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The New England Journal of Medicine Dec 2021Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown.
METHODS
In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke).
RESULTS
Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups.
CONCLUSIONS
Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).
Topics: Aged; Anemia; Barbiturates; Cardiovascular Diseases; Darbepoetin alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Intention to Treat Analysis; Male; Middle Aged; Myocardial Infarction; Renal Insufficiency, Chronic; Stroke
PubMed: 34739196
DOI: 10.1056/NEJMoa2113380 -
The New England Journal of Medicine Dec 2021Among 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... (Comparative Study)
Comparative Study Randomized Controlled Trial
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.).
Topics: Aged; Anemia; Barbiturates; Cardiovascular Diseases; Darbepoetin alfa; Epoetin Alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Intention to Treat Analysis; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Renal Insufficiency, Chronic; Stroke
PubMed: 34739194
DOI: 10.1056/NEJMoa2113379 -
JAMA Internal Medicine Jun 2022Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA)... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported.
OBJECTIVE
To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete.
INTERVENTIONS
Randomized 1:1 to daprodustat or darbepoetin alfa.
MAIN OUTCOMES AND MEASURES
The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability.
RESULTS
A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa.
CONCLUSIONS AND RELEVANCE
This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03029208.
Topics: Anemia; Barbiturates; Darbepoetin alfa; Erythropoietin; Female; Glycine; Hematinics; Hemoglobins; Humans; Iron; Male; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 35377393
DOI: 10.1001/jamainternmed.2022.0605 -
Clinical Journal of the American... May 2020Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11-13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9-11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We enrolled 491 patients with CKD without diabetes, and an eGFR of 8-20 ml/min per 1.73 m. Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m, and 50% reduction in eGFR).
RESULTS
Mean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; =0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; =0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; =0.66).
CONCLUSIONS
Targeting a higher hemoglobin level (11-13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9-11 g/dl) in patients with advanced CKD without diabetes.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Darbepoetin alfa; Disease Progression; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Japan; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Young Adult
PubMed: 32245781
DOI: 10.2215/CJN.08900719 -
Clinical Journal of the American... Aug 2020Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy...
BACKGROUND AND OBJECTIVES
Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 g once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population.
RESULTS
Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa.
CONCLUSIONS
Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
201754, Clinicaltrials.gov, NCT02969655.
Topics: Aged; Anemia; Barbiturates; Biomarkers; Darbepoetin alfa; Double-Blind Method; Female; Glycine; Hematinics; Hemoglobins; Humans; Japan; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome
PubMed: 32723804
DOI: 10.2215/CJN.16011219 -
Nephrology, Dialysis, Transplantation :... Aug 2021Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD).
METHODS
This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed.
RESULTS
Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52-1.25), P = 0.339; MACE+: 0.90 (0.61-1.32), P = 0.583].
CONCLUSIONS
Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.
Topics: Anemia; Calcium Carbonate; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Magnesium; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34077510
DOI: 10.1093/ndt/gfab191 -
The Cochrane Database of Systematic... Feb 2023Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014.
OBJECTIVES
To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD.
SEARCH METHODS
In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion.
DATA COLLECTION AND ANALYSIS
Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data. AUTHORS' CONCLUSIONS: The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.
Topics: Adult; Humans; Hematinics; Epoetin Alfa; Darbepoetin alfa; Biosimilar Pharmaceuticals; Network Meta-Analysis; Erythropoiesis; Anemia; Renal Insufficiency, Chronic; Hypertension; Thrombosis; Dyspnea; Myocardial Infarction
PubMed: 36791280
DOI: 10.1002/14651858.CD010590.pub3 -
Advances in Therapy Oct 2021Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD).... (Randomized Controlled Trial)
Randomized Controlled Trial
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).
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.
Topics: Anemia; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Kidney Failure, Chronic; Renal Dialysis; Renal Insufficiency, Chronic; Research Design
PubMed: 34537926
DOI: 10.1007/s12325-021-01904-6 -
Advances in Therapy Oct 2021This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients.
METHODS
Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized.
RESULTS
In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups.
CONCLUSION
Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.
Topics: Erythropoietin; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34523074
DOI: 10.1007/s12325-021-01903-7