 (42) | 162 (40) |
| Vitamin K antagonist use at randomization, n (%) | |||
| No | 258 (96) | 131 (96) | 389 (96) |
| Yes | 12 (4) | 6 (4) | 18 (4) |
| History of diabetes, n (%) | |||
| No | 165 (61) | 84 (61) | 249 (61) |
| Yes | 105 (39) | 53 (39) | 158 (39) |
| Insulin use at randomization, n (%) | |||
| No | 215 (80) | 108 (79) | 323 (79) |
| Yes | 55 (20) | 29 (21) | 84 (21) |
IQR, interquartile range; BP, blood pressure; ESA, erythropoiesis-stimulating agent; TIBC, total iron binding capacity; hsCRP, high-sensitivity C-reactive protein.
Dialysis access type at baseline was missing for two participants.
Post hoc analysis.
A risk score for 2-year cardiovascular mortality and morbidity in a hemodialysis population has been developed (29) and was calculated at baseline for each participant on hemodialysis.
Cardiovascular disease history was defined as having a yes response to any of the following medical history conditions: angina pectoris, myocardial infarction, stroke, coronary artery disease, transient ischemic attack, heart failure, atrial fibrillation, cardiac arrest, and/or valvular heart disease.
There were some imbalances in cardiovascular risk factors between groups. Considering those baseline cardiovascular risk factors with ≥4% difference between groups, the cardiovascular risk score distribution for the medium-risk tertile and prior myocardial infarction were higher in the daprodustat group, whereas history of thromboembolic events, left ventricular hypertrophy, and arrhythmia were higher in the epoetin group. Thirty-nine percent of participants in both groups had diabetes, with 55 (20%) of the participants in the daprodustat group and 29 (21%) of the participants in the epoetin group receiving insulin. More participants in the epoetin group were current smokers (Table 1).
Efficacy Outcomes
Hemoglobin levels were similarly stable between groups over the course of the study (Figure 2, Table 2). The adjusted mean treatment difference for the primary end point (the mean change in hemoglobin from baseline to the average during the evaluation period) was −0.05 g/dl (95% CI, −0.21 to 0.10), demonstrating noninferiority of daprodustat to epoetin. The adjusted mean treatment difference in the per-protocol population (daprodustat-epoetin) was −0.06 g/dl (95% CI, −0.22 to 0.11), further supporting noninferiority of daprodustat to epoetin. Several other planned supportive analyses were consistent with the primary result (Supplemental Figure 2).
Figure 2.
Mean postrandomization hemoglobin data by visit showed that hemoglobin levels were similarly stable between groups (intent-to-treat population). Error bars indicate 95% confidence intervals (95% CIs). Baseline and visits on or before day 1 include only pretreatment values. Postrandomization values include all available observed and imputed hemoglobin values (on and off treatment). The dashed vertical lines represent the evaluation period (week 28 to week 52). The horizontal reference lines represent the hemoglobin analysis range (10–11.5 g/dl). The hemoglobin target range for dose changes is 10–11 g/dl. Fup, follow-up; Scr, screening; Wk, week.
Table 2.
Primary analysis of postrandomization hemoglobin change from baseline to the average during the evaluation period (intent-to-treat population)
| Outcome | Daprodustat, n=270 | Epoetin, n=137 |
|---|---|---|
| Participants with all 7 observed hemoglobin values during the evaluation period, n (%) | 186 (69) | 92 (67) |
| Participants with observed and imputed hemoglobin values during the evaluation period, n (%) | 66 (24) | 36 (26) |
| Participants with only imputed hemoglobin values during the evaluation period, n (%) | 18 (7) | 9 (7) |
| No. of participants with baseline and evaluation period hemoglobin, n (%)a | 270 (100) | 137 (100) |
| Baseline hemoglobin, g/dl, mean (SD) | 10.44 (0.83) | 10.59 (0.93) |
| Evaluation period (weeks 28–52) hemoglobin, g/dl, mean (SD)a | 10.45 (0.55) | 10.51 (0.85) |
| Adjusted mean change from baseline (SE)b | −0.04 (0.045) | 0.02 (0.066) |
| Adjusted mean treatment difference from daprodustat to epoetin (95% CI)b,c | −0.05 (−0.21 to 0.10) | |
Postrandomization values include on- and off-treatment values. 95% CI, 95% confidence interval.
Hemoglobin values during the evaluation period include both observed and imputed values.
On the basis of an analysis of covariance model with terms for treatment, baseline hemoglobin, and region.
Two-sided 95% CI for the adjusted mean difference.
The secondary end point, comparing the proportion of hemoglobin responders (participants with mean hemoglobin in the analysis range between 10 and 11.5 g/dl during the evaluation period), was higher for daprodustat (80%) versus epoetin (64%), with a nominally significant difference in response proportion (16%; 95% CI, 6% to 27%) favoring daprodustat (P<0.01) (Table 3). Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period (Table 3).
Table 3.
Analysis of hemoglobin responders during the evaluation period (intent-to-treat population)
| Outcome | Daprodustat, n=270 | Epoetin, n=137 |
|---|---|---|
| Participants with evaluable hemoglobin during the evaluation period | 215 | 107 |
| Mean evaluation period hemoglobin above 11.5 g/dl, n (%) | 3 (1) | 9 (8) |
| Mean evaluation period hemoglobin within 10.0–11.5 g/dl, n (%) | 172 (80) | 68 (64) |
| Mean evaluation period hemoglobin below 10.0 g/dl, n (%) | 40 (19) | 30 (28) |
| Hemoglobin responder: participants with mean evaluation period hemoglobin 10.0–11.5 g/dl, n (%) | 172 (80) | 68 (64) |
| Difference in response proportion for daprodustat versus epoetin, % (95% CI)a | 16 (6 to 27) | |
| One-sided P valueb | <0.01 | |
Evaluable values are on-treatment values that are not taken within the 8 weeks following a red blood cell or whole blood transfusion or a postrandomization nonrandomized erythropoiesis-stimulating agent treatment. 95% CI, 95% confidence interval.
Two-sided 95% CI for the difference in response proportion.
Treatment group comparisons are on the basis of a Cochran–Mantel–Haenszel test adjusted for region. One-sided P value on the basis of the test of the null hypothesis: responder rate (daprodustat versus epoetin) ≤0 versus alternative: difference >0.
In exploratory analyses of hemoglobin variability, hemoglobin excursions <7.5 g/dl were rare, occurring three times with daprodustat and twice with epoetin. Excursions ≥12 g/dl occurred more often with epoetin (n=23 [21%]; 49 episodes) than with daprodustat (n=31 [14%]; 35 episodes). Additionally, the mean (SD) percentage of time that hemoglobin was ≥12 g/dl during the evaluation period was longer with epoetin (7% [19.51]) than with daprodustat (2% [8.57]). The proportion of participants with hemoglobin increases >2 g/dl over 4 weeks was ≤2% with each treatment during each 4-week period throughout the trial.
Overall, the results of post hoc subgroup analyses were consistent with the primary analysis, with little or no heterogeneity between subgroups. The subgroup analysis of high-sensitivity C-reactive protein by quartiles did indicate heterogeneity (P=0.01), with the pattern observed being similar in quartiles 1 and 3 and dissimilar in quartiles 2 and 4 (Supplemental Figure 3). Further analyses of the baseline ESA hyporesponder subgroups showed nominal noninferiority but not superiority of daprodustat to epoetin among both hyporesponders (mean treatment difference, −0.01 g/dl; 95% CI, −0.18 to 0.16) and non-hyporesponders (mean treatment difference, −0.29 g/dl; 95% CI, −0.72 to 0.14), suggesting that baseline ESA hyporesponders were not more responsive to daprodustat than epoetin.
Intravenous Iron Use and Changes in Iron Parameters
The principal secondary end point, comparing the average monthly on-treatment intravenous iron dose per participant during the evaluation period, was numerically lower for daprodustat than epoetin, but the difference between groups was not statistically significant (Supplemental Tables 7 and 8). Total iron and total iron binding capacity increased in the daprodustat group by week 4 and remained higher than the epoetin group throughout the trial (Figure 3, A and B). TSAT was similar between groups throughout the trial (Figure 3C). Serum ferritin and hepcidin declined at a similar rate in both arms during the trial (Figure 3, D and E).
Figure 3.
Daprodustat was associated with improved iron kinetics compared with epoetin. Change over time in (A) total iron, (B) total iron binding capacity, (C) transferrin saturation, (D) ferritin, and (E) hepcidin by visit (intent-to-treat population). Error bars indicate 95% CIs. Baseline and visits on or before day 1 include only pretreatment values. The dashed vertical lines represent the evaluation period (week 28 to week 52). EOT, end of trial.
Evaluation of the Dose-Adjustment Algorithm
The mean hemoglobin and median study treatment doses were stable throughout the trial in both groups (Figure 4, Supplemental Figure 4).
Figure 4.
Mean evaluable hemoglobin and median most recent daprodustat and epoetin dose by visit were stable throughout the trial in both groups (intent-to-treat population). Error bars indicate first and third quartiles.
Rescue Therapy and Transfusions
The need for rescue therapy was low, with six (2%) participants in the daprodustat group and three (2%) in the epoetin group discontinuing study treatment due to meeting the rescue criteria. Transfusions, as rescue therapy or to treat an acute event (e.g., gastrointestinal hemorrhage), were administered to 21 (8%) in the daprodustat group (overall rate of 22.40 U/100 person-years) versus 16 (12%) in the epoetin group (52.38 U/100 person-years).
Safety
There were no significant differences in the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent drug-related AEs, and treatment-emergent serious adverse events (SAEs), including fatal SAEs between groups (Supplemental Table 9). Hypertension was the most common TEAE (daprodustat: n=24 [9%]; epoetin: n=15 [11%]) and treatment-emergent drug-related AE (daprodustat: n=5 [2%]; epoetin: n=3 [2%]). The incidence of TEAEs leading to study treatment discontinuation was also similar between groups (daprodustat: n=20 [7%]; epoetin: n=8 [6%]). The nature of SAEs observed was similar between groups. The most frequent SAEs were pneumonia (daprodustat: n=9 [3%]; epoetin: n=5 [4%]) and arteriovenous fistula thrombosis (daprodustat: n=7 [3%]; epoetin: n=3 [2%]). Nine participants had treatment-emergent fatal SAEs (daprodustat: n=6 [2%]; epoetin: n=3 [2%]); all fatal SAEs were considered unrelated to study treatment by investigators. The incidence of potential adverse events of special interest (AESIs) was generally similar between treatment groups for each category of AESI. The most frequent AESI category was death, stroke, myocardial infarction, heart failure, thromboembolic events, and thrombosis of vascular access (daprodustat: n=52 [19%]; epoetin: n=27 [20%]) (Supplemental Table 10).
Although the trial was not designed for formal MACE evaluation, these events were adjudicated. First occurrence of adjudicated MACE was similar in daprodustat (n=33 [12%]) and epoetin (n=14 [10%]), and more participants receiving daprodustat (n=7 [3%]) experienced nonfatal stroke versus epoetin (n=0) (Supplemental Table 11). Further exploratory evaluation of stroke events, including one fatal stroke with daprodustat contained within all-cause mortality, was performed, and results are summarized in Supplemental Table 12. Median (minimum, maximum) time to onset was 142 days (44, 344); median (minimum, maximum) dose just prior to the event and maximum dose received any time prior to the event were 4 mg (0, 16) and 12 mg (8, 20), respectively.
The proportions of participants on antihypertensives were similar at baseline (daprodustat: n=202 [75%]; epoetin: n=101 [74%]) and week 52 (daprodustat: n=205 [76%]; epoetin: n=108 [79%]). The change in postdialysis BP parameters from baseline to week 52 was similar between groups (Supplemental Table 13). Fewer postdialysis BP elevation episodes occurred with daprodustat (n=151 [56%]) than epoetin (n=91 [67%]). The ratio of model-estimated BP elevation rate was 0.70, which was nominally significant (one-sided P=0.009). The rate of worsening hypertension was 16.2/100 person-years in the daprodustat group versus 21.4/100 person-years in the epoetin group (Supplemental Table 10).
Reviews of clinical laboratory values, vital signs (heart rate and weight), and electrocardiogram values revealed no notable differences between groups.
Discussion
These results demonstrate that the HIF-PHI daprodustat dosed orally three times weekly is effective in maintaining hemoglobin in participants with CKD undergoing hemodialysis switched from an ESA. Nominal superiority of daprodustat over epoetin in hemoglobin responders was demonstrated, and this is supported by the proportion of participants with hemoglobin above and below that analysis range who favored daprodustat (Table 3). However, this could reflect differences in the dosing protocols. Nevertheless, this trial provides evidence for daprodustat dosing and management to convert patients on hemodialysis from ESAs while maintaining hemoglobin in the desired range.
We also examined the hemoglobin response in patients with ESA hyporesponsiveness, which remains a concern in managing anemia among patients who are receiving dialysis (20). Some trials have shown better responsiveness in patients with high-sensitivity C-reactive protein and high ESA doses (21), and others have not (17,22), including our trial. Future trials designed to test this population will be needed.
Previously, efficacy for treating anemia in patients with CKD undergoing hemodialysis has been demonstrated with daily administration of daprodustat and other HIF-PHIs (22–25). However, administering HIF-PHIs during hemodialysis treatment offers certainty and convenience, and in-center administration improves adherence. Despite different half-lives (i.e., roxadustat has a longer half-life than daprodustat), both compounds are effective when dosed three times weekly (23,26). We demonstrate that daprodustat dosed three times weekly maintained a mean hemoglobin comparable with epoetin throughout the 52-week treatment period.
HIF-PHIs correct anemia through dose-dependent increases in hypoxia-inducible factor–regulated gene expression, including erythropoietin, duodenal iron transporters, ferroportin, and serum transferrin (23). Enhanced erythropoiesis decreases hepcidin, and therefore, more iron is released (23). Compared with the epoetin group, we observed that daprodustat increased serum iron, transferrin, and total iron binding capacity, whereas TSAT remained relatively stable. Ferritin and hepcidin declined similarly in both study arms. These results are consistent with other HIF-PHIs in the hemodialysis population (22,24,26).
Although daprodustat was associated with improved iron kinetics compared with epoetin, we did not observe a significant reduction in the monthly intravenous iron dose compared with epoetin. Both trial arms received less intravenous iron during the evaluation period compared with baseline. In a trial of daprodustat in Japanese patients with CKD undergoing hemodialysis, Akizawa et al. (24) reported that daprodustat dosed daily decreased intravenous iron use compared with darbepoetin treatment. That trial also showed that daprodustat increased serum iron and transferrin levels, but unlike our data, daprodustat decreased hepcidin levels to a greater extent than darbepoetin treatment (24). However, in the study of Akizawa et al. (24), patients had much lower baseline ferritin and hepcidin levels than in our trial. This may make them more dependent on intestinal iron absorption and therefore potentially more responsive to an HIF-PHI–mediated increase in iron absorption. Preliminary data with roxadustat may show an intravenous iron-sparing effect relative to ESA therapy in some of their trials studying patients with CKD undergoing hemodialysis (23). Differences in intravenous iron-sparing effects of HIF-PHI across trials may be due to differences in trial designs and duration, patient comorbidities, iron status, iron dosing protocols, or inherent differences among the HIF-PHI molecules themselves.
Preclinical and early clinical trials suggested that HIF-PHIs may treat CKD-associated anemia without inducing hypertension (27,28), whereas ESAs may cause or exacerbate hypertension (18). We did not observe any significant differences in systolic BP, diastolic BP, or mean arterial pressure between treatment groups. Predefined BP elevations were less common in the daprodustat group; however, the use of postdialysis BP to assess BP control may have missed a differential effect of daprodustat on 24-hour BP control. Other trials have also not confirmed that HIF-PHI use results in lower BP than ESA therapy (23).
Strengths of this trial included the double-blind, double-dummy randomized design. The limited exclusion criteria, global recruitment, and diverse hemodialysis population allowed this to reflect the real-world population of patients on maintenance hemodialysis. Furthermore, there was a balanced rate of discontinuation of study treatment and rescue in both arms. Limitations included the use of a hemoglobin target range of 10–11 g/dl, which is the recommended range in the United States but is narrower than elsewhere in the world. The study was also limited by the lack of power to formally test cardiovascular end points. The 52-week duration of the study limited exposure to both drugs, potentially reducing the ability to evaluate safety. However, the cardiovascular safety of daprodustat has been assessed in the much larger and longer ASCEND-D trial, which demonstrated that once daily daprodustat was noninferior to ESAs in the time to first occurrence of adjudicated MACEs, and there was no imbalance in stroke events between treatments (17).
In conclusion, oral daprodustat administered three times weekly during hemodialysis was effective for maintaining hemoglobin in patients with CKD undergoing hemodialysis switched from an ESA. Daprodustat was generally well tolerated, with similar drug discontinuation rates and AE and SAE rates between arms.
Disclosures
C.K. Bailey is an employee of and holds stock in GSK. A.R. Cobitz works for GSK; hence, the projects for which A.R. Cobitz is responsible are funded through GSK. A.R. Cobitz reports GSK stock and options. J. Connaire is an employee of DaVita Clinical Research and InterMed Consultants; reports consultancy agreements with Diality, Dynavax, GSK, Relypsa, Inc., and Sanifit; ownership interest in DaVita, Inc.; research funding from Akebia, Ardelyx, AstraZeneca, Chinook, Goldfinch Bio, GSK, Merck, Otsuka, Sanifit, Sera Trials, and Travere; and an advisory or leadership role with GSK and Sanifit. D.W. Coyne reports consultancy agreements with Ardelyx, AstraZeneca, Fibrogen, FMC-RTG, GSK, Medibeacon, Otsuka, Reata, and Vifor; research funding from AstraZeneca, Bayer, Fibrogen, GSK, and Medibeacon; and honoraria from Ardelyx, AstraZeneca, Fibrogen, FMC-RTG, GSK, Medibeacon, Otsuka, Reata, and Vifor. T.L. Dimino is an employee of and holds stock in GSK and reports other interests or relationships as a member of the American College of Cardiology and a member of the American College of Physicians/American Society of Internal Medicine. C. Huang reports employment with GSK and ownership interest in Allena Pharmaceuticals, Alpine 4 Holdings Inc., Apple Inc., Ardelyx Inc., Bank of America Corp., Berkshire Hathaway Inc., Carnival Corp., Cormedix Inc., Disney Walt Co., FedEx Corp., GlaxoSmithKline, Kala Pharmaceuticals Inc., Ke Hldgs Inc. Sponsored Ads, Lexicon Pharmaceuticals Inc., Marimed Inc., Nike Inc. Class B Com, Nokia Oyj Adr Each Repr 1 Ord Npv, Norwegian Cruise Line Hldg Ltd., Sundial Growers Inc., Twitter Inc., and Zomedica Corp. C. Huang’s wife reports employment with Best Care Geriatric Consultants, LLC. S.-G. Kim reports research funding from Akebia, Alexion, Bayer, Chinook, Fibrogen, GSK, JW Pharma, and VALOR; consulting fees from AstraZeneca and GSK; honoraria for lectures from AstraZeneca and Bayer; honoraria from GSK; and an advisory or leadership role with Korean Society of Diagnostic and Interventional Nephrology and Korean Society of Nephrology. R.D. Lopes reports grants and personal fees from Bristol-Myers Squibb and Pfizer; personal fees from Bayer AG and Boehringer Ingelheim; research grants from Amgen Inc., GSK, Medtronic PLC, and Sanofi Aventis; and consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, GSK, Medtronic, Merck, Pfizer, and Portola. M. Orias reports consultancy agreements with AstraZeneca, George Clinical, and GSK; honoraria from AstraZeneca and PPD/George Clinical; speakers bureau for AstraZeneca; and other interests or relationships with the American Society of Nephrology, International Society of Nephrology, and Sociedad Latinoamericana de Nefrología e Hipertensión. V. Patel reports employment with Spark Therapeutics Inc. and ownership interest in Roche Holdings. V. Patel is a former employee of and holds stock in GSK. A. Rastogi is a medical director for DaVita; reports consultancy agreements with Akebia, Ardelyx, AstraZeneca, Aurinia, Chiesi Global Inc., Chinook Therapeutics, Fresenius Medical Care-Vifor, GSK, Otsuka, Sanofi S. A., Tricida, Inc., and Vifor Pharma Inc.; research funding from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Gilead, GSK, Idorsia Pharmaceuticals, Ltd., Kadmon Corporation, LLC, the National Institutes of Health, Novo Nordisk, Omeros Inc., Palladio Biosciences, Pfizer, Protalix Biotherapeutics Ltd., Reata Pharmaceuticals, Inc., Regulus Therapeutics, Summit Therapeutics, and Sanofi; honoraria from Amgen, AstraZeneca, Aurinia, Baxter, Bayer, Fresenius Medical Care, Genzyme/Sanofi, Janssen, Natera, and Vifor Pharma Inc.; an advisory or leadership role with Amgen, AstraZeneca, Aurinia, Baxter, Bayer, Fresenius Medical Care, Genzyme/Sanofi, Janssen, Natera, and Vifor Pharma Inc.; and speakers bureau for Amgen, AstraZeneca, Aurinia, Baxter, Bayer, Fresenius Medical Care, Genzyme/Sanofi, Janssen, Natera, and Vifor Pharma Inc. S. Shah reports honoraria from Abbvie, Astellas, and GSK; consultancy fees from Biotest; and speakers bureau for Astellas. A.K. Singh reports consultancy agreements with Bayer and GSK; research funding from GSK; honoraria from GSK; and an advisory or leadership role with Nephrology Times. C. Wanner reports consultancy agreements with Akebia, Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Chiesi, FMC Idorsia, Gilead, GSK, Lilly, Merck Sharp Dohme, MSD, Mundipharma, Reata, Sanofi, Takeda, Triceda, and Vifor; grants and consultancy fees from Boehringer Ingelheim, Sanofi Genzyme, and Shire; research funding from an Idorsia grant to the institution and a Sanofi grant to the institution; honoraria from Amgen, Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Chiesi, Eli-Lilly, FMC, Sanofi, and Takeda; serving as President of the European Renal Association (ERA); and other interests or relationships with ERA.
Funding
Funding for the Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Three Times Weekly Dosing in Dialysis study was provided by GlaxoSmithKline.
Supplementary Material
Acknowledgments
Editorial support in the form of writing assistance, assembling figures, grammatical editing, and referencing was provided by Katie Ryan of Fishawack Indicia, Ltd., United Kingdom, part of Fishawack Health, and it was funded by GSK.
The results presented in this paper were presented as a poster at the American Society of Nephrology Annual Meeting held November 4–7, 2021.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Author Contributions
C.K. Bailey, A.R. Cobitz, J. Connaire, C. Huang, and V. Patel conceptualized the study; D.W. Coyne, S.-G. Kim, R.D. Lopes, A. Rastogi, and S. Shah were responsible for data curation; C.K. Bailey, A.R. Cobitz, J. Connaire, D.W. Coyne, T.L. Di Mino, C. Huang, S.-G. Kim, R.D. Lopes, M. Orias, V. Patel, A. Rastogi, S. Shah, A.K. Singh, and C. Wanner were responsible for formal analysis; D.W. Coyne wrote the original draft; and C.K. Bailey, A.R. Cobitz, J. Connaire, D.W. Coyne, T.L. Di Mino, C. Huang, S.-G. Kim, R.D. Lopes, M. Orias, V. Patel, A. Rastogi, S. Shah, A.K. Singh, and C. Wanner reviewed and edited the manuscript.
Data Sharing Statement
Within 6 months of this publication, anonymized individual participant data, the annotated case report form, the protocol, the reporting and analysis plan, dataset specifications, the raw dataset, the analysis-ready dataset, and the clinical study report will be available for research proposals approved by an independent review committee. Proposals should be submitted to www.clinicalstudydatarequest.com. A data access agreement will be required.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.00550122/-/DCSupplemental.
Supplemental Material. Methods.
Supplemental Table 1. Inclusion, exclusion, and stopping criteria.
Supplemental Table 2. Study objectives and end points.
Supplemental Table 3. Daprodustat starting dose.
Supplemental Table 4. Dose information for daprodustat and epoetin alfa.
Supplemental Table 5. Study treatment dose adjustment schemes.
Supplemental Table 6. Rescue algorithm for anemia management.
Supplemental Table 7. On-treatment average monthly intravenous iron use (intent-to-treat population).
Supplemental Table 8. On-treatment average monthly intravenous iron dose during day 1 to week 52 (intent-to-treat population).
Supplemental Table 9. Adverse events (safety population).
Supplemental Table 10. Overview of treatment-emergent potential adverse events of special interest (safety population).
Supplemental Table 11. Summary of the first occurrence of adjudicated MACE during the time period for follow-up of cardiovascular events (intent-to-treat population).
Supplemental Table 12. Summary of participants with adjudicated fatal and nonfatal stroke (intent-to-treat population; post hoc analysis).
Supplemental Table 13. Summary of analysis of change from baseline to week 52 in on-treatment postdialysis BP parameters (intent-to-treat population).
Supplemental Figure 1. Study design.
Supplemental Figure 2. Supportive analyses of the primary efficacy end point.
Supplemental Figure 3. Adjusted means for the analysis of postrandomization hemoglobin change from baseline to the evaluation period by subgroup (intent-to-treat population; post hoc analysis).
Supplemental Figure 4. Stacked bar chart of assigned dose by visit for (A) daprodustat and (B) epoetin alfa (intent-to-treat population).
References
- 1.Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK: Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 44: 94–111, 2004 [DOI] [PubMed] [Google Scholar]
- 2.Stauffer ME, Fan T: Prevalence of anemia in chronic kidney disease in the United States. PLoS One 9: e84943, 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Yang JY, Lee TC, Montez-Rath ME, Paik J, Chertow GM, Desai M, Winkelmayer WC: Trends in acute nonvariceal upper gastrointestinal bleeding in dialysis patients. J Am Soc Nephrol 23: 495–506, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wish JB: Assessing iron status: Beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 1[Suppl 1]: S4–S8, 2006 [DOI] [PubMed] [Google Scholar]
- 5.Macdougall IC: Intravenous iron therapy in patients with chronic kidney disease: Recent evidence and future directions. Clin Kidney J 10[Suppl 1]: i16–i24, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339: 584–590, 1998 [DOI] [PubMed] [Google Scholar]
- 7.Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; TREAT Investigators : A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361: 2019–2032, 2009 [DOI] [PubMed] [Google Scholar]
- 8.Coyne DW: The health-related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial. Kidney Int 82: 235–241, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Cizman B, Sykes AP, Paul G, Zeig S, Cobitz AR: An exploratory study of daprodustat in erythropoietin-hyporesponsive subjects. Kidney Int Rep 3: 841–850, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Panichi V, Rosati A, Bigazzi R, Paoletti S, Mantuano E, Beati S, Marchetti V, Bernabini G, Grazi G, Rizza GM, Migliori M, Giusti R, Lippi A, Casani A, Barsotti G, Tetta C; RISCAVID Study Group : Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: Results from the RISCAVID study. Nephrol Dial Transplant 26: 2641–2648, 2011 [DOI] [PubMed] [Google Scholar]
- 11.Coyne DW, Fishbane S: The value of intravenous iron: Beyond the cave of speculation. J Am Soc Nephrol 31: 896–897, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Holdstock L, Cizman B, Meadowcroft AM, Biswas N, Johnson BM, Jones D, Kim SG, Zeig S, Lepore JJ, Cobitz AR: Daprodustat for anemia: A 24-week, open-label, randomized controlled trial in participants with chronic kidney disease. Clin Kidney J 12: 129–138, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Koury MJ, Haase VH: Anaemia in kidney disease: Harnessing hypoxia responses for therapy. Nat Rev Nephrol 11: 394–410, 2015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Meadowcroft AM, Cizman B, Holdstock L, Biswas N, Johnson BM, Jones D, Nossuli AK, Lepore JJ, Aarup M, Cobitz AR: Daprodustat for anemia: A 24-week, open-label, randomized controlled trial in participants on hemodialysis. Clin Kidney J 12: 139–148, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lee FS: At the crossroads of oxygen and iron sensing: Hepcidin control of HIF-2α. J Clin Invest 129: 72–74, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Schwartz AJ, Das NK, Ramakrishnan SK, Jain C, Jurkovic MT, Wu J, Nemeth E, Lakhal-Littleton S, Colacino JA, Shah YM: Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. J Clin Invest 129: 336–348, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Więcek A, Blackorby A, Cizman B, Cobitz AR, Davies R, Dole J, Kler L, Meadowcroft AM, Zhu X, McMurray JJV; ASCEND-D Study Group : Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med 385: 2325–2335, 2021 [DOI] [PubMed] [Google Scholar]
- 18.Amgen : Epogen Prescribing Information, 2018. Available at: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/epogen/epogen_pi_hcp_english.pdf. Accessed December 16, 2021
- 19.Rubin DB: Statistical Analysis with Missing Data, New York, John Wiley & Sons, 1987 [Google Scholar]
- 20.Luo J, Jensen DE, Maroni BJ, Brunelli SM: Spectrum and burden of erythropoiesis-stimulating agent hyporesponsiveness among contemporary hemodialysis patients. Am J Kidney Dis 68: 763–771, 2016 [DOI] [PubMed] [Google Scholar]
- 21.Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP: Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 381: 1011–1022, 2019 [DOI] [PubMed] [Google Scholar]
- 22.Eckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, Farag YMK, Fishbane S, Hubert H, Jardine A, Khawaja Z, Koury MJ, Maroni BJ, Matsushita K, McCullough PA, Lewis EF, Luo W, Parfrey PS, Pergola P, Sarnak MJ, Spinowitz B, Tumlin J, Vargo DL, Walters KA, Winkelmayer WC, Wittes J, Zwiech R, Chertow GM: Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med 384: 1601–1612, 2021 [DOI] [PubMed] [Google Scholar]
- 23.Haase VH: Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease. Kidney Int Suppl (2011) 11: 8–25, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue T, Endo Y, Hara K, Cobitz AR: Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: A randomized, double-blind, phase 3 trial. Clin J Am Soc Nephrol 15: 1155–1165, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Provenzano R, Fishbane S, Szczech L, Leong R, Saikali KG, Zhong M, Lee TT, Houser MT, Frison L, Houghton J, Little DJ, Peony Yu KH, Neff TB: Pooled analysis of roxadustat for anemia in patients with kidney failure incident to dialysis [published retraction appears in Kidney Int Rep 7: 665, 2022]. Kidney Int Rep 6: 613–623, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 26.Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, Chen J, Luo L, Zuo L, Liao Y, Liu BC, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP: Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 381: 1001–1010, 2019 [DOI] [PubMed] [Google Scholar]
- 27.Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U: Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects. PLoS One 9: e111838, 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, Chan DT, Leong R, Poole L, Zhong M, Saikali KG, Franco M, Hemmerich S, Yu KH, Neff TB: Roxadustat (FG-4592): Correction of anemia in incident dialysis patients. J Am Soc Nephrol 27: 1225–1233, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Anker SD, Gillespie IA, Eckardt KU, Kronenberg F, Richards S, Drueke TB, Stenvinkel P, Pisoni RL, Robinson BM, Marcelli D, Froissart M, Floege J; On behalf the ARO Steering Committee (collaborators) : Development and validation of cardiovascular risk scores for haemodialysis patients. Int J Cardiol 216: 68–77, 2016 [DOI] [PubMed] [Google Scholar]
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