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Efficacy and cost-effectiveness of darbepoetin alfa once every 4 weeks versus continuous erythropoietin receptor activator once every 4 weeks for anemia correction in patients with chronic kidney disease not on dialysis
Park, G. N., Lee, K. H., Moon, J. E., Choi, S. J., Park, M. Y., Kim, J. K., Yu, B. C.
Kidney research and clinical practice. 2024
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Abstract
BACKGROUND For anemia management in patients with chronic kidney disease not on dialysis, darbepoetin alfa (DA), which has a shorter half-life but is more inexpensive than continuous erythropoietin receptor activator (CERA), is preferred in Korea. This study evaluated the efficacy, safety, and cost-effectiveness of once-in-4-weeks DA compared with once-in-4-weeks CERA in patients with chronic kidney disease not on dialysis. METHODS In this randomized, prospective, non-inferiority study, 40 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis were randomized 1:1 to the DA group and CERA group. They received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in hemoglobin levels between baseline and efficacy evaluation period and hemoglobin response rates during the correction period. The secondary outcomes included differences in adverse events and costs. RESULTS DA was non-inferior to CERA for anemia correction; the mean difference in the change in hemoglobin levels between the groups was -0.070 g/dL (95% confidence interval, -0.730 to 0.590 g/dL). Hemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks; p < 0.001). CONCLUSION Once-in-4-weeks DA safely corrects anemia in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis and is more cost-effective than once-in-4-weeks CERA.
PICO Summary
Population
Patients with chronic kidney disease not on dialysis (n= 40).
Intervention
Darbepoetin alfa (DA), (n= 20).
Comparison
Continuous erythropoietin receptor activator (CERA), (n= 20).
Outcome
The patients received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in haemoglobin levels between baseline and efficacy evaluation period and haemoglobin response rates during the correction period. DA was non-inferior to CERA for anaemia correction; the mean difference in the change in haemoglobin levels between the groups was -0.070 g/dL (95% confidence interval [-0.730, 0.590 g/dL]). Haemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks).
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An Analysis of Vascular Access Thrombosis Events From the Proactive IV irOn Therapy in hemodiALysis Patients Trial
Thomson PC, Mark PB, Robertson M, White C, Anker SD, Bhandari S, Farrington K, Jardine AG, Kalra PA, McMurray J, et al
Kidney international reports. 2022;7(8):1793-1801
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Abstract
INTRODUCTION Treatment of anemia in dialysis patients has been associated with increased risk of vascular access thrombosis (VAT). Proactive IV irOn Therapy in hemodiALysis Patients (PIVOTAL) was a clinical trial of proactive compared with reactive i.v. iron therapy in patients requiring hemodialysis. We analyzed the trial data to determine whether randomized treatment arm, alongside other clinical and laboratory variables, independently associated with VAT. METHODS In PIVOTAL, 2141 adult patients were randomized. The type of vascular access (arteriovenous fistula [AVF], arteriovenous graft [AVG], or central venous catheter [CVC]) was recorded at baseline and every month after randomization. The associations between clinical and laboratory data and first VAT were evaluated in a multivariate analysis. RESULTS A total of 480 (22.4%) participants experienced VAT in a median of 2.1 years of follow-up. In multivariable analyses, treatment arm (proactive vs. reactive) was not an independent predictor of VAT (hazard ratio [HR] 1.13, P = 0.18). Diabetic kidney disease (HR 1.45, P < 0.001), AVG use (HR 2.29, P < 0.001), digoxin use (HR 2.48, P < 0.001), diuretic use (HR 1.25, P = 0.02), female sex (HR 1.33, P = 0.002), and previous/current smoker (HR 1.47, P = 0.004) were independently associated with a higher risk of VAT. Angiotensin receptor blocker (ARB) use (HR 0.66, P = 0.01) was independently associated with a lower risk of VAT. CONCLUSION In PIVOTAL, VAT occurred in nearly 1 quarter of participants in a median of just >2 years. In this post hoc analysis, randomization to proactive i.v. iron treatment arms did not increase the risk of VAT.
PICO Summary
Population
Adult patients requiring haemodialysis enrolled in the PIVOTAL trial, in 50 sites across the UK (n= 2,141).
Intervention
High-dose of intravenous iron administered proactively (n= 1,093).
Comparison
Low-dose of intravenous iron administered reactively (n= 1,048).
Outcome
The associations between clinical and laboratory data and first vascular access thrombosis (VAT) were evaluated. A total of 480 (22.4%) participants experienced VAT in a median of 2.1 years of follow-up. In multivariable analyses, treatment arm (proactive vs. reactive) was not an independent predictor of VAT (hazard ratio [HR] 1.13). Diabetic kidney disease (HR 1.45), arteriovenous graft (AVG) use (HR 2.29), digoxin use (HR 2.48), diuretic use (HR 1.25), female sex (HR 1.33), and previous/current smoker (HR 1.47) were independently associated with a higher risk of VAT. Angiotensin receptor blocker use (HR 0.66) was independently associated with a lower risk of VAT.
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Two Phase 3 Studies on Ophthalmologic Effects of Roxadustat Versus Darbepoetin
Sepah YJ, Nguyen QD, Yamaguchi Y, Otsuka T, Majikawa Y, Reusch M, Akizawa T
Kidney international reports. 2022;7(4):763-775
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Editor's Choice
Abstract
INTRODUCTION Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD). METHODS Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non-DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment. RESULTS In CL-0307, 302 patients (roxadustat, n = 150; DA, n = 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, n = 131; DA, n = 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point. CONCLUSION In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.
PICO Summary
Population
Patients with anaemia of chronic kidney disease (CKD), (2 randomised controlled trials: CL-0307 (n= 302 dialysis-dependent (DD) patients) and CL-310 (n= 262 non-DD patients)).
Intervention
Roxadustat (CL-0307, n= 150); (CL-310, n= 131).
Comparison
Darbepoetin alfa (DA) (CL-0307, n= 152); (CL-310, n= 131).
Outcome
Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of non-DD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.
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Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy
Jhund PS, Petrie MC, Robertson M, Mark PB, MacDonald MR, Connolly E, Anker SD, Bhandari S, Farrington K, Kalra PA, et al
JACC. Heart failure. 2021
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Editor's Choice
Abstract
OBJECTIVES The study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients. BACKGROUND Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat. METHODS The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial. RESULTS Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event. CONCLUSION Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).
PICO Summary
Population
Haemodialysis patients enrolled in the PIVOTAL trial (n= 2,141).
Intervention
Intravenous iron administered proactively in a high-dose regimen (n= 1,093).
Comparison
Low-dose regimen administered reactively (n= 1,048).
Outcome
A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group. There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group. Most patients presented with pulmonary oedema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event.
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Prolonged Blood Storage and Risk of Posttransfusion Acute Kidney Injury
Adegboye J, Sapatnekar S, Mascha EJ, Shah K, Lioudis M, Essber H, Cohen B, Rivas E, Heddle NM, Eikelboom JW, et al
Anesthesiology. 2021
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Editor's Choice
Abstract
BACKGROUND Erythrocyte transfusions are independently associated with acute kidney injury. Kidney injury may be consequent to the progressive hematologic changes that develop during storage. This study therefore tested the hypothesis that prolonged erythrocyte storage increases posttransfusion acute kidney injury. METHODS The Informing Fresh versus Old Red Cell Management (INFORM) trial randomized 31,497 patients to receive either the freshest or oldest available matching erythrocyte units and showed comparable mortality with both. This a priori substudy compared the incidence of posttransfusion acute kidney injury in the randomized groups. Acute kidney injury was defined by the creatinine component of the Kidney Disease: Improving Global Outcomes criteria. RESULTS The 14,461 patients included in this substudy received 40,077 erythrocyte units. For patients who received more than one unit, the mean age of the blood units was used as the exposure. The median of the mean age of blood units transfused per patient was 11 days [interquartile range, 8, 15] in the freshest available blood group and 23 days [interquartile range, 17, 30] in the oldest available blood group. In the primary analysis, posttransfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk (95% CI) of 0.94 (0.86 to 1.02; P = 0.132). The secondary analysis treated blood age as a continuous variable (defined as duration of storage in days), with an estimated relative risk (95% CI) of 1.00 (0.96 to 1.04; P = 0.978) for a 10-day increase in the mean age of erythrocyte units. CONCLUSIONS In a population of patients without severely impaired baseline renal function receiving fewer than 10 erythrocyte units, duration of blood storage had no effect on the incidence of posttransfusion acute kidney injury.
PICO Summary
Population
Hospitalized patients enrolled across four countries in the Informing Fresh versus Old Red Cell Management (INFORM) trial (n= 14,461).
Intervention
Transfusion with freshest available erythrocyte units (n= 4,777).
Comparison
Transfusion with oldest available erythrocyte units (n= 9,684).
Outcome
The median of the mean age of blood units transfused per patient was 11 days in the freshest available blood group and 23 days in the oldest available blood group. In the primary analysis, post-transfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk of 0.94.
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Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials
Provenzano R, Szczech L, Leong R, Saikali KG, Zhong M, Lee TT, Little DJ, Houser MT, Frison L, Houghton J, et al
Clinical journal of the American Society of Nephrology : CJASN. 2021;16(8):1190-1200
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Abstract
BACKGROUND AND OBJECTIVES We evaluated the efficacy and cardiovascular safety of roxadustat versus placebo by analyzing data pooled from three phase 3 studies of roxadustat in patients with non-dialysis-dependent CKD and CKD-related anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In the three phase 3, double-blind studies of roxadustat versus placebo evaluating the treatment of CKD-related anemia in patients not requiring dialysis, the primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy. The primary cardiovascular safety end point was a composite measure of major adverse cardiovascular events (MACE; all-cause mortality, myocardial infarction, stroke). MACE plus (MACE+; MACE plus unstable angina and heart failure requiring hospitalization) and all-cause mortality were key secondary safety end points. These safety end points were adjudicated. RESULTS A total of 4277 patients with non-dialysis-dependent CKD were randomized (roxadustat, n=2391; placebo, n=1886). Baseline characteristics were comparable between groups; the mean (SD) hemoglobin was 9.1 (0.7) g/dl and mean eGFR was 20 (12) ml/min per 1.73 m(2). Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7 (95% confidence interval [95% CI], 1.7 to 1.8). Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively; hazard ratio [HR], 0.26; 95% CI, 0.21 to 0.32). There were no increased risks of MACE (HR, 1.10; 95% CI, 0.96 to 1.27), MACE+ (HR, 1.07; 95% CI, 0.94 to 1.21), all-cause mortality (HR, 1.08; 95% CI, 0.93 to 1.26), or individual MACE+ components in patients treated with roxadustat versus those treated with placebo. CONCLUSIONS Roxadustat was more effective than placebo at increasing hemoglobin in patients with non-dialysis-dependent CKD and anemia, while decreasing transfusion rate and being noninferior to placebo with respect to risk of MACE. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER A Study of FG-4592 for the Treatment of Anemia in Chronic Kidney Disease Patients Not Receiving Dialysis, NCT01750190; Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS), NCT01887600; Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis, NCT02174627.
PICO Summary
Population
Patients with non–dialysis-dependent chronic kidney disease (CKD) and CKD-related anaemia from the three trials: ALPS, ANDES, and OLYMPUS (n= 4,277).
Intervention
Roxadustat (n= 2,391).
Comparison
Placebo (n= 1,886).
Outcome
Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in haemoglobin averaged over weeks 28-52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7. Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively). There were no increased risks on the measures of major adverse cardiovascular events (MACE), MACE and unstable angina and heart failure requiring hospitalization (MACE+), all-cause mortality, or individual MACE+ components in patients treated with roxadustat versus those treated with placebo.
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Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES)
Csiky B, Schömig M, Esposito C, Barratt J, Reusch M, Valluri U, Sulowicz W
Advances in therapy. 2021
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Editor's Choice
Abstract
INTRODUCTION Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months. METHODS Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively. RESULTS Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea. CONCLUSION Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.
PICO Summary
Population
Patients with end-stage kidney disease on dialysis enrolled in the European multicentre PYRENEES study (n= 836).
Intervention
Roxadustat (n= 415).
Comparison
Erythropoiesis-stimulating agent (ESA), (n= 421).
Outcome
The least squares means of the treatment difference (roxadustat - ESA) for haemoglobin change from baseline to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively. The proportions of patients who achieved target haemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Serious treatment-emergent adverse events (TEAEs) occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhoea.
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Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis
Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, et al
The New England journal of medicine. 2021
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Editor's Choice
Abstract
BACKGROUND Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).
PICO Summary
Population
Patients with chronic kidney disease undergoing dialysis (n= 2,964).
Intervention
Daprodustat (n= 1,487).
Comparison
Erythropoiesis-stimulating agent (ESA), (n= 1,477).
Outcome
The mean (±SE) change in the haemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per decilitre in the daprodustat group and 0.10±0.02 g per decilitre in the ESA group (difference, 0.18 g per decilitre, which met the pre-specified non-inferiority margin of -0.75 g per decilitre). During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group, which also met the pre-specified non-inferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups.